Medical Radiology

Radiation Oncology

Series Editors

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

For further volumes:

http://www.springer.com/series/4353
Branislav Jeremić
Editor

Advances in Radiation
Oncology in Lung Cancer
Second Edition

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

123
Editor
Branislav Jeremić
Institute of Lung Diseases
Institutski put 4
21204 Sremska Kamenica
Serbia
e-mail: nebareje@gmail.com

ISSN 0942-5373
ISBN 978-3-642-19924-0 e-ISBN 978-3-642-19925-7
DOI 10.1007/978-3-642-19925-7
Springer Heidelberg Dordrecht London New York

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For
Aleksandra and Marta
Foreword

Worldwide, lung cancer remains the most enigmatic and difficult malignancy to
treat in a definitive fashion. It is estimated that there are more than 1.35 million
cases in the world in 2010 representing about 13% of all malignant diseases
with which physicians have to deal. Lung cancer represents about 31% of all
cancer related deaths in the world. More people die of lung cancer than of the
next three common causes of cancer related deaths.
In spite of incredible efforts at prevention, early diagnosis, new and inno-
vative technologies relative to treatment, the outcome remains dismal with no
significant improvement in the overall five year survival rate in the last 25 years.
The survival at five years measured by surveillance, epidemiology, and end
results program is about 15%, a number which has not changed significantly
for 30 years.
The present volume edited by Professor Branislav Jeremic represents a
contemporary statement of all the aspects in the evolution of treatment of lung
cancer. It represents the opinions stated by the world’s leading lung cancer
specialists and covers not only basic science for lung cancer clinical investiga-
tions, but histology and staging, and a wide range of fundamental treatment
considerations. The effort looks at current treatment strategies for non small
cell and small cell lung cancers evaluated in the context of detail with due
attention to novel approaches that may promise further improvement in
outcome.
The various types of treatment related toxicities are discussed along with
issues of quality of life and prognostic factors.
The volume deals not only with a major statement relative to angiogenesis in
lung cancer but also the aspects of molecular biology and genetics for the
disease process, along with the clinical investigations having to do with bron-
choscopy, pathology, radiologic images, PET/CT studies for staging and
evaluation of treatment outcome as well as surgical staging.
A significant point is the role for surgery alone or in combination with
radiation therapy with or without systemically administered chemotherapy as
well as the statement relative to the impact for immunotherapy in terms of
management.
Sections deal with the basic aspects of appropriate, proper radiation therapy
administration, reviewing conventional radiotherapy along with stereotactic
radiation therapy and with data presented having to do with IMRT/IMAT,
cyberknife, tomotherapy, proton therapy, and carbon ion therapy.

vii
viii Foreword

One of the most difficult issues relative to lung cancer is the identification of
chemotherapeutic agents that would be of significant impact in changing the
outlook and prospects for survival for the patients. Data presented in the
volume deal with novel chemotherapy agents as well as novel targeted agents
and how they might best be combined to improve outcome.
The volume is an important statement of the contemporary status in the
multiple aspects of this complicated and difficult disease process and would be
an important statement for basic scientists and clinicians in all aspects of
treatment. It also makes significant statements relative to epidemiological
studies that would be appropriate in terms of efforts to establish technologies
for earlier diagnosis and more effective combined multimodal treatment
programs.

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

Lung cancer is the cancer with the highest incidence (1.61 million cases in 2008;
12.7% total cancer cases) and is the major cancer killer in both sexes across the
world (1.38 million deaths in 2008; 18.2% of total cancer mortality). Due to
moving tobacco industry focus from developed to a developing world, more
than 50% of new cases now occur in the latter one. This large shift is seen in the
past decade, with anticipated continuation of this trend as rates of cigarette
smoking continue to rise in newly industrialised countries. It is, therefore, not a
surprising fact that it represents a big burden to national health care systems
worldwide with hundreds of thousands of patients succumbing to it every year.
Radiation therapy remains the cornerstone of modern treatment approaches
nowadays. It is so in both histologies (nonsmall cell and small cell) and in all
stages of the disease. It is also so in both curative and palliative setting and is
deemed by many as the most cost-effective treatment option in lung cancer.
Being now more than 110 years old, this treatment modality passed a long way
in its technological and biological development. Integrated well with numerous
diagnostic approaches and other two important treatment options (surgery and
chemotherapy), it continuously change and adapt to the growing demands of
both modern society and successfully assimilate within the framework of
computerised domain. Indeed, there seems to be very few competitors among
medical disciplines that have so broadly embraced novel computer-driven
technological aspects as is the case with radiation therapy.
This, updated and second edition of the book initially published in 2004 is
very much about it: constant research and development in the field of radiation
oncology as the vital part (ingredient, one may say!) of our comprehensive and
very much orchestrated approach in the diagnosis and treatment of lung cancer.
While intervening seven years may deem too short for any major leaps in this
field, I am sure this second edition will stand the test of time as the necessary
checkpoint in the global development in this field.
To demonstrate this premise, the skeleton of the first edition remained,
though updated. More substance is now provided as to keep the pace with novel
technological and biological advances in the field, becoming new standards of
care almost daily. Various, non-radiation oncology aspects are also now
included in the book with the same goal. Ultimately, composition of the book is
such that it aims not only radiation oncologists but other lung cancer specialists
which, I firmly believe, would largely benefit from it.

ix
x Preface

In this effort, I have had great pleasure and very much privilege of having a
distinguished faculty joining me. The faculty that dedicated their professional
lives to the fight against lung cancer and have continuously provided substantial
contribution in this field. The faculty that have built and steamed towards the
same: more comprehensive understanding of basic premises of biology and
technology, its successful incorporation in the diagnosis and treatment of the
disease finally ending up in state-of-the-art approaches of the second decade of
the new millennium.
I would also like to thank my former and current staff colleagues with whom
I have collaborated in sometimes distant, but beautiful places. This is especially
so in cases of those still living and working in developing countries. From such
collaboration, I grew up not only as a better and more mature medical pro-
fessional, but also a better human being.
I would also like to express my gratitude to Alexander von Humboldt
Foundation, Bonn, Germany for their continuous support since 1998. Special
thanks go to Ms. Daniela Brandt and Ms. Martina Wiese from Springer who
did super job which successfully ends up here with you. Without them, the
expiring year would simply be impossible to imagine and the final shape would
not be thoroughly and timely reached.

Belgrade Branislav Jeremić

Contents

Part I Basic Science of Lung Cancer

Molecular Biology and Genetics of Lung Cancer . . . . . . . . . . . . . . . . . 3

Dusan Milanovic

Angiogenesis and Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Wenyin Shi and Dietmar W. Siemann

Part II Clinical Investigations

Interventional Pulmonology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Branislav Perin, Bojan Zarić, and Heinrich D. Becker

Pathology of Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Mary Beth Beasley

Radiologic Imaging of Lung Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Palmi Shah and James L. Mulshine

PET/CT for Staging and Diagnosis of Lung Cancer . . . . . . . . . . . . . . . 75

Sigrid Stroobants

Surgical Staging of Lung Cancer for Advances in Radiation

Oncology of Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Farhood Farjah and Valerie W. Rusch

Part III Basic Treatment Considerations

Lung Cancer Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

Sidhu P. Gangadharan, Walter J. Lech, and David J. Sugarbaker

Radiation Response of the Normal Lung Tissue and Lung Tumors . . . . 119
Hiromitsu Iwata, Taro Murai, and Yuta Shibamoto

xi
xii Contents

Radiation Time, Dose, and Fractionation in the Treatment

of Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Daniel Gomez, Melenda D. Jeter, Ritsuko Komaki, and James D. Cox

3D Radiation Treatment Planning and Execution . . . . . . . . . . . . . . . . . 143

Mary K. Martel

Four-dimensional Radiation Therapy for Non-Small Cell Lung

Cancer: A Clinical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Max Dahele, Johan Cuijpers, and Suresh Senan

PET and PET/CT in Treatment Planning. . . . . . . . . . . . . . . . . . . . . . . 173

Michael P. Mac Manus and Rodney J. Hicks

Target Volume Definition in Non-Small Cell Lung Cancer . . . . . . . . . . 187

Lucyna Kepka and Milena Kolodziejczyk

The Radiation Target in Small-Cell Lung Cancer. . . . . . . . . . . . . . . . . 201

Gregory M. M. Videtic

Radiation Sensitizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

Anthony M. Brade and Zishan Allibhai

Radioprotectors and Chemoprotectors in the Management

of Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
Ritsuko Komaki, Zhongxing Liao, James D. Cox,
Kathy A. Mason, and Luka Milas

Systemic Therapy for Lung Cancer for the Radiation Oncologist . . . . . 247
Chandra P. Belani

Combined Radiotherapy and Chemotherapy: Theoretical

Considerations and Biological Premises . . . . . . . . . . . . . . . . . . . . . . . . 267
Branislav Jeremic, Dusan Milanovic, and Nenad Filipovic

Radiotherapy and Second Generation Drugs . . . . . . . . . . . . . . . . . . . . 275

Michael Geier and Nicolaus Andratschke

Radiotherapy and Third Generation Concurrent

Chemotherapy Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
Ross Bland, Puneeth Iyengar, and Hak Choy

Part IV Current Treatment Strategies in Early-Stage Non-Small

Cell Lung Cancer

Conventional Radiation Therapy in Early Stage

Non-small-cell Lung Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
Branislav Jeremić, Sinisa Stanic, and Slobodan Milisavljevic
Contents xiii

Stereotactic Ablative Radiotherapy for Early Stage Lung Cancer . . . . . 343

John H. Heinzerling and Robert D. Timmerman

Postoperative Radiotherapy for Non-Small Cell Carcinoma . . . . . . . . . 363

Ellen Kim and Mitchell Machtay

PDT-Lung. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
Ron R. Allison

The Role of Radiofrequency Ablation in the Treatment

of Stage 1 Non-Small Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . 381
John M. Varlotto, Julia A. Shelkey, and Rickhesvar P. Mahraj

Part V Current Treatment Strategies in Locally Advanced

Non-Small Cell Lung Cancer

Lung Dose Escalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399

Bradford S. Hoppe and Kenneth E. Rosenzweig

Radiochemotherapy in Locally Advanced Non-small-Cell

Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
Branislav Jeremić, Francesc Casas, and Asuncion Hervas-Moron

Tri-Modality Therapy in Locally Advanced Non-Small-Cell

Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
Jan P. van Meerbeeck and Elke Vandenbroucke

Prophylactic Cranial Irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445

Jason Francis Lester

Palliative External Beam Thoracic Radiation Therapy

of Non-Small Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
Stein Sundstrøm

Intraoperative Radiotherapy in Lung Cancer: Methodology

(Electrons or Brachytherapy), Clinical Experiences
and Long-Term Institutional Results . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Felipe A. Calvo, Javier Aristu, Sergey Usychkin, Leire Arbea,
Rosa Cañón, Ignacio Azinovic, and Rafael Martinez-Monge

Brachytherapy for Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477

A. Polo, M. Castro, A. Montero, and P. Navío

Part VI Current Treatment Strategies in Small Cell Lung Cancer

Limited-Disease Small-Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . 491

Branislav Jeremić, Željko Dobrić, and Francesc Casas
xiv Contents

Radiation Therapy in Extensive Disease Small Cell Lung Cancer . . . . . 505

Branislav Jeremić and Luhua Wang

Prophylactic Cranial Irradiation in Small-Cell Lung Cancer . . . . . . . . 513

Michael C. Stauder and Yolanda I. Garces

Part VII Treatment in Specific Patient Groups and Other Settings

Radiation Therapy for Lung Cancer in Elderly . . . . . . . . . . . . . . . . . . 523

Branislav Jeremić and Željko Dobrić

Radiation Therapy for Recurrent Disease. . . . . . . . . . . . . . . . . . . . . . . 543

Branislav Jeremić, Jai Prakash Agarwal, and Sherif Abdel-Wahab

Radiation Therapy for Metastatic Disease . . . . . . . . . . . . . . . . . . . . . . 561

Dirk Rades

Advances in Supportive and Palliative Care

for Lung Cancer Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575
Michael J. Simoff

Part VIII Treatment-Related Toxicity

Hematological Toxicity in Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . 597

Francesc Casas, Ferran Ferrer, and Núria Viñolas

Radiation-Induced Lung and Heart Toxicity . . . . . . . . . . . . . . . . . . . . 609

Liyi Xie, Xiaoli Yu, Zeljko Vujaskovic, Mitchell S. Anscher,
Timothy D. Shafman, Keith Miller, Robert Prosnitz, and Lawrence Marks

Spinal Cord Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627

Timothy E. Schultheiss

Radiation Therapy-Related Toxicity: Esophagus. . . . . . . . . . . . . . . . . . 637

Voichita Bar Ad and Maria Werner-Wasik

Brain Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647

C. Nieder

Part IX Quality of Life Studies and Prognostic Factors

Quality of Life Outcomes in Radiotherapy of Lung Cancer . . . . . . . . . 661

M. Salim Siddiqui, Farzan Siddiqui, and Benjamin Movsas

Prognostic Factors in Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . 675

Frank B. Zimmermann
Contents xv

Part X Technological Advances in Lung Cancer

Intensity-Modulated Radiation Therapy and Volumetric-Modulated

Arc Therapy for Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
Inga S. Grills and Victor S. Mangona

Image-Guided Robotic Stereotactic Ablative Radiotherapy

for Lung Tumors: The CyberKnife . . . . . . . . . . . . . . . . . . . . . . . . . . . 715
Billy W. Loo Jr. and Iris C. Gibbs

Advances in Radiation Oncology of Lung Cancer . . . . . . . . . . . . . . . . . 725

Deepak Khuntia and Minesh P. Mehta

Image-Guided Radiotherapy in Lung Cancer . . . . . . . . . . . . . . . . . . . . 735

Percy Lee and Patrick Kupelian

Proton Therapy for Lung Cancer: State of the Science . . . . . . . . . . . . . 743

David A. Bush

Carbon Ion Radiotherapy in Hypo-Fractionation Regimen

and Single Dose for Stage I Non-small-Cell Lung Cancer . . . . . . . . . . . 753
T. Miyamoto, N. Yamamoto, M. Baba, and T. Kamada

Part XI Biological Advances in Lung Cancer

Novel Cytotoxic Agents in Combination with Radiation

in the Management of Locally Advanced Non-Small
Cell Lung Cancer: Focus on Pemetrexed
and Nab-Paclitaxel [Abraxane] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765
Corey J. Langer

Novel Targeted Agents and Radiopharmaceuticals in Lung Cancer. . . . 773

Martin J. Edelman and Nadia Ijaz

Part XII Clinical Research in Lung Cancer

Translational Research in Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . 793

Deepinder Singh, Kevin Bylund, and Yuhchyau Chen

Clinical Research in Radiation Oncology of Lung Cancer:

Why We Fail(ed)? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809
Branislav Jeremić

Pitfalls in the Design, Analysis, Presentation, and Interpretation

of Randomized Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819
Richard Stephens
xvi Contents

New Directions in the Evaluation and Presentation

of Clinical Research in Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 827
Noelle O’Rourke, Fergus Macbeth, and Elinor Thompson

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837
Contributors

Ron R. Allison Greenville, NC, USA; e-mail: ALLISONR@ecu.edu

Nicolaus Andraschke Munich, Germany; e-mail: n_andratschke@yahoo.de
Mary Beth Beasley New York, NY, USA; e-mail: mbbeasleymd@yahoo.com
Chandra P. Belani Hershey, PA, USA; e-mail: cbelani@hmc.psu.edu
William Blackstock Winston Salem, NC, USA; e-mail: ablackst@wfubmc.edu
Anthony Brade Toronto, Canada; e-mail: Anthony.brade@rmp.uhn.on.ca
David Bush Loma Linda, CA, USA; e-mail: dbush@dominion.llumc.edu
Felipe Calvo Madrid, Spain; e-mail: fcalvo.hgugm@salud.madrid.org
Francesc Casas Barcelona, Spain; e-mail: fcasas@clinic.ub.es
Y. Chen e-mail: yuhchyau_chen@urmc.rochester.edu
Hak Choy Dallas, TX, USA; e-mail: Hak.Choy@utsouthwestern.edu
James D. Cox Houston, TX, USA; e-mail: jcox@mdanderson.org
Martin Edelman Baltimore, MD, USA; e-mail: medelman@umm.edu
Yolande Garces Rochester, MN, USA; e-mail: garces.yolanda@mayo.edu
Inga Grills Royal Oak, MI, USA; e-mail: igrills@beaumont.edu
Lucyna Kepka Warsaw, Poland; e-mail: lucynak@coi.waw.pl
Ritsuko Komaki Houston, TX, USA; e-mail: rkomaki@mdanderson.org
Patrick Kupelian Los Angeles, LA, USA; e-mail: pkupelian@mednet.ucla.edu
Corey Langer Philadelphia, PA, USA; e-mail: corey.langer@uphs.upenn.edu
Percy Lee Los Angeles, LA, USA; e-mail: percylee@mednet.ucla.edu
Jason Lester Cardiff, Wales, UK; e-mail: jason.lester@velindre-tr.wales.nhs.uk
Bill Loo Stanford, CA, USA; e-mail: bwloo@stanford.edu
Fergus R. Macbeth Cardiff, Wales, UK; e-mail: Fergus.Macbeth@nice.org.uk
Mitchell Machtay Cleveland, OH, USA; e-mail: mitchell.machtay@
uhhospitals.org

xvii
xviii Contributors

M. McManus e-mail: michael.macmanus@petermac.org

Lawrence B. Marks Chapel Hill, NC, USA; e-mail: marks@med.unc.edu
Mary K. Martel Houston, TX, USA; e-mail: mmartel@mdanderson.org
Minesh P. Mehta Chicago, IL, USA; e-mail: mineshpmehta@gmail.com
Tadaaki Miyamoto Chiba, Japan; e-mail: t-miyamoto@min-iren-c.or.jp
Benjamin Movsas Detroit, MI, USA; e-mail: BMOVSAS1@hfhs.org
James L. Mulshine Chicago, IL, USA; e-mail: James_L_Mulshine@rush.edu
Carsten Nieder Bodo, Norway; e-mail: Carsten.Nieder@nordlandssykehuset.no
Branislav Perin Sremska Kamenica, Serbia; e-mail: bperin@eunet.rs
Alfredo Pol Madrid, Spain, e-mail: alfredo.polo@mac.com
Dirk Rades Luebeck, Germany; e-mail: Rades.Dirk@gmx.net
Kenneth Rosenzweig New York, NY, USA; e-mail: ken.rosenzweig@
mountsinai.org
Valerie Rusch New York, NY, USA; e-mail: ruschv@mskcc.org
Dietmar W. Siemann Gainsville, FL, USA; e-mail: siemadw@ufl.edu
Michael Simoff Detroit, MI, USA; e-mail: msimoff1@hfhs.org
Richard Stephens London, UK; e-mail: richardjamesstephens@gmail.com
Timothy E. Schultheiss Duarte, CA, USA; e-mail: schultheiss@coh.org
Suresh Senan Amsterdam, The Netherlands; e-mail: s.senan@vumc.nl
Yuta Shibamoto Nagoya , Japan; e-mail: yshiba@med.nagoya-cu.ac.jp
Stein Sundstrom Trondheim, Norway; e-mail: Stein.Sundstrom@stolav.no
Sigrid Stroobants Antwerp, Belgium; e-mail: Sigrid.Stroobants@ua.ac.be
David J. Sugarbaker Boston, MA, USA; e-mail: dsugarbaker@partners.org
Robert Timmerman Dallas, TX, USA; e-mail: robert.timmerman@
utsouthwestern.edu
Jan Van Meerbeeck Ghent, Belgium; e-mail: Jan.VanMeerbeeck@uzgent.be
John Varlotto Hershey, PA, USA; e-mail: jvarlotto@hmc.psu.edu
Gregory Videtic Cleveland, OH, USA; e-mail: VIDETIG@ccf.org
Maria Werner-Wasik Philadelphia, PA, USA; e-mail: maria.werner-wasik@
mail.tju.edu
Frank B. Zimmermann Basel, Switzerland; e-mail: FZimmermann@uhbs.ch
 Molecular Biology and Genetics
of Lung Cancer
Dusan Milanovic
Contents
1 Introduction..............................................................
2 Genetical Changes Detected with Microarray.....
3 Nkx2.1 .......................................................................
4 EML4-ALK ..............................................................
5 LKB 1........................................................................
6 c-MYC .......................................................................
7 KRAS ........................................................................
8 Bcl-2...........................................................................
9 MET ..........................................................................
10 EGFR ........................................................................
11 p53 .............................................................................
D. Milanovic (&)
Department of Radiation Oncology,
University Hospital Freiburg,
Robert Koch Strasse 3, 79106 Freiburg, Germany
e-mail: dusan.milanovic@uniklinik-freiburg.de
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_310, Ó Springer-Verlag Berlin Heidelberg 2011
12 Other Factors ........................................................... 12
13 Conclusion ................................................................ 13
3 References.......................................................................... 13
4
5
Abstract
6 DNA Microarray technology allowed analysis of
7 gene expression profile of lung cancer (NSCLC
and SCLC). Better understanding of the molecu-
7
lar and biological basis of this disease has led to
8 the identification of a number of druggable
9 targets. In the last years, targeted therapies with
10 small molecule kinase inhibitors showed promis-
ing clinical activity in lung carcinoma but after
11
some period of time development of resistance
12 was common event observed in patients treated
with these drugs. There is an urgent need not only
to clarify important molecular-biological mecha-
nism that contributes to the development of
resistance to molecular targeted therapies but also
to identify other important druggable targets
which are crucial for development and progres-
sion of this disease.
1 Introduction
Lung carcinoma is a disease which is characterized
with several genetical and molecular biological
changes which contributed to carcinogenesis by the
activation of oncogenes or inactivation of tumor
suppressor genes. In this chapter mainly genetical and
molecular biological changes which are detected in
past 6–7 years will be discussed.
3
4 D. Milanovic
2 Genetical Changes Detected
with Microarray
To detect genetic changes in lung carcinoma single
nucleotide polymorphism (SNP) arrays was per-
formed and 51 NSCLC primary tumor samples, 26
NSCLC cell line samples, 19 SCLC primary tumor
samples and 5 SCLC cell line samples, were analyzed
(Zhao et al. 2005). In both NSCLC and SCLC, the
most frequent copy number gains (C3 copies) were
found in chromosome arm 5p (NSCLC 25%, SCLC
43%) while maximum degrees of copy number loss at
a given locus chromosome where detected most fre-
quently in chromosome arms 8p (33%) and 9p (26%)
in NSCLC and in chromosome arms 3p (68%) and 4q
(58%) in SCLC. In one SCLC cell-line quantitative
realtime PCR revealed of the amplification of
8q12–13 region (copy number of 89.9). In two SCLC
primary tumor samples, this amplification was also
found. 12p11 amplification was detected in two
NSCLC specimens and 22q11 amplification in four
NSCLC specimens. High level amplifications of
tyrosin kinase genes were found in three NSCLC
tumor specimens for EGFR (independent of kinase
domain mutational status), in two specimens for
FGFR1 and in one specimen for ERBB2 and MET.
In one other microarray analysis from samples of
21 patients with lung squamous cell cancer, HSN,
GCS, BTAK, TTK, cyclin E2 and NLK gene were
highly upregulated and while ANG, PTPTM, and
C1-Inh were highly down-regulated (Talbot et al.
2005). These findings were validated with reverse
transcription-PCR.
Other groups were analyzed 371 samples of lung
adenocarcinoma (ADC) using SNP arrays (Weir et al.
2007). They detected a total of 57 significantly recur-
rent events. The most frequent genomic alteration
in lung adenocarcinoma was a copy-number gain of
chromosome 5p, which is found in 60% of total sam-
ples. The most significant focal deletions, detected in
3% of all samples, involve CDKN2A/CDKN2B, well-
known tumor suppressor genes localized on chromo-
some 9p21 which protein products inhibit Cdk4 and
Cdk6 cyclin dependet kinases. Three additional dele-
tions were also detected—deletions of the 50 untrans-
lated region of PTPRD (a gene encoding a tyrosine
phosphatase), homozygous deletions of PDE4D
(encodes the major phosphodiesterase responsible for
degrading cyclic AMP in airway epithelial cells) sin-
gle-gene deletion occurs within AUTS2, a gene of
unknown function in chromosome 7q11.22. Somatic
mutations in AUTS2 or PDE4D were not detected
while in 11 of 188 samples of PTRD somatic mutations
were identified—three of the mutations encode pre-
dicted inactivating changes in the tyrosine phosphatase
domain indicating that PTPRD is one probable cancer-
associated gene. The TP53 locus which is normaly
mutated in *50% of lung adenocarcinomas in this data
series shows no homozygous deletions. The amplifi-
cation events were observed in 1–7% of all samples.
Fourteen of the 24 regions of recurrent amplification
contained a known protooncogene but only EGFR,
KRAS and ERB2 was earlier reported to be mutated in
lung adenocarcinoma. The amplification peak was
detected on chromosome 5p to the telomerase catalytic
subunit gene, TERT.
Eight tumors with amplicons (a piece of DNA
formed as the product of natural or artificial amplifi-
cation events) in chromosome 5p15 delineate a region
containing ten genes including TERT. These results
indicate that TERT may be the target of the amplifi-
cation contributing to cellular immortalization.
Chromosome 6p21.1 was focal amplificated in four
samples in a region containing two genes, one of
which (VEGFA) encodes vascular endothelial growth
factor suggesting a possible mechanism for increased
angiogenesis and response to antiangiogenic therapy.
Amplification of regions containing several cell cycle
genes, such as CDK4, CDK6 and CCND1was also
observed.
Amplification of chromosome 14q13.3, which
contain only MBIP and NKX2-1 genes was found in
*12% of samples. Based on genomic and functional
analyzes, NKX2-1 (NK2 homeobox 1 TITF1),was
identified as a novel proto-oncogene candidate which
was found in ca.12% samples of lung adenocarci-
noma. This gene is located in the minimal 14q13.3
amplification interval and encodes a lineage-specific
transcription factor.
Using array comparative genomic hybridization,
karyotype analysis of 33 small-cell lung cancer
(SCLC) tumors, 13 SCLC cell lines, 19 bronchial
carcinoids was performed (Voortman et al. 2010).
In SCLC tumors, recurrent copy number (CN) gains
were observed on chromosomes 1, 3q, 5p, 6p, 12, 14,
17q, 18, 19 and 20 and recurrent CN losses on
chromosomes 3p, 4, 5q, 10, 13, 16q and 17p.
Molecular Biology and Genetics of Lung Cancer
In bronchial carcinoids, recurrent CN gains were
detected on chromosomes 5, 7 and 14, and recurrent
CN losses were observed on chromosomes 3, 11 and
22q. In SCLC tumors, genes encoding members of the
PI3K-AKT-mTOR pathway and apoptotic regulating
proteins had relatively high frequencies of gene copy
number alterations (CNA).
3 Nkx2.1
Nkx2-1 also known as the thyroid transcription factor
1 (TTF-1) or thyroid-specific enhancer-binding pro-
tein is one NK2-related homeobox transcription fac-
tor. This is a 38-kDa nuclear protein that is encoded
by a gene located on chromosome 14q13 (Guazzi
et al. 1990). During early embryogenesis is this
expressed in the thyroid, lung bronchial epithelium,
ventral neuroepithelium and ganglionic eminence of
the forebrain. Mice embryo formed lobar bronchy by
embryonic day 11.5–12 which start branching to form
segmental bronchy by embryonic day 12.5–13. In
Nkx2.1 homozygous mice branching of lobar bronchy
did not happen. This failure is still evident in
embryonic day 14–15 (Kimura et al. 1996). It has
been found that Nkx2.1 is expressed consistently
throughout the life stages and uniformly in the ter-
minal respiratory unit (TUR), which contain periph-
eral airway cells and small-sized bronchioles (Yatabe
et al. 2002). In one clinical study, 72% of investigated
64 specimen of lung ADC expressed Nkx2.1 that
showed high correlation with surfactant apoprotein
(Yatabe et al. 2002). Morphologically, these parts
with Nkx2.1 expression were similar to terminal
TUR. The TTF-1-positive and -negative ADC based
on their clinicopathologic features and expression of
various cancer-associated genes showed important
difference—TF-1-positive ADC were prevalent of
female and nonsmoker. Also negative p53 staining,
less frequent RB loss and preserved expression of p27
were observed. The authors conclude that Nkx2.1
may be a lineage marker for TUR and suggested that
molecular pathogenesis may be partially character-
ized by cellular lineage. Nkx2.1 may be a candidate
for ‘‘lineage-survival oncogene’’, which could explain
‘‘lineage-specific dependency’’ mechanism in carci-
nogenesis (Garraway and Sellers 2006). It means that
some specific transcription factor, which is a master
regulator of the specific cellular lineage during
5
embryogenesis, may become an oncogene when it is
deregulated in certain genetic contexts. It has been
shown that a population of lung ADC cell lines
expressing Nkx2.1, which most probably represent
cells originating from the TRU lineage, showed clear
dependence on the persistent Nkx2.1 expression
(Tanaka et al. 2007). The specific and significant
growth inhibition and apoptosis in theses cells were
induced when Nkx2.1 was inhibited by RNA inter-
ference (RNAi). On the other hand, in the same study
it has been reported that in cohort consisting of 214
patients with NSCLC, including 174 adenocams only
in four (2.3%) patients an increase amount of more
than 2.5-fold of the Nkx2.1 gene was detected. One
tendency of higher frequency of increased gene cop-
ies at metastatic sites than at primary sites has been
observed.
The aim of one meta-analysis was to assess the
possible role of Nkx2.1 as prognostic factor for sur-
vival in subgroup of patients with lung ADC
(Berghmans et al. 2006). Eight studies were meta-
analyzed and it has been observed that Nkx2.1 posi-
tivity is associated with better survival in NSCLC,
mainly in early- and locally-advanced stages and in
adenocarcinomas.
In one lung adenocarcinoma model, which was
induced by lentiviral-mediated somatic activation of
oncogenic Kras and deletion of p53, each mouse
developed between 5 and 20 lung tumors (Winslow
et al. 2011). Despite the synchronously initiations of
tumors, only a subset of them becomes malignant
suggesting that malignant progression requires addi-
tional changes on molecular level. Mice lived
8–14 months after tumor initiation and developed
macroscopic metastases to the draining lymph nodes,
pleura, kidneys, heart, adrenal glands and liver. With
identification of the lentiviral integration sites was
possible to a make difference between metastatic and
non-metastatic tumors and to determine gene
expression alterations. Cross-species analysis identi-
fied Nkx2.1 as a candidate suppressor of malignant
progression. In this mice model, low Nkx2.1 expres-
sion was characterized with high malignant and
poorly-differentiated primary tumors. In non-meta-
static primary tumors, Nkx2.1 expression was a
10-fold higher in metastic. In almost all lymph nodes
and distant macrometastases Nkx2-1 expression was
low/absent. Expression of exogenous Nkx2-1 in
tumors, which were induced with lentiviral vector
6 D. Milanovic
expressing Nkx2-1, restricted tumor progression,
resulting in fewer tumors of advanced-histopatholo-
gical grades. In gain- and loss-of-function experi-
ments in cells derived from metastatic to non-
metastatic tumors have demonstrated that Nkx2-1
controls tumor differentiation and limits metastatic
potential in vivo. With different functional analysis
was shown that Nkx2-1 inhibits tumor growth partly
by repressing the embryonically restricted chromatin
regulator Hmga2, which is highly expressed in
embryonic lung but not in any normal adult lung cells.
On the other hand, they are a lot of functional
clinical data supporting oncogenic activity of NKX2.1
in lung ADC where it is focally ampflied in *10% of
samples (Kwei et al. 2008). In conclusion, NKX2.1
can have both oncogenic and tumor suppressive
functions in lung ADC, demonstrate its role as a dual
function lineage factor.
The implications, which could have NKX2.1 in
treatment of lung ADC, warrant further preclinical
studies. Normally in adults, expression of NKX2.1 is
localized in peripheral airway cells and small-sized
bronchioles and it is questionable, if this target is
druggable and how any pharmacolgogical manipula-
tion with NKX2.1 will influence lung function.
4 EML4-ALK
The echinoderm microtubule-associated protein-like
4 (EML4)-anaplastic lymphoma kinase (ALK) fusion
oncogene (EML4-ALK) is an aberrant fusion gene
which represents one of the newest target oncogen in
NSCLC. It encodes a cytoplasmic chimeric protein
with constitutive kinase activity. EML4 and ALK
are localized oppositely oriented on short arm of
chromosome 2 (2p21 and 2p23); either gene may be
inverted to generate their common fusion gene
product.
The derived protein consists of the amino-terminal
portion of EML4 and the intracellular region of the
ALK. EML 4 consist of an N-terminal basic region, a
hydrophobic domain (HELP) for the association to
microtubules and the WD repeats that is necessary for
protein-interactions.
In EML4-ALK fusion protein, the N-terminal half
of EML4 including basic region, the HELP domain
and portion of the WD-repeat region, is fused to
the intracellular juxtamembrane region of ALK.
The coiled-coil domain within this portion of EML4
is responsible for constitutive dimerization and acti-
vation of EML4-ALK.
Overexpression of EML4-ALK in mouse 3T3
fibroblasts caused development of transformed foci in
cell culture and subcutaneous tumors in nude mice
(Soda et al. 2007). To investigate role of EML4-ALK
in lung carcinogenesis one transgenic mice model was
established (Soda et al. 2008). Remarkably, all of
investigated mice, which expressed EML4-ALK
specifically in lung alveolar epithelial cells, devel-
oped hundreds of adenocarcinoma nodules in both
lungs within a few weeks after birth. The treatment of
mice with oral specific small molecule inhibitor of the
kinase activity of ALK resulted in rapid disappear-
ance of tumors. These results were confirmed as
important carcinogenic role of EML4–ALK.
In humans, EML4–ALK fusion gene is not observed
frequently; it may be detected only in 2 to 7% of all
NSCLC patients. The EML4-ALK translocation is most
frequently seen in patients with adenocarcinomas, in
young adults, and in patients who have never smoked
or who are light smokers (Koivunen et al. 2008).
Interestingly, this translocation is generally detected in
NSCLC with wild type RAS or EGFR (Wong et al.
2009). The treatment of NSCLC patients carrying the
ALK fusion gene with crizotinib, an high specific,
small molecule ALK inhibitor, caused tumors shrink-
age or stabilization in 90% of 82 patients (Kwak
et al. 2010).
Despite the early impressive response to this
therapy, development of resistance was observed
usually within 1 year (Choi et al. 2010). In in vitro
condition, one model was established in which
resistance in highly sensitive EML4-ALK–positive
NSCLC cell was generated by increasing doses of
crizotinib (Katayama et al. 2011). Cells which were
resistant to intermediate doses of crizotinib developed
amplification of the EML4-ALK gene while develop-
ment of a gatekeeper mutation, L1196M, within the
kinase domain, was the main reason for resistance to
higher crizotinib doses. The same mutation was
described by one patient with EML4-ALK-positive
non-small-cell lung cancer who became resistant to
crizotinib after successful treatment for 5 months.
Treatment with crizotinib was ineffective against cells
harboring this mutation (Choi et al. 2010). The
treatment of these cells or human NSCLC H3122 CR
Xenografts, which were induced by implantation of
Molecular Biology and Genetics of Lung Cancer
crizotinib pretreated and resistant cells, with other
two structurally different ALK inhibitors, NVP-
TAE684 and AP26113, were highly active. Interest-
ingly, these resistant cells harboring gatekeeper
mutation, L1196M were highly sensitive to the Hsp90
inhibitor 17-AAG (Katayama et al. 2011).
Despite the development of resistance to the first
class of EML4-ALK inhibitors this fusion product
remains a very attractive target for future drug
development. Based on preclinical findings, combi-
nation of EML4-ALK inhibitors with Hsp90 inhibi-
tors, which are already investigated in Phase I–II
clinical trials, could represent an attractive strategy to
overcome the resistance.
5 LKB 1
LKB1 also known as Serine/threonine kinase 11 (STK
11) is a protein kinase which plays essential role
in the regulation of the cell energetic checkpoint
through the phosphorylation and activation of aden-
osine monophosphate-dependent kinase (AMPK). In
humans, LKB1 is encoded by LKB1/STK 11 gene,
which is localized on 19p chromosome (Jansen et al.
2009). Germline mutation of LKB1/STK11 gene is
responsible for appearance of Peutz–Jeghers or
hereditary intestinal polyposis syndrome (Beggs et al.
2010). This autosomal dominant disorder is charac-
terized by development of benign hamartomatous
polyps in the gastrointestinal tract and mucocutaneous
pigmented lesions occurring on different locations of
the body, most frequently around/in mouth. Also
persons with a this syndrome have an increased risk
for developing colorectal, stomach, pancreas, breast,
lungs, ovaries, uterus and testicles carcinoma.
LKB1 inactivation are common event in lung ADC.
It has been shown that 33% (6 of 20 primary tumors and
two of four cell lines) of lung ADC harbor LKB1/STK11
gene inactivation. By mapping of the short arm of
chromosome 19 from lung ADC samples it has been
found that LKB1/STK11 gene is located in the minimal-
deleted region (Sanchez-Cespedes et al. 2002). The
tumor-suppressor function of Lkb1 was investigated in
one mouse model (Ji et al. 2007). Previously it has been
presumed that the tumor-suppressor activity of LKB1 is
caused by activation of p53 and/or the Ink4a/Arf locus.
In this model, mice with tumors, characterized with
LKB1 loss and Kras activation, developed more
7
metastasis and lived shorter than mice which have p53
or Ink4a/Arf deficient tumors. In case of LKB1
reconstitution in NSCLC lines lacking p16INK4a, ARF
and p53 antitumors effects were observed, suggesting
that LKB1 anti-tumor effects are p16INK4a, ARF and
p53 independent. The anti-metastatic effect of
LKB1was also INK4a/ARF and p53 independent. In
the same study, 144 human NSCLC samples were
analyzed for KRAS and LKB1 mutations; 27 of 80% of
ADCs (34%) harbored predominantly (19/80) single-
copy mutation or deletion. The same alteration of
LKB1 was also observed in other histological types of
NSCLC—in 8 of 42 samples of squamous cell carci-
noma, 6 showed single-copy mutation or deletion as a
predominant lesion. NEDD9, VEGFC and CD24 were
identified as targets of LKB1 repression in human lung
cancer cell lines and mouse lung tumors. In other study
it was found that LKB1 genetic alterations favorably
appear in a subset of poorly-differentiated lung ADC
from smoking male patients (Matsumoto et al. 2007).
To explain potential role in treatment of lung
carcinoma, additionally in vitro and in vivo experi-
ments are necessary.
6 c-MYC
c-MYC proto-oncogene is located on chromosome
8 in humans and encodes an MYC transcription
factor (Vennstrom et al. 1982). It is assumed that
c-MYC regulate expression of 15% of all genes.
During the emrbyogenesis c-MYC is broadlly
expressed in different tissues and targeted gene dis-
ruption of both c-MYC alleles in embryonic stem
cells caused embryonic lethality at day 9.5–10.5
indicating crucial MYC roll in development (Davis
et al. 1993). In adults, MYC is expressed in tissues
that posses high proliferative capacity. In normal
dividing cells, c-MYC expression is maintained at a
relatively constant intermediate level. In neoplastic
disease, where MYC is activated, its expression is
moderate to very high (Pelengaris et al. 2002) .
MYC family of transcription factors contain the
carboxy-terminal basic-helix-loop-helix-zipper
(bHLHZ) domain. bHLH domain binds to DNA
while zipper domain allows the dimerization with
its partner Max, another bHLH transcription factor
(Amati et al. 1993). This dimerization is necessary for
Myc-dependent transactivation and its oncogenic and
8 D. Milanovic

Fig. 1 Signaling pathways

involved in the pathogenesis DNA
Activation/Production
Inhibition
of lung carcinoma Damage Mechanism unknown
HDM2
p21(ARF)
p14(ARF) p16(INK4A)
Cell
Cycle p53 Cdk4/6:cyclin D
RTK IGF
Telomerase E2F RB:E2F PTEN

Akt PI3K
Gene
Expression MAPK MEK Raf Ras RTK Growth Factors

Rho Rac
Myc:Mad
Receptor Neuropeptides
Myc:Max
Cells CAM Bax
Apoptosis Bcl-2
ECM Integrins

proliferative properties. Additionally to its role as a
transcriptional factor, MYC also has a fundamental
role global chromatin structure by regulating histone
acetylation both in gene-rich regions and at sites
far from any known gene. On the other hand,
MYC overexpression can activate the proapoptotic
BCL2 family protein BAX, resulting in release of
cytochrome c and apoptosis (Pelengaris et al. 2002).
To attenuate the antitumorigenic effects of MYC
other compensatory genetic and epigenetic alterations
are required to facilitate tumor growth. It has been found
that overexpression of an antiapoptotic protein MCL 1,
stimulates tumor progression in transgenic mice with
either spontaneous mutations in Kras or experimental
introduction of activated RAS only in case of MYC
paralell overexpression (Allen et al. 2011). By patients
with NSCLC, MCL1 overexpression alone was not a
prognostic marker, but if overexpression of MCL 1 was
accompanied by MYC overexpression, significantly
poorer overall survival was observed.
Principally, Myc could be an attractive therapeutic
target for treating a different type of neoplastic dis-
ease, but on the other hand it would be possible that
therapeutic inhibition of myc may inhibit proliferation
of normal cells resulting in serious side effects.
Abnormal expression is observed in *20% of
NSCLC and *30% of SCLC (Salgia and Skarin 1998).
Systemic MYC inhibition by reversible, systemic
expressed of a dominant-interfering MYC mutant was
investigated in one Ras-induced lung ADC mouse
model. As a result, incipient and established lung
tumors were rapidly regressed. It is very interesting
that this work for the first time provides information
of MYC role in the maintenance of Ras-dependent
lung tumors in vivo. The side effects of systemic
MYC inhibition were observed in normal regenerat-
ing tissues, but they were well rapidly and completely
reversible (Soucek et al. 2008). In one study, genetic
alterations that define prognosis of patients with
early-stage lung ADC were investigated (Iwakawa
et al. 2011). Hundred and sixty-two speciemens of
stage I lung ADC were analyzed. It has been found
that MYC amplification correlated with poor prog-
nosis. These authors conclude that MYC amplifica-
tion may be used as a prognostic marker of patients
with early-stage lung ADC (Fig. 1).
To determine possible role of MYC inhibition as a
novel therapeutic strategy, additional in vivo experi-
ments should be performed specially concering its
safety profile.
7 KRAS
The proto-oncogene KRAS, together with HRAS
and NRAS belongs to the Ras subfamily of small
GTP-ase. RAS plays a very important role in the
EGFR downstream signaling cascade and can activate
other important pathways such the serine/threonine
kinase RAF, mitogen-activated kinases ERK1 and
ERK2, phosphatidyl inositol 3-kinase and other pro-
teins that translocate to the nucleus resulting in the
transcription and cell proliferation (Vakiani and Solit
2011).
Molecular Biology and Genetics of Lung Cancer 9

RAS can be activated by mutations in different Table 1 Molecular abnormalities in lung cancer
tumor types. Approximately 20% of human tumors Frequency of Abnormality (%)a
have activating point mutations in RAS (usually in NSCLC SCLC
codons 12, 13 and 61). About 85% of all RAS
Growth Signals
mutations are found in KRAS, 15% in NRAS and
Ras 25 \1
less than 1% in HRAS (Downward 2003). KRAS
mutation is detected in 10–30% of lung adeno- Akt 70–90 65
carcinomas, is very rarely found in other NSCLC Myc 20–60 20–30
form and is not present in SCLC. It has been EGFR 50 0–50
found that TBK1, non-canonical IjB kinase, HER2/neu 30 30
which activate antiapoptotic signals involving c-Kit 30–40 50
cREL and BCL-XL is essential for development of Neuropeptides *50 *50
KRAS-driven lung tumors (Barbie et al. 2009). IGF *90 *90
KRAS can induce IL-8 overexpression, one che-
Tumor Suppressor Genes
mokine which plays important role in cell growth,
RB 15–30 [90
tumor cells migration and angiogenesis (Sunaga
et al. 2011). In 89 NSCLC surgical specimens IL-8 p16(INK4A) inactivation 50–70 0–20
expression was significantly higher in male 3p deletions 70 90
patients, smokers, elderly patients, in patients with FHIT inactivation 40–70 70
pleural involvement and KRAS mutated adeno- RASSF1A silencing 50 90
carcinomas. In one study, the relationship between Apoptosis
KRAS amplification, detected by Fluorescence in p53 40–50 60–75
situ hybridization and mutation was investigated in
Bcl-2 20–35 71
two cohorts of patients. In one cohort (538 Swiss
Replicative Potential
patients) the prevalence of KRAS amplification
was 13.7%; in other cohort (402 patients from Telomerase 80–100 80–100
New York) the prevalence of KRAS amplification Angiogenesis
was 15.1%. Patient with KRAS amplification had a VEGF 75 75
larger, less-differentiated and aggressive tumors, COX-2 [70 Not reported
with characteristic angiolymphatic invasion. Metastasis
Especially in adenocarcinoma subset harboring N-CAM, non-adhesive not reported 90
activating KRAS mutations, KRAS amplification
Laminin-5 inactivation 20–60 65–85
was observed, suggesting a synergistic relationship a
See text for selected references
between amplification and mutation. The presence
of KRAS amplification was not associated with
nodal involvement or survival. The prognostic role
of KRAS mutations in NSCLC have been inves-
tigated in various clinical studies. Despite of 8 Bcl-2
conflicting results, a meta-analysis has revealed
that RAS mutations may have some prognostic Bcl-2 is a member of Bcl-2 genes family which plays
value for determination of a poor prognosis an important role in the regulation of apoptosis. Bcl-2
(Mascaux et al. 2005). On the other hand, one is encoded by BCL-2 gene which has been implicated
review data strongly suggests that KRAS muta- in a different neoplastic disease including lung
tions cannot be used as a factor which can predict carcinoma. So far, 15 mammalian family members
response to conventional chemotherapy (Loriot divided in three subfamilies were identified—Bcl-2,
et al. 2009). Because of its interaction with dif- BAX and BH 3. Some of them act as proapoptotic
ferent crucial pathways involved in carcinogenesis, (BAX and BH3 family members) some as antiapo-
KRAS inhibition could represent an attractive ptotic factors (Bcl-2 family members). The product of
therapeutic approach Table 1. bcl-2 is a 26 kDa protein which is mainly located in
10
the inner mitochondrial membrane. The most impor-
tant function of Bcl-2 is an inhibition of apoptosis and
prolongation of cell survival by arresting cells in the
G0/G1 phase of cell cycle. The ratio of proapoptotic
to antiapoptotic members will determinate the cells
response for apoptotic signal (Chao and Korsmeyer
1998). Bcl-2 overexpression is frequently observed in
SCLC (*90%) (Jiang et al. 1995), where it can be
found seldom in patients with NSCLC (*25%)
(Pezzella et al. 1993). It has been demonstrated in in
vitro conditon that in SCLC cell lines which were
resistant to conventional chemotherapeutics Bcl-2
was upregulated. In phase I dose-escalation trial
in patients with heavily pretreated SCLC, one
highly-potent and selective inhibitor of Bcl-2 family,
Navitoclax, caused durable single-agent response in
heavily pretreated patients (Gandhi et al. 2011).
There are a lot of controversy reports according to
the prognostic role of Bcl-2 in lung carcinoma patients.
One meta-analysis, including 25 trials with totaly 3370
participants, shows that patients with Bcl-2-positive
tumors had significantly better survival than those with
Bcl-2-negative tumors (Martin et al. 2003). In the same
meta-analysis, in case of patients with SCLC, data on
Bcl-2 expression were insufficient to give an definitive
conclusion if Bcl-2 expression may be used as a
prognostic marker in this patients population.
Specific inhibition of Bcl-2 with Navitoclax has a
promising activity in pre-treated patients with SCLC
and future clinical development should clarify if
this inhibition may have a place in routine clinical
treatment of SCLC.
9 MET
c-MET is a proto-oncogene which encodes the tyrosine
kinase receptor for HGF/SF1 (hepatocyte growth fac-
tor/scatter factor). Structurally, HGF/SF is a large,
multi-domain protein showing structural similarity
with plasminogen, the proenzyme of plasmin, whose
primary role is the degradation of fibrin in the vascu-
lature. HGF/SF consists of six domains: an amino-
terminal domain (N), four KRINGLE DOMAINS
(K1–K4) and a serine proteinase homology (SPH)
domain, which lacks enzymatic activity as a result of
mutations in essential residues. MET kinase catalytic
activity is induced upon MET activation by HGF and it
is responsible for transphosphorylation of the tyrosines
D. Milanovic
Tyr 1234 and Tyr 1235, which involve different signal
transducers such as GRB2, SHC, SRC and the p85
regulatory subunit of phosphatidylinositol-3 kinase
(PI3K) and Gab1. Gab1, member of protein-docking
family, is a most important coordinator of cellular
response to MET. The interaction between Gab1 and
MET causes Gab1 phosphorylation which is respon-
sible for activation of multiple signal transduction
pathway such as RAS, PI3K, STAT, beta-catenin and
Notch (Birchmeier et al. 2003).
HGF/SF1 plays a fundamental role in embryolog-
ical development; mice lacking HGF/SF1 cannot
complete development and die in utero. The most
affected organs are liver and placenta (Schmidt et al.
1995). Liver of this mice shows defective structure
with enlarged sinusoidal space and dissociated
parenchymal, frequently apoptotic cells. Other fun-
damental embryogenetic process such as muscle
development (Bladt et al. 1995), nervous system
formation, bone remodeling and angiogenesis are
highly affected by MET (Maina and Klein 1999).
During the organogenesis c-MET transcripts are
detected in epithelia of lung, kidney and intestine while
HGF/SF1 is expressed in neighborhood mesenchyme
(Schmidt et al. 1995). In the adult tissue, the most
important role of HGF/SF is regulation of response to
tissue damage. The rising serum level of circulating
HGF/SF1 and increased HGF/SF expression are
observed after liver, kidney, heart or injury of other
organs (Michalopoulos and DeFrances 1997; Matsum-
oto and Nakamura 2001; Nakamura et al. 2000).
In carcinogenesis, HGF/Met signaling plays
important role, especially in tumor invasiveness and
metastatic spread. Activation of MET in tumors can
occur most frequently through ligand-dependent
autocrine or paracrine mechanisms. Other oncogene,
such as activated RAS can induce MET overexpres-
sion (Mazzone and Comoglio 2006). Deregulation of
the HGF/MET signaling pathway may occur through
different mechanisms, including HGF and/or MET
overexpression, MET gene amplification, mutations
or rearrangements (Birchmeier et al. 2003).
Strongly MET expression was observed in 60%
NSCLC and 25% SCLC (Ma et al. 2005, 2007).
Despite the rapid clinical response in NSCLC
patient with EGFR exon 19 mutant treated with
Gefitinib or Erlotinib, the vast majority of them will
develop resistance to quinozoline-based drug treat-
ment. By approximately 50% of patients reason to
Molecular Biology and Genetics of Lung Cancer
therapy failure is occurrence of a secondary mutation
in EGFR (T790M) (Kosaka et al. 2006).
It has been reported that resistance to gefitinib in
one gefitinib-sensitive EGFR exon 19 mutant NSCLC
HCC827 lung cancer cell-line was caused by focal
amplification of the MET proto-oncogene (Engelman
et al. 2007). In this cell line, where ERBB3/PI3K/Akt
signaling pathway is required for gefitinib induced
apoptosis, resistance was induced exposing these cells
to increasing concentrations of this drug for 6 months.
This resistance cell-line was known as HCC827 GR
and in comparison to parental cell-line it showed
marked focal amplification within chromosome
7q31.1–7q33.3, which contains the MET proto-
oncogene. In this cell-line increased MET amplifica-
tion (5–10 times) was observed and sequencing ana-
lysis provided no evidence of mutations in MET. The
treatment of resistant cells with specific MET tyrosine
kinase inhibitor, PHA-665752 in the combination
with gefitinib-caused growth inhibition and induced
apoptosis. In the same cells, gefitinib alone markedly
reduced phosphorylation of EGFR, but without sig-
nificantly effects ERBB3 and Akt phosphorylation. In
contrast, gefitinib in combination with PHA-665752
completely suppressed ERBB3 and Akt phosphor-
ylation in these cells, suggesting that observed resis-
tance to gefitinib is a consequence of increased
MET signaling. In other experiments it has been
found that MET amplification caused continuing
activation of PI3K/Akt signaling in the presence of
gefitinib by maintaining ERBB3 phosphorylation.
To evaluate clinical relevance of these findings, 18
tumors of patients with NSCLC, who initially
responded to treatment with gefitinib or erlotinib, but
after some period showed tumor regrowth, were
analyzed for MET copy status. MET amplification
was detected in 4 out of 18 (22%) gefitinib/erlotinib-
resistant tumor specimens. Notably, dual inhibition of
Met/EGFR was investigated in an globally random-
ized, double-blind phase II study (OAM4558g)
(Spigel et al. 2011). One hundred and twenty-eight
NSCLC patients were equally randomized to receive
MetMAb, a monovalent monoclonal antibody that
specifically binds the Met receptor, plus erlotinib or
placebo plus erlotinib in second/third line treatment.
It has been found that addition of MetMab to erlotinib
in these patients significantly improved PFS and OS
(12.6 vs. 3.8 months). The toxicity was similar in
both treatment arms. An overall survival benefit from
11
dual EGFR/MET inhibition was observed in MET
FISH ? NSCLC as well as in FISH-/IHC+.
Targeting EGFR with gefitinib or erlotinib and
MET with specific inhibitors may represent a prom-
ising strategy to treat lung cancer. This new thera-
peutic approach already reveals promising response in
patients with lung carcinoma.
10 EGFR
The epidermal growth factor receptor (EGFR; ErbB-1)
is the cell-surface receptor which belongs together with
other three closely related receptor tyrosine kinases—
HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4
(ErbB-4) to family of ErbB family of receptors. EGFR
is a monomeric 170-kD transmembrane glycoprotein
which consists of an extracellular ligand-binding
domain, a transmembrane lipophilic segment and an
intracellular protein kinase domain with the regulatory
COOH-terminal segment. The receptor exists as an
inactive monomer but after ligand-binding (epidermal
growth factor, transforming growth factor a(TGFa),
Heparin-binding EGF-like growth factor, betacellulin,
amphiregulin), EGFR dimerization occurs. It results in
activation of the intracellular domain of receptor and
autophosphorylation of several tyrosine residues in the
C-terminal domain of EGFR. These events lead to the
initiation of a cascade of biochemical intracellular
events that are involved in the mitogenic signal trans-
duction of malignant cell. Phosphorylated tyrosine
residues play important role as a docking site for pro-
teins SH2, Grb2 and Shc and enzymes such as phos-
pholipase C, phosphatidylinositol-3 kinase (PI-3K)
and the Src family kinases. These proteins are impor-
tant for initiation of multiple intracellular signal
transduction cascades that cause activation of many
downstream pathways of EGFR such as ras/mitogen-
activated protein kinase (MAPK), PI-3K/Akt and sig-
nal transducer and activator of transcription (STAT)
pathways (Hynes and Lane 2005).
In normal embryologyical development, EGFR
plays important role in development of lungs, eyes,
epidermis, hair and central nervous system (Liu and
Neufeld 2007). The lungs from EGFR mutant mice
showed undifferentiated epithelium in the respira-
tory bronchioles and alveoli and increased amounts
of cells in the alveolar septae (Sibilia and Wagner
1995).
12
EGFR is overexpressed in 50% of NSCLC; the
highest rate (80%) is detected in squamous cell car-
cinoma (Meert et al. 2002).
EGFR amplification is detected in ca. 30% of
patients with squamous cell and 15% with ADC of
lungs. EGFR kinase domain mutations may be found
in approximately 40% of Asian patients while in the
USA, these mutations are detected in ca. 10% in
tumor specimens. In SCLC, amplification and kinase
domain mutations are very rare events. The most
frequently occurring EGFR kinase domain mutations
(*80%) are in-frame deletions within exon 19
(Godin-Heymann et al. 2007) or the L858R mutant
within exon 21 (point mutation) (Mulloy et al. 2007)
which occur most frequently in women, nonsmokers
and ADC histology. The most dramatic clinical
response to EGFR targeted therapies with small
molecule tyrosine kinase inhibitors such as Gefitinib
or Erlotinib, occur in patients which tumors harboring
these mutations (Pao et al. 2004). On the other hand,
some of EGFR mutations, which occur in exons
18–21 are associated with resistance to small mole-
cule EGFR inhibitors (Wu et al. 2008). In *5% of
patients with NSCLC small insertions or duplications
in exon 20 may be detected. Consisting with in vitro
data, which showed that such mutations are less
sensitive to EGFR TKIs, patients with tumors har-
boring exon 20 insertions show progressive disease
during therapy with EGFR TKIs (Wu et al. 2008).
Despite the early response to EGFR TKIs, most of
patients with exon 19 and exon 21 mutations will
progress. This acquired resistance may be caused by
development of T790M mutation, which is encoded
by exon 20 (Inukai et al. 2006), L747 S (exon 19)
(Costa et al. 2008), D761Y (exon 19) (Balak et al.
2006) and T854A (exon 21) (Bean et al. 2008). On the
other hand, different genetic changes, such as muta-
tions in PIK3CA (Kawano et al. 2006), crosstalk
between EGFR and insulin-like growth factor recep-
tor 1 (Sharma et al. 2010), loss-of PTEN expression
(Sos et al. 2009) may cause resistance to EGFR TKIs
in spite of present drug-sensitive EGFR mutations.
Tumors, with wild type EGFR, are generally resistant
to gefitinib treatment (Mok et al. 2009). Somatic
mutations in other genes may be reason for this drug
insensitivity. For example, activating mutations of
KRAS (codons 12 and 13 in GTPase domain) are
detected in 15–25% of NSCLC or BRAF mutations,
which are detected in 2–3% NSCLC specimens, may
D. Milanovic
also be reason for gefitinib resistance (Linardou et al.
2008; Pratilas et al. 2008). As described previously,
translocations in ALK, MET amplification and
increased expression of HGF may contribute to gefi-
tinib resistance in NSCLC with wild-type EGFR.
For some patients with EGFR mutations, treatment
with small tyrosin kinase inhibitors represents a valu-
able alternative for conventional chemotherapy or new
therapeutic option in the case of therapy failure.
To expand therapeutical window of EGFR inhibition,
the complex molecular mechanism which caused
resistance, should be better understood. Also the
combination with other targeted therapies may play
important role in treatment of lung cancer in the future.
11 p53
p53 is a protein that in humans is encoded by the
TP53 gene (Matlashewski et al. 1984). p53 plays
important role in apoptosis, genomic stability and
inhibition of angiogenesis. In multi-cellular organism
it is acting as a tumor suppressor by activation of
DNA repair, induction of growth arrest by holding the
cell cycle at the G1/S regulation point on DNA
damage recognition and initiation of apoptosis, in
case of irreparable DNA damage. Because of its
suppressor role, p53 has been described as ‘‘the
guardian of the genome’’. In case of TP 53 mutation,
tumor suppression is severely impaired (Millau et al.
2008). TP 53 mutations can be found in 60–75% of
lung cancer including both NSCLC and SCLC (Oli-
vier et al. 2002). Majority of mutations are missense
mutations in exons 5–8 (Bodner et al. 1992).
12 Other Factors
Cyclooxygenase-2 (COX2) and COX1 are two COX
enzymes which are responsible for the conversion of
arachidonic acid to prostaglandins (PGs) and other
bioactive lipids. COX2 plays key role in inflammatory
response and it has been found that inflammation may
have tumor promoting effects. COX2 may be upregu-
lated with different stimuli such as interleukin (IL)-1,
tumor necrosis factor a, platelet-derived growth factor
and epidermal growth factor. In neoplastic disease,
COX2 may play important role in angiogenesis,
apoptosis and tumor invasiveness. This enzyme is
Molecular Biology and Genetics of Lung Cancer
frequently overexpressed in NSCLC (*70%) while in
SCLC overexpression is not detected. Elevated COX2
protein levels and increased mRNA levels were asso-
ciated with poor prognosis of patients with NSCLC
(Wolff et al. 1998). Preclinical data showed that treat-
ment of mice with selective COX2 inhibitor celecoxib,
as a sole compound (Fulzele et al. 2006) or in the
combination with docetaxel may significantly inhibit
growth of A549 lung tumor xenografts (Shaik et al.
2006).
In one double-blind randomized clinical phase III
trial (CYCLUS study) 319 patients were randomized
to receive celecoxib 400 mg or placebo in addition to
palliative chemotherapy. This study failed to dem-
onstrate survival benefit in patients who were treated
with celecoxib and chemotherapy (Koch et al. 2011).
PI3K/AKT/mTOR pathway is an intracellular
signaling pathway which is involved in the regulation
of a number of cellular processes, such as transcrip-
tion, migration, angiogenesis, cell growth, prolifera-
tion, apoptosis and glucose metabolism. PI3K is
activated by several hormones including insulin,
growth factors such as EGF, IGF, PDGF, NGF and
HGF by signals derived from receptors for extracel-
lular matrix molecules such as integrins, by several
forms of cellular stress such as oxidative stress or cell
swelling, and by activation of Ras. Akt is constitu-
tively activated at high rates in both NSCLC and
SCLC (65%) (Brognard et al. 2001).
The p16INK4a is a tumor suppressor protein acting
as an inhibitor of CDK4 and CDK6, the D-type cyclin-
dependent kinases which are responsible for initiation
of phosphorylation of the retinoblastoma tumor sup-
pressor protein, RB, which is encoded by the RB1 gene
located on chromosome 13q14.1–q14.2. RB1 expres-
sion is deregulated in 15–30% of NSCLC and[90% of
SCLC, but without prognostic significance (Shimizu
et al. 1994).
Loss-of heterozygosity (LOH) in 3p is also com-
mon genetic alteration detected in almost all types of
lung cancer (Wistuba et al. 2000), but its contribution
to lung cancer development is yet to be clarified.
13 Conclusion
Despite the intensive research and development,
prognosis of patients with inoperable NSCLC and
SCLC remain poor. Microarray data, which are
13
obtained in last years, combined with synthetic
lethality strategies may provide a new challenge to
develop relevant in vitro and in vivo model for
both of main histological entities of lung carcinoma.
Relevant model will open new therapeutic windows
for testing new drug candidates which should be used
for treating these, until now, refractory disease.
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 Angiogenesis and Lung Cancer
Wenyin Shi and Dietmar W. Siemann

Contents
1 Introduction..............................................................
2 Angiogenesis .............................................................
3 Angiogenesis in Lung Cancer ................................
4 Anti-Angiogenic Therapy........................................
4.1 Drugs that Block Angiogenic Factors ......................
4.2 Drugs that Inhibit Endothelial Cell Function ...........
4.3 Drugs that Block Breakdown
of Extracellular Matrix..............................................
4.4 Drugs that Target Survival Factors of Neovessels...
5 Vascular Disrupting Therapies ..............................
6 Conclusions ...............................................................
References..........................................................................
Abstract
Lung cancer is one of the most frequent causes of
17 cancer deaths worldwide. Current treatment regi-
18 mens with conventional anticancer therapies offer
only a limited survival benefit. There clearly exists
19
a need for the development of new therapeutic
23 strategies. Recent evidence suggests that angio-
24
genesis is critical to lung cancer progression and
30
related to poor prognosis. Consequently tumor
31 angiogenesis, a process that features an imbalance
31 between pro and antiangiogenic mediators, is
32 being targeted by novel therapies in the treatment
33
of lung cancer. A variety of therapeutic approaches
and agents have been developed to compromise the
33
growth and/or function of tumor vasculature. In
October 2006, bevacizumab was the first antian-
giogenic agent approved by the US Food and Drug
Administration for the treatment of advanced,
nonsquamous, nonsmall cell lung cancer in com-
bination with platinum-based chemotherapy. Other
antiangiogenic agents are actively being evaluated
in pre-clinical and clinical settings.

1 Introduction

Lung cancer is a significant public health problem in

W. Shi (&)
Department of Radiation Oncology, the United States and the world. In the United States,
Thomas Jefferson University, lung cancer ranks as the second most common cancer
111 S 11 ST Suite G301, among both men and women. In 2010, an estimated
Philadelphia, PA 19107, USA
222,520 new cases of lung cancer were diagnosed in
e-mail: wenyin.shi@jefferson.edu
the United States; a number representing approxi-
D. W. Siemann
mately 14.6% of all new cancers diagnosed. Lung
Department of Radiation Oncology,
Shands Cancer Center, University of Florida, cancer is the most common cause of cancer-related
Gainesville, FL 32610, USA deaths in both female and male, accounting for

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 17
DOI: 10.1007/174_2011_260, Ó Springer-Verlag Berlin Heidelberg 2011
18
157,300 deaths in 2010 (Jemal et al. 2010). Although
the incidence of lung cancer is now declining in men,
the incidence in women continues to increase (Weir
et al. 2003), probably due to changing smoking habits.
According to World Health Organization histo-
logic classification schemes (WHO 1979), there are
four primary pathological types of lung cancer: small-
cell carcinoma, squamous-cell carcinoma, adenocar-
cinoma and large-cell carcinoma. However, for ther-
apeutic purposes, lung cancer is generally divided into
small-cell lung cancer (SCLC) or non-small-cell lung
cancer (NSCLC) with the latter representing approx-
imately 80% of all lung cancer patients (Edwards
et al. 2005).
Although prevention and early detection are critical
to improve treatment outcomes, these have proven
difficult in lung cancer. A major reason is that only
approximately 15% of lung cancers are discovered
while still localized. Local treatment for early-stage
disease, particularly surgical interventions, can
improve patient survival, yet less than 50% of patients
are cured, principally due to the presence of undetected
occult local or metastatic disease (Mountain and Her-
mes 2003; Posther and Harpole 2006). Radiotherapy
and chemotherapy typically are applied in more
advanced disease. Still, survival in patients with lung
cancer remains poor. The 5 year survival rate for all
stages combined is only 5–15% (Comis 2003; Kepka
et al. 2009). The majority of patients die from disease
progression locally, at distant sites, or both.
Pathologic staging, which incorporates factors
such as tumor size and grade, nodal status and pres-
ence or absence of distant metastases, provides the
best prediction of treatment outcome (Mountain 2000;
Beadsmoore and Screaton 2003). However, because
the growth of primary tumors and metastases is
angiogenesis dependent (Folkman 1971, 2002), a
great deal of attention has recently been paid to the
role of this process not only in lung cancer formation,
progression, and prognosis, but also in the develop-
ment of novel therapeutic strategies for this disease.
In October 2006, the anti-angiogenic agent bev-
acizumab was granted a labeling extension by the US
Food and Drug Administration for the first-line
treatment of advanced, nonsquamous, NSCLC in
combination with platinum-based chemotherapy
(Sandler et al. 2006). Many other agents that target
tumor-associated vasculature are under development
and/or in various phases of clinical trial assessment.
W. Shi and D. W. Siemann
2 Angiogenesis
Angiogenesis is a process that allows the develop-
ment and formation of new blood vessels from a pre-
existing vascular network. This process is complex
and involves multiple sequential, interactive steps as
well as a variety of cells, soluble factors, and the
extracellular matrix. The sequential steps include:
degradation of basement membranes, migration and
proliferation of endothelial cells, lumen formation,
and stabilization of neovessels. Under physiological
circumstances, angiogenesis is a rare event in adults,
occurring almost exclusively in the female repro-
duction system (Folkman 1995; Risau 1997). It is
normally suppressed and observed only transiently.
However, angiogenesis can be activated in response
to tissue damage, and it is associated with a variety of
pathological conditions including cancer (Folkman
2002). While angiogenesis in itself is not sufficient for
continued tumor growth, its absence severely com-
promises or halts the expansion of a tumor cell pop-
ulation. Indeed, it is believed that tumors can not
grow to a size larger than a few cubic mm without
initiating the angiogenic process (Folkman 1971,
1975, 2002). Furthermore, there is evidence that
angiogenesis may be present in pre-malignant lesions
such as epithelial dysplasia even prior to development
of invasive cancer (Fontanini et al. 1995; Keith et al.
2000).
A balance of pro- and anti-angiogenic factors
carefully regulates the angiogenic potential of endo-
thelial cells. While tightly controlled under normal
physiological conditions, this rigid control is absent in
angiogenesis associated with tumors. Indeed altera-
tions of the expression and/or function of pro-angio-
genic and anti-angiogenic molecules that disrupt the
normal balance appear to be responsible for tumor
angiogenesis. The regulatory factors involved may
mediate any one of a cascade of steps in the process
of angiogenesis. As a consequence the characteristics
of endothelial cells and associated perivascular
structures (pericytes, vascular smooth muscle cells)
can be dramatically altered.
Vascular endothelial growth factor (VEGF) is the
most potent and specific growth factor for endothelial
cells. VEGF can increase vascular permeability,
induce endothelial cell proliferation and migration,
activate proteases for extra-cellular matrix
Angiogenesis and Lung Cancer
degradation, and inhibit apoptosis of endothelial cells
(Senger et al. 1986; Connolly et al. 1989; Watanabe
and Dvorak 1997; Ferrara 2002). VEGF is comprised
of a family of five isoforms which bind with high
affinity to tyrosine kinase associated receptors that are
present on endothelial cells (Ferrara et al. 2003).
Another class of endothelial cell specific molecules is
the angiopoietin family. It includes at least four
members (angiopoietins 1–4) of which Ang-1 and
Ang-2 appear to be most relevant. Ang-1 and Ang-2 are
secreted proteins that interact bind the Tie-2 receptor
with similar affinities but with opposing functional
effects; Ang-1/Tie-2 signaling controls vessel quies-
cence and stability while Ang-2/Tie-2 association
allows for vessel plasticity and destabilization (Papa-
petropoulos et al. 1999). The Ang-2/Tie-2 interaction
sensitizes the vasculature to growth factors, such as
VEGF, to stimulate endothelial cells, angiogenesis and
vascular remodeling (Holash et al. 1999).
In addition, there are numerous non-specific
angiogenic growth factors that can also affect endo-
thelial cells. These include platelet-derived growth
factor (PDGF), basic fibroblast growth factor (bFGF/
FGF-2), acidic fibroblast growth factor (aFGF/FGF-
1), fibroblast growth factor-3 (FGF-3/int-2), fibroblast
growth factor-4 (FGF-4/hst/K-FGF), hepatocyte
growth factor/scatter factor (HGF/SF), transforming
growth factor-a (TGF-a), transforming growth factor-
b (TGF-b), tumor necrosis factor-a (TNF-a), granu-
locyte colony stimulating factor, interleukin-8,
pleiotropin, and angiogenin, to name just a few
(Moore et al. 1998).
A growing number of endogenous anti-angiogenic
factors also been discovered. To date, these include
endostatin, angiostatin, vasostatin, interferon-a, b, c,
METH-1 and METH-2, antithrombin III, and VEGF
inhibitor (Kerbel 2000, 2008; Gordon et al. 2010).
These factors have great structural diversity and
activity. Some of the most notable, endostatin and
angiostatin, are cleavage fragments of proteins that
normally lack anti-angiogenic activity (O’Reilly et al.
1994; O’Reilly 1997; Takahashi et al. 2010). Table 1
lists endogenous factors that stimulate and inhibit
angiogenesis.
Generally, solid tumors cannot grow beyond *1–
2 mm in diameter without developing their own blood
vessel networks to supply nutrients and dispose of
waste products (Folkman 1990a). Tumors trigger
angiogenesis by producing pro-angiogenic factors
19
and/or suppressing anti-angiogenic factors. The point
at which angiogenesis is triggered by tumor cells is
known as the angiogenic switch (Bergers and Benja-
min 2003). Tumor angiogenesis is a complex, well-
orchestrated, cascade of steps, which initiated by
VEGF induced vasodilation and increased vascular
permeability, extravasation of plasma proteins such as
fibrinogen (Roodink and Leenders 2010), and the
Ang-2 mediated dissociation of pericytes from endo-
thelial cells (Holash et al. 1999). The vascular base-
ment membrane and extracellular matrix surround
existing capillaries are then degraded by proteases
produced by tumor cells (Werb et al. 1999). Subse-
quently, endothelial cells proliferate, invade the sur-
round extracellular matrix and form hollow tubes.
This process involves Delta-like ligand 4/Notch 1
induced differentiation (Roca and Adams 2007).
Finally, blood vessel sprouts fuse with other sprouts
to form vascular loops (Roodink and Leenders 2010;
Ucuzian et al. 2010). Angiogenesis not only permits
further growth of the tumor, but also provides a
pathway for migrating tumor cells to gain access to
the systemic circulation and eventually establish dis-
tant metastases (Folkman 1971, 1990b). Unlike blood
vessels in normal tissue, tumor-associated vasculature
is irregular and unstable, likely due to the over-pro-
duction of pro-angiogenic proteins such as VEGF
(Bergers and Benjamin 2003). Tumor-associated
blood vessels are excessively branched and chaotic.
Targeting tumor vascular supply is widely recognized
as an attractive anti-cancer strategy.
3 Angiogenesis in Lung Cancer
The lungs are highly vascularized and highly depen-
dent on intact vasculature for efficient function.
Endothelial cells lining the lumen surfaces of blood
vessels are not only a mechanical barrier but also play
an essential role in the regulation of blood flow,
vascular permeability, angiogenesis, and metastasis
(Paku 1998; Tuder et al. 2001; Chouaib et al. 2010).
Endothelial cells from normal and tumor tissues not
only differ phenotypically but also in their gene
expression profiles (St Croix et al. 2000). Moreover,
significantly different expression profiles of angio-
genic proteins have been observed between different
lung cancer types (Yamashita et al. 1999; Takase
et al. 2010; Lopez-Campos et al. 2011).
20
Table 1 Endogenous regulatory factors involved in angiogenesis
Pro-angiogenic Factors
Vascular endothelial growth factor (VEGF-A, B, C, D, E)
Placental growth factor
Platelet-derived growth factor (PDGF)
Basic fibroblast growth factor (bFGF/FGF-2)
Acidic fibroblast growth factor (aFGF/FGF-1)
Fibroblast growth factor-3 (FGF-3/int-2)
Fibroblast growth factor-4 (FGF-4/hst/K-FGF)
Hepatocyte growth factor/Scatter factor (HGF/SF)
Transforming growth factor-a (TGF-a)
Transforming growth factor-b (TGF-b)
Tumor necrosis factor-a (TNF-a)
Granulocyte colony stimulating factor
Interleukin-8
Pleiotropin
Angiogenin
Proliferin
Matrix metalloproteinases (MMPs)
Angiopoietin-2
Prostaglandin E1 and E2
Thymidine phosphorylase (TP)
Platelet-derived endothelial cell growth factor (PD-ECGF)
Intergrin
Ephrin
Typically, angiogenesis in tumors has been asses-
sed indirectly by determining intratumoral microves-
sel density (MVD). Blood vessels are usually
immunostained with a pan-endothelial marker, such
as factor VIII-related antigen, and counted (Guidi
et al. 1994). More recently, markers with an increased
ability to highlight the entire tumor vasculature
(CD31, CD34) have replaced factor VIII-related
antigen as the most commonly used pan-endothelial
markers (Miettinen 1993; Hasan et al. 2002). An
international consensus on the methodology and cri-
teria for evaluation of MVD has been put forth
(Vermeulen et al. 1996). MVD is a measure of one
feature of the tumor vasculature, the density of blood
vessels in the regions of tumor with the highest con-
centration of blood vessels, referred to as ‘hot spots’.
While there is evidence, accumulated over the past
10 years, that correlates this parameter with angio-
genic growth factor expression, tumor growth and the
occurrence of distant metastases (Weidner et al. 1993;
W. Shi and D. W. Siemann
Anti-angiogenic Factors
Angiostatin
Endostatin
Vasostatin
Thrombospondin-1 and internal fragment
Vascular endothelial growth factor inhibitor
Fragment of platelet factor-4
Derivative of prolactin
Restin
Proliferin-related protein
SPARC cleavage product
Osteopontin cleavage product
Interferon-a, Interferon-b
METH-1, METH-2
Angiopoietin-2
Antithrombin III fragment
Interferon-inducible protein-10
Tissue inhibitors of metalloproteinases (TIMPs)
Prolactin
Interleukin 1, 6, 12
VEGF soluble receptor
Dll4
McCulloch et al. 1995; Mattern et al. 1996; Takahashi
et al. 2010), there are important aspects of the process
of angiogenesis that MVD does not reflect. For
example, it does not measure the degree of vascular
heterogeneity across the tumor, or the functions of the
microvasculature such as blood flow or extent of
tumor hypoxia.
Results from a number of clinical investigations
now have indicated that increased MVD is associated
with a poor prognosis. Indeed MVD has been shown
to be an independent prognostic factor in a variety of
tumor types, including breast, bladder, ovarian,
prostatic, pancreatic, melanoma, colorectal, and gas-
tric carcinoma (Toi et al. 1993; Dickinson et al. 1994;
Tanigawa et al. 1996; Papamichael 2001; Bono et al.
2002; Khan et al. 2002; Lee et al. 2002; Massi et al.
2002; Gadducci et al. 2003; Herrmann et al. 2007;
Minardi et al. 2008; Mahzouni et al. 2010). Many
studies also have associated the peak vessel density as
measured by MVD with a poor prognosis in NSCLC
Angiogenesis and Lung Cancer
(Macchiarini et al. 1992; Yamazaki et al. 1994;
Trivella et al. 2007; Guo et al. 2009; Medetoglu et al.
2010; Yang et al. 2010; Anagnostou et al. 2011; Wu
et al. 2011). In addition, the incidence of node
involvement increased with MVD and MVD was an
independent variable associated with lymph node
metastasis (Fontanini et al. 1995). The role of MVD
as a prognostic factor in locally advanced completely
resected NSCLC treated with postoperative radio-
therapy and chemotherapy also has been reported
(Angeletti et al. 1996). Since, SCLC is rarely treated
by surgery, this disease has not been as well studied.
Still, despite the paucity of information in this class of
tumors, it should be noted that data available suggest
a similar correlation between MVD and prognosis for
SCLC as has been reported in NSCLC (Fontanini
et al. 2002; Lucchi et al. 2002).
However, not all lung cancer investigations have
demonstrated relationships between vessel density
and outcome. For example, in several recent studies
MVD failed to be a predictor for survival in NSCLC
(Apolinario et al. 1997; Chandrachud et al. 1997;
Pastorino et al. 1997; Decaussin et al. 1999; Ma-
cluskey et al. 2000). A recent meta-analysis also
concluded MVD does not seem to be a prognostic
factor in patients with non-metastatic surgically
treated non-small-cell lung carcinoma (Trivella et al.
2007). These apparently contradictory results may
arise from differences in staining methods, tumor
heterogeneity, and inter-observer variability. Inter-
estingly, in tumors with an ‘‘alveolar pattern’’, where
there is little parenchymal destruction and alveolar
septae are present, prognosis is worse than in tumors
showing an ‘‘angiogenic pattern’’ (Pezzella et al.
1997). This suggests that some lung cancers may be
capable of co-opting the existing vascular bed thereby
relying less on new vessel formation. In this cir-
cumstance MVD is unlikely to be of prognostic util-
ity. Also, while in general, MVD is an important
prognostic indicator, it has not yet been shown to be a
useful measure for assessment of anti-angiogenic
treatments (Hlatky et al. 2002). There are a number of
potential reasons for this. Firstly, determination of
treatment effect, rather than prediction of prognosis,
requires serial measurement. Generally, only small
samples of tumor can be obtained in a serial manner.
Since MVD by definition measures the peak vessel
density, use of small samples may affect accuracy and
it is technically difficult to sample similar areas of
21
tumor repeatedly. Secondly, while MVD reflects
some aspects of the angiogenic process, it may not be
a measure of the relative dependence of a particular
tumor on angiogenesis, and changes in MVD do not
necessarily correlate with changes in tumor growth
rate.
The expression level of angiogenic factors, either
quantified within tumor tissue or after secretion into
body fluids, provides another indirect measure of
tumor angiogenesis. The latter approach is particu-
larly appealing as it provides a noninvasive means of
investigating tumor angiogenic activity with potential
diagnostic and prognostic implications. A number of
such studies have been reported for lung cancer
patients.
In NSCLC a significant role of increased VEGF
and a correlation of VEGF expression with poor
prognosis have been found (Bonnesen et al. 2009;
Carrillo de Santa Pau et al. 2009; Chen et al. 2010;
Feng et al. 2010; Lin et al. 2010; Rades et al. 2010a).
VEGF-receptor (KDR) expression by endothelial
cells has also been associated with poor prognosis in
NSCLC (Koukourakis et al. 2000; Seto et al. 2006). A
similar association between VEGF expression and
poor prognosis also was reported in SCLC (Ohta et al.
1996; Salven et al. 1998). In addition to determining
tissue and tumor VEGF protein and mRNA expres-
sion, it is also possible to measure VEGF concentra-
tions in body fluids. When this was done in lung
cancer patients, serum or plasma VEGF levels were
observed to increase with tumor stage progression
(Takigawa et al. 1998; Matsuyama et al. 2000;
Tamura et al. 2002). Also, patients with elevated
serum or plasma VEGF levels at diagnosis had a
poorer response to therapy and worse survival (Salven
et al. 1998; Tamura et al. 2001). When measured in
bronchoalveolar lavage fluid, raised VEGF levels
were noted in patients with advanced NSCLC before
and during treatment (Ohta et al. 2002). However,
other studies failed to find a relationship between
NSCLC prognosis and serum VEGF level (Brattstrom
et al. 1998). This is perhaps not surprising, since there
are pitfalls in the measurement of circulating VEGF
levels. For example, platelets contain a large amount
of VEGF, and depending on how samples are han-
dled, varying amounts of platelet associated VEGF
may be released. Consequently the use of plasma
rather than serum samples for measurement of VEGF
has been recommended (Webb et al. 1998). Since,
22
VEGF is one of the most potent and specific factors of
tumor angiogenesis, the clinical possibilities of uti-
lizing VEGF associated measurements as markers of
tumor growth and/or response to therapy remains an
area of intense interest, particularly for those thera-
pies that target the VEGF pathway (Drevs 2003;
Mihaylova et al. 2007; Dalaveris et al. 2009; Carrillo-
de Santa Pau et al. 2010).
Basic FGF is another potent stimulator of angio-
genesis that is often over-expressed in lung cancer
patients (Guddo et al. 1999). Indeed high serum bFGF
levels have been correlated with poorer prognosis
(Strizzi et al. 2001; Ruotsalainen et al. 2002; Rades
et al. 2010). However, there also are several con-
flicting findings regarding bFGF. These include the
absence of a relationship between bFGF level and
MVD (Brattstrom et al. 1998; Ueno et al. 2001) and
the lack of correlation between bFGF expression and
survival (Volm et al. 1997). Also, in NSCLC patients,
serum bFGF did not differ between clinical stages
(Ueno et al. 2001). Finally, one study has reported
that elevated levels of serum bFGF in NSCLC
patients were related to a better outcome (Brattstrom
et al. 1998). In light of these observations it would
appear that the value of bFGF as a surrogate marker
for tumor angiogenesis in lung cancer remains
uncertain.
Several other angiogenic molecules, such as matrix
metalloproteinases, epidermal growth factor receptor,
angiopoietin-2, thymidine phosphorylase, hepatocyte
growth factor also have been investigated in NSCLC
patients. In some of these studies these factors were
found to be inversely correlated with prognosis (Ab-
delrahim et al. 2010; Dudek et al. 2010; Gordon et al.
2010).
Finally, a range of non-invasive imaging technol-
ogies including ultrasound, positron emission
tomography (PET), computed tomography (CT) and
nuclear magnetic resonance imaging (MRI) are
available, or under development, that have the
potential to measure various aspects of tumor vascu-
lature, angiogenesis, and their relation to tumor
metabolism, proliferation, and growth.
CT can be performed with contrast medium to
measure vascular characteristics including blood flow,
blood volume, mean fluid transit time, and capillary
permeability (Miles et al. 2000). Perfusion CT has
been suggested as a reliable biomarker of tumor
angiogenesis in NSCLC (Miles 2003). Perfusion CT
W. Shi and D. W. Siemann
reflects tumor vascular perfusion and angiogenesis
(Purdie et al. 2001; Tateishi et al. 2002; Yi et al. 2004;
Ng et al. 2009). It has been used to differentiate
between benign and malignant lung nodules (Swensen
et al. 2000), prediction of clinical outcome (Goh et al.
2009; Park et al. 2009), and monitor antiangiogenic
therapy in NSCLC (Ng et al. 2007a, 2007b). Although
perfusion CT has a clear role in the assessment of
vascular response in early phase clinical trials, further
validation studies are required before these measure-
ments will be accepted as surrogate markers in phase
III trials.
A variety of MRI methodologies have been used to
investigate tumor vasculature. These include the use
of gadolinium (Gd-DTPA) in dynamic contrast
enhanced MRI (DCE-MRI), high molecular weight
contrast agents to measure vessel permeability and
blood volume, gradient-recalled echo sequences to
measure a combination of blood oxygenation and
blood flow (BOLD), and the change in BOLD signal
seen while breathing high oxygen content gases to
assess vessel maturity (Pathak et al. 2010). Gd-based
agents have been used to assess early vascular chan-
ges following anti-angiogeneic treatment. Treatment
with bevacizumab significantly decreased tumor
vascular permeability as measured by gadodiamide
(Varallyay et al. 2009). The spatial heterogeneity of
response to a VEGF-receptor tyrosine kinase inhibitor
was evident in a study using both low and high
molecular weight Gd-based contrast agent (Li et al.
2005). DCE-MRI has been used in the clinic to
determine changes following anti-angiogenic treat-
ment (Batchelor et al. 2007; Jain et al. 2009). How-
ever, high molecular weight contrast agents are not
yet readily available clinically, and the BOLD con-
trast method is dependent on the field gradient used,
making both comparisons between measurements
made on different MR machines and serial measure-
ments difficult. DCE-MRI using Gd-DTPA is
becoming increasingly widespread in microcircula-
tion research (Hawighorst et al. 1999) and assessment
of changes in microcirculation following treatment
intervention (Galbraith et al. 2002, 2003; Jayson et al.
2002). Yet this method too has limitations. These are
primarily the consequence of the inherent character-
istics Gd-DTPA which result in the measured
parameters reflecting a combination of blood flow,
vessel permeability and surface area, rather than
being able to discriminate these individual
Angiogenesis and Lung Cancer
physiological parameters. Finally, commonly used
methods lack a directly measured arterial input
function which affects accuracy and reproducibility of
the technique (Galbraith et al. 2002).
The use of PET imaging in oncology is becoming
widespread, principally using the uptake of 18F
labeled fluorodeoxy glucose (FDG) as a measure of
tumor metabolism. This is proving to be useful in the
assessment of tumor response to therapies, as changes
in FDG uptake can be detected earlier than traditional
assessment by CT (Kostakoglu and Goldsmith 2003).
In NSCLC, PET has advantages over conventional
imaging techniques in its ability to discriminate
mediastinal lymphadenopathy, particularly for
assessment of response following radiation therapy
(Erdi et al. 2000).
PET methodologies useful for more direct assess-
ment of tumor vasculature include 15O labeled water
for measurement of blood flow, and 11C labeled car-
bon monoxide for measurement of blood volume
(Hoekstra et al. 2002). Although the resolution
obtained with PET is poorer compared with DCE-
MRI or CT, it has the advantage that absolute blood
flow measurements can be obtained. However, the
very short half life of 15O makes this technique fea-
sible only where a cyclotron is on site. This method
has been used for the assessment of response to
treatment with agents that directly damage tumor
vasculature (Anderson et al. 2003).
VG67e, an 124I iodinated monoclonal antibody
which binds to human VEGF-A, was used for
assessment of tumor VEGF levels non-invasively
(Collingridge et al. 2002). Similarly, HuMV833, a
fully human antibody to VEGF-A labeled with 124I,
allows imaging of VEGF distribution in tumors
(Jayson et al. 2002). A variety of different 11C and
18
F-labelled small molecular MMP inhibitors have
been developed but, corresponding data from murine
tumor models could not confirm that this class of
tracers allows the monitoring of tumor-induced
angiogenesis (Haubner et al. 2010). Great efforts have
been made to develop radiolabeled RGD peptides for
the non-invasive determination of avb3 expression for
monitoring angiogenesis process. The most studied
PET tracer is [18F]Galacto-RGD (Schnell et al. 2009).
Recently, the SPECT tracer [99mTc]NC100692 was
introduced by GE healthcare for imaging avb3
expression in humans (Bach-Gansmo et al. 2008). The
available data indicate significant potential for
23
radiolabeled RGD peptides and the use of PET as
markers of activated endothelial cell proliferation and
tumor angiogenesis (Schnell et al. 2009; Haubner
et al. 2010).
Color Doppler ultrasonography can be used to
measure flow velocity in tumor blood vessels.
Parameters obtained include vascularity index, peak
flow velocity, and flow resistance index. These
parameters have been used to improve discrimination
between benign and malignant tumors (Strobel et al.
2000), to give prognostic information, and to monitor
the changes in tumor vascularity after treatment (van
der Woude et al. 1995). Alternatively, ultrasound
techniques using microbubble contrast agents have
also been developed for measurement of blood flow,
and have potential utility in both pre-clinical and
clinical settings (Leong-Poi et al. 2003; Deshpande
et al. 2010). Still, the resolution of ultrasound, and the
reduced blood velocity in smaller arterioles and cap-
illaries mean that flow in these vessels is not mea-
sured by this technique. In addition, bulk tissue
movements that produce artifacts can be a problem in
some organs such as lung (Eriksson et al. 1991).
Imaging tumors that are surrounded by aerated lung
also is technically difficult. Finally, poor accessibility
to anatomical areas for deep seated tumors, and
operator dependence remain challenges for use of
these ultrasound methodologies.
4 Anti-Angiogenic Therapy
The complex process of tumor angiogenesis offers
many possible targets for anti-angiogenic strategies.
Strategies vary from regulation of angiogenic factor
expression in tumors, to endogenous inhibitors of
angiogenesis. There are currently over 3,000 clinical
trials employing such strategies (
http://cancertrials.nci.nih.gov/). Based on their bio-
logical activities, these strategies can be categorized
into several broad classes. One class of agents spe-
cifically targets angiogenic growth factors. It includes
tyrosine kinase inhibitors of VEGF/bFGF, as well as
antibodies or antisense oligonucleotides directed
against pro-angiogenic growth factors or their recep-
tors. A second class of agents includes those designed
to inhibit endothelial cell function, such as thalido-
mide and endostatin. A third class consists of matrix
metalloproteinase inhibitors, compounds that block
24
the degradation of the basement membrane. Agents
that target survival factors of neovascular blood sup-
ply, such as integrin antagonists comprise yet another
class.
4.1 Drugs that Block Angiogenic Factors
4.1.1 Inhibitors of VEGF and Its Receptors
The central role of VEGF and its receptor system in
tumor angiogenesis has made it a promising target of
anti-angiogenic therapies. Strategies include the use
of (i) specific VEGF antibodies to neutralize circu-
lating VEGF, (ii) antisense oligonucleotides or RNA
to disrupt VEGF expression and (iii) VEGF-receptor
antibodies, or receptor associated tyrosine kinase
inhibitors, to block VEGF signaling (Kim et al. 1993;
Witte et al. 1998; Solorzano et al. 2001; Shi and
Siemann 2002; Teng et al. 2010).
Bevacizumab (Avastin, Genentech Inc., South San
Francisco, CA) is a monoclonal antibody that targets
VEGF. It was first approved in metastatic colon
cancer when used in combination with chemotherapy
(Hurwitz et al. 2004). It was subsequently approved
for use in combination with carboplatin and paclitaxel
for first-line treatment of patients with unresectable
nonsquamous NSCLC (Sandler et al. 2006). New
studies also provided support for its use with other
chemotherapy agents, as well a potential role in the
treatment of SCLC (Horn et al. 2009; Patel et al.
2009; Spigel et al. 2009; Jalal et al. 2010).
Bevacizumab at a dose of 15 mg/kg when com-
bined with carboplatin and paclitaxel to previously
untreated patients with advanced or recurrent NSCLC
showed promising results in a pivotal phase II trial. It
showed a significant increase in time to progression:
7.4 versus 4.2 months, compared to chemotherapy
alone (Johnson et al. 2004). However, when tumors of
squamous histology, and tumors that were centrally
located close to large blood vessels with necrosis or
cavitation were treated with bevacizumab, they
showed a tendency to cause bleeding. This resulted in
four fatal episodes of major hemoptysis (Johnson
et al. 2004).
The role of bevacizumab was fully established in
2006 through a phase III trial (E4599) (Sandler et al.
2006). A total of 878 patients with stage IIIB or IV
NSCLC were randomized to paclitaxel and carboplatin
alone or paclitaxel, carboplatin, and bevacizumab at
W. Shi and D. W. Siemann
15 mg/kg. Because of the serious bleeding events
during the phase II trial, patients with squamous-cell
carcinoma, and hemoptysis were excluded. Patients
with brain metastases were also excluded with the
concern of brain hemorrhage. Response rate was 35%
in the bevacizumab arm and 15% in the control arm.
There is a significant improvement in progression-free
survival (6.2 vs. 4.5 m) and overall survival (12.3 vs.
10.3 m) for the patients treated with bevacizumab.
There were 15 deaths related to bevacizumab com-
pared to two associated with chemotherapy (Sandler
et al. 2006). Nonetheless, the advantages gained
through the use of bevacizumab far outweigh the risk
involved.
In the AVAiL (Avastin in Lung Cancer) trial,
1,043 patients with advanced nonsquamous cell
NSCLC were randomized to six cycles of cisplatin,
gemcitabine and bevacizumab or placebo. Bev-
acizumab was administered either 7.5 or 15 mg/kg.
The patients continued bevacizumab or placebo as
maintenance until progression (Reck et al. 2009). The
bevacizumab group showed significantly improved
progression-free survival, 6.7 and 6.5 months for the
high-dose and low-dose bevacizumab groups respec-
tively, compared to 6.1 months in placebo group.
There was no significant difference in overall survival
between groups. Subgroup analysis also suggested
that the high dose (15 mg/kg) and low dose (7.5 mg/
kg) of bevacizumab yielded similar efficacy and
safety profile. The regimen was overall well tolerated.
Slightly higher rates of pulmonary hemorrhage of all
grades were observed (7% for the low-dose bev-
acizumab group and 9.7% for the high-dose bev-
acizumab group), compared with 4.9% for
chemotherapy alone group (Reck et al. 2009).
A recent meta-analysis evaluated the efficacy of
bevacizumab plus chemotherapy compared to che-
motherapy alone in previously untreated locally
advanced or metastatic NSCLC (Botrel et al. 2011). It
included four trials and 2,200 patients. The response
rate was higher in patients who received the combi-
nation of chemotherapy plus bevacizumab 7.5 mg/kg
(RR = 0.58; CI95% = 0.46–0.74; p \ 0.00001) and
Bev 15 mg/kg (RR = 0.53; CI95% = 0.45–0.63;
p \ 0.00001) with moderate heterogeneity at dose of
15 mg/kg. The progression-free survival time was
longer in patients who received chemotherapy plus
bevacizumab 7.5 mg/kg (HR = 0.78, CI95% =
0.68–0.90; p = 0.0005) and bevacizumab 15 mg/kg
Angiogenesis and Lung Cancer
(HR = 0.72, CI95% = 0.65–0.80; p \ 0.00001) with
moderate heterogeneity. Differences in these end
points remained in favor of chemotherapy plus bev-
acizumab when the analysis was made using the
random-effects model. Overall survival was longer in
patients who received CT plus bevacizumab 15 mg/
kg (HR = 0.89, CI95% = 0.80–1.00; p = 0.04).
Severe haematologic toxicities (grade [3), neutrope-
nia, and febrile neutropenia were more common
among the patients who received bevacizumab. The
study concluded that the combination of chemother-
apy plus bevacizumab increased the response rate and
progression-free survival of patients with NSCLC.
With respect to overall survival the benefits of bev-
acizumab remains uncertain (Botrel et al. 2011).
Currently, bevacizumab is being evaluated for
combination with other chemotherapeutic agents,
such as docetaxel, oxaliplatin, and pemtrexed. The
combination of bevacizumab with carboplatin and
pemetrexed, followed by maintenance pemerexed and
bevacizumab showed impressive overall response rate
of 55%, a progression-free and median survival time
of 7.8 and 14.1 months, respectively (Patel et al.
2009). It becomes one primary option for patients
with the characteristics described in the trial.
Bevacizumab also been evaluated in the mainte-
nance setting in the management of NSCLC. The
ATLAS phase III trial compared bevacizumab with or
without erlotinib after completion of a first-line che-
motherapy regimen that included bevacizumab
(Miller VAOCP et al. 2009). The trial was stopped
early because progression-free survival was
4.8 months for the combined arm and 3.7 months for
the bevacizumab alone arm (p = 0.0012). Overall
survival was not significantly different.
Currently, bevacizumab is contraindicated for
patients with brain lesions or squamous carcinomas
owing to the risk of cerebrovascular bleeding and
hemoptysis. However, the prospective PASSPORT
trial raised another perspective concerning the safety
of bevacizumab in the setting of brain metastases
(Socinski et al. 2009). In this study, treatment of na
patients with previously treated brain metastases
received bevacizumab with platinum-based doublet
therapy or erlotinib at physician’s discretion. Second-
line patients received either bevacizumab with single-
agent chemotherapy or erlotinib at physician’s dis-
cretion as well. For 106 patients, no grade C2 central
nervous system hemorrhages were reported; two
25
grade 5 events were observed but both were pul-
monary hemorrhages. Forthcoming trials should
clarify this perspective. The ongoing AVAstin in
Squamous tumor trial will likely also helps define the
role of bevacizumab and provides answers to the
question of whether radiation therapy before chemo-
therapy combined with bevacizumab might minimize
the risk of bleeding.
Numerous efforts have focused on identifying
subgroups of patients that may benefit more from the
addition of bevacizumab. Biomarker studies accom-
panying ECOG 4599 suggest that single nucleotide
polymorphism in VEGF, EGF, intercellular adhesion
molecule-1, and WNK lysine deficient protein kinase
1 may predict response (Zhang et al. 2009). Hyper-
tension, one side effect of bevacizumab treatment has
also been suggested to be a biomarker of clinical
benefit of bevacizumab from several studies
(Schneider et al. 2008a; Rini et al. 2010; Osterlund
et al. 2011). However, contrary to these observation, a
retrospective analysis of six trials in colorectal, breast,
and renal cell carcinoma showed that treatment
induced hypertension was predictive of overall sur-
vival and progression-free survival in only one study
(Hurwitz et al. 2010). The predictive value of bev-
acizumab-induced hypertension might not extend to
all cancers or all treatment regimens. The measure-
ment of concentrations of circulating protein is an
attractive biomarker strategy, as blood is easily
accessible. However, concentrations of circulating
VEGF before treatment were not correlated with
efficacy of bevacizumab in an analysis of four phase
III trials (Bernaards et al. 2010). Still, VEGF levels
are dynamic, and changes related to pretreatment
values might have predictive value (Loupakis et al.
2007; Zahiragic et al. 2007; Lu et al. 2008; Willett
et al. 2009). Changes in concentrations of numerous
other proteins putatively related to angiogenesis also
have been documented after the start of bevacizumab
treatment (Wedam et al. 2006; Dowlati et al. 2008;
Willett et al. 2009; Jubb and Harris 2010). Currently,
only circulating intercellular adhesion molecule one
has shown any predictive value in terms of survival
benefit with bevacizumab in a phase III trial (Dowlati
et al. 2008; Jubb and Harris 2010). Polymorphisms of
components of the VEGF pathway also have been
proposed to predict benefit from bevacizumab treat-
ment (Schneider et al. 2008b; Schultheis et al. 2008).
However, these findings have not been validated and
26
the prognostic importance of these polymorphisms in
patients treated undergoing bevacizumab therapy has
not been established.
Bevacizumab has also been evaluated in the
management of SCLC. For example, one ECOG study
added bevacizumab to cisplatin and etoposide for up
to four cycles and continued bevacizumab as main-
tenance for up to 1 year in patients with extensive-
stage SCLC (Horn et al. 2009). The study showed a
median progression-free survival of 4.7 months,
median overall survival of 10.9 months, and 1 year
overall survival of 38.1%. This outcome compares
favorably with historical data established with etop-
side-cisplatin alone. In another multicenter phase II
trial, patients with extensive SCLC received irino-
tecan, carboplatin, and bevacizumab. Patients who
had no progression also received maintenance bev-
acizumab (Spigel et al. 2009). The objective respon-
sive rate was 84%, median time to progression was
9.13 months, median overall survival was
12.1 months, and 1 and 2 year overall survivals were
51 and 14%, respectively. This result compares
favorably with larger randomized trials using che-
motherapy alone. Another recent trial from the Hoo-
sier Oncology Group included patients with relapsed
chemosensitive SCLC (Jalal et al. 2010). Patients
receiving paclitaxel and bevacizumab had a median
survival time of 30 weeks and the addition of bev-
acizumab to paclitaxel did not improve outcomes in
relapsed chemosensitive SCLC. Thus the role of
bevacizumab remains not fully defined in SCLC.
Aflibercept (VEGF-trap/AVE0005, Regeneron
Pharmaceuticals, Tarrytown, NY) is a fully human
soluble fusion protein that binds circulating VEGF-A
and placental growth factor, preventing binding to the
cell surface membrane receptors (Teng et al. 2010). It
is engineered by combining domains from VEGFR-1
and VEGFR-2 with the Fc domain of human IgG
(Riely and Miller 2007). A phase I trial of aflibercept
showed dose-limiting toxicities of rectal ulceration
and proteinuria at a 7 mg/kg dose given intravenously
every 2 weeks, and 4 mg/kg was advanced as the
phase II dose (Lockhart et al. 2010). In a multicenter
phase II trial evaluating the efficacy and safety of
intravenous aflibercept in patients with platinum- and
erlotinib-resistant lung adenocarcinoma (Leighl et al.
2010) 98 patients were enrolled; 89 were evaluable
for response. Median progression-free survival was
2.7 months, and overall survival was 6.2 months. Six
W. Shi and D. W. Siemann
and 12 month survival rates were 54 and 29%,
respectively. Common grade 3/4 toxicities included
dyspnea (21%), hypertension (23%), and proteinuria
(10%). Two cases of grade 5 hemoptysis were
reported, as well as one case each of tracheoesopha-
geal fistula, decreased cardiac ejection fraction,
cerebral ischemia, and reversible posterior leukoen-
cephalopathy. Aflibercept has minor single agent
activity in heavily pretreated lung adenocarcinoma,
but appears to be well tolerated with no unexpected
toxicities. Phase III trials in this setting are ongoing.
Other efforts are exploring the role of aflibercept in
lung cancer in combination with platinum-based
doublets and single-agent docetaxel (Riely and Miller
2007).
Ramucirumab, (IMC-1121B, ImClone systems
Inc) is a fully humanized monoclonal antibody that
blocks the binding of the VEGF ligand to the extra-
cellular domain of VEGFR-2. A phase I trial in
patients with advanced solid malignancies has shown
it to be well tolerated with favorable response rates
(Spratlin et al. 2010). It is currently in Phase II studies
in colorectal, prostate, liver, non-small-cell lung and
ovarian cancers, as well as melanoma and recurrent
glioblastoma multiforme as well as three phase III
studies in breast cancer (NCT00703326), gastric
cancer or gastroesophageal junction adenocarcinoma
(NCT00917384), and hepatocellular carcinoma
(NCT01140347). Three additional phase III studies of
ramucirumab with or without paclitaxel in metastatic
gastric adenocarcinoma (NCT01170663), in second-
line metastatic colorectal cancer (NCT01183780), and
in second-line non-small-cell lung cancer
(NCT01168973) are planned.
IMC-18F1 (ImClone Systems, Inc) is a humanized
monoclonal antibody against VEGFR-1 that has
demonstrated antitumor activity in preclinical studies
(Schwartz et al. 2010). A phase I study of patients
with advanced solid tumors who no longer responded
to standard therapy just closed, and the results are
pending. Three phase II studies are open in colorectal,
breast, and bladder, urethra, ureter, or renal pelvis
carcinoma.
An alternative approach to interrupt VEGF activity
that has received a great deal of attention is the use of
small molecule compounds to inhibit VEGF-receptor
associated tyrosine kinases. Most of these agents bind
to the ATP-binding site of the receptor, thus inhibit-
ing the activation of the receptor and subsequent
Angiogenesis and Lung Cancer
Table 2 Tyrosine kinase inhibitors and their targets
TKI VEGFR1 VEGFR2
Vandetanib + +
Cediranib + +
Sorafenib + +
Sunitinib + +
Axitinib + +
Vatalanib + +
Motesanib + +
Pazopanib + +
BIBF1120 + +
downstream signaling. In addition to inhibiting
VEGFR2 associated signaling, many such inhibitors
target other tyrosine kinases. Simultaneous targeting
of several kinases offers a theoretical advantage over
single kinase inhibitors because most cancers have
complex and often redundant signaling pathways.
However, a potential disadvantage is the potential for
toxicity resulting from off-target kinase inhibition; a
possibility that may have particular relevance when
these agents are combined with chemotherapy.
Table 2 provides a listing of the stages of clinical
development of various anti-angiogenic tyrosine
kinase inhibitors and their targets.
Vandetanib (Zactima, AZD6474, AstraZeneca
Pharmaceuticals, Wilminton, DE) is an oral anilino-
quinazoline that inhibits VEGFR1, VEGFR2, VEG-
FR3, RET, and EGFR (Ciardiello et al. 2003). Phase I
studies identified a maximum tolerated daily dose of
300 mg. Hypertension and prolongation of QTc were
the most common adverse effects (Holden et al.
2005). In a randomized phase II trial versus gefitinib,
progression-free survival was 11 and 8.1 weeks for
vandetanib and gefitinib, respectively (Natale et al.
2009). In another phase II trial, two doses of vande-
tanib were tested with docetaxel compared with
docetaxel alone in NSCLC patients previously treated
with platinum-based chemotherapy. The progression-
free survival favored the two arms with vandetanib
(Heymach et al. 2008). These results led to four phase
III trials, ZEST, ZEAL, ZEPHYR, and ZODAIC. The
ZODAIC trial enrolled 1,391 patients, who were
randomized to vandetanib with docetaxel or placebo
with docetaxel. Vandetanib plus docetaxel led to a
significant improvement in PFS versus placebo plus
docetaxel (hazard ratio [HR] 0.79, 97.58% CI
27
VEGFR3 PDGFR EGFR KIT Other
+ RET
+ + +
+ + + RAF, FLT3
+ + + FLT3, RET
+
+ + +
+ + + RET
+ + +
FGFR
0.70–0.90; p \ 0.0001); median PFS was 4.0 months
in the vandetanib group versus 3.2 months in the
placebo group. The trial also showed that the addition
of vandetanib to docetaxel provided a significant
improvement in PFS in patients with advanced
NSCLC after progression following first-line therapy
(Herbst et al. 2010). The ZEAL trial enrolled 534
patients, who were randomized to receive vandetanib
with pemetrexed or placebo with pemetrexed. The
results showed that there was no significant difference
in PFS or overall survival between the treatment
arms. Statistically significant improvements in
objective response rate (19 vs. 8%; p \ 0.001) and
time to deterioration of symptoms (HR, 0.71;
p = 0.0052; median, 18.1 weeks for vandetanib and
12.1 weeks for placebo) were observed in patients
receiving vandetanib. Adding vandetanib to pemetr-
exed also increased the incidence of some adverse
events, including rash, diarrhea, and hypertension,
while showing a reduced incidence of nausea, vom-
iting, anemia, fatigue, and asthenia with no reduction
in the dose intensity of pemetrexed. The vandetanib
combination showed a significantly higher objective
response rate and a significant delay in the time to
worsening of lung cancer symptoms versus the pla-
cebo arm as well as an acceptable safety profile in this
patient population. However, this study did not meet
the primary end point of statistically significant PFS
prolongation with vandetanib plus pemetrexed versus
placebo plus pemetrexed (de Boer et al. 2011). The
ZEST trial included 1,240 patients, who were ran-
domized to vandetanib 150 or 300 mg/d, or erlotinib.
There was no significant improvement in PFS for
patients treated with vandetanib versus erlotinib
(hazard ratio [HR], 0.98; 95.22% CI, 0.87–1.10;
28
p = 0.721); median PFS was 2.6 months for vande-
tanib and 2.0 months for erlotinib. There was also no
significant difference for the secondary end points of
overall survival (HR, 1.01; p = 0.830), objective
response rate (both 12%), and time to deterioration of
symptoms for pain (HR, 0.92; p = 0.289), dyspnea
(HR, 1.07; p = 0.407), and cough (HR, 0.94;
p = 0.455). Both agents showed equivalent PFS and
overall survival in a preplanned non-inferiority anal-
ysis. The trial concluded that in patients with previ-
ously treated advanced NSCLC, vandetanib showed
antitumor activity but did not demonstrate an efficacy
advantage compared to erlotinib. There was a higher
incidence of some adverse effects with vandetanib
(Natale et al. 2011). The ZEPHYR trial randomized
patients to vandetanib or placebo. The results reported
in abstract form showed that vandetanib improved
progression-free survival by nearly 40%. However,
there was no improvement in overall survival and
since this was the primary study endpoint, it was
considered a negative trial.
Cediranib (Recentin, AZD2171, AstraZeneca
Pharmaceuticals, Wilminton, DE) is a potent VEGFR2
inhibitor that also inhibits VEGFR1, VEGFR3, and
PDGFR (Wedge et al. 2005). As a single agent, it was
well tolerated at doses up to 45 mg given daily (Laurie
et al. 2008). In a phase II chemotherapy combination
trial in patients with previously untreated advanced
stage NSCLC, the response rate was high (38%).
However, increased toxicities were reported when
daily dose of 30 mg were given (Goss et al. 2010). As a
result the BR.29 trial was recently opened using a daily
dose of 20 mg (http://australiancancertrials.gov.au).
Sorafenib (Nexavar, BAY 43-9006, Bayer Phar-
maceuticals Corporation, West Haven, CT) is a raf
and VEGFR inhibitor with activity against PDGFR
and KIT. It has proven activities in renal cell carci-
noma and hepatocellular carcinoma (Escudier et al.
2007; Rimassa and Santoro 2009). In the phase III
ESCAPE trial, which randomize patients to carbo-
platin and paclitaxel, with and without sorafenib in
first-line treatment for advanced NSCLC, the primary
endpoint of overall survival was not met. The study
was terminated early as a result of the detrimental
effect of sorafenib on patients with squamous-cell
carcinoma and lack of efficacy in nonsquamous car-
cinoma patients (Scagliotti et al. 2010). A large phase
II trial, E2501, enrolled more than 300 patients and
compared sorafenib with placebo in patients with
W. Shi and D. W. Siemann
NSCLC after failure with two prior regimens of
chemotherapy. After a 2 month lead in period during
which all patients received active drug, those with
stable disease were randomized to sorafenib or pla-
cebo. The median progression-free survival was 3.6
and 2 months in the sorafenib and placebo arms,
respectively (Clement-Duchene and Wakelee 2010).
A phase III trial of sorafenib versus placebo is
ongoing.
Sunitinib (Sutent, SU11248, Pfizer Inc, New York)
is an inhibitor of VEGFR, PDGFR, KIT, FLT3, RET,
and CSF-1R. It is approved for the treatment of
advanced renal cell carcinoma and imatinib-resistant
gastrointestinal stromal tumors (Heng and Koll-
mannsberger 2010). In a phase II trial, 63 patients
with NSCLC received daily 50 mg doses of sunitinib
initially for 4 weeks then followed by 2 weeks of
treatment in a 6 week cycle. The overall response rate
was 11.1%. The median progression-free survival and
overall survival were 12 and 23.4 weeks, respectively
(Socinski et al. 2008). In another phase II trial patients
with advanced NSCLC received continuous daily
dosing of sunitinib (37.5 mg). Median PFS was
11.9 weeks (95% CI 8.6, 14.1) and median OS was
37.1 weeks (95% CI 31.1, 69.7). The 1 year survival
probability was 38.4% (95% CI 24.2, 52.5). Treat-
ment was generally well tolerated (Novello et al.
2009). A phase III trial investigating sunitinib and
erlotinib combination is ongoing.
Axitinib (AG-013736, Pfizer Inc. New York) is a
tyrosine kinase inhibitor with activity against VEG-
FR, PDGFR, and c-kit (Hu-Lowe et al. 2008; Kelly
and Rixe 2010). In a phase I study, the maximum
tolerated dose was 5 mg when given twice daily. The
main adverse effects were hypertension, seizure,
abnormal liver functions, and mesenteric vein
thrombosis with pancreatitis (Rugo et al. 2005). In a
phase II study that evaluated the efficacy of axitinib as
a single agent in NSCLC, the response rate was 41%,
progression-free survival was 4.9 months, and median
overall survival was 14.8 months (Schiller et al.
2009). Phase II evaluations of axitinib plus paclitaxel
and carboplatin, and axitinib plus cisplatin and
pemetrexed as well as a phase III trial evaluating
axitinib as a single agent in advanced NSCLC are
ongoing. Vatalanib (ptk787, zk-222584, Novartis/
Schering AG, Berlin, Germany) is a VEGFR,
PDGFR, and KIT inhibitor (Scott et al. 2007). It is
currently being studied in phase II/III trials. In a phase
Angiogenesis and Lung Cancer
II study of vatalanib monotherapy in previously
treated NSCLC, this agent showed moderate efficacy.
The response rate was 10% and overall survival was
7 months (Gauler et al. 2007). A phase I/II trial of
vatalanib and pemetrexed with or without cisplatin for
lung cancer is ongoing.
Motesanib (AMG 706. Amgen, Thousand Oaks,
CA) is an orally active multikinase inhibitor (Polve-
rino et al. 2006). Phase I studies in solid tumors
showed a maximum tolerated daily dose of 125 mg
(Rosen et al. 2007). A phase II trial randomized
patients with advanced NSCLC to motesanib or
bevacizumab in combination with paclitaxel and
carboplatin. The efficacy of daily motesanib or bev-
acizumab plus carboplatin and paclitaxel was esti-
mated to be comparable. Toxicity was higher but
manageable in both motesanib arms. Efficacy and
tolerability of daily 125 mg doses of motesanib plus
carboplatin and paclitaxel in advanced nonsquamous
NSCLC were investigated in a phase III study. This
trial was closed due to a higher early mortality and a
higher rate of hemoptysis in patients with squamous
histology but was reopened with exclusion of this
patient population.
Pazopanib (GW786034, GlaxoSmithKline, Phi-
ladephia) is a VEGF, PDGFR, and KIT inhibitor
currently in phase III development for advanced renal
cell carcinoma and phase II development for
NSCLC.(Altorki et al. 2010; Sternberg et al. 2010). In
a phase II trial proof-of-concept study, it examined
safety and efficacy of short-term, preoperative paz-
opanib monotherapy in patients with operable stage I/
II NSCLC. Patients scheduled for resection received
oral pazopanib 800 mg/d for 2–6 weeks preopera-
tively. Short-duration pazopanib was generally well
tolerated and demonstrated single-agent activity in
patients with early stage NSCLC. Several target genes
were dysregulated after pazopanib treatment, vali-
dating target-specific response and indicating a per-
sistent pazopanib effect on lung cancer tissue. Further
clinical evaluation of pazopanib in NSCLC is planned
(Altorki et al. 2010).
BIBF1120 (Vargatef, Boehringer-Ingelheim, In-
gelheim, Germany) is an oral indolinone derivative
that inhibits VEGFR2, FGFR, and PDGFR. Phase I
trial investigations established a 200 mg twice daily
dose for subsequent phase II evaluation (Mross et al.
2010). A phase II double-blind study investigated
efficacy and safety of two doses of the triple
29
angiokinase inhibitor BIBF 1120 in patients with
relapsed advanced non-small-cell lung cancer. The
median PFS was 6.9 weeks, with no significant dif-
ference between treatment arms. Median overall sur-
vival (OS) was 21.9 weeks. Continuous treatment
with BIBF 1120 was well tolerated, with no difference
in efficacy between treatment arms. PFS and objective
response with single-agent treatment in advanced
disease warrants further exploration (Reck et al.
2011). Phase III placebo control trials of BIBF 1120
in combination with docetaxel or pemetrexed are in
progress.
Finally, ribozyme constructs that target VEGF-
receptor mRNA are also under development. Pre-
clinical studies with these constructs induced inhibi-
tion of growth in both primary and metastatic Lewis
lung carcinoma (Oshika et al. 2000; Pavco et al. 2000;
Fabbro and Manley 2001). A phase I trial of anti-Flt-1
ribozymes was carried out in patients with advanced
cancer. Minor clinical responses were observed with
14 of 20 patients maintaining stable disease for 1–
6 months (Fabbro and Manley 2001).
4.1.2 Non-Specific Agents
Thalidomide (Celgene, Summit, NJ) has been shown
to inhibit angiogenesis, though the mechanism of
action is poorly understood. It may be mediated
through inhibition of TNF-a, VEGF, and bFGF
expression by tumor cells, cell surface receptors
inhibition, and/or effects on the immune system
(D’Amato et al. 1994; Li et al. 2003). Thalidomide
has shown limited efficacy in a phase II NSCLC trial
in combination with first-line carboplatin/irinotecan
(Miller et al. 2006). In another phase II trial, thalid-
omide was used with irinotecan and gemcitabine in
chemonaive patients with advanced NSCLC. The
median time to disease progression was 4 months.
The 1 and 2 year survival rates were 36 and 27%,
respectively (Jazieh et al. 2009). Thalidomide was
also evaluated in the setting of neoadjuvant therapy
with carboplatin, gemcitabine in stage IIB and III
NSCLC. Response rates were 70% and overall sur-
vival was 3.6 years (Dudek et al. 2009). Unfortu-
nately, in a large randomized double-blind placebo-
controlled trial of thalidomide in combination with
gemcitabine and carboplatin in advanced NSCLC,
thalidomide in combination with chemotherapy did
not improve survival overall, but increased the risk of
thrombotic events (Lee et al. 2009). Thalidomide was
30
also evaluated in the maintenance therapy for exten-
sive-stage SCLC after response to chemotherapy.
Thalidomide 200 mg daily is well tolerated when
given as maintenance therapy for ES-SCLC after
induction chemotherapy (Dowlati et al. 2007).
Lenalidomide (Revlimid, CC-5013. Celgene,
Summit, NJ) is a thalidomide analogue that is a
licensed for the treatment of multiple myeloma and
myelodysplastic syndrome (Galustian and Dalgleish
2009). A phase I study of lenalidomide in solid
tumors led to a recommended dosing protocol of
25 mg/day for 4 weeks followed by a 2 week rest
period for lenalidomide use in patients with solid
tumors (Miller et al. 2007). Lenalidomide was also
evaluated in a phase I trial in combination with
docetaxel and carboplatin in patients with advanced
solid tumors. The results showed that in combination
with docetaxel 60 mg/m2 and carboplatin AUC 6 on
Day 1, lenalidomide 5 mg orally daily on days 1–14
of a 21-day cycle was the maximum tolerated dose
without the use of prophylactic growth factors (Kal-
madi et al. 2007). A phase II trial (NCT00179686) in
NSCLC was completed and results are pending.
Pomalidomide (Actimid, CC-4047, Celgene, NJ), a
third generation thalidomide analogue (Lacy and
Tefferi 2011), is being evaluated in a phase I/II study
as maintenance therapy in patients with extensive-
stage SCLC (NCT00537511).
Cyclooxygenase 2 (COX2), an enzyme that is
involved in prostaglandin synthesis, is frequently up-
regulated in NSCLC, and may be a marker of worse
prognosis (Dannenberg et al. 2001). It also may pro-
mote angiogenesis, prevent apoptosis, and induce
resistance to radiation therapy. Inhibitors of COX2
have been widely used for inflammatory conditions,
and their anti-cancer activity has only recently begun to
be explored. A phase II study in combination with
preoperative paclitaxel and carboplatin in patients with
Stage I–IIIA NSCLC (Altorki et al. 2003) reported
encouraging response rates, but definitive demonstra-
tion of the potential benefit of such combinations
awaits randomized trials. Another phase II trial eval-
uated celecoxib in combination with paclitaxel, car-
boplatin, and radiotherapy in patients with inoperable
stage IIIA/B non-small-cell lung cancer, but this trial
was terminated because it did not meet the predeter-
mined goal of 80% overall response rate. In unselected
patients, the addition of celecoxib to concurrent che-
moradiotherapy with inoperable stage IIIA/B NSCLC
W. Shi and D. W. Siemann
failed to improve survival (Mutter et al. 2009). A phase
II study of celecoxib and docetaxel in NSCLC patients
with progression after platinum-based therapy also
failed to improve the response rate and survival com-
pared with docetaxel alone (Schneider et al. 2008).
Apricoxib, another COX2 inhibitor, was evaluated in a
phase I trial in combination with erlotinib in advanced
NSCLC. Apricoxib plus erlotinib was well tolerated
and yielded a 60% disease control rate. A phase II trial
is currently investigating 400 mg/day dose of apric-
oxib plus 150 mg/day erlotinib in patients selected on
the basis of in urinary PGE-M changes (Reckamp et al.
2011).
4.2 Drugs that Inhibit Endothelial Cell
Function
Endostatin, a 20 kDa C-terminal proteolytic fragment
of collagen XVIII, has been identified as a potent
endogenous inhibitor of angiogenesis. In murine
models, the growth of Lewis lung tumors was mark-
edly suppressed by systemic endostatin therapy. At a
dose of 20 mg/kg once daily, there was almost com-
plete regression of established primary tumors
(O’Reilly et al. 1997). However, in patients, no clin-
ical responses were observed (Thomas et al. 2003). A
few patients did demonstrate changes in their
dynamic CT scans suggestive of a decline in micro-
vessel density, but overall no consistent effect of
endostatin on tumor vasculature was seen. Other
studies have noted measurable effects of endostatin on
tumor blood flow and metabolism and the induction
of tumor and endothelial cell apoptosis but again
these occurred in the absence of demonstrable anti-
tumor effects (Herbst et al. 2002). Endostar is a novel
recombinant human endostatin expressed and purified
in Escherichia coli with an additional nine-amino acid
sequence and forming another his-tag structure (Ling
et al. 2007). It was evaluated in a phase II study of
cisplatin/etoposide for extensive-stage small-cell lung
cancer. The addition of rh-endostain to cisplatin and
etoposide in patients with ED-SCLC results in
slightly improved PFS and OS relative to historical
controls who received this chemotherapy regimen
alone. This regimen appears to be well tolerated
(Zhou et al. 2011).
TNP-470 (Takeda Chemical Industries Ltd, Osaka,
Japan), a synthetic analog of fumagillin, is an
Angiogenesis and Lung Cancer
angiogenesis inhibitor that blocks the growth of new
blood vessels by inhibiting methionine aminopepti-
dase, an enzyme critically important for endothelial
cell proliferation (Sin et al. 1997). In the clinic, partial
responses were observed in 6 out of 16 NSCLC
patients treated with TNP470 (Herbst et al. 2002)
suggesting that further evaluation of TNP-470, par-
ticularly in combination with chemotherapy, may be
warranted.
4.3 Drugs that Block Breakdown
of Extracellular Matrix
To form new blood vessels, endothelial cells of
existing blood vessels must degrade the underlying
basement membrane and invade into the stroma of the
neighboring tissue. The processes of endothelial cell
invasion and migration require the cooperative
activity of plasminogen activators and matrix
metalloproteinases (MMPs). The MMPs are a family
of structurally related zinc-dependent endopeptideas-
es collectively capable of degrading extracellular
matrix. Their activities are controlled at different
levels (Liekens et al. 2001; Gialeli et al. 2011): (i)
their expression is up-regulated by angiogenic growth
factors, (ii) they need to be activated proteolytically,
and (iii) their activities are negatively impacted by
their inhibitors (tissue inhibitors of metalloproteinases
(TIMPs)). Ultimately, an imbalance between MMPs
and TIMPs is responsible for an invasive phenotype
(Gialeli et al. 2011). In light of such rationale, the
inhibition of MMPs has been extensively studied as
an approach to inhibit the growth and invasion of
neoplastic cells (Vihinen and Kahari 2002). Unfor-
tunately, clinical outcomes with these agents have
been large and very disappointing.
Marimastat was the first orally administrated syn-
thetic MMP inhibitor and was the first to be evaluated
in SCLC. It inhibits the activity of MMP-1, 2, 3, 7,
and 9. The principle toxicity of marimastat observed
in several phase I–II clinical studies was the appear-
ance of a dose-limiting inflammatory polyarthritis that
consisted of joint stiffness and pain (Steward 1999).
Marimastat was tested in two phase III SCLC studies
in which patients were treated with chemotherapy
with or without thoracic radiotherapy. After com-
pleting the cytotoxic therapy, patients were random-
ized to receive placebo or marimastat. The results
31
showed no significant difference in survival (Shep-
herd et al. 2002). Similarly, Prinomastat (AG3340), a
more selective MMP inhibitor with activity against
MMP-2, 3, 9, and 14 failed to demonstrate efficacy in
stage IIB/IV NSCLC patients (Bissett et al. 2005). A
phase I study with CGS 27023A (MMI270), a MMP
inhibitor with activity against MMP-1, 2, 3, 9, and 13,
that was carried out in patients with solid tumors,
including lung cancer patients (Levitt et al. 2001),
also resulted in no positive tumor responses. Finally,
when BAY12-9566, an inhibitor of MMP-2 and 9 was
evaluated in SCLC and stage III NSCLC patients,
both trials were closed before reaching their accrual
goal because the results showed a detrimental effect
on patient survival (Hidalgo and Eckhardt 2001).
Studies with two other MMP inhibitors are
ongoing. Neovastat (AE-941) is a naturally occurring
MMP inhibitor derived from shark cartilage extract
that has shown antitumor/antimetastatic properties in
animal models and few side effects in more than 800
patients (Gingras et al. 2003). A phase III random-
ized study of induction platinum-based chemother-
apy and radiotherapy with or without neovastat in
patients with unresectable stage IIIA or IIIB NSCLC
has now been completed. The addition of neovastat
to chemo-radiotherapy did not improve overall sur-
vival in patients with unresectable stage III NSCLC.
This study does not support the use of shark carti-
lage-derived products as therapy for lung cancer (Lu
et al. 2010). Another agent, BMS-275291, inhibits a
broad range of MMPs known to be associated with
the growth and spread of tumors (Poulaki 2002). It is
currently in phase II/III trials, as an adjunct to
standard chemotherapy, in advanced or metastatic
NSCLC patients. In a randomized phase III NCI-
Canada-clinical trials group sponsored study (BR.18)
BMS-275291 in combination with paclitaxel and
carboplatin in advanced NSCLC increased toxicity
and but failed to improve survival (Leighl et al.
2005).
4.4 Drugs that Target Survival Factors
of Neovessels
A number of factors influence endothelial cell sur-
vival with VEGF being perhaps the most notable.
Indeed it is now recognized that anti-VEGF thera-
peutic approaches, in addition to their other actions,
32
may directly affect endothelial cell survival (Gerber
et al. 1998; Caron et al. 2009).
Another approach that also aims to affect endo-
thelial cell survival targets integrins. Integrins are
heterodimeric transmembrane proteins consisting of a
and b subunits with large ectodomains and short
cytoplasmic tails. They control cell motility, differ-
entiation, and proliferation via interactions with
extracellular matrix molecules. Integrins avb3 and
avb5 are up-regulated on proliferating endothelial
cells in angiogenic blood vessels (Brooks et al. 1994).
The avb3 integrin, an adhesion receptor for extracel-
lular matrix components with an exposed RGD
sequence, is an attractive target for anti-angiogenic
therapy because it is almost exclusively present on the
cell surface of activated endothelial cells. It is con-
sidered a survival factor for angiogenic vessels
(Eliceiri and Cheresh 1999). Antibodies against avb3
have been shown to inhibit adhesion-dependent signal
transduction by angiogenic factors, leading to apop-
tosis of activated endothelial cells. Consequently,
these agents block endothelial tube formation and
angiogenesis in tumors (Brooks et al. 1994). Cilen-
gitide (EMD 121974, Merck, Darmstadt, Germany), a
cyclic RGD pentapeptide, is an inhibitor of v3 and v5
integrin receptors. No efficacy data are currently
available in lung cancer.
5 Vascular Disrupting Therapies
An alternative to targeting tumor blood vessels on the
basis of interfering with the process of tumor cell
induced new vessel formation (i.e., anti-angiogenic
therapies) is to develop agents that specifically com-
promise the function of existing vasculature in solid
tumors. Such approaches aim to cause direct damage
to the established tumor endothelium and thus lead to
extensive secondary neoplastic cell death (Denekamp
1990; Siemann and Shi 2003). These vascular dis-
rupting agents and their therapeutic application may
be broadly divided into two categories: biological
agents and small molecule drugs.
Biological approaches include targeted gene ther-
apy, antibodies to neovascular antigens, and fusion
proteins targeting specific endothelial cell receptors.
Although investigations utilizing these approaches
have, to date, been confined to preclinical investiga-
tions, encouraging results have been reported. For
W. Shi and D. W. Siemann
example, endothelial cell specific promoter elements
and vectors with restricted cellular tropisms have
been examined (Trepel et al. 2000). The strategy of
linking antibodies or peptides that recognize tumor-
associated vasculature to toxins or pro-coagulant/pro-
apoptotic effector molecules that can induce endo-
thelial cell damage also has been explored. The utility
of such ligand-directed targeting is supported by
recent in situ studies in preclinical tumor models that
demonstrated not only the localization of the thera-
peutic moiety to tumor vessels but also the induction
of thrombi formation and the selective destruction of
vasculature (Nilsson et al. 2001; Veenendaal et al.
2002).
In the category of small molecule drugs, two
classes of agents that selectively disrupt the tumor
vessel network have entered clinical trials. The first
includes flavone acetic acid (FAA) and its potent
analog 5,6-dimethylxanthenone-4-acetic acid
(DMXAA, vadimezan, ASA404) (Baguley 2003;
Baguley and McKeage 2010). The mechanism of
action of these agents appears to be largely indirect,
through the induction of cytokines, particularly TNF-
a (Philpott et al. 1997; Ching et al. 2004; Baguley and
Siemann 2010), although the ability of ASA404 to
induce targeted pro-inflammatory response within
tumor tissue may also critically contribute to its
action (Philpott et al. 1997; Ching et al. 2004;
Baguley and Siemann 2010). Vadimezan was evalu-
ated in a phase II study combined with carboplatin
and paclitaxel in previously untreated NSCLC. The
best overall tumor response was partial response,
which was seen in 37.9% of patients by independent
assessment and in 46.7% by investigator assessment.
Median time to tumor progression was 5.5 months by
investigator assessment and median survival was
14.9 months (McKeage et al. 2009). The phase II
results led to its advancement to two randomized,
double-blind, placebo-controlled phase III trials in
advanced NSCLC; the first (ATTRACT-1) as first-
line therapy and the second (ATTRACT-2) as second-
line therapy (McKeage et al. 2009). Both combina-
tions employed vadimezan at a dose of 1,800 mg/m2
(calculated as the free base) for the second treatment
arm and were administered every 3 weeks for up to
six cycles. The ATTRACT-1 study utilized paclitaxel
(200 mg/m2) and carboplatin (AUC 6 mg/ml/min) as
standard therapy. There were no safety concerns and
no unexpected adverse effects when compared with
Angiogenesis and Lung Cancer
the phase II data, but the trial was halted when interim
data analysis failed to show a survival advantage (
http://www.antisoma.com). The ATTRACT-2 trial,
which utilizes docetaxel (75 mg/m2) as standard
therapy in patients with Stage IIIb/IV disease remains
ongoing.
The second class includes a group of tubulin-
binding agents, most notably combrestastatin A4
disodium phosphate (Fosbretabulin, CA4DP) and the
phosphate prodrug of N-acety-colchinol (ZD6126).
The principal mechanism of action of this class of
drugs is believed to be the selective disruption of the
cytoskeleton of proliferating endothelial cells that
leads to thrombus formation and a secondary ische-
mic tumor cell death (Galbraith et al. 2001; Kanthou
and Tozer 2002; Siemann 2011). Fosbretabulin was
evaluated in a phase I trail with carboplatin and
paclitaxel in patients with advanced cancer. Dose-
limiting toxicity of grade 3 hypertension or grade 3
ataxia was seen in two patients at 72 mg/m2.
Responses were seen in 22% patients with ovarian,
oesophageal, small-cell lung cancer, and melanoma
(Rustin et al. 2010). Phase II trial in NSCLC are
ongoing. ZD6126 is currently under phase II trial.
Other vascular disrupting agents, including
AVE8062, NPI-2358, ABT-751, TZT-1027, CYT997,
Dolastatin 10, MPC-6827, OXi4503, EPC2407, MN-
029, and BNC105 are in early clinical trial develop-
ment (Siemann 2011).
Optimal treatment strategies with agents that
damage the existing tumor vessel network will ulti-
mately likely combine such therapeutics with con-
ventional therapies including radiotherapy and
chemotherapy for maximum treatment effect (Sie-
mann and Horsman 2002; Siemann and Rojiani
2002). In addition, preclinical investigations suggest
that vascular disrupting approaches are likely to be
complimentary to, rather than to duplicate anti-
angiogenic strategies. Evidence suggests that anti-
angiogenic agents may be especially well suited for
micrometastatic disease or early-stage cancer (Lo-
zonschi et al. 1999), whereas vascular disrupting
agents may be particularly effective against large
bulky and late stage tumors (Landuyt et al. 2001;
Siemann and Shi 2003). Indeed data are beginning to
emerge that combining these two strategies may
provide particularly beneficial therapeutic effects.
One current trial (NCT00653939) is designed to test
the efficacy of the combination of carboplatin,
33
paclitaxel, bevacizumab, and fosbretabulin in patients
with chemotherapy na lung cancer.
6 Conclusions
Angiogenesis plays a critical role in the progression
and prognosis of lung cancer. Although still in early
stages of development, therapeutic strategies directed
against the tumor blood vessel network represents a
promising advance in the management of lung cancer
patients. The recent demonstration of improvement in
survival in colorectal cancer with bevacizumab
treatment is the first clinical validation of anti-
angiogenic therapy, providing hope that similar ben-
efits may be seen in other tumor types including lung
cancer. Ultimately, such endeavors are likely to
incorporate both anti-angiogenic and vascular dis-
rupting strategies in combination with conventional
anti-cancer measurements.
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 Interventional Pulmonology
Branislav Perin, Bojan Zarić, and Heinrich D. Becker

Contents Abstract
Interventional pulmonology is relatively new field
1 Introduction.............................................................. 46 within pulmonary medicine focused on use of
1.1 Diagnostic Interventional Pulmonology advanced bronchoscopy methods and interven-
Techniques ................................................................. 46
1.2 Therapeutic Interventional Pulmonology
tional techniques in diagnosis and therapy of
Techniques ................................................................. 48 respiratory diseases. Various respiratory disorders
may result in central airway obstruction (CAO),
References.......................................................................... 52
and central airway obstruction can cause signifi-
cant morbidity and mortality. Exact data on
incidence and prevalence of central airway
obstruction are not available, but epidemiological
studies investigating lung cancer are suggesting
that CAO is frequent and significant part of
morbidity and mortality in lung cancer patients.
These studies suggest that 20-30% of lung cancer
patients are experiencing complications due to
CAO, and that 40% of lethal outcomes are related
to CAO. The treatment of patients with CAO
requires not only understanding of etiology,
physiology, diagnostic and therapeutic procedures
but also availability of multidisciplinary team com-
posed of interventional pulmonologists, thoracic
surgeons, pulmonologists, oncologists, anesthesi-
ologists and radiologists. Evaluation of procedures
and their efficacy is extremely difficult; randomiza-
tion of studies in this field is extremely complicated.
In one hand it is difficult to find patients with
comparable disorder and comorbidity, on the other
B. Perin (&)
B. Zarić hand all of the patients are critically ill and random-
Institute for Pulmonary Diseases of Vojvodina, ization in this case is unethical. That is the reason why
Clinic for Pulmonary Oncology, Faculty of Medicine,
University of Novi Sad, Novi Sad, Serbia the majority of studies are retrospective analyses.
e-mail: bperin@eunet.rs One thing is for certain—the use of novel technology
H. D. Becker and interventional procedures leads to improvement
Department for Interdisciplinary Endoscopy, in survival and quality of life of patients with CAO.
Thoraxklinik, Heidelberg, Germany

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 45
DOI: 10.1007/174_2011_206, Ó Springer-Verlag Berlin Heidelberg 2011
46
The primary question is no more ‘‘Is therapy
helpful?’’ but ‘‘Which therapy is best for particular
patient?’’.
1 Introduction
In recent years interventional pulmonology tech-
niques have found their place in the palliative treat-
ment of lung cancer invading central airways (trachea
and principal bronchi). The curative effect of inter-
ventional techniques is reported in number of studies
with very different success ratio, but with excellent
potential and perspective. Increase in number and
variety of these techniques led to the development of
internationally accepted guidelines for their use.
The choice of specific interventional technique in the
treatment of lung cancer patients with central airway
stenosis (CAO) depends on several factors: patient’s
general condition and co-morbidities, type and
characteristics of airway stenosis and availability of
techniques and trained personnel.
Interventional techniques can be divided into diag-
nostic and therapeutical. Diagnostic interventional
techniques, among others are: autofluorescence bron-
choscopy (AFB), endobronchial ultrasound (EBUS),
electromagnetic navigation bronchoscopy and narrow
band imaging bronchoscopy. Therapeutic techniques
are divided into ones with imminent desobstruction of
central airways and ones with delayed effect. Thera-
peutical interventional pulmonology techniques can be
curative or palliative. In cases of carcinoma in situ or
early invasive lung cancer, interventional pulmonology
can offer a variety of techniques with curative effect.
Photodynamic therapy (PDT), cryotherapy, electro-
cautery (EC), argon plasma coagulation (APC) and
brachytherapy are reported to have curative potential,
in cases of early-stage lung cancer. Bronchoscopic
treatment of early-stage lung cancer requires precise
and accurate staging of the disease, using all available
advanced techniques for staging, e.g., positron emis-
sion tomography, endobronchial ultrasound and auto-
fluorescence or narrow-band imaging bronchoscopy to
make a distinction between non-invasive and invasive
bronchial carcinoma and to determine nodal status with
reliable accuracy.
Palliative interventional pulmonology techniques
are aimed at relieving of symptoms of malignant CAO.
Techniques with imminent effect are laser resection,
B. Perin et al.
electrocautery, argon plasma coagulation and place-
ment of tracheobronchial stents. Other therapeutic
interventions can proceed, after the initial treatment
and re-opening of the airway. Interventional pulmon-
ology techniques with delayed effect can improve the
control of symptoms and quality of life (QoL), and
addition of specific chemoradiotherapy regimen can
have certain impact on disease-free period and survival.
Every symptomatic malignant CAO must be con-
sidered as a potentially fatal one. Adequate bron-
choscopic evaluation can offer appropriate indication
for imminent interventional technique for rapid air-
way desobstruction. Interventional pulmonology
techniques are extremely expensive and they should
be available only to the top respiratory institutions.
Deployment of these techniques requires a multidis-
ciplinary team of interventional pulmonologists,
anesthesiologists, thoracic surgeons, radiologists and
oncologists. Institutions where interventional tech-
niques are implemented need to have appropriate
facilities, well-trained personnel and a variety of
interventional techniques available at any time
(Colt, Murgu 2010; Sutedja 2003; Wahidi et al 2007).
1.1 Diagnostic Interventional
Pulmonology Techniques
1.1.1 Autofluorescence Videobronchoscopy
Autofluorescence imaging videobronchoscopy (AFI) is
one of the new systems of autofluorescence bronchos-
copy designed for thorough examination of bronchial
mucosa. The integration of autofluorescence and vid-
eobronchoscopy provides clear images of normal and
pathologically altered bronchial mucosa. Major indi-
cations for AFI include evaluation of early-stage
lung cancer and detection of pre-cancerous lesions.
However, in recent years the indications for AFI are
widening and this tool might find its place in daily
routine bronchoscopic practice. With new indications
for AFI, such as evaluation of tumor extension or fol-
low-up after surgical resection, this tool might be more
often used by bronchoscopists. Sharp learning curve
and clear designation between healthy and pathologi-
cally altered mucosa make this technology acceptable
for young and inexperienced bronchoscopists.
One of the major disadvantages of AFI is low
specificity in detection of pre-malignant lesions and
early-stage lung cancer. This disadvantage could be
Interventional Pulmonology
overcome with the appearance of new and improved
technologies in autofluorescence such as: addition of
backscattered light analysis, ultraviolet spectra, fluo-
rescence-reflectance or dual digital systems. Quanti-
tative image analysis is also one of the ways to improve
objectivity and minimize observer errors. However,
one of the most appropriate solutions would be addition
of AFI to narrow-band imaging (NBI), and merging of
two technologies into one videobronchoscope. New
systems for autofluorescence, such as autofluorescence
imaging–AFI (Olympus Co, Tokyo, Japan), SAFE-
3,000 (Pentax Co, Japan), D-Light AF system
(Karl Storz, Tuttlingen, Germany) or Onco-LIFE
(Xillix Technologies Corp. Richmond, Canada), pro-
duce clear, high-quality images of bronchial mucosa.
Images generated by the new systems are easy to inter-
pret and characteristic. In the mentioned systems auto-
fluorescence and white light videobronchoscopy are
incorporated into one scope, making it easy to switch
between modes of examination. On the AFI examination
normal mucosa appears green, while pathologically
altered mucosa is magenta or red-brownish (Yarmus,
Feller-Kopman 2010; Yasufuku 2010).
1.1.2 Narrow-Band Imaging
Narrow-band imaging (NBI) is a new endoscopic
technique designed for detection of pathologically
altered sub-mucosal and mucosal microvascular
patterns. The combination of magnification video-
bronchoscopy and NBI showed great potential in
detection of pre-cancerous and cancerous lesions of the
bronchial mucosa. The preliminary studies confirmed
supremacy of NBI over white light videobronchoscopy
in the detection of pre-malignant and malignant
lesions. Pathological patterns of capillaries in bron-
chial mucosa are known as Shibuya’s descriptors
(dotted, tortuous and abrupt ending blood vessels).
When respiratory endoscopy is concerned, the NBI is
still a ‘‘technology in search of proper indication’’.
More randomized trials are necessary to confirm the
place of NBI in the diagnostic algorithm, and more
trials are needed to evaluate the relation of NBI to
autofluorescence videobronchoscopy, and white light
magnification videobronchoscopy. Considering the
fact that NBI examination of the tracheo-bronchial tree
is easy, reproducible and clear to interpret, it is certain
that the NBI videobronchoscopy will play a significant
role in the future of lung cancer detection and staging.
The NBI system uses a blue narrow band, with the
47
wave length ranging from 390 to 445 nm, for imaging
the capillaries of the surface mucosal layer. A green
narrow band (of the wave length from 530 to 550 nm)
is used to visualize the thick blood vessels inside the
membranes. This approach provides a better contrast
on the mucosal surface, reduces examination time and
eliminates futile biopsies.
The use of the NBI technology in the detection of
lung cancer started with the development of magni-
fying videobronchoscopy and integration of these two
systems. Most recent publications confirm that NBI
enables better visualization of the bronchial mucosa
and differentiation between malignant and non-
malignant tissue. NBI proves to be more efficient in
the detection of pre-cancerous lesions, especially
angiogenic squamous dysplasia (ASD), than the white
light videobronchoscopy alone. The learning curve
for NBI videobronchoscopy is sharp, and that fact
makes the NBI useful even when used by an inex-
perienced bronchoscopist. It is believed that the
combination of NBI with autofluorescence video-
bronchoscopy will give even better results in lung
cancer detection.
1.1.3 Endobronchial Ultrasound
There are currently two major types of endobron-
chial ultrasound (EBUS), linear and radial. Linear
EBUS is commonly used for mediastinal staging of
lung cancer, or real-time TBNA (transbronchial
needle aspiration). This approach enables the bron-
choscopist to visualize lymph nodes even smaller
than 1 cm in diameter, allowing accurate nodal
staging. The technique is proven to be completely
complementary with mediastinoscopy. On the other
hand real-time EBUS guided TBNA allows more
comfortable mediastinal re-staging which is neces-
sary after neoadjuvant radiochemotherapy. Radial
endobronchial probe allows insertion of the probe
through the working channel of the diagnostic
bronchoscope. It can also be used for mediastinal
staging; however, this technique enables excellent
insight into the pulmonary parenchyma. Radial
EBUS is routinely used for diagnosis of peripheral
lung cancers, as well as for the assessment of tumor
penetration into the bronchial wall. Considering the
fact that up to nine layers of bronchial wall can be
visualized by radial EBUS, this technique is irre-
placeable for the assessment of bronchial wall in
early-stage lung cancer.
48
Fig. 1 White light videobronchoscopy image of the tumor in
the distal part of intermediary bronchus
Comparative images of white light videobron-
choscopy, AFI, NBI and radial EBUS on the same
lesion are presented in Figs. 1, 2, 3, 4.
1.1.4 Novel Diagnostic Techniques
in Interventional Pulmonology
There are several newly developed techniques that
entered the arena of diagnostic interventional pul-
monology in the last years. Electromagnetic naviga-
tion (EMN) bronchoscopy is successfully deployed as
a guiding tool for diagnosis of peripheral lung cancer.
In recent years other techniques are available:
enhanced bronchoscopic navigation, confocal fluo-
rescence microscopy (endoscopy), optical coherence
tomography and ultrathin bronchoscopy (Yarmus,
Feller-Kopman 2010; Yasufuku 2010).
1.2 Therapeutic Interventional
Pulmonology Techniques
1.2.1 Techniques with Imminent Effect
1.2.1.1 Nd:YAG Laser Photoresection
‘‘Light amplification of stimulated emission of
radiation’’ or LASER is one of the most explored
principles in interventional pulmonology. Laser
beam delivers energy in form of the heat to the target
B. Perin et al.
Fig. 2 Autofluorescence imaging (AFI) videobronchoscopy
image of the tumor in the distal part of intermediary bronchus
tissues. The result is vaporization, coagulation and
necrosis of the targeted tissue. There are several types
of lasers used in practice (Nd:YAG, CO2, argon, dye,
diode, and YAP:Nd), only Nd:YAG (neodym-
ium:yttrium aluminium garnet) is widely used in
pulmonology. The effects of laser beam depend on
several factors, among others, power density,
absorption and scattering ratio of soft tissues and
delivery system but one of the most important factors
determining biological effect of laser on soft tissues is
the wavelength of the laser light. Wavelength of laser
determines the absorption and through the effect of
delivered heat energy on the tissue. The wavelength
of Nd:YAG laser is 1,064 nm, it is in invisible range
of infrared region and needs a pilot light (usually red)
for its guidance.
Major indication for laser photoresection is
malignant or non-malignant central airway obstruc-
tion due to intraluminal growth of malignant or
benign tissue. Lesions most suitable for laser resec-
tions are situated centrally (trachea and mainstream
bronchi), short in length (B4 cm), with visible distal
bronchial lumen and functional lung distal to the
obstruction.
Nd:YAG laser re-section can be carried out via
flexible bronchoscopy or the combination of rigid and
flexible bronchoscopy under general anesthesia. The
initial power setting is usually about 40 W, with pulse
Interventional Pulmonology
Fig. 3 Narrow band imaging videobronchoscopy image of the
tumor in the distal part of intermediary bronchus
Fig. 4 Linear endobronchial ultrasound (EBUS) image of the
tumor in the distal part of intermediary bronchus
duration of 0.5–1 s. The tip of the probe is aimed
1 cm proximally and parallel to the lesion. Tissue
effect of Nd:YAG laser can be adjusted either by
increasing the power setting or by moving the tip of
the probe further or closer to the target lesion. The
result will be vaporization, coagulation or necrosis of
the tissue. The depth of penetration of laser beam is
not immediately visible, so frequent re-analysis of the
49
lesion is advisable. Laser re-section is usually per-
formed under general anesthesia, as a precaution
oxygen concentration should be kept under 40% in
order to prevent airway fire.
Absolute contraindication is extraluminal disease;
relative contraindications include recent myocardial
infarction, ventricular arrhythmias, conduction
abnormalities, hypotension, decompensated heart
failure, severe obstructive lung disease, extensive
tumor involvement, unresolved coagulopathies and
sepsis.
The overall complication rate of Nd:YAG laser
resection is generally low. Possible complications
include hypoxemia intraoperatively and post-opera-
tively, hemorrhage, airway perforation, airway fire
(burns), pneumothorax and fistulae formation. After
the treatment patient should be observed in the
recovery room for a reasonable period of time
because of the possibility of bronchospasm or
laryngospasm. With adequate precaution measures
taken complication rate is usually less than 5%
(Colt, Murgu 2010; Sutedja 2003; Wahidi et al
2007).
1.2.1.2 Electrocautery
Electrocautery (EC) represents a contact form of
electrosurgery. Electron flow between the tip of the
probe and the tissue is a result of voltage difference
between these two surfaces. Electrons are then
transmitted through a tiny gap of air between these
two surfaces. Created electrical current is affecting
target tissue in the form of heat, causing coagulation,
carbonization or vaporization of the tissue. The cur-
rent leaves the body through a grounding plate, usu-
ally applied on patient’s arm. The effects of EC
depend on power setting, tissue resistance, time of
application and the applied mode of EC. Low voltage,
low power and high amperage will cause coagulation.
High voltage, high power and low amperage will
cause carbonization. There is ‘‘cut’’ mode and
‘‘blended’’ mode of EC, the last one is preferred for
its ability to combine cutting and coagulation. Some
authors divide EC coagulation in three types; soft—to
avoid carbonization, hard—for deeper tissue pene-
tration and spray—for surface haemostasis. Indica-
tions for EC are the same as for laser re-section,
and often EC is used as a cheaper alternative to laser
re-section. Intraluminal obstruction of major airways
due to benign or malignant tissue proliferation is most
50
common indication for its use. Absolute contraindi-
cations are extraluminal disease and a pacemaker
susceptible to electrical interference.
Electrocautery can be carried out via rigid or
flexible bronchoscopy, or the combination of these
two techniques. When rigid bronchoscopy is per-
formed EC is performed under general anesthesia.
Analgosedation modality can be used in flexible
bronchoscopy EC. A specially isolated ceramic-tip
flexible bronchoscope is used for EC, and the patient
is electrically grounded with a pad or a plate. Limiting
inhaled oxygen fraction and avoiding flammable
materials (plastic endotracheal tube or tracheobron-
chial stents) are necessary precaution measures. There
are several types of EC probes designed to achieve
wanted effects on target tissue. Blunt probe is usually
used for coagulation and carbonization, knife causes
coagulation and blend, and snare is designed for
blend. Coagulative effect of EC significantly corre-
lates with histologic tissue damage effect on the tar-
geted tissue.
Possible complications of EC include airway per-
foration, electrical shocks and hemorrhage, however,
only mild hemorrhage has been reported in published
studies. Precaution measures for application of EC
include limited power setting (40 W), low inspired
oxygen concentration (B40%), short burst time
(B2 s) and the use of isolated bronchoscope. EC
seems to be good alternative to laser resection; it is
cheap and safe technique for urgent airway debulking.
1.2.1.3 Argon Plasma Coagulation
Argon plasma coagulation (APC) is a form of non-
contact electrosurgery that uses ionized argon gas
transformed into plasma in order to create electrical
current. When high voltage spark (5,000–6,000 V)
ignites argon gas, the gas is ionized into plasma.
Monopolar current of ionized plasma affects target
tissue in the form of heat, producing coagulative and
necrotic effect on target tissue. Plasma seeks the way
of least resistance, targeting directly wide surface of
tissue. Closed current circuit is necessary for argon
plasma to flow; the tip of the probe must therefore be
situated less than a centimeter from the tissue. If the
distance between the tip of the probe and the tissue is
more than 1 cm, the circuit will be open and the effect
will be lost. The current leaves the body through a
grounding plate usually situated under patient’s lower
back.
B. Perin et al.
The effect of APC depends on power setting,
application time and conductivity of the tissue.
Coagulated tissues have higher resistance and higher
resistance lowers conductivity and limits penetration.
At power setting of 40–120 W and burst time less
than 2 s, the penetration depth is limited to less than
5 mm. One of major benefits of APC is the fact that
the lesions situated laterally to the probe or the lesions
‘‘around the corner’’ can be successfully treated, in
contrast to laser or electrocautery. Disadvantages of
APC include low penetration ability; therefore the
treatment of bulky tumor masses APC is not recom-
mendable. In that case other interventional techniques
usually must follow APC. Repeated bronchoscopic
checkups are also usually required in order to remove
all the necrotic debris from the airways.
Indications for APC are similar to EC or laser
resections. They include intrinsic airway obstruction
due proliferation of malignant or benign tissue. Most
suitable lesions have large endobronchial component
with visible distal bronchial lumen and functional
pulmonary tissue. The major indication for APC is
hamostasis in hemoptysis. Since APC affects wide
surface it is a recommendable technique for hem-
optysis control. APC is successfully used in re-section
of granulation tissue proliferating through the pores of
metallic stent; there are also reports of use in the
treatment of respiratory papillomatosis and post-
transplantation benign tracheobronchial stenosis.
There are no absolute contraindications for APC use,
except for extraluminal disease. Relative contraindi-
cations are the same as for laser re-sections and EC.
APC can be carried out via flexible bronchoscopy
alone; however, the combination of flexible and rigid
bronchoscopy allows better control of bursts and
adequate removal of debris during the intervention.
The technique is usually performed under general
anesthesia and requires all the necessary precautions
for safe general anesthesia. Oxygen concentration
should be under 40% and all flammable materials e.g.,
silicone stents or endotracheal tube, should be avoi-
ded. Initial settings for application of APC include:
power at 30–80 W, burst time of 2–3 s and argon gas
flow 0.3–2 L/min. The flexible probes for APC are
1.5 or 2.3 mm in diameter and usually 200 cm long.
Probes can easily pass through working channel of
flexible bronchoscope. The tip of the probe must
protrude at least 1 cm off the tip of the bronchoscope.
In makes the visualization field clear and prevents
Interventional Pulmonology
possible burning of the bronchoscope. The probe must
be kept 1 cm from the target tissue in order to keep
the flow of plasma. During the procedure the debris
should be removed with forceps or with suction.
Possible complications include airway perforation
(pneumomediastinum or pneumothorax), airway fire
and damage to the bronchoscope. Incidence of these
complications is less than 1%. Limitation of oxygen
concentration on less than 40%, keeping power set-
tings under 80 W with application time less than 5 s,
minimizes the probability of these complications.
In conclusion, APC is recommendable technique for
the management of hemoptysis and for removing of
CAO.
1.2.1.4 Tracheobronchial Stents
Tracheobronchial stents have four major indications
in interventional pulmonology; (1) extrinsic com-
pression from tumors or enlarged lymphnodes, (2)
stabilizing airway patency after removal of endo-
bronchial malignancy, (3) sealing of tracheo-oesoph-
ageal fistulas and (4) treatment of benign central
airway obstruction. Tracheobronchial stents are divi-
ded into two large groups; silicone and metallic
stents. Metallic stents can be balloon expandable and
self-expanding. Baloon expandable metallic stents are
currently out of date, and rarely used. Both types of
stents have certain advantages and disadvantages,
also, both types of stents have specific indications and
complications. Commonly used in these days are
hybrid stents, made of metal wire mesh and covered
with silicone (UltraflexÒ [Boston scientific] and Aero
stentÒ [Alveolus]). Silicone stents are adjustable to
the airway architecture, easily removed, with no in
growth of granulation or tumor tissue, non-reactive in
the means of mucosa irritation, their expansion is
easily controlled and they are cheaper than metallic
stents. However, placement of silicone stents requires
rigid bronchoscopy under general anesthesia, the
placement is rather complicated, and one of most
common problems is dislocation. Some authors
complain that the decreased inner diameter leads to
impaired mucus clearance and formation of mucus
plugs. Metallic stents are easily delivered via flexible
bronchoscope, stable in place and the position of the
stent is confirmed on fluoroscopy. On the other hand,
once placed these stents are permanent, the position
of the stent can not be adjusted and removal of the
stents is dangerous because it may cause a perforation
51
of the airway, serious bleeding and trauma. Confir-
mation of stent position requires fluoroscopy; tissue
(benign or malignant) grows through the stent
requiring additional re-sections and these stents are
expensive. Most suitable stents at the current moment
are hybrid ones, metallic fully covered stents. The
best solution for the treatment of obstruction with
carinal involvement is Y shaped dynamic stent. The
dynamic stent is a hybrid stent made of silicone with
steel claps.
One of techniques for urgent airway debulking
usually precedes stent insertion in malignant and
benign central airway obstruction (CAO). With laser
resection, EC or APC intraluminal component can
be easily removed and stent application can follow.
In such situation one usually decides to place silicone
or hybrid stent.
The ideal stent of the future should be easy to insert
and remove, with low possibility of migration, rigid
enough to support the airway and flexible enough for
adaptation to airway structure. It should be biologi-
cally inert to minimize granulation tissue formation,
available in different sizes and not too expensive.
There are some feasibility studies going on, in order to
investigate the successfulness of tracheobronchial
stents made of bioabsorbable materials.
1.2.2 Techniques with Delayed Effect
1.2.2.1 Bronchoscopic Balloon Dilatation
Balloon dilatation (bronchoplasty) can be successfully
used for the treatment of malignant and non-malignant
central airway obstruction. This technique is success-
fully used for the treatment of post-intubation or post-
transplantation stenoses or as an introductory technique
in the treatment of malignant obstruction before stent-
ing. Standard procedure requires assessment of the
endoscopic lesion, with detection of its proximal and
distal ending. Guide-wire is then inserted through the
working channel of the bronchoscope and placed into
the region of the obstruction. Balloon catheter is placed
through the guide-wire under fluoroscopy control.
Balloon inflation and deflation is followed endoscopi-
cally and fluoroscopically, the dilatation can be
repeated several times. Major indications include
the preparation of the stenotic bronchial segment for
the implantation of the stent or brachytherapy
catheter. Possible complications include perforation of
the bronchi or re-stenosis.
52
1.2.2.2 Endobronchial Brachytherapy
Endobronchial brachytherapy (EBBT) allows appli-
cation of maximal radiotherapy dose directly to tumor
with minimal damage for surrounding tissue.
High-dose rate endobronchial brachytherapy
(HDR-EBRT) is one of the commonly used interven-
tional pulmonology techniques with delayed effect in
the treatment of malignant endobronchial obstruction.
This technique found its place in all of the guidelines
for the use of interventional pulmonology in lung
cancer. Major number of studies reported influence of
HDR EBBT on the time to progression in advanced
lung cancer treatment. As a part of multi-modality
treatment of advanced lung cancer, HDR EBBT might
influence survival in patients with malignant central
airway obstruction. High-dose rate EBBT can be used
as a sole technique for desobstruction, in non-urgent
cases of bronchial obstruction. In cases where bron-
chial obstruction is urgent, EBBT can safely follow
laser resection, electrocautery or argon plasma coag-
ulation. Palliative effect of EBBT is recognized in
majority of the studies that investigated its effect on
dyspnea, cough, post obstructive pneumonia, hem-
optysis and other symptoms of lung cancer. In recent
studies HDR EBBT was used for treatment of early-
stage lung cancer and benign central airway obstruc-
tion. HDR EBBT was successfully combined with
photodynamic therapy in the treatment of bulky lung
cancer. In the future HDR EBBT in combination with
electromagnetically navigated bronchoscopy could
find its place in the treatment of inoperable peripheral
lung cancer. However, precise protocols for HDR
EBBT do not exist. Still, there are major differences in
timing of fractions and total dose. Therefore, there are
significant differences in the appearance of early and
B. Perin et al.
late complications of HDR EBBT. While early studies
showed small percentage of complications, latter
studies revealed more frequent complications, espe-
cially hemoptysis. Usually reported complication rate
is less than 5%, however, in some studies complica-
tions appeared at the rate of 35%.
1.2.2.3 Other Techniques
Cryotherapy is one of the techniques for debulking of
central airways. It is based on application of extre-
mely low temperatures (under -40°C) in order to
freeze and destroy malignant tissue. The effect of
cryotherapy depends on the speed of freezing and
thawing, lowest temperature, number of freeze thaw
cycles and cellular amount of water. Freezing under
-40°C with speed of 100°C/min experimentally
destroys 90% of the cells.
Photodynamic therapy represents activation of
photosensitive substance with non-thermal laser light.
This results in phototoxic reaction, which leads to
cellular death. This technique is suitable for the
treatment of early-stage superficial lung cancer.
References
Colt HG, Murgu SD (2010) Interventional bronchoscopy from
bench to bedside: new techniques for early lung cancer
detection. Clin Chest Med 31(1):29–37
Sutedja G (2003) New techniques for early detection of lung
cancer. Eur Respir J 21(39):57–66
Wahidi MM, Herth FJF, Ernst A (2007) State of the art:
interventional pulmonology. Chest 131:261–274
Yarmus L, Feller-Kopman D (2010) Bronchoscopes of the
twenty-first century. Clin Chest Med 31(1):19–27
Yasufuku K (2010) Early diagnosis of lung cancer. Clin Chest
Med 31(1):39–47
 Pathology of Lung Cancer
Mary Beth Beasley

Contents
1 Introduction.............................................................. 53
2 Adenocarcinoma ...................................................... 54
2.1 Background ................................................................ 54
2.2 Bronchioloalveolar Carcinoma, Adenocarcinoma
in situ and Minimally Invasive Adenocarcinoma .... 55
2.3 ‘‘Mixed Subtype’’ Adenocarcinoma ......................... 56
2.4 Mucinous Adenocarcinomas ..................................... 57
2.5 Adenocarcinoma Conclusions and Areas in Need
of Further Study ........................................................ 58
3 Squamous Cell Carcinoma ..................................... 58
4 Molecular Testing in Lung Cancer ....................... 59
5 Pathology of Lung Carcinomas Treated With
Radiation and/or Neo-adjuvant Therapy ............. 60
References.......................................................................... 60
Abstract
Over the past decade, the diagnosis, treatment
and management of lung cancer has evolved
substantially, in large part to the development of
novel chemotherapeutic agents and targeted
therapy in particular. As such, accurate classifi-
cation of lung carcinomas from a histologic
standpoint has become increasingly critical for
appropriate patient management. Much of the
focus of lung cancer pathology in the past
decade has concentrated on adenocarcinoma.
As such, the aim of this chapter will primarily
focus on the evolution of this cancer subtype and
review the recently published adenocarcinoma
classification prepared jointly by the International
Association for the Study of Lung Cancer, the
American Thoracic Society and the European
Respiratory Society. Squamous cell carcinoma
will also be discussed, particularly in regard to
accurate discrimination from adenocarcinoma.
The role of the pathologist in molecular testing will
be reviewed, particularly as it relates to specimens
obtained from radiologic procedures. Finally, given
that the scope of this publication is radiation
oncology, the histologic changes and evaluation
of tumors which have undergone radiation and/or
neo-adjuvant therapy will be discussed.

1 Introduction
M. B. Beasley (&)
Mount Sinai Medical Center, Multiple subtypes of lung carcinoma have always
One Gustave L. Levy Place,
New York, NY 10128, USA existed from a pathologic standpoint, and the current
e-mail: mbbeasleymd@yahoo.com World Health Organization (WHO) classification is

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 53
DOI: 10.1007/174_2011_304, Ó Springer-Verlag Berlin Heidelberg 2011
54 M. B. Beasley

Table 1 2004 World Health Organization classification of carcinoma, with clinicians primarily being concerned
pulmonary malignant epithelial tumors (Travis et al. 2004) with whether a carcinoma was small-cell carcinoma
Pre-invasive lesions (SCLC) or non-small-cell carcinoma (NSCLC), the
Squamous cell carcinoma in situ later typically comprising squamous cell carcinoma
Atypical adenomatous hyperplasia (SCC), adenocarcinoma (ADC) and large cell carci-
Diffuse idiopathic neuroendocrine cell hyperplasia
noma. This clinical grouping has traditionally existed
as treatment for SCLC differed from that of NSCLC,
Squamous cell carcinoma
but did not differ significantly among the subtypes of
Variants-papillary, clear cell, small cell, basaloid
NSCLC (Travis et al. 2004; Beasley et al. 2005;
Adenocarcinoma Lim et al. 2008). The advent of expanded chemo-
Adenocarcinoma, mixed type therapeutic options and targeted therapies has shifted
Acinar adenocarcinoma this paradigm and placed a greater role on the
Papillary adenocarcinoma pathologist in regard to accurate subtyping of tumors
Bronchioloalveolar carcinoma as well as molecular testing (Pirker et al. 2010; Travis
Non-mucinous
et al. 2011). Clearly, the variety of malignant lung
tumors is myriad; however, the scope of this article
Mucinous
will focus on the evolving issues involving the most
Mixed
commonly encountered tumors, namely adenocarci-
Solid adenocarcinoma with mucin production noma and squamous cell carcinoma, with particular
Variants focus on adenocarcinoma. Practical issues regarding
Fetal adenocarcinoma tumor diagnosis and molecular testing as they pertain
Mucinous ‘‘colloid’’ carcinoma to specimens obtained from interventional radiolo-
Mucinous cystadenocarcinoma gists will also be discussed. The chapter will end with
Signet ring cell adenocarcinoma a brief discussion of the histologic features encoun-
tered in tumors which have undergone pre-operative
Clear cell adenocarcinoma
or neo-adjuvant therapy.
Small-cell carcinoma
Combined small-cell carcinoma
Large-cell carcinoma 2 Adenocarcinoma
Large-cell neuroendocrine carcinoma
Combined large-cell neuroendocrine carcinoma 2.1 Background
Other variants-basaloid carcinoma, lymphoepithelioma-like
carcinoma, clear cell carcinoma, large-cell carcinoma with Adenocarcinoma now represents the most common
rhabdoid phenotype subtype of lung carcinoma. The current WHO clas-
Adenosquamous carcinoma sification divides adenocarcinoma into acinar, papil-
Sarcomatoid carcinoma lary, bronchioloalveolar and solid types, along with
Variants-pleomorphic carcinoma, spindle cell carcinoma,
several other variants including mucinous carcino-
giant cell carcinoma, carcinosarcoma and pulmonary mas. The WHO classification also includes a category
blastoma of ‘‘mixed type adenocarcinoma’’ which, given the
Carcinoid tumor known histologic heterogeneity of lung carcinomas,
Typical carcinoid encompasses up to 90% of all lung adenocarcinomas
Atypical carcinoid and thus provides minimal information of clinical
relevance (Travis et al. 2004). As such, a new clas-
Salivary gland tumors—mucoepidermoid carcinoma, adenoid
cystic carcinoma, epithelial-myoepithelial carcinoma sification of adenocarcinoma was recently proposed
jointly by the International Association for the Study
of Lung Cancer (IASLC), the American Thoracic
presented in Table 1 (Travis et al. 2004). In spite Society (ATS) and the European Respiratory Society
of this, the role of the pathologist has traditionally (ERS). This new classification scheme, which will be
been relatively limited in the management of lung referred to as the ‘‘IASLC classification’’ in this text,
Pathology of Lung Cancer 55

Table 2 IASLC/ATS/ERS adenocarcinoma classification

(Travis et al. 2011)
Pre-invasive lesions
Atypical adenomatous hyperplasia
Adenocarcinoma in situ (B3.0 cm, formerly
bronchioloalveolar carcinoma)
Non-mucinous
Mucinous
Mixed mucinous/non-mucinous
Minimally invasive adenocarcinoma (B3.0 cm lepidic
predominant tumor with B5 mm of invasion)
Non-mucinous
Mucinous
Mixed mucinous/non-mucinous Fig. 1 Adenocarcinoma with non-mucinous lepidic growth
(H and E 2009). Non-mucinous tumor cells grow along pre-
Invasive adenocarcinoma
existing alveolar septa. Tumors consisting purely of this growth
Lepidic predominant (formerly non-mucinous BAC pattern pattern are classified as adenocarcinoma in situ in the IASLC
with [5 mm of invasion) classification system
Acinar predominant
Papillary predominant
Micropapillary predominant into non-mucinous and mucinous subtypes (Travis
Solid predominant with mucin production
et al. 2004). The term ‘‘lepidic’’ refers to growth
along pre-existing alveolar walls and derives from the
Variants
greek word ‘‘lepis’’ meaning ‘‘scales’’. As strictly
Invasive mucinous adenocarcinoma (formerly mucinous
bronchioloalveolar carcinoma)
defined, isolated non-mucinous BAC generally
appears as a ground glass lesion radiographically and
Colloid carcinoma
is associated with a nearly 100% 5-year survival, as
Fetal (low and high grade)
first noted by Noguchi et al. (1995) and subsequently
Enteric supported by other studies (Suzuki et al. 2002,
Sakurai et al. 2004a; Borczuk et al. 2009). The BAC
is presented in Table 2 (Travis et al. 2011). The pri- terminology has unfortunately been inappropriately
mary issues addressed by the new classification which applied by pathologists and clinicians alike, which has
differ significantly from the WHO classification are led to much confusion in the literature. In an attempt
the issue of bronchioloalveolar carcinoma (BAC) and to emphasize the strict definition and prognostic
the heterogeneous nature of the ‘‘mixed subtype’’ of implications, the IASLC classification has proposed
adenocarcinoma, and the issue of mucinous carcino- that the term ‘‘adenocarcinoma in situ (AIS)’’ be used
mas of the lung. The classification also emphasizes for solitary lesions with pure lepidic growth (Fig. 1).
the need to accurately discriminate between ADC and The IASLC classification retains the current WHO
SCC and the importance of appropriate tissue man- definition for BAC but additionally emphasizes that
agement for molecular testing. papillary and micropapillary growth patterns, as well
as significant intra-alveolar tumor cells should be
2.2 Bronchioloalveolar Carcinoma, absent (Travis et al. 2011).
Adenocarcinoma in situ A second significant change in the IASLC classi-
and Minimally Invasive fication is the addition of a category of ‘‘minimally
Adenocarcinoma invasive adenocarcinoma (MIA)’’. Several studies
have evaluated the impact on survival of the amount
In the WHO classification, BAC is defined as an of stromal invasion present in a tumor otherwise
adenocarcinoma with pure lepidic growth without showing non-mucinous lepidic growth (Suzuki et al.
stromal, pleural or vascular invasion, and is divided 2002; Sakurai et al. 2004a, b; Yim et al. 2007;
56 M. B. Beasley

Borczuk et al. 2009). Based on these studies, tumors

with 5 mm of invasion or less have the same excellent
prognosis as those with pure lepidic growth. As such,
the newly proposed category of MIA applies to
tumors with 5 mm or less of invasion in any one
focus, with the invasive component defined as any
histologic subtype other than lepidic growth or any
tumor cells infiltrating a fibroblastic stroma. The term
MIA is not used if the tumor invades lymphatics,
blood vessels or pleura, or if tumor necrosis is pres-
ent, even if the invasive focus is \5 mm overall
(Travis et al. 2011).
A cautionary note in regard to both AIS and MIA
is that both designations apply to tumors which are
localized and 3.0 cm or less in size. This is primarily Fig. 2 Pulmonary adenocarcinoma with papillary morphol-
ogy. Note the branching papillary structures with fibrovascular
because the majority of the research on these tumors cores (H and E 2009)
has been done on stage 1 adenocarcinomas and the
implications in larger tumors are as of yet uncertain.
Additionally, both diagnoses require that the entire
tumor be histologically completely evaluated, and
thus these designations should be made only on
resected specimens and are not appropriate diagnoses
for small biopsy or cytology specimens. Further, both
AIS and MIA refer predominantly to non-mucinous
tumors (Travis et al. 2011). While a mucinous sub-
type of BAC is present in the WHO classification and
is retained in the IASLC classification of AIS and
MIA, mucinous tumors meeting the strict criteria are
exceedingly rare and almost always contain signifi-
cant foci of invasion (Travis et al. 2004, 2011).

Fig. 3 Pulmonary adenocarcinoma with micropapillary mor-

2.3 ‘‘Mixed Subtype’’ Adenocarcinoma
Using the current WHO classification, up to 90% of
all lung ADC fall into the category of ‘‘mixed sub-
type’’ (Beasley et al. 2005). As one would expect, this
encompasses a markedly heterogeneous group of
tumors of differing clinical significance. In an attempt
to address this issue, the IASLC classification rec-
ommends that tumors with multiple growth patterns
should be classified by the predominant growth pat-
tern, and further recommends that any additional
patterns be indicated in 5% increments. In addition to
the lepidic growth pattern discussed above, the
IASLC classification retains acinar, papillary and
solid patterns as forms of invasive carcinoma, and
formally recognizes the micropapillary pattern which
was not included in the current WHO classification.
phology, characterized by small free-floating tufts of tumor
surrounding a fibrotic core (H and E 4009)
The IASLC classification emphasizes that papillary
and micropapillary growth are forms of invasive
carcinoma, which is not always intuitive from a his-
tologic standpoint as these growth patterns may show
extensive intra-alveolar involvement rather than
conventional stromal invasion (Travis et al. 2011).
Papillary carcinoma is defined as carcinoma forming
true papillae with a fibrovascular core (Fig. 2). The
micropapillary pattern, in contrast, consists of small
tufts of tumor radiating from a central fibrotic core
(Fig. 3). This subtype of adenocarcinoma has been
associated with aggressive behavior and an increased
incidence of lymph node metastases in stage 1 tumors
Pathology of Lung Cancer 57

(Amin et al. 2002; Miyoshi et al. 2003; Hoshi et al.

2004; Makimoto et al. 2005; Kuroda et al. 2006;
Kawakami et al. 2007; Kamiya et al. 2008; Borczuk
2009).
Histologic growth patterns have been associated
with behavior and to a certain degree with certain types
of mutations. Predominant solid and micropapillary
growth are generally associated with more aggressive
behavior, predominant lepidic growth with a more
favorable prognosis, and acinar and papillary growth
with an intermediate prognosis (Travis et al. 2011). In
regard to mutational status, epidermal growth factor
receptor (EGFR) mutations are found more commonly
in tumors with lepidic or papillary growth whereas
mucinous tumors frequently harbor KRAS mutations
and lack EGFR mutations (Dacic 2008, Dacic et al.
2010; Sartori et al. 2009; Hata et al. 2010) Solid tumors
with signet ring morphology have been correlated with
the presence of EML4-ALK translocations (Rodig et al.
2009). Therefore, it is hoped that the more detailed
information provided in the IASLC classification will
provide more meaningful information to the clinician
in regard to prognosis and potential management.

2.4 Mucinous Adenocarcinomas

In the past decade it has become increasingly clear
that mucinous carcinomas differ markedly from their
non-mucinous counterparts, not only morphologi-
cally, but also on immunohistochemical and molec-
ular grounds (Copin et al. 2001; Rossi et al. 2004;
Brownlee et al. 2005; Finberg et al. 2007; Pirker et al.
2010; Travis et al. 2011). As previously stated, the
vast majority of tumors previously classified as
mucinous BAC contains areas of invasion and it is
extremely rare to encounter a mucinous tumor with
lepidic growth that would meet the strict criteria for
AIS or MIA (Fig. 4a, b). The IASLC classification
includes the categories of invasive mucinous carci-
noma (which would encompass most tumors previ-
ously classified as mucinous BAC) and colloid
carcinoma (characterized by dissecting pools of
extracellular mucin containing free-floating tumor).
The uncommon fetal adenocarcinoma, in which
glandular components resemble those of embryonic
lung, is retained as well, while mucinous cystadeno-
carcinoma has been dropped as such tumors are
generally felt to be variants of colloid carcinoma.
Fig. 4 Invasive mucinous carcinoma characterized by areas of
lepidic growth along pre-existing alveolar septa (a, H and E
4009) and invasive (b, H and E 2009) growth
Signet ring carcinoma is not included as a formal
category, as this is felt to be primarily a cytologic
change and it is unclear if it is independently corre-
lated with a worse prognosis or if the association is
due to the fact that signet ring cells are more often
associated with solid growth, which itself has a poor
prognosis (Travis et al. 2011). It is recommended that
this feature be included as a descriptor, however,
given its association with EML4-ALK translocations
(Rodig et al. 2009). Finally, enteric adenocarcinoma
has been included as a formal category. These tumors
have morphologic and immunohistochemical overlap
with gastrointestinal and colorectal carcinomas,
which is problematic for the pathologist if there is an
issue of whether a tumor is primary or metastatic.
Whether these tumors have unique clinical or
molecular features is currently uncertain (Rossi et al.
2004; Inamura et al. 2005; Travis et al. 2011).
58
2.5 Adenocarcinoma Conclusions
and Areas in Need of Further Study
In summary, a variety of changes have been made to
the classification of adenocarcinoma in hopes of
creating a more clinically relevant system. It should
be noted that as knowledge of molecular biology of
adenocarcinoma continues to grow and novel thera-
peutic agents are developed, it is likely that the
classification will evolve. There are additionally
several areas that need additional study, particularly
as the vast majority of information is gleaned from
studies of low stage tumors. Additionally, how the
IASLC classification will be incorporated into the
forthcoming revision of the WHO classification is
currently in progress. Finally, the updated classifica-
tion post-dates the 7th edition of the AJCC staging
guidelines and this will need to be rectified. In par-
ticular, the implications for staging in regard to
tumors with prominent lepidic growth which fall
outside the category of MIA is unclear and further
study is needed to determine if the stage should be
based on overall tumor size or the size of the invasive
component alone.
3 Squamous Cell Carcinoma
SCC is now the second most common type of lung
carcinoma behind ADC, for reasons that are not
entirely clear. From a pathologic standpoint, features
definitively supporting squamous differentiation
include overt keratinization or intercellular bridge
formation (Fig. 5). In small biopsies, these features
may not be obvious, particularly in poorly-
differentiated tumors, and it has become more critical
to accurately separate SCC from ADC for optimal
patient management. This is primarily due to treat-
ment management in regard to chemotherapy.
Patients with SCC should not receive the vascular
endothelial growth factor (VEGF) inhibitor bev-
acizumab due to the increased risk of life-threatening
hemorrhage (Cohen et al. 2007). Conversely, EGFR
tyrosine kinase inhibitors such as erlotinib and gefi-
tinib are primarily recommended for patients with
advanced ADC harboring EGFR mutations, particu-
larly those in exons 19 or 21 (Mitsudomi et al. 2005;
Mok et al. 2009; Maemondo et al. 2010). Addition-
ally, pemetrexed is recommended for patients with
M. B. Beasley
Fig. 5 Squamous cell carcinoma with classic features of
keratin pearl formation in the center of a tumor nest (H and
E 4009)
ADC of tumors with so-called ‘‘non-squamous’’ his-
tology (Scagliotti et al. 2008, 2009a, b).
On conventional hematoxylin and eosin (H and E)
stained sections, discriminating between SCC and
ADC is usually straightforward; however, ancillary
methods may be needed to discriminate between the
two when overt features of differentiation are lacking.
Several studies have evaluated various immunohis-
tochemical techniques in regard to discriminating
SCC and ADC. While there is no consensus on which
combination is most optimal, in general, a panel
consisting of p63, CK5/6, thyroid transcription factor-
1 (TTF-1) and a mucin stain such as mucicarmine
will resolve the majority of cases, although ulti-
mately a small percentage will remain unclassifiable.
A staining pattern of p63 positive, CK5/6 positive,
TTF-1 negative and mucin negative supports a diag-
nosis of SCC while the reverse staining pattern
supports a diagnosis of ADC (Wu et al. 2003; Camilo
et al. 2006; Kargi et al. 2007; Loo et al. 2010;
Nicholson et al. 2010; Terry et al. 2010). A small
percentage of ADC will show focal staining for p63
and, unless the finding is extensive, this should not be
taken as evidence of co-existent squamous differen-
tiation in the presence of diffuse TTF-1 positivity
(Terry et al. 2010). Additionally, while mucinous
ADC is generally not easily confused with SCC, it
should be noted that mucinous ADC are generally
TTF-1 negative but these tumors will be positive for
mucin stains and negative for p63 and CK5/6 (Rossi
et al. 2004; Travis et al. 2011).
Pathology of Lung Cancer
4 Molecular Testing in Lung Cancer
The advent of targeted therapy has placed greater
emphasis on molecular testing for the optimal treat-
ment of lung cancer, particular in patients with
advanced disease. EGFR mutations are of particular
interest due to the response of tumors harboring
mutations, particularly those in exons 19 and 21, to
EGFR tyrosine kinase inhibitors such as gefitinib and
erlotinib (Mitsudomi et al. 2005; Dacic 2008; Mok
et al. 2009; Maemondo et al. 2010; Mitsudomi et al.
2010). Conversely, tumors harboring K-RAS muta-
tions are generally unresponsive to these agents
(Dacic 2008; Dacic et al. 2010). EML4-ALK trans-
locations are also of particular interest as their pres-
ence is associated with response to crizotinib (Soda
et al. 2007). Other mutations which are not frequently
found in lung carcinomas but are of increasing clini-
cal interest include BRAF and PIK3CA HER2, and
MET, among others. While there has been some
correlation with clinical features and certain histo-
logic types as discussed above, these features alone
cannot be used to select patients for mutation testing
(Mitsudomi et al. 2005; Dacic 2008; Mok et al. 2009;
Douillard et al. 2010).
Testing for these genetic alterations generally
requires either DNA sequencing (EGFR, KRAS) or
fluorescence in situ hybridization (EML4-ALK). As
such, in addition to adequate material for potential
ancillary studies for tumor subtyping as discussed
above, adequate material must be available for
molecular testing as well in order to optimize patient
therapy (Dacic 2008; Pirker et al. 2010; Travis et al.
2011). As the majority of lung cancers are not
resected and are diagnosed by small biopsy or cytol-
ogy specimens, it is important for the pathologist to
develop an appropriate strategy for optimizing tissue
for ancillary and molecular testing.
Biopsy specimens typically received from radiol-
ogists include needle core biopsies as well as fine
needle aspirations. While both types of specimens
yield small amounts of material and thus pose similar
issues in management for additional studies, com-
munication is particularly critical for fine needle
aspirations. For needle aspiration cytology specimens,
adequate material must be present in a cell block
59
preparation in order to perform ancillary testing. Such
testing cannot be consistently or reliably performed
on smear preparations in most institutions. As such,
communication between the radiologist and patholo-
gist is of extreme importance in the setting of fine
needle aspirations in particular to try to ensure that as
much material as possible is submitted for a cell block
in order to maximize the potential for ancillary testing
(Rekhtman et al. 2011; Travis et al. 2011).
In general, both tissue biopsies and cytology
materials submitted for cell block are suitable for
molecular testing. Specimens should ideally be fixed
in 10% neutral buffered formalin and acidic fixatives
or those containing heavy metals such as Bouin’s,
B-5 or Zenker’s are to be avoided as these inhibit
molecular analysis. Similarly, tissue which has been
decalcified is inappropriate for molecular testing
(Gillespie et al. 2002; Srinivasan et al. 2002; Pirker
et al. 2010). All small biopsies pose similar issues of
tissue management whether small tissue biopsies or
cytology cell blocks, with a primary difference
being that tumor enrichment via microdissection can
be performed more easily on tissue specimens as
opposed to cell blocks. Otherwise, while sensitivity
and specificity may vary with the precise sequencing
technique used, a specimen should optimally contain
a minimum of 500 tumor cells and tumor cells should
comprise at least 25% of the specimen, although some
authors have recommended 50% as an ideal minimum
(Pirker et al. 2010). Recognition of these require-
ments and development of an appropriate strategy for
optimizing the amount of tumor obtained at the time
of biopsy should maximize the amount of information
that the pathologist is able to provide from a small
sample and minimize the need to obtain addition
tissue for the sole purpose of molecular testing.
In conclusion, there is increasing importance in
accurate subclassification of tumors formerly lumped
together as NSCLC, as well as an expanding need for
molecular testing. As most lung cancers are diagnosed
on small biopsies or cytology specimens, frequently
obtained from radiologists, the pathologist is required
to ‘‘do more with less’’. Appropriate communication
between the pathologist and radiologist in regard to a
strategy for optimal tissue management is essential
for appropriate patient management (Travis et al.
2011).
60
Fig. 6 Adenocarcinoma following pre-operative radiation and
chemotherapy. A focus of residual adenocarcinoma is present
in the lower left, while the adjacent tissue shows hemorrhage,
fibrosis, inflammatory infiltrates and occasional foamy macro-
phages (a). Elsewhere, viable tumor is absent and only foamy
macrophages and necrosis are present (b) (H and E 4009)
5 Pathology of Lung Carcinomas
Treated With Radiation and/
or Neo-adjuvant Therapy
Administration of neo-adjuvant therapy prior to the
resection of pulmonary carcinomas has become more
commonplace and is particularly aimed at stage IIIA
carcinomas. Initial studies suggest that tumors exhib-
iting a complete histologic response or those that show
extensive response, with\10% of the gross tumor mass
containing histologically viable tumor, have a survival
advantage (Junker et al. 1997a, b, 2001). Histologic
evidence of tumor response consists of coagulative or
infarct-like necrosis, fibrosis, foam cell and/or giant
cell infiltration and mixed inflammatory cell infiltrates
M. B. Beasley
(Fig. 6a, b). Typically a region of necrosis is sur-
rounded by a rim of foamy macrophages and inflam-
matory cells. Cholesterol cleft formation may be
present and a giant cell reaction may occur. Residual
tumor cells tend to have greater cytologic atypia and
pleomorphism in comparison to corresponding pre-
treatment specimens. The pattern of response present
does not appear to be related to the type of neo-adjuvant
therapy administered (i.e., chemotherapy plus radiation
therapy vs. chemotherapy alone), or with the type of
chemotherapy administered. Squamous carcinomas
tend to show a significantly greater degree of response
than adenocarcinomas (Junker et al. 1997a, b, 2001;
Liu-Jarin et al. 2003). Although the degree of fibrosis
tends to correlate with radiographic evidence of size
reduction, radiologic evidence of size regression does
not seem to significantly correlate with the degree of
histologic tumor response (Liu-Jarin et al. 2003).
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 Radiologic Imaging of Lung Cancer
Palmi Shah and James L. Mulshine

Contents Abstract
Recent advances in technology like faster, high
1 Introduction.............................................................. 63 resolution CT scanners, new data in lung cancer
2 Overview ................................................................... 64 screening combined with many changes in the
classification, staging and novel therapies for lung
3 Radiologic Imaging.................................................. 64
3.1 Detection .................................................................... 64 cancer are redefining the role imaging plays in
3.2 Staging ....................................................................... 68 detection, staging and management of the disease.
3.3 PostTherapy Imaging................................................. 72 This chapter describes the utility and limitations of
4 Conclusions ............................................................... 72 the different radiological modalities in various
stages of the disease. Since it is the mainstay in
5 Future........................................................................ 72
lung cancer management emphasis is placed on the
References.......................................................................... 73 application of CT imaging. PET-CT has been
discussed separately in this volume.

1 Introduction

Lung cancer rapidly rose in incidence in the 20th

century and became the leading cause of cancer-related
mortality. As we move into the 21st century the inci-
dence is unlikely to decline secondary to the rising
number of cases in the developing world (Toh 2009).
Challenges associated with identifying, diagnosing and
treating the disease are reflected by the steady 5-year
mortality of 13% in the last 15 years.
Lung cancer was the most commonly diagnosed
cancer as well as the leading cause of cancer death in
males in 2008 globally. Among females, it was the fourth
P. Shah most commonly diagnosed cancer and the second lead-
Department of Radiology, Rush University,
ing cause of cancer death globally. It accounted for 13%
Chicago, IL, USA
(1.6 million) of the total cases and 18% (1.4 million) of
J. L. Mulshine (&)
the deaths in 2008 globally (Jemal et al. 2011).
Department of Internal Medicine,
Rush University, Chicago, IL, USA Lung cancer remains the leading cause of cancer-
e-mail: James_L_Mulshine@rush.edu related death in the United States.

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 63
DOI: 10.1007/174_2011_267, Ó Springer-Verlag Berlin Heidelberg 2011
64
Rapid technological advances in the 21st century
have contributed to the now validated value of
imaging in lung cancer from screening, diagnosis,
staging, therapy planning to treatment monitoring.
Advancements in multi-detector CT (Computed
Tomography), MRI (Magnetic Resonance Imaging),
PET (Positron Emission Tomography), now inte-
grated PET- CT in conjunction with endobronchial
and transesophageal ultrasound have further enhanced
and refined the vital role imaging plays in disease
detection and management.
The staging and management of the disease is a
multidisciplinary process with multiple clinical and
nonclinical modalities playing a complimentary role
with each other. The utility of each modality is getting
better defined with the push for earlier detection, need
for accurate staging and the need to complement the
newer and varied therapy choices available today.
In this chapter we will discuss the role of radiologic
imaging in lung cancer with emphasis on CT. PET-CT
which also constitutes a mainstay of lung cancer
management is used for initial radiologic staging and
also plays a significant role in the evaluation of tumor
recurrence and treatment monitoring, is discussed in a
separate chapter and will not be detailed here.
2 Overview
The 2004 World health organization (WHO) (Travis
et al. 2004) classification of primary lung tumors
divided them by their light microscopy features into-
small-cell cancer and non-small-cell cancer
(NSCLC). NSCLC includes adenocarcinoma includ-
ing bronchioloalveolar cell carcinoma (BAC), squa-
mous cell carcinoma and large cell carcinoma.
A new pathological classification for adenocarci-
nomas has just been introduced in which the terms
BAC and mixed subtype adenocarcinoma are no
longer used. For resection specimens, new concepts
are introduced such as adenocarcinoma in situ (AIS)
and minimally invasive adenocarcinoma (MIA). AIS
and MIA are usually nonmucinous but rarely may be
mucinous (Travis et al. 2011). The term BAC has still
been used here for description because of familiarity,
however it’s use in the future is discouraged.
Invasive adenocarcinomas are subclassified by the
predominant pattern after using comprehensive his-
tologic subtyping to recognize the heterogeneity of
P. Shah and J. L. Mulshine
these cancers and to introduce more immunohisto-
chemical staining to keep up with the new novel
targeted therapies now available.
Clinical presentations of these various subtypes of
lung cancer are varied and overlapping. In addition it is
believed that 25% of patients with lung cancer are
asymptomatic at the time of diagnosis while the
symptomatic patients present with symptoms ranging
from mild cough, hemoptysis or chest pain to seizures,
dependant on tumor location and tumor spread.
Correspondingly, the imaging findings of these
tumors similarly are wide and varied and knowledge
of these would facilitate in timely diagnosis, appro-
priate imaging and help guide optimal management
strategies.
As a background to the discussion of imaging it is
important to introduce the new TNM classification of
lung cancer (7th edition) released by the American
joint committee on cancer in 2010 (AJCC 2010) along
with the revised nomenclature for lymph nodes as
detailed in the international association for the study
of lung cancer (IASLC) lymph node map. The new
staging classification elucidates stage clustering that
is more homogenous in their clinical behavior and
outcome.
3 Radiologic Imaging
Various modalities with their imaging manifestations
have been listed under the following outline, which
follows the course of the disease.
Detection
Staging
Recurrence
3.1 Detection
3.1.1 Chest Radiographs
These form the frontline and the most frequently used
modality for evaluation of symptoms related to the
cardiopulmonary system.
Frequently lung cancers are incidentally diagnosed
on chest radiographs done for an unrelated reason.
Nodules and masses may be detected. It is rare to
detect a nodule less than 1 cm on chest radiographs
secondary to limitations in sensitivity (Kundel 1981).
When detected the first step involves the search for
Radiologic Imaging of Lung Cancer
older studies. If upon review with old studies it is
established that the nodule has been stable in size for
2 years, it is likely benign.
Nodules or masses may be peripheral or central.
Peripheral nodules and masses are easier to detect due
to the more favorable signal to noise ratio when the
lesion is silhouetted by the air filled normal lung tis-
sue. In this location detected cancers are more com-
monly adenocarcinomas.
On radiographs the nodule may display a range of
features including ill defined/spiculated margins or a
thick-walled cavity. Squamous cancers more fre-
quently are found centrally and often present as cav-
itating lesions. Eccentric or stippled calcification may
be present, and this presentation is more common
with adenocarcinomas. All other forms of calcifica-
tion are considered benign.
Bronchioloalveolar cell carcinoma—mucinous
form can present with segmental or lobar opacity
like pneumonia. They can also present as single or
multiple pulmonary nodules.
Central lesions can present as hilar masses, which
adds to the opacity at the hilum. These cancers may
result in compromise of airflow and therefore are
often associated with non-resolving pneumonias,
consolidations or persistent atelectasis. These pro-
cesses are often in a lobar or segmental distribution.
In addition the functional consequence of a large
central lesion is the finding of bronchial cut off on the
radiographs. This results in either complete atelectasis or
partial obstruction. These changes may result in a
hyperlucent lung ipsilaterally. Central lesions are more
common with small-cell and squamous cell carcinomas.
In regionally advanced cancer associated with
mediastinal invasion and mediastinal lymph node
involvement a variety of findings including a widened
mediastinum, thickened right paratracheal stripe, loss
of concavity of the aortopulmonary window, con-
vexity of the mediastinum and splaying of the carina
have been described.
More advanced disease can present with rib/osse-
ous destruction in association with peripheral tumors,
pleural effusions or thickening. Linear opacities
radiating from the mass to the periphery or diffuse
interstitial thickening can be seen with lymphangitic
carcinomatosis. Metastatic osseous involvement may
also be visible on the radiograph.
Multiple studies have shown a poor detection rate
for early lung cancer on chest radiographs even in
65
screening studies. The Mayo Chest Radiography
Lung Cancer Screening Project (Muhm et al. 1983)
showed that 45 of the 50 peripheral lung cancers were
initially missed, and 12 of the 16 central cancers were
visualized in retrospect but were overlooked initially.
These results reflect the challenge of visualizing early
lung cancer given the limited capabilities of chest
x-ray detection. Another study by Heelan et al. found
that 65% of cancers were missed on the initial chest
radiograph (Heelan et al. 1989). More recently the
preliminary result from the NLST screening trial
also found a statistically significant difference in the
sensitivity of CT scans to detect lung cancers in
comparison to chest radiographs (National Cancer
Institute 2010).
In contrast to the disappointing chest-x-ray
screening studies, a recent report has suggested that
the true lung cancer mortality reduction from spiral
based screening to be over 30% and possibly as high
as 60% based on computer modeling or other com-
parative approaches (Henschke et al. 2010). Given the
legacy of lung cancer screening, research into defin-
ing the optimal approach to deliver effective lung
cancer screening services is essential in allowing cost
effective and robust lung cancer screening, to be
implemented and allow sustained lung cancer mor-
tality reduction.
3.1.2 CT Scans
As with chest radiographs when evaluating for early
lung cancer many new cancers are now found to be
located in the periphery of the lung. It has been pro-
posed that this location is the result of small particle
size of tobacco consumption products that are being
emitted from the end of filtered cigarettes. However
this air-filled space is a particularly favorable location
for x-ray-based imaging.
The widespread availability, faster speed, better
contrast, increased specificity and the exquisite sen-
sitivity of CT scanners make them the primary
modality for the initial evaluation of solitary pul-
monary nodules, mediastinal or hilar masses.
Sometimes lung cancers are detected on the inci-
dental lung images of CT scans of contiguous body
parts or CT done to evaluate other non-specific
abnormalities seen initially on radiographs.
Low-dose CT screening has attracted considerable
recent attention in the wake of the recent release of
the preliminary findings of the National Lung Cancer
66
Screening trial (NLST). The NCI released to the press
that their researchers had found, in interim analyses,
20.3% fewer lung cancer deaths among those who
were screened with low-dose helical CT compared
with those who were screened with chest x-rays.
This was the magnitude of benefit that was the
basis of the trial design of the NSLT since it was
thought that reducing lung cancer mortality by 20%
was consistent with the threshold for a significant
screening benefit.
It is important to emphasize that the data derived
from the NLST was obtained from a very specific
population group—individuals at high risk for
developing lung cancer due to present or past heavy
smoking, aged 55–74, and the observed mortality
benefit may not necessarily apply to the general
population (The National Lung Screening Trial 2010).
As we await more definitive release of the full results
from the trial many are hopeful that we are looking at
a shift in paradigm in the struggle to detect the cancer
early and subsequent decrease in lung cancer-related
mortality.
3.1.2.1 Peripheral Tumors
Solitary pulmonary solid nodules and imaging features
of lung cancer:
Characterization of solitary pulmonary nodules is
enhanced by CT scans. Non-contrast CT is usually
adequate. Some reports have suggested that the use of
contrast may enhance nodule detection and can help
in increasing specificity for lung cancers. This
approach incurs considerable increase in cost, the
potential of renal failure related to the osmotic load of
the contrast agent. Also due to recent advances the
proposed benefit of this approach has been superseded
by PET-CT.
Lung cancer nodule detection is complicated by
the occurrence of a large number of pulmonary nod-
ules that can be frequently found in the lung of
smokers. An approach to permit the differentiation of
nodules that are benign from those having malignant
potential is to measure the growth of this nodules
across a time interval.
The classical criteria for malignancy in a solitary
pulmonary nodule at baseline CT is size greater than
3 cm (90%). A recent study used increase in volume
of 25% or more measured using non proprietary
software extrapolated to calculate estimated volume
doubling time, as a measure to allow for greater
P. Shah and J. L. Mulshine
differentiation between benign and malignant nod-
ules. Nodules with volume doubling time of less than
400 days were viewed as suspicious and further
evaluated for malignancy. This study stated detection
sensitivity of 95% and a specificity of 99% for
nodules with volumes between 50 and 500 mm3
(van Klaveren et al. 2009).
Margin evaluation also helps in increasing the spec-
ificity for detection of lung cancer. A lobulated margin
indicates uneven growth and is a finding that increases
the potential for lung cancer (Libby et al. 2004).
Spiculated margins in adenocarcinomas are known
to confer a worse prognosis in comparison to lobu-
lated margins (Aoki et al. 2001).
The presence of ‘‘corona radiata’’, multiple strands
extending from the tumor, indicating tumor extension
or fibrotic response is best seen on CT (Klein and
Braff 2008a, b). Pleural tail and tethering are addi-
tional features highly concerning for tumor.
Calcification may be present in 6–10% of
bronchogenic carcinomas on CT (Zerhouni et al.
1986). Both small and non-small-cell carcinomas can
show calcification, which is typically amorphous,
stippled or cloud like. Eccentric calcifications are also
identified in lung cancers and usually represent
granulomas engulfed by the carcinoma.
Other features like convergence of vessels, inva-
sion of pulmonary vasculature, internal necrosis,
cavitation (usually squamous cell cancers) with thick
shaggy walls ([15 mm) all contribute to increasing
suspicion for malignancy and are more reliably
assessed on CT scans.
Groundglass density/nonsolid/part solid nodules:
Screening CT data has revealed that a high number of
malignant nodules can have ground glass density
(Henschke et al. 2002). These tend to be adenocar-
cinomas with bronchioloalveolar cell component or
bronchioloalveolar carcinomas.
These nodules may be purely groundglass in den-
sity (nonsolid nodules) or may have central solid
component, when they are termed, part solid nodules.
Studies have shown that for nodules less than 3 cm, if
the groundglass component is larger than 50%, there
was a lower incidence of vessel invasion and regional
lymph node spread (Aoki et al. 2001). These patients
also had a statistically significant better prognosis
than patients with nodules with a greater than 50%
solid component (Aoki et al. 2000).
Radiologic Imaging of Lung Cancer
Fig. 1 a,b,c Three different patients showing a Spiculated
nodule b Lobulated nodule c Groundglass/non solid nodule
Of particular note is that these tumors may show
no or low metabolic activity on PET imaging and
should be viewed with suspicion in spite of the PET
appearance.
Resection is usually recommended in a high-risk
patient (Klein and Braff 2008a, b).
Air bronchograms and cystic/bubbly lucencies
within the nodule are more frequently associated with
adenocarcinomas with bronchioloalveolar cell com-
ponent and bronchioloalveolar carcinomas (Kuriyama
et al. 1991; Zwirewich et al. 1991 (Fig. 1).
Rate of growth of nodules is important to assess for
establishment of stability, which would indicate a
benign process. The absence of growth of a nodule
over a period of 2 years is generally an indicator of a
benign process. Calculated as nodule doubling time
we do know that benign processes have doubling time
of less than 30 days or more than 450 days (Gorlova
et al. 2005).
Although once considered reliable we now know
that some of the ground glass nodules can grow at a
much slower rate and these require long-term follow-
up (Yankelevitz et al. 1997).
Many computer aided detection (CAD) systems
are available for improving detection of nodules on
chest radiographs and CT scans, which serve as sec-
ond readers and help in enhancing the detection
accuracy by the radiologist, who still remains the
primary reader. Newer systems for segmentation and
volumetric analysis of nodule size, increase accuracy
and reliability for assessing subtle nodule/mass
dimension changes to better evaluate response to
therapy (Revel et al. 2004). Awat et al. demonstrated
a statistically significant improvement in performance
for lung nodule detection of all study participants
67
using the CAD system (P \ 0.1), with a true positive
rate of 94% (Awai et al. 2004).
More importance is expected in the future although
as of now visual assessment and identification of
growth by cross-sectional diameter remains the
mainstay for assessment for change (Padhani and
Ollivier 2001).
3.1.2.2 Central Tumors
Most unilateral mediastinal masses are lung cancers
in adults. Use of IV (intravenous) iodinated contrast is
preferred in the evaluation of central lesions, for
detecting vascular invasion and evaluating mediasti-
nal involvement.
Small and squamous cell carcinomas occur more
frequently in the central location and because of their
proximity to the central airways and vessels can cause
postobstructive atelectasis and consolidations/pneu-
monias associated with hilar enlargement.
Contrast-enhanced CT scan (CECT) may be useful
in evaluation of these tumors as the contrast helps in
delineating the tumor from surrounding atelectatic
changes. The tumor usually enhances less than the
surrounding atelectasis. This is helpful in planning
radiotherapy and estimating tumor volume. The ben-
efits of using contrast in thoracic imaging should be
evaluated relative to the issues of increased cost and
the potential of iodine-related side effects as well as
the potential for renal complications especially in the
setting of an elderly patient with underlying renal
compromise.
Additional findings of alteration of shape of lobar
consolidation or atelectasis secondary to tumor bulk,
like bulging of fissures may indicate underlying
neoplasm.
Findings of airway narrowing, displacement or
obstruction would also suggest an underlying mass.
A central mass may be visible. Persistent consolida-
tion for greater 2 weeks may also be suggestive of the
presence of neoplastic disease (Fig. 2).
Endobronchial tumors may present as nondepen-
dant masses in the airway when small, or may be
associated with distal mucus plugging or segmental/
lobar atelectasis when occlusive.
Finally CT has a growing role in guiding needle
and core biopsies from suspicious lesions, for tissue
sampling, to establish the diagnosis of cancer or in
allowing research studies with regard to selecting
personalized molecular therapies.
68
Fig. 2 CECT showing left upper lobe central tumor as
hypodense area as compared to surrounding consolidation
3.1.3 PET-CT
The utility of evaluation of solitary pulmonary nodules
by PET-CT is well-established secondary to its high
negative predictive value for lesions that are benign,
making it invaluable. This has been detailed elsewhere.
The relative value of PET-CT compared to nodule
growth rate determined by volumetric CT is an impor-
tant area for further comparative effectiveness research.
3.1.4 MRI
Long scanning times, respiratory and cardiac motion
artifact and limited sensitivity to detect calcifications
and endobronchial tumors renders MRI less useful in
evaluation for and of lung cancer as compared to CT.
It may have a role in evaluation of patients with
central tumors with surrounding atelectasis and con-
solidation in whom iodinated contrast is contraindi-
cated. The tumor shows different signal intensities on
T2 weighted images and postgadolinium-enhanced
T1 weighted images as compared to the surrounding
parenchymal changes (Erasmus and Sabloff 2008).
MRI however plays a critical role in evaluation
and staging of Pancoast tumors secondary to its
ability to determine vertebral body, spinal and bra-
chial plexus invasion better.
3.2 Staging
As with most cancers survival and prognosis in lung
cancer depends on the cell type of the cancer and the
stage at which it is detected. The staging system has
P. Shah and J. L. Mulshine
been established to reflect management options and
survival.
Refinements in the TNM classification of lung
cancers were released in the 7th edition of American
joint committee on cancer in 2010 based on a com-
prehensive reevaluation effort and were revised to
more accurately reflect survival in the different dis-
ease stages.
Lung carcinomas are still divided into small and
non-small-cell carcinomas for the marked differences
in natural history and response to therapy. Note
should be made that non-small-cell cancers, small-
cell cancers and carcinoids now have the same TNM
staging systems (AJCC 2010).
For the sake of radiotherapy planning small-cell
carcinomas are classified into limited and extensive
disease. Limited disease is confined to the same
hemithorax but also includes involvement of the
contralateral mediastinal and supraclavicular lymph
nodes (Simon and Turrisi 2007). Imaging plays an
extended role in identifying extensive disease.
3.2.1 Chest Radiographs
There is a limited role these play in staging lung
cancers due to their poor sensitivity in detecting
advanced disease. Mediastinal invasion is poorly
detected but may be suggested by an elevated dia-
phragm, which would indicate phrenic nerve
involvement. An advanced stage may be suggested by
the size of the tumor by osseous destruction or
mediastinal widening on the initial evaluation.
3.2.2 CT Scans
The newer and faster spiral contrast-enhanced multi-
slice computed tomography (CECT) offers exquisite
anatomic detail, and is the ideal choice to assess size
of the tumor and its relationship to the surrounding
anatomical structures like the fissures and to the
pleura and chest wall. Issues around quality control
and measures to improve lung quantitation have been
extensively discussed with the work of the Quantita-
tive Imaging Biomarker Alliance.
CT scans also play a big role in disease quantifi-
cation and helps in the initial radiological staging of
the tumor. Usually they are performed prior to bron-
choscopy as detection of extensive disease may pre-
clude the need for the same. They are also helpful in
determining therapy options and help in treatment
planning.
Radiologic Imaging of Lung Cancer
Accurate staging of the tumor is essential as ther-
apeutic options depends on stage of the disease, in
addition to the cell type and the clinical and func-
tional status of the patient.
In the appropriate clinical context surgically
resectable tumor is usually stage III A or lower for
non-small-cell cancers. Adjuvant radiation and che-
motherapy are offered to certain stage IIA and III A
disease and surgical options may be offered in IIIB
disease if preoperative therapy downstages the tumor.
All non-surgical candidates are offered various com-
binations of radiotherapy and chemotherapy depend-
ing on the nature of the cancer presentation.
Small-cell cancer comprises about 15% of lung
cancer, and is a neuroendocrine cancer, that is only
treated surgically in the uncommon situation when it
presents as an isolated nodule. Chemotherapy with
radiotherapy is the mainstay of regionally confined
presentations but disseminated disease is generally
treated initially with chemotherapy only.
Chest CT for suspected lung carcinoma should be
extended inferiorly to include the adrenal glands
secondary to the propensity of adrenal metastatic
disease. The debate between a contrast versus non-
contrast study continues. For visualization of enlarged
hilar lymph node and 2R (high paratracheal) lymph
node, a contrast study is more sensitive (Patz et al.
1999). A single study found no differences in detec-
tion of liver or adrenal metastases with or without
contrast (Cascade et al. 1998).
Key factors in evaluation for staging would include
staging the primary tumor (T category), intrathoracic
lymph node (N category) detection, distant pulmonary
spread and extrathoracic spread (M category).
Primary tumor size and local and endobronchial
spread determines the T category and primary tumor
size is highly co-related with eventual clinical
outcome.
There are new subdivisions in the T1 and T2
stages, which are determined by size. Tumor less than
3 cm is T1 lesions while those between 3 and 7 cm
are now categorized under the T2 category (UyBico
et al. 2010).
Additional detection of visceral pleura invasion
may be suggested by puckering although more accu-
rate determination is made by pathology. Central
tumors with associated atelectasis and obstructive
pneumonitis extending to the hilar region but not
involving the entire lung are considered T2 tumors.
69
CECT or MRI may be necessary to accurately eval-
uate this as the primary lesion will enhance less than
the surrounding atelectasis and the collapsed lung
may show hypodense mucus filled bronchi (UyBico
et al. 2010).
Endobronchial lesions more than 2 cm distal to the
carina also belongs in this category. These findings
are easily assessed on CT with the help of mutiplanar
reformatting.
Detection of a satellite nodule in the same lobe as
the primary tumor and size greater than 7 cm would
now shift the tumor to a T3 category. Endobronchial
lesions less than 2 cm distal to the carina but not
involving the carina; tumors with local invasion of the
chest wall, diaphragm, mediastinal pleura and parietal
pericardium; superior sulcus tumors; and tumors with
atelectasis and obstructive pneumonitis affecting the
entire lung are still considered stage T3 neoplasms
(UyBico et al. 2010).
Chest wall invasion may be suggested by rib ero-
sions, vertebral destruction and focal chest wall mass.
Detection of this alters the surgical technique. Some
of the other CT signs described to suggest parietal
pleura and chest wall invasion are obtuse angle
between tumor and pleura, loss of the extrapleural fat
plane, pleural thickening and extrapleural soft tissue.
Localised chest pain however still is the most specific
indicator of chest wall invasion (Akata et al. 2008).
CT and MRI are approximately equally sensitive and
specific for the same varying from 63 to 90% and 83
to 86%.
The distinction between T3 and T4 lesions is
crucial as this draws the line between surgical versus
non-surgical therapy (Fig. 3).
Separate tumor nodules in the same lung but not in
the same lobe as the primary lesion, which were
previously considered metastatic (M1) but due to
more favorable clinical behavior are now classified as
T4 disease. T4 tumors may also invade the heart,
great vessels, trachea, carina, esophagus or vertebral
body (UyBico et al. 2010).
Both CT and MRI, with multi-detector CECT
being superior in most instances, detect mediastinal
invasion. Clear encasement of vital structures like
trachea, esophagus, great vessels, etc. is evidence of
T4 disease and mediastinal invasion.
Mere contact is not enough to suggest invasion and
circumferential contact of less than 90 degrees or
preservation of mediastinal fat planes\3 cm or tumor
70
Fig. 3 CECT showing bilateral enlarged mediastinal lymph
nodes indicating at least N3 disease in NSLC. Subtle bony
metastases in the vertebral body and small bilateral pleural
effusions
and pleura contact \3 cm are reliable indicators of
non-invasion, but one should always be careful to
exclude a patient from surgery based on CT criteria
alone (Bittner and Felix 1998; Hierholzer et al. 2000).
In addition, the presence of a malignant pleural
effusion, pleural dissemination or pericardial disease
now constitutes metastatic disease (M1a) and is no
longer in the T category (UyBico et al. 2010). These
may be seen as complex pleural and pericardial
effusions measuring more than fluid density on CT or
may demonstrate the presence of internal-enhancing
nodules or plaques.
The presence of localized interlobular thickening
which may be smooth or nodular with thickening of the
peribronchovascular interstitium usually starting
around the tumor could indicate lymphangitic carci-
nomatosis, easily seen on CT scans even in early stages.
Contralateral pulmonary nodules also constitute
M1a disease and are detected on the lung windows of
the regular CT scan (UyBico et al. 2010).
Intrathoracic lymph node staging determines the
nodal category (N) of the disease and is an important
predictor of outcome. Surgery is not considered in N3
disease, which is constituted by contralateral lymph
node enlargement and all significantly large lymph
nodes in the ipsilateral or contralateral supraclavicular
or scalene stations.
The position of the mediastinal and hilar lymph
nodes is described according to the new map and
P. Shah and J. L. Mulshine
divisions provided by The IASLC Lung Cancer
Staging Project (Rusch et al. 2009).
Enlargement of a lymph node is the most validated
sign for metastatic involvement, however is not very
specific. A short axis dimension of 1 cm or greater is
a significant size and suspicious for metastatic dis-
ease, although the predictive accuracy of this criterion
is limited (Lau and Harpole 2000).
Additional changes including internal necrosis and
convexity of the lymph node and prescence of fatty
hilum are useful when present.
When using these criteria to determine lymph node
involvement the reported sensitivity and specificity of
CT is only about 50–65% (Arita et al. 1996; Primack
et al. 1994). The most accurate method of lymph node
staging still remains via surgery and mediastinal
lymph node dissection. However the importance in
detection of these lymph nodes via CT is vital to help
guide sites of lymph node biopsy.
It is known that normal sized FDG negative
mediastinal lymph nodes on CT and PET can have
malignant involvement in their mediastinal nodes.
The ACCP guidelines state that invasive preoperative
mediastinal staging should be performed in these
patients especially in the presence of central tumors
(Detterbeck et al. 2007).
M category of the disease, especially extrathoracic
disease may be assessed by dedicated CT of the abdo-
men or contiguous CT to include the entire liver. These
are usually adequate to evaluate the liver and adrenal
glands, constituting extrathoracic spread. One study
demonstrated no significant increase in detection of
liver or adrenal metastases with contrast as compared to
a non-contrast examination (Cascade et al. 1998),
however the debate to use or not to use routine iodin-
ated contrast for liver and adrenal metastases continues.
Imaging the upper abdomen should be done as a
routine in small-cell cancer secondary to the high
incidence of metastases at the time of initial diagnosis
(Ravenel et al. 2010).
Adrenal nodules greater than 3 cm in size over-
whelmingly are metastatic nodules. If the adrenal
nodule is indeterminate on the staging CT a dedicated
adrenal protocol contrast-enhanced CT or chemical
shift MRI can help further characterize this.
The same is true for liver metastases. Dedicated
triple phase CT of the liver or postcontrast liver MRI
can be used as adjunct imaging in confounding cases
(Ravenel et al. 2010).
Radiologic Imaging of Lung Cancer
Fig. 4 CECT showing left apical pancoast tumor with chest
wall invasion, rib and vertebral body destruction
Although postcontrast head CT can detect intra-
cranial metastases, MRI with contrast remains the
most sensitive examination.
Finally CT imaging is also used to guide in
radiofrequency ablation of tumors in patients who are
poor surgical candidates (Fig. 4).
3.2.3 Endoscopic Ultrasound
Newer techniques like endoscopic ultrasound can
evaluate lymph nodes in the vicinity of the esophagus,
trachea or main bronchi, and therefore improve the
accuracy of endoscopic mediastinal lymph node
sampling techniques. Endobronchial ultrasonography
(EBUS) can be performed to visualize and sample
lymph node stations 2R/2L, 4R/4L and 7, as well as
hilar stations. In short lymph node stations close to
the trachea and the main bronchi can be sampled via
this technique. The lymph node stations sampled are
the same as those sampled by cervical mediastinos-
copy (Vansteenkiste et al. 2010).
Esophageal ultrasonography (EUS) helps in visu-
alization and sampling of the lymph node stations 4L,
and levels 7, 8 and 9. This is complementary to the
other techniques, like endobronchial ultrasound and
mediastinoscopy as lymph nodes at levels 8 and 9
are not accessible by EBUS or mediastinoscopy
(Vansteenkiste et al. 2010).
Published meta-analyses on EUS and EBUS gui-
ded tissue diagnosis, reported a pooled sensitivity of
90% and 94%, respectively, for CT-enlarged or PET-
positive mediastinal lymph nodes with a prevalence
of malignant N2/3 disease of 68% (Gu et al. 2009).
71
3.2.4 MRI
The utility of MRI is limited in the evaluation of the
primary tumor except for imaging in Pancoast or
apical tumors. Here mutiplanar MRI with contrast
would be the imaging modality of choice given the
increased sensitivity in detecting spread to the bra-
chial plexus especially above T1, subclavian vessel
involvement and greater than 50% vertebral body
involvement all of which may make the tumor
inoperable.
Central tumors, which cannot be evaluated by CT
with iodinated contrast, could potentially be imaged
with MRI.
Chest wall invasion is equally well assessed by CT
and MRI as detailed above.
Extrathoracic spread to the brain and spine are
better assessed with postcontrast MRI as compared to
CT. Sensitivity of MRI is significantly higher here.
Routine staging MRI of the brain with contrast should
be considered in small-cell cancers secondary to the
high frequency of intracranial metastases (Ravenel
et al. 2010).
Chemical shift imaging for adrenal nodules or
masses can be considered when CT is indeterminate.
Liver MRI could be utilized as a problem-solving tool
for indeterminate or discordant CT and PET-CT
findings (Ravenel et al. 2010).
3.2.5 Bone Scans
The utilization of bone scans for staging is progres-
sively declining with the increased availability of
PET-CT, which has higher sensitivity and specificity
in evaluation of osseous metastases (Marom et al.
1999). If a PET-CT is not available or is not being
considered a bone scan should be performed as part of
the initial staging work up, especially in small-cell
cancer.
New onset bony pain, hypercalcemia, raised alka-
line phosphatase or pathologic fractures are usually
assessed by a bone scan during the course of the
disease.
Radiographs, CT scan or MRI of the affected
region usually follows a positive bone scan.
3.2.6 V/Q (Ventilation and Perfusion) Scans
Preoperative V/Q scan help quantify individual lung
function to help in determining if the patient is a
surgical candidate, and also in planning extent and
type of surgery to ensure that the patient can survive
72
with the residual postoperative lung function. Venti-
lation and perfusion fractions between the two lungs
are estimated.
3.2.7 PET-CT
This youngest modality in the available technology
for lung cancer imaging has emerged as the front-
runner for more accurate radiologic staging in bulky
primary lung cancer. This imaging tool can be fre-
quently used as one stop shopping for complete
evaluation of the tumor and the extent of disease. A
statistically significant percentage of patients maybe
upstaged or downstaged by the PET-CT scan.
3.3 PostTherapy Imaging
Postradiation therapy imaging with CECT is subop-
timal to evaluate response to therapy in most cases
secondary to the surrounding changes which can
simulate both radiation-induced fibrosis or spread of
tumor. Some of the secondary signs, which may
indicate tumor response, are the actual diminished
size of tumor or internal necrosis posttreatment.
Tumor recurrence within radiation-induced fibrosis is
particularly difficult to detect by CT in the early
stages and PET-CT maybe a more sensitive exami-
nation for the same.
Response to chemotherapy is easier to evaluate
with objective decrease in tumor volume and absence
of progressive or new parenchymal and mediastinal
disease.
Size estimation can be done using unidimensional
RECIST criteria or bidimensional WHO criteria.
Recent work has suggested that quantitative image
processing of serial CT scans acquired before and after
therapy administration may be a useful approach.
Complications which can occur secondary to
therapy are better imaged with CT especially che-
motherapy induced parenchymal toxicity.
Very few reports in the literature exist on imaging
for local recurrence. There is no good evidence-based
data to support routine surveillance imaging (Walsh
et al. 1995) after therapy for local or distant recurrent
disease. However it is the accepted norm at most
centers and may have more relevance as more tailored
surgical approaches become more common. Follow-
up imaging after therapy, which may or may not
include chemotherapy, radiation therapy and surgery,
P. Shah and J. L. Mulshine
is generally routine but the frequency of such studies
is not rigorously validated.
CT is also used to detect second primary lesions in
these patients. Second metachronous primary tumor
risk is estimated to occur in 1–2% patients per year
(Johnson 1998).
4 Conclusions
CT scan is the time-tested modality playing a key role
in all aspects of the disease from screening, detection
to staging and treatment monitoring. Multiple other
modalities and disciplines play complementary roles
in accurate preoperative and pretherapy staging of the
tumor helping to formulate the best management plan
for the patient.
It should be emphasized that no patient should be
denied definitive treatment based on indeterminate
imaging findings and when in doubt the answer would
be to obtain histologic confirmation.
5 Future
Low-dose chest CT screening for lung cancer in the
aim of reducing mortality may soon become an
accepted form of screening. Newer CT image acqui-
sition techniques have been developed to facilitate
4-D imaging (time being the 4th dimension), and to
decrease radiation dose using methods like iterative
reconstruction (Sieren et al. 2010).
Dual energy CT scans are also being touted as
improving detection and characterizing the lung
lesions without significant change in radiation dose.
Newer nodule detection software and rapidly
advancing software algorithms for segmentation and
3-D volumetric evaluation of nodules and masses will
further refine detection and treatment monitoring.
Dynamic and diffusion-weighted (DWI) MRI are
in development and evaluation to improve specificity
in differentiating benign versus malignant nodules
(Sieren et al. 2010).
As we further explore these new horizons, deter-
mine their clinical utility, aiming to develop safer and
more accurate form of imaging, one also hopes to see
progress in targeted imaging to complement the rap-
idly advancing tailored therapy, while we slowly
unlock the secrets of lung cancer development.
Radiologic Imaging of Lung Cancer
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 PET/CT for Staging and Diagnosis
of Lung Cancer
Sigrid Stroobants

Contents
1 Basic Principles and Technical Improvement .....
1.1 Tracers........................................................................
1.2 Conventional Versus Time-of-Flight (TOF)-PET ....
1.3 Technical Advances in Hybrid Systems...................
2 Diagnosis of Solitary Pulmonary Nodules ............
2.1 Strategies to Reduce the Number
of False Positives.......................................................
2.2 Strategies to Reduce the Number
of False Negatives .....................................................
3 Staging of Non-Small Cell Lung Cancer ..............
3.1 T-Staging....................................................................
3.2 N-Staging ...................................................................
3.3 M-Staging ..................................................................
4 Small-Cell Lung Cancer .........................................
5 Implementation in Clinical Practice .....................
References..........................................................................
Abstract
Positron emission tomography (PET) is an imaging
75 technique, which allows for accurate non-invasive
76 measurements of metabolic pathways in tissues of
76
76
man in vivo. The most frequently used tracer in
PET oncology is the glucose analog 18F-fluoro-2-
79
deoxy-glucose (FDG). The preferential accumulation
79 of FDG in neoplastic cells permits differentiation
between benign and malignant tissue. The ability to
80 perform whole-body imaging within one examina-
80 tion without increasing the radiation burden makes it
80 an ideal technique to ‘‘screen’’ patients for cancer
81 deposits. Also in thoracic oncology, FDG-PET has
81
proven its superiority over other imaging techniques
83 in staging nodal and metastatic disease. However, the
85 poor anatomic detail of PET can lead to errors in
86
diagnosis and staging. Through the integration of
computer tomography (CT) and PET into one
machine, form and function are merged to create a
better imaging tool. In this chapter, we will highlight
the recent developments in hybrid machinery
(time-of-flight PET, PET-MR) and review the role
of integrated PET/CT in the diagnosis and staging of
lung cancer.

1 Basic Principles and Technical

Improvement

Positron emission tomography (PET) is a functional

S. Stroobants (&)
imaging modality which uses small amounts of phar-
Department of Nuclear Medicine,
University Hospital Antwerp, maceuticals labeled with positron-emitting radioiso-
Wilrijkstraat 10, 2650 Edegem, Belgium topes for metabolic imaging. Because of their similarity
e-mail: sigrid.stroobants@uza.be

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 75
DOI: 10.1007/174_2011_323, Ó Springer-Verlag Berlin Heidelberg 2011
76 S. Stroobants

to naturally occurring atoms in the human body, unstable. They decay by emission of a positron, which is
positron emittors as carbon-11 (11C), nitrogen-13 (13N), the subatomic, positively charged, antiparticle of the
and fluor-18 (18F) can be incorporated in biological negatively charged electron. A positron transverses a
molecules, without significantly influencing their short distance through the tissue (0.6 mm for 18F) until it
physiological and biochemical interactions. This allows combines with an electron in the surrounding media
in vivo imaging of metabolic pathways and receptor– (annihilation). This generates a pair of photons which
ligand interactions at pico-to-nanomolar sensitivities. travel in nearly opposite directions (180° apart) with an
energy of 511 keV each. These opposite photons can be
detected by detector pairs installed in a ring-shaped
1.1 Tracers
pattern in the PET camera. Photons that simultaneously
interact with these detectors are registered as decay
Although, there are numerous PET tracers described
events along a line-of-response (LOR). Based on these
in the literature, evidence of PET in oncology mainly
records, tomographic images of the regional radioac-
rests upon the glucose analog 18F-fluoro-deoxyglu-
tivity distribution are reconstructed (emission images).
cose (FDG), capitalizing that cancer has higher glu-
In conventional PET, the actual location where the
cose metabolism than most tissues (Pauwels et al.
annihilation occurred along the LOR is not measured,
1998). Since PET relies on the detection of metabolic
which inherently generates blurring in the reconstructed
alterations observed in cancer cells, this examination
image. The availability of faster detectors and electron-
yields data independently of associated structural
ics allows to measure the time difference between
characteristics. However, since FDG accumulation is
detection of each photon pair. In TOF-PET this addi-
not tumor specific but can also be present in inflam-
tional timing information is used to better localize the
mation, clinically relevant positive findings often
event within a small range along each LOR. The better
require confirmation.
localization of each event using TOF combined with
While FDG has made the way for PET in oncol-
more powerful reconstruction algorithms improves the
ogy, clinical practice with other tracers is limited. In
image quality especially in larger patients (Kadrmas
order to reduce tracer uptake in inflammatory tissue,
et al. 2009) (Fig. 1) . This leads to better lesion detection
more cancer-specific tracers were developed. The
and results in faster acquisition times which makes a
most promising one is probably 18F-fluoro-thymidine
typically whole-body PET/CT feasible in 10–15 min.
(FLT), a marker of cell proliferation with no or less
intense uptake in inflammatory tissue (Shields et al.
1998; Yap et al. 2006). In the study of Yang et al.
1.3 Technical Advances in Hybrid
(2010), FLT and FDG-PET were compared for pri-
Systems
mary staging of non-small cell lung cancer (NSCLC)
in 31 patients. FDG proved to be more sensitive for
Interpretation of PET scans is hampered by the lack of
detection of the primary tumor compared to FLT (94
anatomical detail which makes it sometimes difficult
vs. 74%) due to more intense trapping of the tracer
to correctly localize hot spots or differentiate tumor
(mean FDG-SUV = 7.7 vs. mean FLT-SUV = 4.2,
tissue from benign structures with physiological high-
p = 0.002). For nodal staging, FLT proved to be
FDG uptake as seen in muscle, brown fat, gut or
more specific (98 vs. 84%) but less sensitive (65 vs.
inflammation. These challenges are largely resolved
85%). Therefore, the role of FLT-PET for staging will
by the introduction of the combined PET/CT scanner.
be limited. More promising is its use for treatment
Current designs comprise a CT scanner in tandem
response evaluation, especially after targeted therapy.
with a PET scanner with a common patient bed for
both systems. Although the scanner appears exter-
1.2 Conventional Versus Time-of-Flight nally as a single device, internally there is little or no
(TOF)-PET mechanical integration. CT and PET images are
acquired consecutively for the same axial extent with
The biodistribution of the positron-emitting tracers is a simple horizontal translation of the bed. Upon
measured using a PET camera. Positron-emitting iso- completion of the scans, CT and PET images are
topes have an excess of protons and are, therefore, co-registered with fusion software and can be viewed
PET/CT for Staging and Diagnosis of Lung Cancer
Fig. 1 Principle of Time-of-Flight (TOF)–PET (a) which also
integrate the time difference by witch photon pairs are detected
in the reconstruction algorithm, resulting in less noisy images
either separately with linked cursors or superimposed
with a selectable blending of the two modalities.
An additional advantage of PET/CT is the marked
reduction in scan time (-50%) compared to
PET-alone scanners since the CT images can also
be used to generate attenuation correction factors to
be applied to the PET data to generate quantitative
images. CT-based attenuation correction can however
introduce specific artefacts due to patient motion or
dense objects which then propagate into the PET
images (Mawlawi et al. 2006) (Fig. 2). Therefore,
non-attenuation-corrected PET images should also be
reviewed to recognize these artefacts.
Since the installation of the first clinical PET/CT in
2001, the technology has gained widespread use and
all new PET scanners installed today are integrated
PET/CTs. The initial hybrid systems often contained
only a single- or dual-slice CT scanner resulting in
inferior image quality of CT compared to stand-alone
systems. Therefore, initial literature data mostly
included low-dose CT protocols without contrast
enhancement. Modern scanners are however equipped
with the latest generation 16–128 slice-MDCT,
therefore enabling the use of a true diagnostic CT as
part of PET/CT. In this setting, often a multi-step
77
compared to conventional PET. Example of the same patient
scanned twice with an interval of 3 months with conventional
PET (b) and TOF-PET (c)
PET/CT protocol is used starting with a low-dose
non-enhanced CT (for attenuation correction of PET
data) followed by PET and than complemented
with an appropriate contrast-enhanced CT protocol
(De Wever et al. 2009). This could be of particular
importance when PET/CT is used for radiotherapy
planning in patients with centrally located NSCLCs
given the complex anatomical setting (Pfannenberg
et al. 2007) (Fig. 3).
The success of PET/CT in clinical practice and the
advantages of MRI compared to CT with respect to
radiation exposure and tissue characterization
have stimulated interest in the development of hybrid
PET/MR imaging systems (Schlemmer et al. 2009).
The first strategy was to develop a sequential system:
a whole-body MR scanner and a PET scanner within
the same or adjacent room operated by a single
acquisition console and with a table that shuttles
between the two systems. The advantage is that both
machines can still be used separately, but potential
misalignment due to patient motion is higher. The
design of a fully integrated system is more challeng-
ing since conventional PET detectors are based on
relatively bulky photomultipliers (PMTs). PMTs are
very sensitive even to weak-magnetic fields and are
78 S. Stroobants

Fig. 2 Patient with extensive disease SCLC with multiple misalignment between PET and CT. Therefore, when no
liver and bone metastasis on PET (a, b). A liver metastasis in anatomical correlate is seen on CT (d), adjacent slices should
the liver dome is erroneously regarded as a lung metastasis of also be viewed to localize the lesion (e)
fusion images (c) due to a breathing artifact resulting in

Fig. 3 Patient with a NSCLC of the left hilum invading the mediastinum and with retro-obstructive atelectasis (c). The relation
of the tumor with the mediastinal structures is much better visualized on a contrast-enhanced CT (a) compared to low dose CT (b)

therefore not suitable to be used in a combined MR/ within an MRI scanner. Therefore alternative, new
PET scanner. In addition, its size would steal too semiconductor-based light detectors, such as ava-
much space from the open magnet bore if integrated lanche photodiodes (APDs) are replacing PMTs in
PET/CT for Staging and Diagnosis of Lung Cancer
integrated MR/PET. In spring 2011, the first inte-
grated whole-body PET/MR was installed in Munich.
Workflows still need to be optimized (in contrast to
PET/CT, MR is now the most time-consuming part)
and indications which truly benefit from integrated
PET/MR need to be defined. Given the high-equip-
ment costs and lower-throughput capabilities com-
pared to PET/CT, widespread use of PET/MR in the
near future is unlikely (Hicks and Lau 2009).
2 Diagnosis of Solitary Pulmonary
Nodules
Solitary pulmonary nodules (SPNs) represent a
diagnostic challenge and with the increased use of
low-dose spiral CT for lung cancer screening, the
number of coincidental SPNs will only increase (Tan
et al. 2003). The differential diagnosis of an SPN also
includes inflammatory and infectious diseases and
vascular, traumatic or congenital lesions besides can-
cer. In most cases an histopathological proof is aimed
for but this can be challenging in peripheral nodules.
Moreover, in certain patients, who are at increased risk
during invasive procedures or with lower probability
for cancer, it may be desirable to further characterize a
pulmonary nodule by imaging, rather than proceeding
immediately to tissue diagnosis.
Before the PET era, CT was the principal imaging
modality to evaluate indeterminate nodules. Charac-
terization is based on the shape, borders, density and
contrast enhancement (Siegelman et al. 1986;
Swensen et al. 2000). Lesions are usually considered
benign if they show the following features: concentric
calcifications, round shape or a morphologic stability
over 2 years (Yankelevitz and Henschke 1997).
On the contrary, malignant features typically include
ill-defined margins, spiculation, cavitation, invasion
of bronchi or vessels and a doubling time of
\10 months (Gurney et al. 1993). CT has an excellent
sensitivity (96%, range 91–98%) for detection of SPN
but a poor specificity (50%, range 41–58%) (Swensen
et al. 2003). In the past years, FDG-PET has been
studied extensively for characterization of SPNs and
multiple studies have showed that for nodules [1 cm
PET had similar sensitivity but superior specificity as
compared to CT (Gould et al. 2001; Fischer et al.
2001; Ung et al. 2007). In the meta-analysis of Gould
et al. (2001) in 1,474 lesions, an overall sensitivity of
79
97% (range 83–100) and a specificity of 78% (range
52–100) was obtained.
2.1 Strategies to Reduce the Number
of False Positives
False positives occur due to trapping of FDG in
activated granulocytes and/or macrophages in several
inflammatory conditions. Specificity across the
different studies is extremely variable depending on
the prevalence of certain inflammatory or infectious
diseases. A nice pictorial overview of false-positive
findings is given in Shim et al. (2006a).
Several efforts have been made to improve the
specificity of PET. Since the uptake of FDG in benign
lesions tend to be lower compared to that in malignant
tissue, quantification of the FDG uptake was used to
improve the diagnostic accuracy. In the literature, a
SUV above 2.5 is often used to discriminate benign
from malignant nodules but without significant
increase in accuracy (meta-analysis, Gould et al.
2001). In fact, the use of a threshold value can
decrease the sensitivity in small lesions substantially
compared to the simple visual analysis because of
considerable underestimation of the true activity due
to partial volume effects, through which the SUV
measurement drops under the threshold, although the
lesion is clearly visible. In the study of Lowe et al.
(1994), the sensitivity for detecting malignant nodules
\1.5 cm decreased from 100% using visual analysis
to 80% using the threshold SUV value of 2.5.
Not only the amount of FDG uptake but also the
tracer kinetics are thought to be different in benign
and malignant tissue, with continuous uptake in
malignant lesions and a rapid uptake followed by a
fast and then gradual washout in benign masses.
Using dual time point imaging at 1 and 2 h after
tracer injection, an increase of at least 10% in SUV
between the first and the second scan proved to
be more accurate than a SUV threshold of 2.5
(Alkhawaldeh et al. 2008). Unfortunately, dual time
imaging does not increase specificity in granuloma-
tous diseases like sarcoidosis or tuberculosis
(Sathekge et al. 2010) since FDG uptake tends to
increase over time, similar to cancer.
Instead of a binary reading (positive or negative),
maybe it is more appropriate to report the PET result as
a probability of cancer. A large prospective series
80
(n = 585) looked at the accuracy of integrated PET/CT
scan in SPNs B2.5 cm (Bryant and Cerfolio 2006). If
the SUVmax was between 0 and 2.5 there was a 24%
chance of malignancy, if between 2.6 and 4.0 it was
80%, and if[4 it was 96%. It may however be neces-
sary to define the SUV ranges for given probabilities for
each institution individually because of differences in
the patient population and also because the magnitude
of calculated SUV for the same lesion can vary
depending on the PET system and method of attenua-
tion correction utilized (Boellaard 2009).
2.2 Strategies to Reduce the Number
of False Negatives
For detection on PET a critical mass of metabolically
active malignant cells is required. False-negative find-
ings therefore occur in tumors with low-metabolic
activity like carcinoid tumors (Belhocine et al. 2002) or
tumors with low-cell density like mucinous tumors
(Berger et al. 2000) or the alveolar subtype of bron-
choalveolar carcninoma (BAC) (Heyneman and Patz
2002). Nomori et al. (2004) evaluated the performance
of PET in 15 patients with ground glass opacities, a
typical CT pattern for non-invasive BAC. PET was
only positive in 1/10 malignant lesions and false posi-
tive in 4/5 benign lesions (focal pneumonia), resulting
in a sensitivity of 10% and a specificity of 20%.
The sensitivity of PET is also lower in sub-centi-
metric lesions. One study evaluated the performance of
PET in 136 uncalcified nodules \3 cm. All of the 20
lesions \1 cm were negative on PET, eight of who
were malignant (Nomori et al. 2004). Recently, three
studies have reported on the value of selected PET as a
second-step test in lung cancer screening. Pastorino
et al. (2003) applied PET on non-calcified nodules
C7 mm. FDG-PET was positive in 18/20 cancers. One
8 mm adenocarcinoma and one 11 mm predominantly
BAC were missed. In the study by Bastarrika et al.
(2005), PET was applied on nodules [10 mm or
growing nodules C7 mm, with a sensitivity and nega-
tive predictive value of 69 and 71%, respectively. By
including a 3-month follow-up CT after a negative
PET, the authors were able to increase sensitivity and
negative predictive value to 100%. Finally, patients
with indeterminate nodules included in the Danish
Lung Cancer Screening Trial referred for a 3-month
re-scan and PET were retrospectively analyzed
S. Stroobants
(Ashraf et al. 2011). Twenty of the 54 nodules proved to
be malignant (mean diameter 13 mm). In a multivari-
able analysis, both FDG uptake (equal to or greater than
the mediastinal blood pool) and volume doubling time
(VDT \ 1 year) were independently associated with
malignancy but the combination of both was better for
predicting lung cancer than either procedure alone. The
highest sensitivity (90%) was obtained when either
PET or VDT indicated malignancy.
3 Staging of Non-Small Cell Lung
Cancer
Staging of NSCLC is done according to the tumor (T),
node (N), metastasis (M) system.
Recently the classification was updated (7th edi-
tion) and introduces new dimension ranges for T and
a different interpretation of additional tumor nodules,
pericardial and pleural involvement, with consequent
variations in the definition of tumor stages (Goldstraw
et al. 2007; Goldstraw 2009). Currently all the liter-
ature data on impact of PET on TNM stage is based
on the previous classification (Mountain 1997).
3.1 T-Staging
The assessment of the primary tumor extension is
usually based on thoracic CT, occasionally comple-
mented by MRI. Due to the increased image quality of
MDCT, scanners can depict with greater confidence an
invasion of a tumor in surrounding tissues by assess-
ment of preserved mediastinal fat planes and can detect
more and smaller lesions (Verschakelen et al. 2004).
PET on itself does not add much to the assessment of
local resectability because its inferior spatial resolution
does not give more detail of the exact tumor extent or
infiltration of neighboring structures. In recent studies
using PET/CT, it was therefore not surprising that T
stage was more accurately assessed on PET/CT
compared to PET alone (Lardinois et al. 2003; Antoch
et al. 2003; Cerfolio et al. 2004; Shim et al. 2005; De
Wever et al. 2007a). In a minority of the patients, PET/
CT also proved to be superior to CT alone due to a
better discrimination between the tumor and sur-
rounding atelectasis or inflammation and to correct
exclusion of tumor involvement in co-existing lung
nodule(s) in the same lobe (De Wever et al. 2009).
PET/CT for Staging and Diagnosis of Lung Cancer
Some studies also describe an additional value of
PET for detection of pleural metastasis. In a larger
study in 92 patients with pleural effusion, of whom
71% were deemed indeterminate on CT, PET had a
sensitivity, specificity, and accuracy of 100, 71 and
80%, respectively (Schaffler et al. 2004). The speci-
ficity and positive predictive value (PPV) were lower
than described previously, due to the larger number of
benign pleural effusions. One study specifically
looked at the value of PET in dry pleural dissemina-
tion. Since this is often caused by multiple very small
pleural nodules beyond the resolution of a PET sys-
tem, the sensitivity was only 25% (Shim et al. 2006b).
3.2 N-Staging
The accuracy of CT for the prediction of intrathoracic
nodal spread of tumors remains limited and the more
recently developed CT systems do not change this
because nodal staging with CT is only based on size
criteria. The current consensus considers a node
\10 mm in short axis diameter suspect for metastatic
involvement, which results in sensitivity ranging from 52
to 69% and specificity 69 to 82% (Dillemans et al. 1994).
Over the past years, several studies have found that
FDG-PET has a significantly higher sensitivity and
specificity than CT for mediastinal staging and
this superiority has been confirmed in different
meta-analyses (Fischer et al. 2001; Gould et al. 2003;
Silvestri et al. 2007). In the most recent one of Silvestri
et al. data from 44 studies including 2,865 patients,
resulted in a pooled estimates of sensitivity and
specificity for identifying mediastinal metastasis of 74
(95% CI, 69–79%) and 85% (95% CI, 82–88%),
respectively. Corresponding positive and negative
likelihood ratios for mediastinal staging with PET
scanning were 4.9 and 0.3, respectively. These findings
demonstrate that PET scanning is more accurate than CT
scanning for staging of the mediastinum in patients with
lung cancer, though it is far from perfect.
The superiority of FDG-PET is explained by the more
frequent correct identification of ‘‘small malignant
nodes’’ and ‘‘large benign nodes’’. Errors are related to
incorrect localization, minimal tumor load (false nega-
tives) and inflammation on (false positives) (Fig. 4).
Due to the lack of anatomical information in the
PET image, reading of PET scan in the presence of
the CT images is crucial for correct localization of hot
81
spots, therefore it is not surprising that recent studies
comparing integrated PET/CT vs. CT alone or PET
alone show a higher accuracy for the hybrid technique
(De Wever et al. 2009).
While spatial resolution of PET/CT has improved,
the techniques remain inadequate to rule out sub-cen-
timeter tumor deposits (Ikeda et al. 2006). Billè et al.
(2009) evaluated the likelihood of finding mediastinal
N2 disease after a negative PET/CT scan in a con-
secutive cohort of 159 patients. Factors associated with
unforsceen N2 were central tumors, adenocarcinoma
histology, PET/CT hilar N1 disease and CT mediasti-
nal N2 disease. The latter was also recognized in the
meta-analysis of Langen et al. (2006) where a negative
PET scan resulted in a post-PET probability for N2
disease of 5% for LN \ 15 mm, compared to 21% for
LN C 16 mm. These data suggest that these patients
should be referred for invasive surgical staging prior to
possible thoracotomy to prevent too many unnecessary
thoracotomies in this subset.
The PPV of PET is less optimal and therefore tissue
confirmation of PET-positive nodes is always manda-
tory to avoid denial of radical surgery based on
false-positive findings. In the early PET studies, a
lymph node was reported positive when FDG uptake
was more intense than the surrounding background.
False positives were related to the presence of inflam-
matory conditions. The introduction of PET/CT and
TOF-PET however improved the sensitivity resulting in
visualization of ‘‘normal’’ nodes above the mediastinal
background. In the study of Lee et al. (2007), the PPV of
PET/CT was only 56% compared to 68% with
stand-alone PET in a comparable historical cohort.
The drastic increase in false-positive results reinforced
the need for surgical staging. Further studies will need to
clarify how PET-positive nodes should be defined with
TOF-PET-CT to achieve a better accuracy.
3.3 M-Staging
The observation of metastases in patients with
NSCLC implies that a patient can no longer be cured.
Forty percent of the patients with NSCLC have dis-
tant metastases at presentation, most commonly in the
adrenal glands, bones, liver or brain (Quint et al.
1996). The current standard non-invasive staging tests
(including ultrasound, CT, MRI and bone scintigra-
phy) are far from perfect. A systemic relapse develops
82
Fig. 4 Patient with adenocarcinoma of the right upper lobe
and with FDG avid lymph nodes in the right hilum (a) and
subcarinal region (b, c). Metastatic involvement could not be
confirmed with EBUS nor mediastinoscopy so patient
in up to 20% of surgically treated patients in the
period from 3 to 24 months after complete surgical
resection (Pantel et al. 1996).
PET identifies metastatic spread in 5–29% of
patients with negative or equivocal conventional
imaging (Schrevens et al. 2004). In recent studies using
integrated PET/CT, the hybrid modality was signifi-
cantly better than CT or PET alone for extra thoracic
metastases, although it is limited in assessing brain
metastases (De Wever et al. 2007b). While some PET
images can be considered definite proof of multi-focal
metastatic disease, caution is always indicated in soli-
tary extrathoracic PET findings that determine the
S. Stroobants
underwent thoracotomy. Final stage was pT2aN1M0. This case
underlines the importance to always confirm PET positives
nodes with histology
chances for radical therapy. In these patients, a con-
firmatory test is indicated. Accurate localization of
FDG-avid regions on fused PET/CT images reduces the
risk of false-positive interpretations of physiological
phenomena such as uptake in bowel or metabolically
active brown fat. Accordingly, previous estimates of
the impact of PET on the management of lung cancer
are likely to be surpassed in current clinical practice.
Enlarged adrenal glands on CT are found in up to
20% of NSCLC patients, but up to two-thirds of these
lesions are benign adenomas. PET is reported to have
a high sensitivity (reaching 100%) in the detection of
adrenal metastases, which means that an equivocal
PET/CT for Staging and Diagnosis of Lung Cancer
lesion of [1 cm on CT without FDG uptake on PET
will usually not be metastatic. Specificity of PET for
adrenal metastases is also high (between 80 and
100%), due to weak FDG uptake in adenomas.
Attempts are made to improve the specificity by using
SUV thresholds or adrenal/liver uptake ratios.
Recently, Brady et al. (2009) proposed an algorithm
combining density measurement on non-CE (HU [
10) and a SUV threshold (SUV [ 3.1) to define
malignancy. The proposed algorithm for PET/CT
reading proved to be more specific than PET or CT
alone (86 vs. 76 vs. 60% respectively) without loss in
sensitivity (97%) (Fig. 5).
PET scanning appears to have excellent perfor-
mance characteristics in assessing bone metastases,
with specificity, sensitivity, NPV, PPV and accuracy all
exceeding 90%, though false-positive and false-
negative findings are occasionally seen (Silvestri et al.
2007). The accuracy of PET scanning surpassed that of
radionuclide bone scanning in two direct comparative
studies (Hsia et al. 2002; Schirrmeister et al. 2004).
Caution is however required with distal lesions
(e.g. below the knee), which will fall outside the field-
of-view of a standard ‘whole-body’ PET acquisition, or
in osteoblastic lesions which are more readily seen on
Tc-99 m bone scan, as demonstrated in a study on breast
cancer patients (Cook et al. 1998). Because most bone
lesions in NSCLC are in the central skeleton, and nearly
all are osteolytic, PET scan usually replaces bone scan,
except in specific clinical indications.
For liver metastases, PET will have an additional
value to conventional imaging because of its ability to
differentiate indeterminate hepatic lesions. There are
no specific series on the use of PET in patients with
liver metastases from NSCLC. Some general series on
staging NSCLC suggest a superiority of PET by being
more accurate than CT comparable to other tumor
types. In a meta-analysis comparing different imaging
modalities in the detection of colorectal liver metas-
tasis, helical CT, MR imaging at 1.5T and FDG-PET
had similar sensitivities on a per-lesion analysis
(Bipat et al. 2005). In routine clinical practice, CT
therefore remains the standard imaging technique
for the liver. The use of PET is mainly to provide
additional information for the differentiation of
hepatic lesions that are indeterminate on conventional
imaging.
FDG-PET is not sensitive enough to exclude brain
metastases, due to the high-glucose uptake of normal
83
surrounding brain tissue. MRI (or CT) remains the
method of choice to stage the brain.
4 Small-Cell Lung Cancer
Small-Cell Lung Cancer (SCLC) represents only
15–20% of all lung cancers, and is often dissiminated
at the time of diagnosis, thereby obviating the need
for PET in many patients. In contrast to NSCLC, a
two-stage classification scheme is routinely used to
define the extent of disease, which divides SCLC into
limited disease (LD) and extensive disease (ED). LD
is defined as disease confined to one hemithorax, the
mediastinum and the supraclavicular lymph nodes.
All other patients are classified as having ED,
including those with malignant pleural effusion
(Rodriguez and Lilenbaum 2010). Diagnostic proce-
dures commonly used to stage the disease include
chest and abdomen CT, brain CT or MRI, radionu-
clide bone scans and bone marrow aspiration.
The value of PET in staging SCLC has been
evaluated by relatively small, mostly retrospective
studies, all indicating a possible role for PET (Ung
et al. 2007). PET seems to be especially promising in
the detection bone metastasis and supraclavicular
nodes (Fig. 6). CT and MRI outperform FDG-PET
with respect to the detection of brain metastases.
Unlike in NSCLC, studies comparing PET for medi-
astinal staging with histopathology results are lacking.
Probably the accuracy is comparable to that of
NSCLC since in many of these studies, final histology
proved to be SCLC in some patients, without higher
rate of false-positive or -negative results.
In the systematic meta-analysis (Ung et al. 2007),
sensitivity and specificity of PET for staging exten-
sive versus limited-stage disease ranged between
89–100 and 78–95%, respectively. More recent
studies confirm these data with change in stage clas-
sification in 8–17% of the patients. In the study of
Vinjamuri et al. (2008), additional sites of disease
were detected in 13 of 42 patients (32%), mostly
located in bones or supraclavicular nodes. PET
resulted in a change of disease stage in 16%
(upstaging in 4%, downstaging in 12%). Niho et al.
(2007) explored the additional value of PET in 63
patients with LD after conventional workup. ED was
found in 6/63 patients and additional LN involvement
was found 14%. In a recent study Azad et al. (2010) in
84
Fig. 5 Patient with a NSCLC of the right upper lobe and an
indeterminate mass in the left adrenal gland (CT density = 24
HU). PET only showed faint uptake in the adrenal mass (arrow)
with an SUV=2.4 suggestive for adenoma rather than
120 SCLC patients, PET up-staged 10 patients and
down-staged three patients. Overall PET data resulted
in a change of stage in 12% of patients. Fischer et al.
(2007) report on the first prospective study using
PET/CT in 29 patients with SCLC. PET/CT proved to
have a higher sensitivity than conventional workup
(93 vs. 73%) with equal specificity (100%). In their
population PET/CT findings determined a change of
stage in five of 29 patients (17%).
S. Stroobants
metastases. In the latter, adrenal uptake is in mostcases clearly
higher than normal liver uptake. In this case, the diagnosis of
adenoma was confirmed with biopsy
While the results of PET staging are promising, we
need larger prospective trials before definite conclu-
sions can be drawn on the exact role of PET in the
staging SCLC. The reference standard to which PET
compared is variable among the studies, and none of
the studies confirmed all lesions with histologic
results. Future studies should fully report the fre-
quency of correct and incorrect staging changes when
PET is added to conventional tests and link diagnostic
PET/CT for Staging and Diagnosis of Lung Cancer
Fig. 6 Patient with SCLC of the left hilum with bulky
mediastinal involvement (a). PET also revealed hot spots in
the bone (b) which were not visible on CT (c). Upstaging from
performance to outcomes such as improvement in
survival or reduced morbidity. Currently only Azad
et al. (2010) correlated PET stage with survival and
found a longer OS in patients with ED on pre-PET
staging but downstaged to LD after PET, compared to
those with ED on PET (median 10.9 vs. 5.9 months;
log-rank p = 0.037).
5 Implementation in Clinical Practice
Non-invasive lung cancer staging is substantially
improved by the use of PET. The most exciting
feature of PET is that it gives a reasonably cancer-
specific imaging of the entire patient in one single
non-invasive test with a better accuracy than con-
ventional imaging, thus with a potential impact on
stage designation and therapeutic decision. Diagnosis
and staging of lung cancer has become a truly multi-
disciplinary process involving imaging, endoscopic
85
limited to extensive disease was confirmed by biopsy of the hot
spot of lesion in the left sacrum (d)
and surgical technique and one cannot give an
overall recommendation for ‘optimal’ diagnostic
workup since the optimal strategy will depend on the
availability and expertise of the different techniques
as well as specific patient characteristics.
Although PET is the imaging technique with the
highest accuracy for characterization of indeterminate
lung lesions, careful selection of patients taking into
account the likelihood of malignancy is important.
Patients with rapidly growing hypermetabolic nodules
outside areas of endemic tuberculosis/mucosis, should
be referred immediately for surgical resection if the
lesion is easily accessable (VATS) and there is no
contraindications for surgery. For patients with nodules
that are not FDG avid and have a long-doubling time, a
wait and see policy is acceptable. Lastly, for patients
with discordant findings on FDG-PET and volumetric
analysis,the likelihood of cancer is intermediate to high
requiring additional tissue sampling or strict FU (repeat
CT within 3 months) (Gould et al. 2011).
86
When PET/CT is available, it is probably the best
single test to stage a lung-cancer patients. The most
added value is in the detection of distant metastasis
since this implies that the patient is no longer curable.
While some PET/CT images can be considered defi-
nite proof of multi-focal metastatic disease, caution is
always indicated in solitary extrathoracic findings that
determine the chances for radical therapy. In these
patients, a confirmatory test is indicated.
PET/CT is also useful for mediastinal staging but
the clinical impact is less pronounced than initially
anticipated. The high-negative predictive value of
PET creates the possibility to omit invasive staging if
PET suggests absence of LN disease. However one
should be very careful for false-negative PET findings
in particular situations. The spatial resolution of PET/
CT remains inadequate to rule out sub-centimeter
lymph node metastasis and does not obviate the need
for invasive staging procedures in patients with a
higher likelihood of mediastinal lymph node
involvement such as patients with central tumors,
low-FDG uptake in the primary tumor, PET/CT hilar
N1 disease and CT mediastinal N2 disease. If these
rules of interpretation are handled correctly, relevant
LN disease will rarely be missed. Minimal N2-disease
may be discovered at surgical exploration, but
resection in these patients is rewarding. False-positive
findings are due to the fact that FDG uptake is not
tumor specific, and can be found in all active tissues
with high-glucose metabolism, in particular inflam-
mation. Therefore, clinically relevant FDG-avid
mediastinal LNs should always be examined with the
most appropriate tissue sampling technique.
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 Surgical Staging of Lung Cancer
for Advances in Radiation Oncology
of Lung Cancer
Farhood Farjah and Valerie W. Rusch

Contents Abstract
This chapter reviews surgical approaches to deter-
1 Introduction.............................................................. 89 mining T, N, and M status for lung cancer; an
2 Stage Classification and Determination ................ 90 expanded description of individual mediastinal
2.1 T-Stage....................................................................... 90 staging modalities; the evidence for invasive
2.2 N-Stage ...................................................................... 90 mediastinal staging procedures and multi-modality
2.3 M-Stage...................................................................... 92
staging strategies; and staging practices in the
3 Invasive Mediastinal Staging Modalities .............. 93 community at large.
3.1 Transthoracic Needle Biopsy .................................... 93
3.2 Transbronchial Needle Biopsy .................................. 93
3.3 Endobronchial Ultrasound......................................... 94
3.4 Esophageal Endoscopic Ultrasound .......................... 94 Abbreviations
3.5 Cervical Mediastinoscopy ......................................... 94
3.6 Mediastinotomy ......................................................... 95 AJCC American Joint Committee on Cancer
3.7 Extended Cervical Mediastinoscopy......................... 95 CT Computed tomography
3.8 Video-Assisted Thoracic Surgery ............................. 95 EBUS Endobronchial ultrasound
3.9 Limitations of the Literature on Individual EUS Esophageal endoscopic ultrasound
Mediastinal Staging Modalities................................. 95
IASLC International Association for the Study of
4 Randomized Trials of Staging Algorithms ........... 96 Lung Cancer
5 Staging in the Community at Large ..................... 97 UICC International Union Against Cancer
6 General Recommendations ..................................... 97
MRI Magnetic resonance imaging
NSCLC Non-small cell lung cancer
References.......................................................................... 97
PET Positron emission tomography
SCLC Small cell lung cancer
TBNBx Transbronchial needle biopsy
TTNBx Transthoracic needle biopsy
VATS Video-assisted thoracic surgery

1 Introduction
F. Farjah
V. W. Rusch (&)
Thoracic Surgery Service, The purpose of lung cancer staging is to aid thera-
Memorial Sloan-Kettering Cancer Center, peutic decision-making and provide the patient with a
1275 York Avenue, New York,
NY 10065, USA prognosis. ‘‘Surgical staging’’ often refers to the
e-mail: ruschv@mskcc.org combined information obtained from the clinical

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 89
DOI: 10.1007/174_2011_261, Ó Springer-Verlag Berlin Heidelberg 2011
90
findings at operation and from the pathologic review
of a surgically removed specimen. For the purposes of
this chapter, ‘‘surgical staging’’ refers to any invasive
attempt to obtain tissue for pathologic review.
Surgical staging is only one component of a multi-
modality approach to accurate staging. Accuracy has
a direct bearing on appropriate treatment allocation.
Whereas understaged patients may unnecessarily be
exposed to the risks of surgical intervention without
benefit, overstaged patients may be deprived a
potentially curative resection. The goal of this chapter
is to (1) review the state-of-the-art in invasive lung
cancer staging, (2) critically examine the evidence
supporting the use of individual staging modalities
and their use in the context of multi-modality staging
algorithms.
2 Stage Classification
and Determination
The 7th editions of the staging manuals of the
American Joint Committee on Cancer (AJCC) and
International Union Against Cancer (UICC) use
information about the primary site (T), regional nodes
(N), and distant metastases (M) to establish the stage
of lung cancer (American Joint Committee on Cancer
2010; International Union Against Cancer 2009).
Unlike prior editions based on single institution data,
the 7th edition classifications were based on an
analysis of the International Association for the Study
of Lung Cancer (IASLC) database. Included in that
dataset were 81,015 lung cancer patients from 46
institutions and 19 countries. The analysis sought to
identify subgroups based on TNM categories pre-
dicting a unique prognosis (survival rate).
2.1 T-Stage
Determinants of T-stage include tumor size, location,
sequelae of airway obstruction (atelectasis, pneumo-
nitis, etc.), and/or invasion into adjacent structures.
Location is defined by involvement of the main stem
bronchus and distance from the carina. Invasion can
involve virtually any structure in the chest, including
the pleura, great vessels, heart, esophagus, diaphragm,
nerves (i.e., phrenic, recurrent laryngeal, etc.), chest
wall (i.e., ribs, intercostal muscles, etc.), and vertebrae.
F. Farjah and V. W. Rusch
Methods for determining T-stage include com-
puted tomography (CT), magnetic resonance imaging
(MRI), and surgical exploration and/or resection.
Cangemi et al. (1996) reviewed the literature and their
own experience and found that the sensitivity of CT
for detection of T3 or T4 disease was highly variable
and generally low—38–97% for T3 and 31–78% for
T4. MRI had a sensitivity of 84% for correct
T-staging in one series (Manfredi et al. 1996). The
development of higher quality scanners over time has
potentially improved the accuracy of CT and MRI.
Given the inaccuracy of radiographic T-staging,
invasive methods are often needed to resolve uncer-
tainty over T-status. Endoscopic (esophageal) ultra-
sound (EUS) has been evaluated as a minimally
invasive option for T-staging, though it does not
appear to be superior to imaging given a sensitivity of
88% (Varadarajulu et al. 2004). Surgical exploration
is the standard for determining gross invasion. Among
patients with radiographically suspected T4 disease,
29–50% did not have T4 disease on exploration
(Sebastián-Quetglás et al. 2003; Eggeling et al. 2002;
De Giacomo et al. 1997). A video-assisted thoraco-
scopic (VATS) approach to exploration is less morbid
than a standard thoracotomy, but it is unknown
whether the ability to assess T-status is equivalent
among these two approaches. Resection is the gold
standard for T-staging as it allows for pathologic
assessment of size, microscopic invasion, and/or
visceral pleural involvement.
2.2 N-Stage
N-stage is determined by involvement of nodes
spanning an area from the supraclavicular region to
the diaphragm. The IASLC recently resolved
differences between two widely used lymph node
classification schemes—the Naruke map and the
Mountain–Dresler modification of the American
Thoracic Society map (American Joint Committee on
Cancer 2010). Both the UICC and the AJCC now
recommend the use of the IASLC map for describing
nodal involvement in lung cancer (Fig. 1).
Palpable cervical or supraclavicular lymph nodes
may be sampled via fine needle aspiration, core nee-
dle biopsy, or incisional/excisional surgical biopsy in
the outpatient setting. The latter two approaches yield
more tissue and allow for an architectural and
Surgical Staging of Lung Cancer for Advances in Radiation Oncology 91

Fig. 1 The IASLC/MSKCC lymph node map. Reprinted with permission courtesy of the international Association for the study of
Lung Cancer. Copyright Ó 2009 Memorial Sloan-Kettering Cancer Center
92
molecular analysis of the material. A positive result
indicates N3 (stage IIIB) disease precluding the need
for further nodal staging.
Non-invasive and invasive staging modalities are
available to evaluate mediastinal nodes. A key
difference between the two is that mediastinal staging
allows for tissue diagnosis prior to instituting treat-
ment. Two meta-analyses revealed that CT has a
sensitivity of 51–61% and specificity of 79–85% for
detecting mediastinal lymph node metastases, whereas
positron emission tomography (PET) has a sensitivity
of 74–85% and specificity of 85–90% (Silvestri et al.
2007; Gould et al. 2003). Accordingly, up to 26 and
10% of patients may be understaged and overstaged,
respectively. Most reviews and practice guidelines
recommend invasive staging for patients with abnor-
mal nodes on PET (Silvestri et al. 2007; Gould et al.
2003; Ettinger et al. 2010). The significance of un-
derstaging is controversial because it is unclear to
what degree induction therapy as opposed to adjuvant
therapy affects long-term outcomes (Gilligan et al.
2007; Song et al. 2010; Felip et al. 2010). Neverthe-
less, since practice guidelines recommend neoadju-
vant therapy for patients with stage IIIA lung cancer
(Ettinger et al. 2010; Robinson et al. 2007), it is
desirable to avoid understaging. Approximately
6–16% of patients without evidence of N2/N3 disease
on PET will have evidence of occult N2 disease at the
time of resection (Al-Sarraf et al. 2008; Cerfolio et al.
2006; Defranchi et al. 2009; Kanzaki et al. 2011; Lee
et al. 2007). Risk factors for occult N2 include location
of the primary (central versus peripheral), upper lobe
primaries, larger tumors, adenocarcinoma, high stan-
dardized uptake values of the primary on PET, PET
positive N1 nodes, or enlarged nodes on CT (Al-Sarraf
et al. 2008; Cerfolio et al. 2006; Defranchi et al. 2009;
Kanzaki et al. 2011; Lee et al. 2007). In patients with
one or more of these clinical features, invasive medi-
astinal staging should be considered despite normal
mediastinal lymph nodes on PET.
Invasive mediastinal staging definitively addresses
the mediastinum with several important caveats. No
single staging modality can access all nodal stations
(Table 1). Thus, no one invasive staging modality can
be used to evaluate all lung cancer patients, and in
some cases more than one invasive staging modality
may be required. Some invasive staging procedures—
such as EUS and endobronchial bronchial ultrasound
(EBUS)—require technical expertise and unique
F. Farjah and V. W. Rusch
resources, such as a cytotechnologist who can be
present to evaluate specimen quality during the pro-
cedure. As a result, not all staging procedures are
accessible to all providers and patients. Finally, all
invasive staging carries a small risk of complications.
Like T-staging, the decision to pursue invasive stag-
ing of the mediastinum ultimately hinges on whether
the information gained will change management.
The role of intraoperative nodal staging among
those eligible for curative resection is rapidly evolv-
ing. Results of a randomized trial of mediastinal
lymph node sampling versus dissection revealed no
differences in morbidity or mortality (Allen et al.
2006) and no differences in survival in patients with
N0-1 (non-hilar) lymph disease even though lymph
node dissection identified additional metastatic nodes
in a small proportion of patients (Darling et al. 2010).
A retrospective review of national registry data
revealed an association between an increasing number
of lymph nodes and higher survival rates (Ludwig
et al. 2005). For the mean time, the general recom-
mendation from the AJCC is to remove at least 6
lymph nodes and to sample or dissect lymph nodes
from 2R, 4R, 7, 10R, and 11R for right-sided tumors,
and from 5, 6, 7, 10L, and 11L for left-sided tumors
(American Joint Committee on Cancer 2010).
Regardless of side, lower lobe tumors should also
include evaluation of the ipsilateral level 9 node.
2.3 M-Stage
M-stage is determined by extra-thoracic spread of
disease, for instance to the brain, bones, adrenal
glands, contralateral lung, liver, pericardium, kidneys,
and/or subcutaneous tissues, or pleural and/or peri-
cardial effusions. If a tissue diagnosis already exists
based on the primary tumor or nodal disease, and
there is a high suspicion for metastatic disease based
on clinical and radiographic criteria, then it is not
necessary to establish M-stage on pathologic grounds.
However, when faced with uncertainty about the
presence of metastatic disease, the basis for obtaining
tissue confirmation is choosing the site that offers the
highest probability of tissue yield with the lowest risk
to the patient.
Examples of procedures used to establish meta-
static disease include a CT-guided biopsy, excisional/
incisional soft tissue biopsy, thoracentesis, VATS,
Surgical Staging of Lung Cancer for Advances in Radiation Oncology 93

Table 1 Mediastinal lymph nodes accessible by individual staging modalities

2R 2L 4R 4L 5 6 7 8 9R 9L
Transthoracic needle biopsy X X X X
Transbronchial needle biopsy X X X
Endobronchial ultrasound guided biopsy X X X
Esophageal endoscopic ultrasound guided biopsy X X X X X X X
Cervical mediastinoscopy X X X X X
Mediastinotomy X X
Extended cervical mediastinoscopy X X X X X X X
Video-assisted thoracoscopic node biopsy (right) X X X X
Video-assisted thoracoscopic node biopsy (left) X X X X X X

pericardiocentesis, or pericardial window. CT-guided

biopsy is commonly used as an outpatient procedure
for obtaining tissue from viscera, bone, and deep soft
tissues. For more superficial lesions, an incisional/
excisional biopsy may be performed in the clinic.
EUS uses ultrasound visualization to direct a needle
across the esophagus and/or stomach to access
radiographic abnormalities in the retroperitoneum,
left lobe of the liver, and/or left adrenal gland
(LeBlanc et al. 2003). Thoracentesis is an office
procedure involving the introduction of a soft,
removable catheter into the pleural space for evacu-
ation of an effusion. A patient may require a thora-
centesis for a symptomatic or newly diagnosed
effusion. Thoracentesis can establish a diagnosis of
M1 disease in 80% of patients who truly have
malignant pleural effusions, though it may require
three separate pleural fluid specimens reviewed by an
experienced cytologist (Rivera et al. 2007). Per-
forming a VATS procedure for effusions has the
added benefit of inspecting the pleural, mediastinal,
and diaphragmatic surfaces for disease. In patients
with cytologically negative effusions, VATS discov-
ered pleural disease in 60% of patients (De Giacomo
et al. 1997). Pericardiocentesis is an outpatient
procedure involving insertion of a soft, removable
catheter into the pericardial space for evacuation of an
effusion. A pericardial window is a surgically per-
formed procedure where a portion of the pericardium
is removed in addition to evacuation of fluid. This
procedure may be performed either through a subxi-
phoid incision or a right or left VATS procedure.
Pericardial procedures are most often performed to
treat a symptomatic effusion or cardiac tamponade
rather than to establish the presence of M1 disease.
3 Invasive Mediastinal Staging
Modalities
3.1 Transthoracic Needle Biopsy
Transthoracic Needle Biopsy (TTNBx) is an outpatient
procedure using CT guidance to direct a small needle
into enlarged mediastinal lymph nodes. In a review of 5
studies totaling 215 patients, all with clinical N2/N3
disease, the sensitivity and specificity of TTNBx were
89 and 100%, respectively (Detterbeck et al. 2007). The
prevalence of mediastinal nodal disease was 81%, and
only 75% of patients had lung cancer with up to half of
those patients having small cell lung cancer (SCLC).
Approximately 10% of patients required an additional
procedure to decompress a pneumothorax.
3.2 Transbronchial Needle Biopsy
Transbronchial Needle Biopsy (TBNBx) uses a flexible
bronchoscope to pass an aspirating needle across the
airway into a subcarinal (or sometimes a paratracheal)
node for the purposes of sampling. Though a blind
procedure, pre-procedure CT imaging informs target-
ing. This outpatient procedure is performed in either an
endoscopy suite or operating room. Challenges asso-
ciated with sampling paratracheal nodes include
knowing precisely where the nodes are with broncho-
scopic visualization only and the angulation required to
access such nodes. Risks include major hemorrhage,
pneumothorax, and pneumomediastinum, with an
overall major complication rate of 0.3% (Holty et al.
2005).
94
Two systematic reviews provide information about
the diagnostic performance of TBNBx. The first iden-
tified a total of 13 studies stratified into Tier 1 and 2
investigations based on the quality of the study (Holty
et al. 2005). Tier 1 studies yielded a sensitivity and
specificity of 36 and 98%, respectively, whereas in Tier
2 investigations the sensitivity was 82% (specificity not
calculated because the lack of surgical confirmation in
Tier 2 studies). The prevalence of nodes were markedly
different between the 2 tiers (36 and 81%), suggesting
significant differences in the underlying study popula-
tions. Detterbeck et al. (2007) reviewed 17 papers
including 1,339 patients and calculated a sensitivity
and specificity of 78 and 100%, respectively.
3.3 Endobronchial Ultrasound
Endobronchial Ultrasound (EBUS) involves a special
bronchoscope—similar in size to a standard adult
bronchoscope—with a curvilinear probe that provides a
50 degree linear continuous B-mode ultrasound image
with color Doppler capability. There is a biopsy channel
that allows passage of a 22-gauge biopsy needle at a 30
degree angle to the long axis of the bronchoscope.
Optionally, a latex balloon can be placed over the end of
the ultrasound probe to facilitate a fluid interface
between the probe and tracheal or bronchial wall. EBUS
is an outpatient procedure performed in either the
operating room or endoscopy suite. Subcarinal and level
10 or 11 nodes are relatively straightforward to access,
whereas sampling paratracheal nodes may be difficult
because of the angle at which the scope must be placed to
visualize and access these nodes.
Two systematic reviews provide information on
the performance characteristics of this staging
modality. The first review summarized 8 studies with
918 patients and found a sensitivity and specificity of
90 and 100%, respectively. Notably, 14–30% of
patients had SCLC and the prevalence of nodes in this
study was 68%. The second review summarized 10
studies and found sensitivity and specificity to be 88
and 100%, respectively (Adams et al. 2009).
3.4 Esophageal Endoscopic Ultrasound
Esophageal Endoscopic Ultrasound (EUS) is per-
formed using a special endoscope with either a radial
F. Farjah and V. W. Rusch
(360 degree cross-sectional view) or linear (180
degree capital view) ultrasound probe with pulse
wave and color Doppler capabilities. This procedure
is performed on an outpatient basis. Under direct
ultrasound visualization a needle is passed across the
esophagus to access nodes in the mediastinum
(LeBlanc et al. 2003). Complications associated with
EUS have been reported as rare (0.8%) and minor
(fever, strider, sore throat, and cough) (Micames et al.
2007).
Two systematic reviews provide information about
the utility of EUS. Micames et al. (2007) report on 18
studies with 1201 patients using both radial and linear
probes revealing a sensitivity and specificity of 83 and
97%, respectively. Sensitivity and specificity varied
with the presence or absence of enlarged nodes on
CT. Detterbeck et al. (2007) examined 16 studies with
973 patients and found a similar sensitivity and
specificity of 84 and 99.5%, respectively. The prev-
alence of positive mediastinal nodes in that review
was 61%, and the authors again observed variation in
performance characteristics based on radiographic
appearance of nodes.
3.5 Cervical Mediastinoscopy
Mediastinoscopy is a surgical procedure that allows
for direct visualization and biopsy of paratracheal and
subcarinal nodes. The patient is administered a gen-
eral anesthetic, a 2 cm transverse cervical incision is
made, and a mediastinoscope is passed just anterior to
the trachea into the mediastinum. Mediastinoscopy is
an outpatient procedure (Cybulsky and Bennett 1994;
Vallières et al. 1991), although it can also be per-
formed immediately prior to resection. Risks associ-
ated with mediastinoscopy among a series of 2,145
cases included bleeding (0.33%), vocal cord dys-
function (0.55%), tracheal injury (0.09%), pneumo-
thorax (0.09%), and death (0.05%) (Lemaire et al.
2006).
Detterbeck et al. (2007) reviewed 19 studies
including 6505 patients and determined a sensitivity
of 78%. The prevalence of mediastinal node
involvement was 39%. With the addition of a video-
endoscope, the sensitivity was 90%. A national study
revealed that just under half of patients undergoing
mediastinoscopy had documented evidence of lymph
node material submitted to pathology. The proportion
Surgical Staging of Lung Cancer for Advances in Radiation Oncology
of patients with submitted lymph node material was
higher when performed at teaching centers and
comprehensive community cancer centers suggesting
that the diagnostic yield of mediastinoscopy is oper-
ator dependent (Little et al. 2005).
3.6 Mediastinotomy
Mediastinotomy is a surgical procedure that allows
direct visualization and biopsy of mediastinal nodes in
the aortopulmonary window (levels 5, 6). This pro-
cedure is particularly useful for sampling nodes
associated with a left upper lobe primary as these
tumors have a predilection to drain into nodes in the
aortopulmonary window. After administration of
general anesthesia, a 3–6 cm transverse incision is
made over the second intercostal space and a medi-
astinoscope is passed into the mediastinum. The sec-
ond costal cartilage may be resected to improve
exposure. Risks associated with this procedure include
bleeding, infection, injury to the phrenic nerve, and
pneumothorax. A systematic review found the sensi-
tivity of mediastinotomy to be 87% (Detterbeck et al.
2007). It should be noted that the prevalence of nodes
based on imaging ranged from 47 to 77% and that
approximately one-fifth of patients had SCLC.
3.7 Extended Cervical Mediastinoscopy
Extended cervical mediastinoscopy is an alternative
surgical approach to visualize and sample nodes in the
aortopulmonary window. The procedure is similar to
standard cervical mediastinoscopy (see above) except
that the mediastinoscope is directed laterally to the
aortic arch. This procedure is now rarely performed
and has been largely supplanted by EBUS, EUS and
VATS (video-assisted thoracic surgery). The sensi-
tivity ranges from 45 to 51% given a prevalence
ranging from 29 to 48% (Detterbeck et al. 2007).
Though complications were only reported in 0.3% of
patients, the events were severe involving one aortic
injury and one stroke (Detterbeck et al. 2007).
3.8 Video-Assisted Thoracic Surgery
Video-assisted thoracic surgery (VATS) is a surgical
procedure involving access to the hemithorax
95
through small incisions and with the aid of a
video-thoracoscope. This procedure requires general
anesthesia and single lung ventilation. Patients
typically stay in hospital for one day, though it can be
performed as an outpatient procedure. A right-sided
VATS allows access to levels R4, 7, R9, and R10,
whereas a left-sided VATS provides access to levels
5, 6, 7, L8, L9, and L10. Complications occurred in
less than 2% of patients (Detterbeck et al. 2007).
Detterbeck et al. (2007) summarized the results of
7 studies including 419 patients undergoing VATS for
mediastinal lymph node staging. The sensitivity and
specificity were 75 and 100%, respectively (Detter-
beck et al. 2007). The authors note inexplicable and
wide variation in the sensitivity of VATS across
studies (37–100%), which likely reflects differences
in surgeon experience and patient selection.
3.9 Limitations of the Literature
on Individual Mediastinal Staging
Modalities
There are very specific criteria for cohort selection in
most studies of individual mediastinal staging
modalities. Most studies evaluate operated patients
because surgical nodal assessment is considered the
‘‘gold standard’’. By virtue of being selected for
surgical therapy, most of these patients had a low pre-
treatment likelihood of advanced or late stage disease.
Furthermore, operated patients only account for
approximately 25% of all non-small cell lung cancer
(NSCLC) patients (Little et al. 2007; Farjah et al.
2009). Evaluating performance characteristics among
operated patients makes it difficult to generalize the
results to all lung cancer patients. Another criterion for
cohort selection is including only those patients with
radiographically abnormal nodes in nodal stations
accessible by the staging modality of interest. For
instance, studies of TTNBx predominantly included
patients with bulky N2/N3 disease (Detterbeck et al.
2007). Though this approach is rationale for the study
of diagnostic accuracy, it is difficult to compare per-
formance characteristics of individual staging modal-
ities across studies. There are also significant
differences in patient characteristics across investiga-
tions that make it difficult to compare results across
studies, particularly with regard to the proportion of
96
NSCLC and SCLC patients and prevalence of medi-
astinal nodes (Detterbeck et al. 2007).
Another problem with the existing body of litera-
ture is the lack of a uniform reference standard.
Surgery is often times regarded as the ‘‘gold stan-
dard’’ for assessing the performance of a staging
modality, but most studies do not detail the conduct
of an operation with regard to the extent of intra-
operative lymph node evaluation (stations examined,
dissections versus sampling, etc.). The extent of
lymph node evaluation likely varies significantly
across surgeons and institutions. Recently emerging
data may define a future standard for intraoperative
nodal assessment (Darling et al. 2010). Without a
uniform reference standard, it is difficult to compare
the performance characteristics of individual staging
modalities across studies.
Staging modalities are often considered not only in
terms of their diagnostic accuracy but also their risks.
Complications are not reported in a uniform fashion,
and in some cases they are not reported at all. Criteria
exist for grading the severity of adverse events
following procedures and could be used explicitly in
investigations of invasive staging modalities (CTCAE
and National Cancer Institute 2006). Another impor-
tant aspect of measuring risk is establishing a set
period of time for follow-up, particularly since most
staging procedures occur on an outpatient basis. In
order to fairly weigh the risks and benefits of com-
peting invasive staging procedures, a high level of
rigor must be applied to ascertaining complications.
4 Randomized Trials of Staging
Algorithms
To date, there are eight randomized trials comparing
different lung cancer staging algorithms. Some studies
evaluated the use of PET. These trials are also
reviewed because invasive staging was a component
of the overall staging strategy.
Most, though not all trials, suggest that incorpo-
rating PET into a staging algorithm reduces the
number of futile or unnecessary thoracotomies
(van Tinteren et al. 2002; Herder et al. 2006; Maziak
et al. 2009; Fischer et al. 2009). There is conflicting
data on whether PET does so through a mechanism of
better detection of N2/N3 disease (Herder et al. 2006;
F. Farjah and V. W. Rusch
Fischer et al. 2009). It also remains uncertain whether
PET decreases the overall number of staging tests
performed (Herder et al. 2006; Maziak et al. 2009).
PET incorrectly upstages patients more frequently
than conventional work-up with CT, bone scans, and
selective mediastinoscopy (Maziak et al. 2009),
potentially requiring more diagnostic investigations to
confirm PET results. There is no evidence that PET
affects survival (Viney et al. 2004) or direct medical
costs (Herder et al. 2006), though these endpoints
were secondary outcomes in the trials that evaluated
them. One study demonstrated that PET leads to a
clinically important but statistically non-significant
lower median survival (Fischer et al. 2009).
Several trials show that the addition of endoscopic
guided modalities to ‘‘conventional’’ staging led to
higher sensitivity for N2/N3 detection and fewer
futile thoracotomies and surgical interventions
(Annema et al. 2010; Tournoy et al. 2008; Larsen
et al. 2005). When compared to mediastinoscopy
among patients with CT and/or PET evidence of
mediastinal nodal disease, combination EUS/EBUS
resulted in greater sensitivity for N2/N3 disease and
fewer unnecessary thoracotomies without significant
differences in the median number of nodal stations
sampled or complications (Annema et al. 2010).
A small study compared EUS versus mediastinoscopy
in a similar cohort of lung cancer patients and found
that the number of surgical procedures was lower in
the EUS group (Tournoy et al. 2008). However, the
number of mediastinal nodes sampled was signifi-
cantly higher in the mediastinoscopy group. Pre-
liminary results from a different trial found that
incorporating routine EUS into a conventional algo-
rithm consisting of CT and selective TTNBx,
TBNBx, and mediastinoscopy led to fewer unneces-
sary thoracotomies. Only one-third of patients
underwent PET because they were double enrolled in
another trial, and the frequency of PET was higher in
the routine EUS group.
Despite a randomized study design, there are a
number of important limitations that limit the pooling
of results and ability to generalize the findings.
Inclusion criteria varied across investigations. The
control arms of the trials often refer to a ‘‘conven-
tional’’ or ‘‘standard’’ staging algorithm based on
local or national guidelines. Yet, the control algo-
rithms varied significantly across studies suggesting
Surgical Staging of Lung Cancer for Advances in Radiation Oncology
there is no standard, or at least none across countries
and/or the decade of study. Primary endpoints also
varied significantly across studies including for
instance diagnostic performance, futile thoracotomies
(variably defined), and number of staging modalities
utilized to arrive at a final clinical stage. Finally, it is
unclear whether the community at large will have
access to the unique resources and expertise necessary
to utilize certain staging modalities, such as EUS and
EBUS.
5 Staging in the Community at Large
Few studies describe how patients in the community
at large are actually staged. Little et al. (2007) used
the National Cancer Database to describe the use of
individual staging modalities among a nationally
representative sample of lung cancer patients cared
for at 729 hospitals in 2001. Among 40,909 patients,
93 and 19% underwent CT and PET, respectively. CT
and PET revealed abnormal mediastinal lymph nodes
in 56 and 51% of patients, respectively. Overall, 20%
of patients underwent mediastinoscopy. Using the
same database but evaluating only 11,688 resected
patients, 92% underwent CT and 26% underwent PET
(Little et al. 2005). Abnormal mediastinal nodes were
detected in 27 and 28% of patients by CT and PET,
respectively. Overall, 27% of patients underwent
mediastinoscopy, but only 47% of these patients had
documented lymph node material submitted for
pathologic review.
Farjah et al. (2009) evaluated multi-modality
mediastinal staging in 43,912 elderly NSCLC patients
between 1998 and 2002 using the Surveillance, Epi-
demiology, and End-Results database linked to
Medicare claims (Farjah et al. 2009). CT, PET, and
invasive staging—defined by mediastinoscopy,
mediastinotomy, VATS, or EUS—were evaluated.
Most patients (77%) underwent staging with CT only,
whereas only 21 and 2% underwent bi- and tri-
modality staging, respectively. Over the 5 year study
period, there was a dramatic decrease in the use of
single modality staging from 90 to 67% coincident
with a rise in bimodality staging from 10 to 30%. The
rise in bimodality staging was accounted for by a
rapid increase in the use of PET from 2 to 30%. Over
the same period of time, the use of invasive staging
did not change (9–8%).
97
6 General Recommendations
The UICC and AJCC 7th edition staging manuals
define the current standard for classifying lung cancer
stage (American Joint Committee on Cancer 2010;
International Union Against Cancer 2009). All
patients should undergo non-invasive staging with CT
and PET. Those with clear evidence of widely met-
astatic disease should have tissue confirmation of a
cancer diagnosis and a referral to medical and radia-
tion oncology. For cases where there is a plausible
alternative explanation for what appears to be meta-
static disease on CT/PET, invasive staging is indi-
cated to rule out the possibility of metastatic cancer.
In an otherwise resectable patient with PET evidence
of abnormal nodes, invasive staging is indicated to
rule in or out the possibility of mediastinal nodal
metastases. Invasive mediastinal staging should be
considered even if PET reveals no uptake in medi-
astinal nodes when the primary tumor is an adeno-
carcinoma, large, centrally located or in the upper
lobes, and/or has a high standardized uptake value on
PET, and/or there is PET evidence of N1 disease or
CT evidence of abnormal mediastinal nodes. Medi-
astinoscopy, EUS, and/or EBUS are all legitimate
options for evaluating mediastinal lymph nodes. The
decision to use one or more such modalities should be
guided by the nodal distribution of suspected disease
and the availability of appropriate resources and
expertise to safely and effectively conduct these
procedures. For patients with radiographic evidence
of invasion, who are otherwise resectable and have
had an extensive evaluation ruling out mediastinal
node involvement, exploration is indicated to deter-
mine resectability.
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 Lung Cancer Surgery
Sidhu P. Gangadharan, Walter J. Lech, and David J. Sugarbaker

Contents Abstract
Lung cancer is the most common cancer world-
1 Introduction.............................................................. 103 wide. Current estimates project over 222,000 new
2 Preoperative Assessment......................................... 104 cases of lung cancer in the US alone in 2010,
2.1 Diagnosis.................................................................... 104 amounting to over 157,000 deaths. Despite a
2.2 Preoperative Fitness................................................... 108 modest improvement in 5-year survival over the
3 Operative Strategy................................................... 109 past three decades, deaths from lung cancer con-
3.1 Nomenclature and Anatomy ..................................... 109 tinue to exceed cancer deaths from all other sites.
3.2 Extent of Resection ................................................... 109 This chapter updates the role of surgical resection
3.3 Technique of Resection............................................. 110
3.4 Postoperative Course ................................................. 111 in the management of lung cancer. Among the
3.5 Video-Assisted Thoracoscopic Surgery .................... 112 topics reviewed are the diagnostic work-up and
3.6 Radiation Therapy for Patients Undergoing Lung preoperative assessment of suitability for resection,
Resection: T3 Tumors ............................................... 113 open and video-assisted thoracoscopic operative
References.......................................................................... 113 strategies, and recent changes in both the lung
cancer staging and histological classification sys-
tems. Indications for radiation therapy in selected
S. P. Gangadharan
Division of Thoracic Surgery, patients with T3 tumors are also discussed.
Beth Israel Deaconess Medical Center,
185 Pilgrim Road, W/DC 201,
Boston, MA 02115, USA
S. P. Gangadharan
Assistant Professor of Surgery,
1 Introduction
Harvard Medical School,
Boston, MA, USA Lung cancer is the most common cancer in the world,
W. J. Lech
D. J. Sugarbaker (&) with an incidence of 1.52 million cases and
Division of Thoracic Surgery, 1.31 million deaths in the year 2008 (Boyle and Levin
Brigham and Women’s Hospital, 2008). It has been estimated that over 222,000
75 Francis Street, Boston, MA 02115, USA
e-mail: dsugarbaker@partners.org; new cases of lung cancer occurred in the US in
asadams@partners.org 2010, accounting for 15% of all cancer diagnoses
W. J. Lech
(American Cancer Society 2010). More than 157,000
Instructor in Surgery, Americans are expected to die in 2010 as a result,
Harvard Medical School, comprising nearly 28% of all non-melanoma cancer-
Boston, MA, USA related deaths. Over the past three decades the US has
D. J. Sugarbaker experienced a modest, yet statistically significant
The Richard E. Wilson Professor of Surgical Oncology, improvement in 5-year survival, increasing from
Harvard Medical School, Boston, MA, USA

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 103
DOI: 10.1007/174_2011_318,  Springer-Verlag Berlin Heidelberg 2011
104
11.5% for patients diagnosed in 1975 to 16.0% in
2003 (Howlader et al. 2011). However, death from
lung cancer still exceeds that from any other site,
representing 29% of male and 26% of female cancer
deaths in 2010 (American Cancer Society 2010).
The World Health Organization has classified the
histologic subtypes of lung cancer (Travis et al. 2004).
Recently, a multidisciplinary classification of lung
adenocarcinoma was sponsored by the International
Association for the Study of Lung Cancer (IASLC),
American Thoracic Society, and European Respiratory
Society (Travis et al. 2011). For resection specimens,
the term bronchioloalveolar carcinoma (BAC) has been
supplanted by adenocarcinoma in situ (AIS) to describe
small solitary adenocarcinomas with pure lepidic
growth. BAC lesions with less than pure lepidic growth
are termed either minimally invasive adenocarcinoma
(MIA) or lepidic predominant invasive adenocarci-
noma based on depth of invasion, with the former being
characterized by a depth B5 mm. Invasive mucinous
adenocarcinoma (formerly mucinous BAC) as its name
would suggest, is distinguished from MIA by the pres-
ence of mucin. Other subtypes include colloid, fetal,
and enteric adenocarcinoma (Travis et al. 2011).
Surgical resection represents the best chance for
cure of epithelial non-small-cell lung cancers
(NSCLC). Unfortunately, over half of patients present
with lesions that are unresectable because of locally
advanced tumor or systemic spread (Howlader et al.
2011; Silvestri et al. 2003). This chapter provides an
overview of the important surgical aspects of lung
cancer therapy, including preoperative assessment,
operative strategy, adjuvant and neoadjuvant therapy,
and the options for challenging cases such as tumors
invading the mediastinum or chest apex.
2 Preoperative Assessment
2.1 Diagnosis
Patients presenting with lung cancer are usually
symptomatic and describe a history of cough, weight
loss, or dyspnea in 60–75% of cases (Beckles et al.
2003). Hemoptysis, chest or bone pain, fever, or
weakness may occur somewhat less frequently.
Physical examination may elicit signs of advanced
disease including the following: lymphadenopathy in
the supraclavicular or cervical regions, percussion
S. P. Gangadharan et al.
dullness from an effusion, and neck vein distension
from superior vena cava obstruction. After radiologic
confirmation of the presence of tumor, a pathological
diagnosis may be obtained by means of sputum
cytology, bronchial washings or brushings, or fine
needle aspiration. Bayesian theory has been applied to
the undiagnosed pulmonary nodule to estimate like-
lihood of malignancy (Cummings et al. 1986; Gurney
1993; Gurney et al. 1993). This approach considers
the resulting pre-test probability of malignancy, in
conjunction with the patient’s operative risk, and
stratifies the patient into one of three categories:
observation, further non-resectional diagnostic testing
(e.g., sputum cytology, bronchial washings or brush-
ings, fine needle aspiration, PET scan), or surgical
resection (Ost et al. 2003). The patient’s pre-test
probability is highly dependent upon age, smoking
history, and CT scan characteristics of the lesion
(i.e., size [2 cm, spiculations, and rate of growth).
2.1.1 Staging
Once the diagnosis of pulmonary malignancy has
been made or, conversely, the pre-test probability is
sufficient to warrant resection without preoperative
tissue diagnosis, the patient undergoes a staging
workup to assign prognosis and determine the most
appropriate therapy. Verification of clinical stage is
central to the development of a treatment plan and
may be accomplished using multiple modalities, both
invasive (e.g., fine needle biopsy, resection) and non-
invasive (e.g., CT, MRI, FDG-PET scans). Stages I
and II NSCLC are treated with surgical resection.
Patients with locally advanced Stage III tumors are
potential candidates for surgery, depending on the
specific aspects of local invasion (e.g., tumor infil-
tration into the chest wall or carina versus involve-
ment of great vessels or heart) or level of nodal
metastasis. Stage IV cancers exhibiting extensive
metastatic spread are generally outside the realm of
the thoracic surgeon, except for palliative measures,
although solitary metastases may not preclude a
potentially curative lung resection. Patients whose
poor medical condition precludes a pulmonary
resection may still benefit from interventions to
restore and maintain airway patency through bron-
choscopic debridement of tumor, photodynamic
therapy, airway stenting, or brachytherapy.
The staging system for NSCLC is based on
TNM classification. The 7th edition of the
Lung Cancer Surgery 105

• Separate nodule in an ipsilateral lobe (M1) has been

downstaged to T4.
TMN N0 N1 N2 N3
• M1 has been subdivided into M1a and M1b.
• Malignant pericardial or pleural effusion (T4) has
been upstaged to M1a.
T1a IA IIA IIIA IIIB
• Separate nodule in a contralateral lobe (M1) is
subclassified as M1a.
T1b IA IIA IIIA IIIB
• Distant metastasis is now designated as M1b.

2.1.1.1 T Stage
T1 tumors are \3 cm in diameter, surrounded com-
T2a IB IIA IIIA IIIB
pletely by lung parenchyma or visceral pleura and
exhibit invasion no more proximal than a lobar
bronchus. T2 tumors are[3 cm but limited to 7 cm in
T2b IIA IIB IIIA IIIB
diameter, can exhibit invasion of the visceral, but not
parietal pleura, and may involve the mainstem
bronchus no closer than within 2 cm of the carina.
T3 IIB IIIA IIIA IIIB
Atelectasis or obstructive pneumonitis may extend to
the hilum, but not involve an entire lung.
T3 tumors are [7 cm in diameter or exhibit locally
T4 IIIA IIIA IIIB IIIB invasive behavior, involving the parietal pleura, chest
wall (including the superior sulcus), diaphragm, phrenic
nerve, mediastinal pleura, parietal pericardium or a
M1a IV IV IV IV mainstem bronchus\2 cm from the carina. There may
be atelectasis or obstructive pneumonitis involving the
entire lung. In addition, T3 also describes satellite tumor
M1b IV IV IV IV
nodules within the same lobe. T4 tumors invade the
carina, trachea, mediastinum, vertebral body, recurrent
laryngeal nerve, great vessels, heart, or esophagus. If a
Fig. 1 Non-small cell lung cancer staging. 7th edition of
IALSC Staging System separate tumor nodule was present in an ipsilateral lobe,
this would also be considered a T4 lesion.
Chest CT is considered a mainstay for staging
International Lung Cancer Staging System was despite historical data that demonstrate an inability to
published in 2009 (Fig. 1) (Detterbeck et al. 2009), distinguish between T1/T2 and T3/T4 tumors up to
and subsequently adopted by the American Joint one-quarter of the time, (Antoch et al. 2003; Lardinois
Committee on Cancer (AJCC) and the Union et al. 2003) a limitation that may affect the extent of
Internationale Contre le Cancer (UICC) in 2010 surgical resection (Webb et al. 1991). Integrated
(Edge et al. 2010). While the N descriptor remained PET-CT scan may prove more accurate, yielding 98%
unaltered, the T (Rami-Porta et al. 2007) and M correct clinical staging when compared to pathologi-
(Postmus et al. 2007) descriptor classifications have cal staging (Lardinois et al. 2003). Radiologic
been revised extensively to provide greater prog- reconstruction of the tracheobronchial tree is insuffi-
nostic specificity: cient to exclude airway invasion, therefore, our
• T1 (B3 cm) has been subclassified into T1a policy is to perform bronchoscopy to assess the air-
(B2 cm) and T1b ([2 but B3 cm). way before surgical resection. Determination of the
• T2 ([3 cm) has been subclassified into T2a proximal extent of endobronchial tumor invasion
([3 but B5 cm) and T2b ([5 but B7 cm). (i.e., distance from carina) may be accomplished, in
• T2 ([7 cm) has been upstaged to T3. addition to assessment for anatomic abnormalities,
• Separate nodule in the same lobe (T4) has been which might influence the surgical resection. Intra-
downstaged to T3. operatively, frozen section analysis may be useful to
106
Fig. 2 The International
Association for the Study of
Lung Cancer (IASLC) lymph
node map (Rusch et al. 2009)
determine extrapulmonary tumor involvement versus
inflammation or adhesion in some cases (i.e., confirm
T3 or T4 status).
2.1.1.2 N Stage
The lymph node drainage of the lung has been
described previously (Asamura et al. 1999; Naruke
et al. 1978). In 1997, a revised lymph node map (the
S. P. Gangadharan et al.
Mountain–Dresler modification of the ATS map) was
agreed upon by the AJCC and the UICC for the 6th
edition of the staging manual (Mountain and Dresler
1997). N0 cancers have no demonstrable metastases
to regional lymph nodes. N1 represents metastasis to
the ipsilateral peribronchial or hilar lymph nodes, as
well as direct extension of the primary tumor into
intrapulmonary nodes (lymph nodes with double-digit
Lung Cancer Surgery
numbering). N2 lymph nodes are metastases to ipsi-
lateral mediastinal or subcarinal lymph nodes (single-
digit lymph nodes). N3 designates metastasis to
contralateral mediastinal or hilar lymph nodes, or any
scalene or supraclavicular lymph nodes irrespective
of laterality.
For the 7th edition of the staging manual, the
IASLC validated the prognostic influence of the
existing N descriptor as previously defined. There
were, however, some discrepancies between this
nodal map and the one used in Asia. To address this
and another concern about the reproducibility of
determining the boundaries between different nodal
stations during mediastinoscopy or thoracotomy
(Zielinski and Rami-Porta 2007), the IASLC has
developed a new lymph node map that defines six
nodal ‘‘zones’’ encompassing the established nodal
stations (Fig. 2) (Rusch et al. 2009).
Non-invasive lymph node staging can be per-
formed using CT scan, PET scan, MRI, endoscopic
ultrasound (EUS), or endobronchial ultrasound
(EBUS). A meta-analysis (Toloza et al. 2003a) of
studies utilizing the first four of these various
modalities revealed a pooled sensitivity of 57% for
CT, 84% for PET, 100% for MRI, and 78% for EUS.
Specificities were 89% for CT, 82–95% for PET, 91%
for MRI, and 71% for EUS. Subsequent assessment of
the ability of MRI to stage the mediastinum have been
equivocal (Webb et al. 1991). MRI is superior to CT
for characterizing direct invasion into the mediasti-
num, chest wall, diaphragm, or vertebral bodies due
to its ability to detect differences in signal intensity
between tumor and normal tissues, including bone,
fat, vascular structures, and, soft tissue (Shiotani et al.
2000). It greatly facilitates the evaluation of superior
sulcus tumors, particularly when assessing involve-
ment of the neural foramina or tumors abutting the
mediastinum, structures of the chest wall, or dia-
phragm. Currently, MRI would not be considered the
standard imaging modality for evaluation of lymph
nodes in lung cancer. The accuracy of CT/PET scan
with regard to lymph node staging may be enhanced
by the integration of these two technologies (Weng
et al. 2000). We routinely use integrated CT/PET to
stage individuals with enlarged nodes or patients
whose primary tumor demonstrates characteristics
concerning for nodal spread. In a prospective com-
parison of CT versus CT/PET, the sensitivity, speci-
ficity, and accuracy of CT were 70, 69, and 69%,
107
respectively, whereas those of PET/CT were 85, 84,
and 84%, respectively (Shim et al. 2005). In practice,
in cases with very small solitary peripheral tumors
and a negative mediastinum by PET-CT, invasive
staging may sometimes be omitted prior to surgical
resection.
Invasive lymph node staging can be accomplished
by transthoracic needle biopsy, EUS needle biopsy,
mediastinoscopy, thoracoscopy, or more recently,
EBUS with trans-bronchial needle aspiration (EBUS–
TBNA). Meta-analysis of the first four techniques
reveals that cervical mediastinoscopy yields the best
performance profile, with a sensitivity of 81% and
negative predictive value of 91% (Toloza et al. 2003b).
Half of the nodes missed were not accessible through
cervical mediastinoscopy, because this technique only
permits evaluation of the paratracheal and subcarinal
lymph node stations. Further enhancement of sensi-
tivity may be accomplished with the addition of
extended cervical or anterior mediastinotomy tech-
niques (Ginsberg et al. 1987; McNeill and Chamberlain
1966). EBUS-TBNA has expanded the options for
staging NSCLC, extending the ability to sample sta-
tions to the hilar and even interlobar levels. In addition,
its use for obtaining tissue from the primary lesion has
reduced the need for transthoracic biopsy and its risk
for iatrogenic pneumothorax (5–8 vs. 23–38%) (Eber-
hardt et al. 2007). In patients found to have enlarged
nodes on CT, the sensitivity and specificity can be as
high as 94 and 100%, respectively (Herth et al. 2006a).
When the CT was negative, results dropped off only
slightly from 92.3 to 100%, with a negative predictive
value of 96.3% (Herth et al. 2006b). A recent ran-
domized controlled trial comparing mediastinoscopy
versus EUS/EBUS plus mediastinoscopy found that the
addition of EUS/EBUS to mediastinoscopy improved
sensitivity from 79 to 94% (Annema et al. 2010).
A secondary endpoint of this study noted a trend toward
improved sensitivity of 85% for EUS/EBUS alone,
with similar NPV as mediastinoscopy. Nevertheless, a
negative result obtained by EBUS or EUS should still
prompt confirmation of true negativity via mediasti-
noscopy sampling.
With the development of video-assisted medias-
tinoscopy (VAM), further improvements to what is
already considered the gold standard for staging the
mediastinum were obtained. One report on the use of
VAM to stage NSCLC in patients with enlarged
nodes by CT scan demonstrated a sensitivity of
108
97.3% and specificity 100% (Venissac et al. 2003).
In cases of extensive tumor infiltration into the
mediastinum radiologic staging may suffice and
needle aspiration or bronchoscopy may be enough to
obtain pathologic confirmation of diagnosis (Kramer
and Groen 2003; Detterbeck et al. 2003). The utility
of thoracoscopic lymph node staging has not been
fully elucidated (Gossot et al. 1996; Landreneau
et al. 1993a) but it would appear that VATS as an
adjunct to mediastinoscopy is reasonable, especially
for subaortic and para-aortic stations (Van Schil
2007).
When invasive LN sampling is indicated and con-
firmation of positive mediastinal nodal involvement is
not achieved endoscopically, cervical mediastinoscopy
is used as the last preoperative staging step before
planned surgical resection. To minimize the likelihood
that lymph nodes will be read as falsely negative for
tumor metastasis, we send the specimens for perma-
nent section analysis by pathology instead of relying
on frozen section analysis. Thus, the planned pul-
monary resection is deferred to a second operative
setting. The surgical approach to cervical mediasti-
noscopy and lymph node sampling commences with a
small incision above the sternal notch, followed by
dissection between the strap muscles until the pre-tra-
cheal fascia may be breached. Blunt dissection is then
used to enter the mediastinum, and the paratracheal
and subcarinal lymph nodes are exposed and removed
with a biopsy forcep under direct vision (Reed and
Sugarbaker 1996). The morbidity of the procedure is
minimal (Park et al. 2003; Luke et al. 1986). Deter-
mination of IIIB disease (contralateral mediastinal
lymph node involvement, N3) would preclude surgical
resection. Our algorithm for positive N2 nodes
involves preoperative chemoradiation or chemotherapy
alone, prior to re-staging imaging. If there is no pro-
gression of disease, we recommend pulmonary resec-
tion with radical lymphadenectomy.
2.1.1.3 M Stage
The absence of clinical findings may preclude the
need to scan the asymptomatic early-stage lung
cancer patient extensively, as neither survival nor
recurrence rates are affected (Tanaka et al. 1999;
Ichinose et al. 1989). Some authors recommended
radiologic investigation for extrathoracic disease only
if it is warranted by clinical evaluation or in the case
of advanced disease (Stages IIIA or IIIB) (Silvestri
S. P. Gangadharan et al.
et al. 2003). Unnecessary thoracotomy, however, may
be prevented by routine extensive extrathoracic
workup (Anonymous 2001). In addition to head CT or
MRI, we use whole body integrated PET-CT scanning
to further clarify the presence of metastatic disease;
the effect of this technology on survival and recur-
rence is yet to be prospectively determined. Patients
with either solitary brain metastases (Patchell et al.
1990; Burt et al. 1992; Magilligan et al. 1986) or
solitary adrenal metastases (Luketich and Burt 1996;
Porte et al. 2001) may benefit from surgical resection
of the primary lung tumor in addition to the metastatic
lesion. Our strategy in these cases of ‘oligometastatic’
disease is to combine a metastatic workup with cer-
vical mediastinoscopy. If contralateral nodal disease
is not found, then the patient may undergo resection
of the solitary brain or adrenal metastasis, followed
by pulmonary resection as above.
2.2 Preoperative Fitness
Once a patient is determined to be resectable, it is
imperative to assess overall fitness to undergo surgery.
In addition to a careful history and physical that might
reveal the presence of heart failure, coronary insuffi-
ciency, or other co-morbidities, all patients considered
for surgical resection at our institution undergo pul-
monary function testing (PFT) and determination of the
diffusing capacity of the lung for carbon monoxide
(DLCO). In addition, a modified stair-climbing test is
sometimes used to assess a patient’s suitability for
surgery (Brunelli et al. 2002, 2004).
A preoperative forced expiratory volume
(FEV1) [ 2L (60% of predicted) and DLCO [ 60%
of predicted value suggest that the patient will tolerate
pulmonary resection, including pneumonectomy.
The threshold to tolerate a lesser resection is com-
mensurately reduced: FEV1 [ 1L for lobectomy and
FEV1 [ 0.6L for wedge resection (Miller et al.
1981). At our institution, we rely heavily on the
percent of predicted values, as these account for
individual variability in age or size. Despite some
variance in the literature regarding the efficacy of
FEV1 or DLCO in predicting outcome after lung
surgery (Stephan et al. 2000; Ferguson et al. 1988)
further testing to stratify postoperative risk should be
undertaken if the FEV1 or DLCO is less than the
thresholds cited above (Datta and Lahiri 2003).
Lung Cancer Surgery
Calculation of a predicted postoperative FEV1
(ppoFEV1) may be accomplished either by estimation,
using the formula of Juhl and Frost [ppoFEV1 = pre-
operative FEV1 9 (1-(S 9 5.26)/100); S number of
segments to be resected] (Juhl and Frost 1975), or by
quantitative VQ scanning modified after Wernly et al.
(1980) [ppoFEV1 = preoperative FEV1 9 (1-(%
perfusion contributed by affected lung/100 9 S/total
number of segments in affected lung))]. A ppo-
FEV1 [ 40% of predicted and DLCO [ 40% of pre-
dicted have been suggested as threshold values (Datta
and Lahiri 2003; Beckles et al. 2003). Our group has
previously demonstrated that by using a variety of
minimally invasive techniques, limited resections, and
concomitant lung volume reduction, with advanced
anesthetic and perioperative care, curative resections
can be performed in patients with preoperative
FEV1 \ 35% of predicted with a mortality of 1% and
serious morbidity under 5% (Linden et al. 2005). The
determination of operability should be made by a tho-
racic surgeon skilled in these techniques. Exercise test-
ing and calculation of VO2max represents the next level of
testing should the predicted postoperative values
be below threshold values. VO2max [ 20 ml/kg/min
designates an acceptable risk group for surgery.
VO2max \ 10 ml/kg/min confers significantly increased
risk for postoperative death or cardiopulmonary com-
plications following lung surgery (Datta and Lahiri
2003; Beckles et al. 2003).
In patients who are scheduled to undergo pneumo-
nectomy or who may present with cardiac co-morbidity,
we obtain a preoperative echocardiogram to evaluate
ventricular and valvular function, as well to investigate
any pre-existing pulmonary hypertension. Occasion-
ally, right heart catheterization and pulmonary artery
balloon occlusion are used to determine further a
patient’s physiologic response to lung resection.
3 Operative Strategy
3.1 Nomenclature and Anatomy
The scope of surgical resection ranges from wedge
resection to pneumonectomy. The wedge resection
represents a non-anatomic resection of the target
lesion, with a variable margin of lung parenchyma.
The terminology non-anatomic refers to the lack of
dissection of any of the branches of the three
109
bronchopulmonary structures—pulmonary vein, pul-
monary artery or bronchus—or the attendant draining
lymphatics or lymph nodes. Segmentectomy describes
an anatomic resection of the bronchopulmonary seg-
ment. The right upper lobe is comprised of apical,
anterior, and posterior segments; the right middle lobe
is comprised of the lateral and medial segments; and
the right lower lobe is comprised of the superior
segment, as well as the medial, anterior, lateral, and
posterior basal segments. The left upper lobe is
divided into the upper division comprising the api-
coposterior and anterior segments, and the lingula,
which contains a superior and inferior segment. The
left lower lobe is comprised of the superior segment,
and the anteromedial, lateral, and posterior basal
segments. Lobectomy entails removal of an entire lobe
and its lobar pulmonary artery, pulmonary vein, and
bronchus, with attendant lymphatic basin. Bilobec-
tomy is similar resection of two lobes from the same
lung. Sleeve resection denotes the removal of a cir-
cumferential portion of the airway in conjunction
with the parenchymal resection. The remaining
lung requires a bronchial anastomosis in order to
re-establish airway continuity. A sleeve resection can
also be performed on the pulmonary artery, should it
be necessary to resect a circumferential portion of the
vessel with the specimen. Similarly, bronchoplasty or
arterioplasty in conjunction with a pulmonary resec-
tion describe the techniques by which the bronchus or
pulmonary artery is reconstructed after removal of a
non-circumferential portion of the structure during
resection. Pneumonectomy can be intrapericardial or
extrapericardial, in reference to the site of division of
the pulmonary vessels. Extrapleural pneumonectomy
or pleuropneumonectomy refer to the en bloc removal
of the parietal pleura with the entire lung. En bloc chest
wall resection describes the removal of a portion of the
parietal pleura, ribs, and intercostal musculature
attached to the primary specimen of resected lung.
3.2 Extent of Resection
The first lobectomy for lung cancer using a technique
of individual ligation of the hilar structures was per-
formed by Davies in 1912 (Davies 1913). Churchill
refined lung resection with the introduction of the
technique of individual ligation of the bronchopulmo-
nary structures (Churchill and Belsey 1939). Graham
110
reported the first successful pneumonectomy for lung
cancer in 1933 (Graham and Singer 1933). Pneumo-
nectomy remained the operation of choice for lung
cancer until Churchill’s report in 1950, which detailed
long-term survival following lobectomy (Churchill
et al. 1950). The issue of whether sublobar or non-
anatomic resection might similarly suffice was raised
by Jensik et al. (1973). Subsequent investigators have
concluded that a lesser resection in the setting of
impaired cardiopulmonary reserve or advanced age
might be justified (Landreneau et al. 1997; Errett et al.
1985). One argument against applying a strategy of
limited resection to any patient with early-stage lung
cancer has been that it may understage cancers by
virtue of inadequate lymph node sampling. Takizawa
et al. (1998) found a 17% incidence of metastases to
N1 and N2 lymph nodes with radical lymphadenec-
tomy after resection of small (1.1–2.0 cm) peripheral
lung adenocarcinomas, suggesting that an adequate
assessment of the draining lymph node basin may be
important even in these distal T1 tumors. The other
area of contention is whether limited resection could
effect a local and systemic cure. A randomized trial of
lobectomy versus segmentectomy or wedge resection
for T1N0 NSCLC was reported by the Lung Cancer
Study Group in 1995. Although no statistically sig-
nificant difference in survival was found, they did find
an increased overall recurrence rate and locoregional
recurrence in the limited resection group (75% and
threefold, respectively) (Ginsberg and Rubinstein
1995). This increased recurrence after sublobar resec-
tion echoed the findings of Warren and Faber (1994).
Landreneau et al. (1997) examined the outcomes of
lobectomy and wedge resection, both video-assisted
and via open thoracotomy, and found a significant
improvement in 5-year survival curves after lobec-
tomy, although this was explicable by an excess of
non-cancer-related deaths in the limited resection
group. Miller and associates in their retrospective
analysis also found decreased 5-year survival for sub-
lobar resection compared to lobectomy. Importantly,
however, they also found that survival after segmen-
tectomy was statistically better then after wedge
resection, (57 and 27%, respectively), highlighting the
principle of an anatomic segment as the functional
oncologic unit (Miller et al. 2002).
Indeed, when sublobar resection consists of seg-
mentectomy with complete lobar and mediastinal dis-
section (i.e., extended segmentectomy), Yoshikawa
S. P. Gangadharan et al.
et al. (2002) found that for T1 tumors \2 cm in
diameter, 5-year survival (87.1%) was nearly equiva-
lent to lobectomy (87.8%). Schuchert and associates
from the University of Pittsburgh retrospectively
reviewed their experience with sublobar resection, both
segmentectomy and wedge resection, and found no
significant difference in recurrence or cancer-free sur-
vival (Schuchert et al. 2011). For AIS, a Japanese study
demonstrated wedge resection to have a 5-year overall
survival rate and the disease-free survival rate were
both 93%, and the 5-year cancer-specific survival rate
was 100% (Koike et al. 2009). The Cancer and
Leukemia Group B (CALGB) 140503 trial, a ran-
domized study of lobectomy versus sublobar resection
in patients with small peripheral Stage IA NSCLC, is
expected to have an enrollment of 1258 patients with
the primary end point being a comparison of disease-
free survival (National Cancer Institute 2010). Until
the results of this trial are known, the controversy
surrounding the issue will likely continue.
At our institution, we reserve pneumonectomy for
cases in which tumors are too central to fully resect
with lobectomy, and where bronchoplasty or sleeve
resection still would not allow an adequate margin with
parenchymal sparing. Similarly, extensive involvement
of the pulmonary vessels may necessitate pneumo-
nectomy, if arterioplasty is not feasible. Also, in cases
where the cancer crosses the fissure on the left or
crosses the major fissure, involving the upper and lower
lobes on the right, consideration is made to proceed
with pneumonectomy in patients with suitable reserve.
Conversely, limited resection for lung cancer, with
the exception of a pure AIS lesion, is reserved at our
institution for patients with marginal medical status,
advanced age, poor pulmonary reserve, or in some
instances of second primary lung cancer. In all cases the
tumor stage is T1. Every effort is made to adequately
stratify risk preoperatively, to ensure that all potential
candidates for anatomic resection are identified.
3.3 Technique of Resection
We have previously described in detail the steps
for the major pulmonary resections (Sugarbaker
et al. 2001). In brief, after the induction of general
anesthesia, bronchoscopy is performed to assess the
airway for unexpected tumor progression or anatomic
abnormality that would alter the planned resection.
Lung Cancer Surgery
Subcutaneous heparin and prophylactic antibiotics are
administered. Single-lung ventilation is then accom-
plished using a double-lumen endotracheal tube or
single-lumen tube with a bronchial blocker. The
patient is positioned in thoracotomy position—a lat-
eral decubitus position, with the operative side up.
A number of incisions may be used to access the
pleural space. For most anatomic resections, we utilize
a posterolateral thoracotomy incision that begins at a
point midway between the lower half of the scapula and
the spine, and extends to the anterior border of the la-
tissimus dorsi muscle. The serratus muscle is usually
spared, the latissimus muscle is usually divided. The
fifth intercostal space is entered at the superior border
of the sixth rib. Occasionally the sixth space is used, or a
rib may be removed partially or entirely in order to
widen the access to the chest. An anterolateral thora-
cotomy, usually in the fourth intercostal space, is
another alternative. Sufficient analgesia for these inci-
sions is achieved with the combination of a long-acting
local anesthetic and a narcotic via a thoracic epidural
catheter placed preoperatively.
The hilar structures are individually dissected and
divided. Our preference is to divide both vessels and
bronchi using a stapler. Smaller pulmonary arterial
branches are doubly ligated if they are not amenable
to stapler division. Incomplete fissures are also divi-
ded using a stapling device. Lymphadenectomy is
performed.
The margins are inspected by a pathologist upon
removal of the specimen to assure a negative bron-
chial margin. The integrity of the bronchial stump is
checked by testing the stump with ventilatory pres-
sure up to 30 cm of H2O. When the patient has
received neoadjuvant radiation or may receive
postoperative radiation, it is our preference to but-
tress the bronchial stump with an intercostal muscle
pedicle, a pericardial or pleural flap, or a thymic fat
pad. We also buttress after pneumonectomy or
bilobectomy.
3.4 Postoperative Course
Mortality for lung cancer surgery ranges from 2 to 4%
in modern series, with postoperative morbidity
occurring approximately 15–30% of the time
(Deslauriers et al. 1989; Ginsberg et al. 1983;
Knott-Craig et al. 1997; Myrdal et al. 2001; Yano
111
et al. 1997). Myrdal et al. (2001) reviewed their
experience of 616 patients undergoing lung cancer
surgery and found an overall 30-day postoperative
mortality rate of 2.9%, with pneumonectomy con-
ferring a higher risk (5.7%) than lobectomy (0.6%).
The rate of major complication (defined as post-
operative bleeding leading to exploration, respira-
tory failure, bronchopleural fistula, myocardial
infarction, stroke, heart failure, or renal failure) was
8.8%, with a higher rate seen after pneumonectomy
(18.5%) than lobectomy (5.7%). Minor events
occurred in 22%, with supraventricular arrhythmias
accounting for half of these complications. The
mortality and complication rates after bilobectomy
have been previously reported to be comparable to
that of pneumonectomy (Deneuville et al. 1992).
However, more recent series do not report excess
mortality or morbidity after bilobectomy (Damhuis
and Schutte 1996; Cerfolio et al. 2000; Carbognani
et al. 2001).
At the Brigham and Women’s Hospital we use
postoperative clinical pathways to standardize care
after pulmonary resection and to reduce length of
stay. Implementation of patient care pathways for
lobectomy has been reported to reduce both length of
stay and hospital cost. Although 1-day stays after
lobectomy have been reported, a length of stay in the
5-to-7 day range is more common (Cerfolio et al.
2001; Wright et al. 1997) Although 1-day stays after
lobectomy have been reported, Tovar et al. (1998) a
length of stay in the 5-to-7 day range is more com-
mon (Tschernko et al. 1996; Kirby et al. 1995). At our
institution all patients are transferred to a specialized
thoracic surgery intermediate care unit after lobec-
tomy or lesser resection. After 1-to-3 days in this
setting, to permit invasive hemodynamic monitoring,
continuous oxygen monitoring, and frequent pul-
monary toilet/ambulation, patients are transferred to a
regular floor bed on the thoracic surgical unit, which
provides continued specialized nursing care. After
pneumonectomy, our patients are recovered first in a
specialized thoracic intensive care unit, which allows
even more extensive monitoring such as pulmonary
artery catheterization, if indicated. Both hospital and
surgeon-specific experience influence postoperative
mortality for lobectomy and pneumonectomy, with
higher volume correlating with better outcomes in
several large studies (Birkmeyer et al. 2002, 2003;
Hannan et al. 2002).
112
Five-year survival for NSCLC has been reported
by Goldstraw in 2007 (Goldstraw et al. 2007). For
Stage IA tumors the 5-year survival is 73% (T1N0)
and 58% for Stage IB (T2N0). Stage IIA tumors are
46% (T1N1, T2aN1, T2bN0), 36% for Stage IIB
(T2bN1, T3N0). In Stage IIIA, the 5-year survival is
24% (T1-2N2, T3N1-2, T4N0-1). The rate drops in
Stage IIIB (T4N2, T1-4N3) to 9%. For Stage IV
(TxNxM1-2) overall 5-year survival is 13%.
3.5 Video-Assisted Thoracoscopic
Surgery
Video-assisted thoracoscopic surgery (VATS) utilizes
small port accesses to the chest and a videoscope for
visualization, thereby avoiding a full thoracotomy
incision. The ability to perform pulmonary resections
with VATS techniques has provided a less invasive
method to safely diagnose and treat lung cancers
(DeCamp et al. 1995). Initial videoscopic thoracic
surgery was diagnostic or limited to treatment of
pneumothorax, pleural effusion, or other benign con-
ditions (Kopp et al. 1979; Oldenburg and Newhouse
1979; Rodgers et al. 1979; Kapsenberg 1981; Boutin
et al. 1982; Fritsch et al. 1975). VATS lobectomies
for lung cancer were first reported in 1993 (Walker
et al. 1993; Kirby and Rice 1993).
We have described our technique of VATS
lobectomy in detail elsewhere (Sugarbaker et al.
2001). A small incision in the anterior seventh inter-
space is used to place a port for a 5- or 10-mm vid-
eoscope. The entirety of the pleural space and lung
may be inspected for unexpected local or metastatic
spread. For wedge resections, second and third ports
are placed so that a triangulation is achieved over the
tumor, and instruments can be introduced to retract,
dissect, and staple the lung. For formal lobectomies or
segmentectomies we use a 4 cm fourth interspace
accessory incision in the anterior axillary line that
allows access to the hilar structures. No rib spreading
is done. In addition, we employ one posterior 1.5 cm
port near the tip of the scapula for retraction and an
additional small port anteriorly for suction. Dissection
and division of the pulmonary vein, pulmonary artery,
and bronchial structures are accomplished with
endoscopic staplers in similar manner to our open
lobectomy. Mediastinal lymphadenectomy is also
performed. The specimen is removed via an
S. P. Gangadharan et al.
endoscopic bag to avoid seeding the port sites with
shed tumor cells.
The operative mortality for wedge resection for
lung cancer has been reported to be negligible
(Landreneau et al. 1997; Kodama et al. 1997). For
elderly patients undergoing VATS wedge resection,
we have previously shown that the mortality is \1%,
with a morbidity of 9%. VATS lobectomy also has
been accomplished with minimal mortality and mor-
bidity (Gharagozloo et al. 2003; Tatsumi and Ueda
2003; Morgan et al. 2003; Lewis et al. 1999;
McKenna 1998). A recent representative report by
Walker and colleagues describes their experience
with 158 patients undergoing VATS lobectomy. They
report an 11% rate of conversion to open thoracot-
omy, secondary to extent of disease and bleeding in
most cases. The in-hospital mortality rate was 0.6%,
with an overall 30-day mortality rate of 1.8%
(Morgan et al. 2003). In a series of over 1,000 VATS
lobectomy cases, McKenna reported no intraoperative
deaths, and a 30-day mortality rate of just 0.9%, none
of which was secondary to bleeding. The rate of
conversion to open thoracotomy was 2.5% (McKenna
et al. 2006).
The oncologic validity of VATS lobectomy has not
been addressed in a randomized prospective trial, but
retrospective studies report 5-year survival rates for
Stage I and II NSCLC ranging from 60 to 90%, and
locoregional recurrence rates around 5% (Tatsumi
and Ueda 2003; Walker et al. 2003; Sugi et al. 2000;
McKenna et al. 1998). Freedom from cancer-related
or associated death has been reported to be 78% for
Stage I cancers, 51% for Stage II, and 29% for Stage
III (Walker et al. 2003). An adequate lymph node
dissection appears to be possible during VATS
lobectomy (Asamura et al. 1999; Morikawa et al.
1998).
An initial randomized trial of VATS versus open
lobectomy did not demonstrate a statistically signifi-
cant difference in length of stay (Kirby et al. 1995).
A subsequent randomized trial and several non-
randomized trials, however, were able to show a
reduction in length of stay with the minimally inva-
sive technique (Tschernko et al. 1996; Demmy and
Curtis 1999; Ohbuchi et al. 1998). These same trials
have also reported a significant difference in the level
of pain associated with VATS lobectomy (Tschernko
et al. 1996; Morikawa et al. 1998; Demmy and Curtis
1999; Landreneau et al. 1993b). Walker and
Lung Cancer Surgery
associates have shown that the incidence of chronic
pain following VATS lobectomy is 1.2% (Walker
et al. 1996). A recent review (Rueth and Andrade
2010) of VATS lobectomy versus open incorporated
the findings from several large studies on the out-
comes from open (Allen et al. 2006; Boffa et al. 2008)
and VATS lobectomy (Flores et al. 2009; Swanson
et al. 2007). The data strongly support the oncologic
equivalence of VATS compared to open lobectomy
for patients with early-stage NSCLC. VATS was also
associated with fewer postoperative complications
and may have less of a negative biologic impact.
3.6 Radiation Therapy for Patients
Undergoing Lung Resection: T3
Tumors
Adjuvant and neoadjuvant chemotherapy with or
without radiation has been studied extensively for
Stage IIIA (N2) and Stage IIIB (N3) disease.
Radiation therapy, without chemotherapy, does little
to help these patients. For locally invasive, T3,
tumors, radiation therapy alone may make the dif-
ference between clear margins and positive margins.
In general, T3 tumors invading the chest wall are
treated with surgical excision with wide margins
alone, without the need for radiation therapy. Sev-
eral retrospective trials have shown either no benefit,
or a detriment to adding preoperative radiation
therapy to patients with simple chest wall invasion
(Piehler et al. 1982; Albertucci et al. 1992).
Exceptions to this finding are tumors abutting or
involving the vertebral bodies. If the tumor is close
to the vertebral body, one may consider preoperative
radiation in order to shrink the tumor and lessen the
chance that resection of the vertebral body will be
required.
Superior sulcus tumors (Pancoast tumors) represent
a unique subset of tumors that invade the chest apex.
The tumor may involve vertebral bodies, subclavian
vessels, or the brachial plexus. Pancoast tumors are
preoperatively staged by CT, and sometimes MRI, as
T3 or T4 depending on the level of invasion. Lymph
node staging and metastatic workup are undertaken as
for other NSCLC. Positive N2 and N3 nodes are asso-
ciated with a 5-year survival of \10% (Detterbeck
1997; Deslauriers et al. 1994). Treatment of Pancoast
tumors begins with neoadjuvant therapy. These tumors
113
were initially approached with preoperative radiother-
apy alone (Shaw et al. 1961). Recently, however, ret-
rospective studies (Wright et al. 2002; Attar et al. 1998)
as well as a prospective randomized trial (Martin et al.
2001) have shown potential benefit to combining che-
motherapy with preoperative radiation for superior
sulcus tumors.
Surgical approaches to superior sulcus tumors
include extended posterolateral thoracotomy and
anterior cervicothoracic incisions (Shaw et al. 1961;
Dartevelle et al. 1993). Resection usually comprises
the following steps: (1) resection of the chest wall
including first rib and, at times, portions of involved
vertebral bodies; (2) resection of involved nerve roots,
up to the first thoracic nerve root; (3) resection of the
thoracic sympathetic chain; (4) resection of upper
lobe or wedge of involved lung; and (5) lymph node
dissection. Incomplete resection yields a survival rate
which is comparable to that of no resection (Rusch
et al. 2000).
T3 tumors involving the mediastinum are very
difficult to cure. Burt et al. (1987) reviewed 225
patients accrued over an 11-year period at Memorial
Sloan Kettering. The 5-year survival for patients with
T3N2 disease was 8%, which is similar to survival of
patients with lower T stage tumors and N2 disease.
Patients with T3N0 tumors invading the mediastinum
fared no better, with 5-year survival of 10%.
Although prospective trials do not exist, this subset of
patients may very well benefit from neoadjuvant
radiation or chemoradiation.
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 Radiation Response of the Normal Lung
Tissue and Lung Tumors
Hiromitsu Iwata, Taro Murai, and Yuta Shibamoto
Contents
1 Introduction.............................................................. 119
2 Radiation Response of Normal Lung Tissues ......
2.1 Mechanism of Radiation Injury ................................
2.2 Factors Related to Development of Radiation
Pneumonitis................................................................
2.3 Cryptogenic Organizing Pneumonia After
Pulmonary Irradiation................................................
3 Radiation Response of Lung Tumors ...................
3.1 Prediction of Radiosensitivity and Proliferative
Activity of Tumors ....................................................
3.2 Tumor Progression During Waiting Time Before
Radiotherapy ..............................................................
3.3 Radiation Response by Tumor Histology.................
3.4 Haplotypes of Genes Associated with Risk
of Adverse Normal Tissue Reactions .......................
References.......................................................................... 127
H. Iwata
T. Murai
Y. Shibamoto (&)
Department of Radiology,
Nagoya City University Graduate School of Medical
Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku,
467-8601 Nagoya, Japan
e-mail: yshiba@med.nagoya-cu.ac.jp
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_250, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
We reviewed recent investigations on radiation
response of normal lung tissue and lung tumors
120 and also introduced our own investigations. The
120 mechanisms for response of normal lung tissues to
radiation are not yet fully understood. Recent
121
researches have revealed that various cytokines
122 and lung parenchymal cells are involved in the
pathogenesis of radiation response of normal lung
122
tissues. Prediction of tumor and/or normal tissue
122 sensitivity to treatment is being investigated for
tailor-made cancer treatment based on the biolog-
124 ical characteristics. In the near future, it is hoped
125
that the relationship among clonogenic death of
126 target cells, cytokine induction, gene expression
and radiation pneumonitis, and that among radio-
sensitivity, tumor histology, tumor gene expression
and patient characteristics will be clarified. Future
investigations will lead to a step toward an era of
personalized cancer treatment.
1 Introduction
Radiation response of the normal lung tissue and lung
tumors has been studied for nearly 90 years. Pul-
monary damage complicating radiotherapy for breast
cancer was first reported in 1923 (Groover et al.
1923). Pathological changes in lung tissue following
chest wall irradiation have been subsequently repor-
ted in the 1930–1950s (Engelstad 1940; Bergmann
and Graham 1951). Radiotherapy for lung tumors
moved into full swing in the early 1950s. Since then,
119
120
the effect of radiotherapy for lung tumors and lung
function after radiotherapy were reported one after
another. (Sweany et al. 1959; Barton et al. 1960).
During these times, Puck and Marcus (1956) devised
a colony formation method with which survival of
cells became measurable in vitro. This facilitated
tremendous progress in radiation biology at the cel-
lular levels. Most of the important biological phe-
nomena at the cellular and animal levels appeared to
have been clarified by 1980. Thereafter, advances in
molecular biology have brought us much new
knowledge on radiobiology of various normal tissues
and tumors. Although molecular mechanisms for
normal lung tissue reaction and lung tumor cell killing
are not completely clarified yet, many cytokines have
been identified that are involved in the pathogenesis
of normal lung tissue reaction including radiation
pneumonitis. Some of more recent researches aim at
identifying single nucleotide polymorphism of genes,
oncogene expression and angiogenesis that are pos-
sibly related to increased normal lung tissue reaction
and radiosensitivity of lung tumors.
In recent years, the use of stereotactic body
radiotherapy (SBRT) has spread as a new treatment
modality for lung tumors. Along with the develop-
ment of treatment methods and machines, it has
become necessary to evaluate radiation response of
normal lung tissue and lung tumors, especially to
hypofractionated high-dose-per-fraction radiation
delivery. In this article, we review recent investiga-
tions regarding these issues and also introduce our
own investigations on radiation response of normal
lung tissue and lung tumors.
2 Radiation Response of Normal
Lung Tissues
2.1 Mechanism of Radiation Injury
Although the mechanisms for response of normal lung
tissues to radiation are not yet fully understood, recent
researches have revealed that many factors and vari-
ous lung parenchymal cells contribute to the patho-
genesis of radiation response of normal lung tissues
(Kong et al. 2005). Previously, clonogenic death of
target cells has been considered to be a major cause of
normal tissue injury by irradiation. Regarding lung
H. Iwata et al.
injury caused by irradiation, for example, the type II
pneumocyte has been considered to be one of the
most important target cells. The type II pneumocyte
exhibited the earliest response to radiation and a
decrease in lamellar bodies and a corresponding
increase in alveolar surfactant were reported shortly
after radiation (Penney et al. 1982). However, Rubin
et al. (1995) demonstrated radiation-induced damage
progression is the result of an early activation of an
inflammatory reaction leading to the expression and
maintenance of an elevated cytokine cascade and
gene expression following pulmonary irradiation in
mice. Among these cytokines and genes are inter-
leukin 1 (IL-1), IL-6, transforming growth factor
beta-1 (TGF-b1), tumor necrosis factor alpha
(TNF-a), high-molecular-weight mucin-like antigen
KL-6, platelet-derived growth factor, and collagen
and fibronection genes. The pathogenesis of radiation
lung damage is considered to be similar to that of
interstitial pneumonitis. It has also been shown that
inducible nitric oxide synthase (NOS) and nitric oxide
are involved in radiation pneumonitis. Inducible NOS
is strongly expressed in pneumocytes and alveolar
macrophages in idiopathic interstitial pneumonitis.
Peroxynitrite, a potent oxidant produced by the rapid
reaction of nitric oxide and superoxide, is highly
present in such lungs (Worthington et al. 2000; Saleh
et al. 1997). Recent data have also shown that nitric
oxide induces stabilization of hypoxia inducible fac-
tor 1, alpha (HIF-1a) through a mechanism involving
free radicals. Therefore, upregulation of NOS by
radiation may subsequently trigger the HIF/vascular
endothelial growth factor (VEGF) molecular cascade
(Quintero et al. 2006). As for chronic lung injury, Fas/
CD95 and Fas-ligand activation is associated with a
fibrotic response. Fas-ligand protein is present in
infiltrating lymphocytes and granulocytes, and
expression of Fas is upregulated in alveolar and
bronchiolar epithelial cells (Kuwano et al. 1999).
Radiation directly induces Fas expression in cells, and
inflammatory cells consecutively expressing Fas-
ligand may promote apoptosis of pneumocytes. It has
also been shown that activated fibroblasts in the
induction of apoptosis of alveolar epithelial cells may
play a role of chronic lung injury (Martin et al. 2005).
Therefore, if early apoptosis responses in the alveolar
cells are mediated by excess concentrations of Fas-
ligand, then blocking apoptosis early after lung injury
might be beneficial.
Radiation Response of the Normal Lung Tissue and Lung Tumors 121

Table 1 Multivariate analysis of factors associated with the occurrence of C Grade 2 radiation pneumonitis
p Hazard ratio, p Hazard ratio,
95% CI 95% CI
KL-6 (U/ml) 0.04 6.1 (1.1–34.7) 0.02 6.8 (1.5–31.5)
(C500, \500)
Sex 0.10 6.1 (0.7–50.8) 0.10 6.0 (0.7–50.9)
(M, F)
PTV volume (cm3) 0.15 2.6 (0.7–9.1) 0.22 2.2 (0.6–7.5)
(C43, \43)a
Presence of IP 0.56 2.0 (0.2–22.6)
(+, -)
b
V20 Lung (%) 0.64 0.7 (0.1–3.8)
(C6, \6)a
Mean lung dose (Gy) 0.38 2.1 (0.4–11.6)
(C4, \4)a
Differences were tested by logistic regression
PTV planning target volume, IP interstitial pneumonitis, CI confidence interval
a
Divided by the median
b
Percentage of the lung receiving a 20 Gy or higher dose

2.2 Factors Related to Development management of severe radiation pneumonitis after

of Radiation Pneumonitis
Factors such as age, gender, smoking status, location
of tumor, and lung dosimetric factors can also con-
tribute to the lung damage caused by radiation. Pre-
vious reports have shown a correlation between
severe radiation pneumonitis and dose-volume
parameters such as the mean lung dose, V20 (per-
centage of the lung volume receiving C20 Gy), and
V5 (Tucker et al. 2010; Jin et al. 2009). Yet, it seems
that factors other than these physical parameters also
influence the incidence and severity of radiation
pneumonitis. With respect to conventional radiother-
apy cases, recent researchers have revealed that
appropriate inhibition of key cytokines at an early
stage might provide new tools for the effective treat-
ment of radiation pneumonitis (Anscher et al. 2003;
Goto et al. 2001). However, in patients undergoing
SBRT for lung tumors, only a few reports have sug-
gested that the early response of blood markers
mentioned above is a good indicator of severe radia-
tion pneumonitis.
In February 2004, we started SBRT for stage I
NSCLC and lung metastasis with our own protocols
(Baba et al. 2010). During the protocol-based study,
we have investigated the usefulness of KL-6 mea-
surement for predicting the occurrence and
SBRT. The sialylated carbohydrate antigen KL-6 is a
circulating mucin-like glycoprotein with a high
molecular weight that is classified as a cluster 9
human MUC-1 antigen. It has been found to be highly
expressed on type-2 pneumocytes and bronchiolar
epithelial cells (Kohno et al. 1988). MUC-1 is a large
transmembrane glycoprotein that has a rigid structure
protruding 200–500 nm above the plasma membrane
and is found at the surface of normal glandular epi-
thelial cells (Stahel et al. 1994; Hilkens et al. 1992).
The serum levels of KL-6 have been shown to cor-
relate with interstitial pneumonia rather than with
other benign diseases of the lung and other organs
(Kohno et al. 1989; Kobayashi and Kitamura 1995).
Moreover, several reports have shown that KL-6 is
useful for early diagnosis of severe radiation pneu-
monitis in patients undergoing conventional thoracic
radiotherapy (Goto et al. 2001; Matsuno et al. 2006).
However, in patients undergoing SBRT for lung
tumors, only a few reports have suggested that KL-6
is a good indicator of severe radiation pneumonitis
(Hara et al. 2004; Yamashita et al. 2010).
Table 1 shows the results of multivariate analysis
in our patients undergoing SBRT for stage I lung
cancer or lung metastasis. First, six factors that
showed a p value of \0.2 in the univariate analysis
were analyzed, and only the KL-6 level proved to be a
122
2500
2000
1500
KL–6 (U/ml)
1000
*
500 *
*
0 pneumonitis usually occurs within several months
–3 –2 –1 0 1 2 3 4 5
Months
Fig. 1 Serum KL-6 levels (cutoff level: 500 U/ml) of patients
who developed Grade C2 radiation pneumonitis. Month 0
represents the month when radiation pneumonitis first devel-
oped. The asterisks indicate the occurrence of cryptogenic
organizing pneumonia after a decrease in the KL-6 level in
response to steroid administration
significant factor related to the occurrence of [ Grade
2 radiation pneumonitis. Then, three factors (pre-
treatment serum KL-6 level, gender, and PTV vol-
ume) that showed a p value of \0.05 were analyzed,
and again, only the KL-6 level proved to be signifi-
cant. In our study, KL-6 levels increased almost in
accordance with the occurrence of C Grade 2 radia-
tion pneumonitis and decreased in accordance with the
response to steroid administration (Fig. 1). Moreover,
at the onset of Grade 2 or 3 radiation pneumonitis,
KL-6 levels were increased by 1.7 times on average
compared to the pre-treatment level. We think that
serial measurement of serum KL-6 levels before and
after SBRT would help to predict the occurrence of
radiation pneumonitis and manage severe radiation
pneumonitis after SBRT. If it is proven to be accurate
predictors for severe radiation pneumonitis, the blood
markers and the models of recommended dose volume
limits for predicting radiation pneumonitis may permit
us to select low-risk patients for dose escalation to
improve tumor local control and overall survival
without increasing radiation damage. On the other
hand, even if the risk of severe radiation pneumonitis
H. Iwata et al.
is high, lowering the prescribed dose or avoiding
SBRT may be difficult. In such patients, therefore,
pretreatment with blood markers should be used to
predict the occurrence of radiation pneumonitis (Iwata
et al., submitted for publication).
2.3 Cryptogenic Organizing Pneumonia
After Pulmonary Irradiation
Recently, unusual pneumonitis after radiotherapy of
breast-conserving therapy was reported (Ogo et al.
2008; Katayama et al. 2009; Takigawa et al. 2000;
Kubo et al. 2009). It is characterized by lung infiltrates
outside the radiation field, which are different from
radiation pneumonitis. The clinical features resemble
cryptogenic organizing pneumonia (COP). Radiation
after completion of radiotherapy and is generally
limited to the irradiated field; furthermore, migration
of shadows is not observed in radiation pneumonitis.
The incidence was reported to be 1.8–2.9%. We
investigated clinical and radiological features of
unusual pneumonitis like COP occurring after SBRT
of the lung and its incidence (Murai et al. 2010). This
was the first cohort study after SBRT. The incidence
of unusual pneumonitis like COP after SBRT was
4.9%, and appeared to be somewhat higher than that
reported for patients undergoing tangential breast
irradiation (Table 2). The symptoms were sometimes
severe, but steroids were effective. These patients with
unusual pneumonitis like COP had a history of pre-
vious symptomatic radiation pneumonitis before
COP-like pneumonitis. Figure 2 shows the example of
unusual pneumonitis like COP after SBRT for pri-
mary lung cancer. We could not find obvious risk
factors. Further investigation appears to be warranted
to identify its pathogenesis and risk factor.
3 Radiation Response of Lung
Tumors
3.1 Prediction of Radiosensitivity
and Proliferative Activity of Tumors
The necessity for tailor-made cancer treatment based
on the biological characteristics of each tumor has
been advocated since three decades ago. For this
Radiation Response of the Normal Lung Tissue and Lung Tumors 123

Table 2 Representative reported results of unusual pneumonitis like cryptogenic organizing pneumonia occurring after
radiotherapy
Author Treatment N Occurrence frequency (%) Relative factor
Ogo (2008) BCT 2056 1.8 None
Katayama (2009) BCT 702 2.3 Age, tamoxifen
Takigawa (2000) BCT 157 2.5 None
Kubo (2009) BCT 413 2.9 Central lung distance
Total BCT 3328 2.1*
Murai (2010) SBRT 164 4.9* Planning target volume
BCT breast-conserving therapy, SBRT stereotactic body radiotherapy
*
There was a significant difference between representative reported results after BCT and our data after SBRT (p = 0.02, Chi-
square test)

Fig. 2 Chest CT, radiograph and dose distribution of stereo-
tactic body radiotherapy (SBRT) for T2N0M0 primary lung
cancer of a 82-year-old patient. He presented with radiation
pneumonitis around planning target volume with Grade III
dyspnea at 8 months after SBRT (a and b, yellow arrow).
Radiation pneumonitis was resolved using prednisolone.
Unusual pneumonitis like cryptogenic organizing pneumonia
occurred 3 months after resolution of radiation pneumonitis.
Areas receiving more than 0.5 Gy are bounded by white lines
(e and f). Chest radiograph shows newly developed infiltrates in
the right lung outside the volume of [0.5 Gy (c and d, red
arrow)

purpose, prediction of tumor and/or normal tissue
sensitivity to treatment is necessary. To estimate
radiosensitivity of tumor cells, several types of pre-
dictive assays have been proposed. Among them, the
SF-2 assay in which the surviving fraction of tumor
cells at 2 Gy of in vitro irradiation is measured using
colony formation or colorimetric methods was most
intensively investigated (West et al. 1997). However,
the use of the SF-2 assay for radiosensitivity predic-
tion did not become a commonly used tool in clinics.
124
Fig. 3 Rate of increase in
volume and waiting time in
lung adenocarcinoma and
squamous cell carcinoma.
Both subtypes showed a
correlation between the two;
that is, the rate of increase
became higher with
elongation of waiting time.
Volume increase rate (%)
Modified from Murai et al.
(2011)
The reasons for this may include labor intensiveness
and a long waiting time before obtaining assay
results. Shibamoto et al. (1994, 1998) tried to estab-
lish a more rapid assay of radiosensitivity using the
cytokinesis-block micronucleus (MN) test. MN for-
mation represents chromosomal damage and the MN
frequency increases with radiation dose. Using this
assay, a method of simultaneously estimating radio-
sensitivity and proliferative activity of human tumors
was devised (Shibamoto et al. 1994, 1998). Estima-
tion of tumor proliferative activity is also important in
radiotherapy, since rapidly-growing tumors are con-
sidered to be resistant to protracted conventional
radiotherapy. One of the important parameters of
proliferative activity is the potential doubling time
(Tpot). The Tpot which is a doubling time in the
absence of the cell loss is considered to represent
repopulation rates during and after radiotherapy better
than the volume doubling time. The Tpot varies
greatly according to the histology of each tumor.
Radiosensitivity and proliferative activity character-
istics of primary lung cancers determined using this
assay were published previously (Shibamoto et al.
1998). The data showed that a high proliferative
activity was associated with an increased recurrence
rate after operation. However, differences in
H. Iwata et al.
Adenocarcinoma Squamous cell carcinoma
400
p = 0.02 p < 0.001
300
200
100
0 8 16 24 32 0 8 16 24 32
Waiting time (weeks)
proliferative activity and radiosensitivity according to
histological type of tumor were not clarified.
3.2 Tumor Progression During Waiting
Time Before Radiotherapy
An important issue to be addressed in clinical radio-
therapy is the influence of waiting time (WT) before
cancer treatment. The use of SBRT for stage I lung
cancer is rapidly increasing, so long WTs seem to
have become a problem in many institutions. In head-
and-neck cancer, long WTs are known to adversely
affect treatment outcome; in a meta-analysis by Chen
et al. (2008), the relative risk of local recurrence was
estimated to increase by 1.15 times if patients were
required to wait for a month or longer before the
initiation of definitive radiotherapy. Murai et al.
(2011) investigated the relationship between WT and
disease progression in patients undergoing SBRT for
lung adenocarcinoma (AD) or squamous cell carci-
noma (SQ). The median WT was 42 days (range,
5–323 days). Figure 3 shows the correlation between
WT and rate of increase in volume in both AD and
SQ. The median volume doubling time of AD and SQ
was 170 and 93 days, respectively. Thirty-six tumors
Radiation Response of the Normal Lung Tissue and Lung Tumors 125

(23%) did not show volume increase during Adenocarcinoma (n=32)

WTs [ 25 days. In 41 patients waiting for B4 weeks, Squamous cell carcinoma (n=23)
no patient showed T-stage progression, whereas in 25
of 120 (21%) patients waiting for [4 weeks, T stage 100
progressed from T1 to T2 (p = 0.001). In 10 of 110
(9.1%) T1 ADs and 15 of 51 (29%) T1 SQs, T stage 80

Overall survival(%)
progressed (p = 0.002). The risk of T-stage progres-
sion in T1 lung cancer was significantly higher in the 60

group waiting for longer than 4 weeks. Therefore, this

40
study supports the recommendation of the British
Thoracic Society (1998) that the WT should be less
20
than 4 weeks in patients undergoing curative surgery.
In addition, 4 weeks may be appropriate for accept-
0
able WT before SBRT, although the WT should be as
short as possible. 0 12 24 36 48 60 72

100

3.3 Radiation Response by Tumor 80

Histology Local control (%)
60
Radiation sensitivity is known to differ with tumor
histology. In primary lung cancer, small cell carci- 40
nomas are generally considered to be more radio-
sensitive than adenocarcinomas and squamous cell 20

carciniomas, but this impression may be largely due

0
to the rapid response of small cell carcinomas to
radiation. Ultimate local control rates might not be so 0 12 24 36 48 60 72
different among the three histological subtypes of
100
lung cancer (Ruckdeschel 1998; Brodin et al. 1991).
Disease-free survival (%)

During carbon-ion radiotherapy performed at the 80

National Institute of Radiological Sciences, Chiba,
squamous cell carcinomas tended to show lower local 60
control rates than melanomas and adenoid cystic
carcinomas (Mizoe et al. 2004). During proton ther- 40
apy and carbon-ion radiotherapy performed for head-
and-neck cancer at Hyogo Ion Beam Medical Center, 20
a similar trend was also experienced (Murakami et al.
2009). A similar trend was also observed for particle 0
therapy of primary lung cancer. We evaluated the 0 12 24 36 48 60 72
clinical outcome of particle therapy for stage I non- Time (months)
small-cell lung cancer (Iwata et al. 2010). Figure 4
shows overall survival, local control and disease-free Fig. 4 Overall survival, local control, and disease-free sur-
vival curves for patients treated with proton therapy according
survival curves according to histology in patients
to histology. Patients with adenocarcinoma had a higher local
treated with proton therapy. The local control rates control rate than those with squamous cell carcinoma
were higher for adenocarcinoma than for squa- (p = 0.022), although the overall and disease-free survival
mous cell carcinoma (p = 0.02). This is in contrast to rates were not different (p = 0.19 and 0.061, respectively).
Modified from Iwata et al. (2010)
the laboratory and clinical observations for
126
radiosensitivity of NSCLC cells to X-rays (Shibamoto
et al. 1998; Koukourakis et al. 1996). The differences
in radiosensitivity shown by histology should also be
investigated further, and more studies are necessary to
prove whether these observations are correct. At
present, it may be concluded that particle radio-
therapy is efficacious against adenocarcinoma, which
may not be well responsive to conventional
radiotherapy.
With respect to radiotherapy for lung metastasis,
large-scale data on outcome according to the primary
site or histology have not been reported to the best of
our knowledge. Milano et al. (2008) reported that
patients with oligometastatic disease in the lung,
brain, or liver etc. from primary breast cancer had a
significantly better outcome than those with other
primary tumors. On the other hand, it was reported
that oligometastases confined to one organ from
colorectal cancer treated by SBRT showed a 3-year
local control of 66% and a 5-year local control rate of
only 24% (Kang et al. 2010). Also, recent data have
shown that 3-year local control rate after SBRT using
3 fractions for isolated colorectal lung metastases was
as low as 53% (Kim et al. 2009). Although the total
dose is related to local control rates (Kang et al.
2010), a recent phase II study on lung metastasis from
variable primary cancers treated by SBRT revealed a
2-year local control rate of greater than 90%
(Rusthoven et al. 2009). Herfarth et al. (2001)
observed that poorer control is achieved by SBRT for
liver metastasis of colorectal cancer than for metas-
tases with other histology (45 vs. 91%, respectively,
at 18 months). There were many reports with radio-
therapy for brain metastasis according to histology.
Brain metastases of renal cell carcinoma, colorectal
cancer, and melanoma etc. were reported as radiore-
sistant (Meyners et al. 2010; Wronski et al. 1997;
Kruser et al. 2008). With respect to our data, lung
metastases from variable primary cancers treated by
SBRT showed a 3-year local control of 88% in 70
lesions. In this study, the 3-year local control rate was
lower for colorectal cancer metastases than for
metastases from other primary tumors (57 vs. 93%,
p = 0.0052; unpublished data). Thus, metastases
from colorectal cancer seem to be generally more
radioresistant than those from other primary tumors.
However, since tumor cells could develop resistance
following antitumor treatment failure, it is necessary
to evaluate the radiation sensitivity in relation to
H. Iwata et al.
previous systemic chemotherapy or local therapy in
future studies.
In the near future, it is hoped that the relationship
among clonogenic death of target cells, cytokine
induction, gene expression, and radiation pneumoni-
tis, and that among radiosensitivity for each tumor
histology, tumor gene expression and patient charac-
teristics will be clarified. Future discoveries will lead
a step toward an era of personalized cancer treatment.
3.4 Haplotypes of Genes Associated
with Risk of Adverse Normal Tissue
Reactions
The RadGenomics project started in April 2001 at the
National Institute of Radiological Sciences in Japan
(Iwakawa et al. 2002). This project promotes analysis
of genes that are expressed in response to irradiation,
identification of their allelic variants in the human
population, development of an effective procedure for
quantitating individual radiosensitivity, and analysis
of the relationship between genetic heterogeneity and
susceptibility to irradiation. Major groups of genes
investigated in the project include DNA repair genes,
genes for programmed cell death, genes for signal
transduction, and genes for oxidative processes.
In a recent report, the global haplotype association
analysis (p \ 0.05 and false discovery rate \0.05)
indicated that estimated haplotypes in six loci were
associated with the risk of early adverse skin reactions
(EASR) with breast cancer (Suga et al. 2007). In the
CD44 gene, the haplotype GGTT significantly
increased the risk of EASRs compared with the most
common haplotype GGTC (odds ratio = 2.17; 95%
CI, 1.07–4.43). Five haplotypes, CG in MAD2L2,
GTTG in PTTG1, TCC and CCG in RAD9A, and
GCT in LIG3 were associated with a reduced EASR
risk. Results of similar analyses in patients with
uterine cervical cancer have recently published; two
haplotypes were associated with an increased risk of
early adverse reaction in the gastrointestinal tract
(Ishikawa et al. 2011). Cervical cancer patients who
have both risk haplotypes of NPAT-ATM and AU-
RKA showed significant association with an increased
risk of an early intestinal reaction to radiation therapy
(odds ratio = 3.24; 95% CI, 1.52–6.92).
Correlation between pulmonary toxicities and
single nucleotide polymorphisms of genes is also
Radiation Response of the Normal Lung Tissue and Lung Tumors
being investigated in the RadGenomic project, along
with the breast cancer and uterine cervical cancer
studies. Radiation pneumonitis is one of the major
normal tissue reactions investigated in this collabo-
ration. Analyses are ongoing and the results will be
obtained in the near future.
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 Radiation Time, Dose, and Fractionation
in the Treatment of Lung Cancer
Daniel Gomez, Melenda D. Jeter, Ritsuko Komaki,
and James D. Cox
Contents
1 Non-Small Cell Lung Cancer.................................
1.1 Dose Escalation with Standard Fractionation ..........
1.2 Large-Dose Fractionation and Stereotactic Body
Radiation Therapy .....................................................
1.3 Dose Escalation with Hyperfractionation .................
1.4 Accelerated Fractionation..........................................
1.5 Reducing the Target Volume with 3D Conformal
Radiation Therapy .....................................................
1.6 Intensity-Modulated Radiation Therapy ...................
1.7 Accounting for Tumor Motion .................................
1.8 Proton Therapy ..........................................................
1.9 Concurrent Chemotherapy.........................................
2 Small Cell Lung Cancer .........................................
2.1 Use of Combined Chemotherapy and Thoracic
Radiation Therapy .....................................................
2.2 Concurrent Therapy...................................................
2.3 Radiation Dose to the Thorax...................................
References.......................................................................... 139
D. Gomez
M. D. Jeter
R. Komaki
J. D. Cox (&)
Division of Radiation Oncology, Unit 97,
The University of Texas MD Anderson Cancer Center,
1515 Holcombe Boulevard, Houston,
TX 77030, USA
e-mail: jcox@mdanderson.org
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_268, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
Radiation therapy has been an important component
130 of potentially curative treatment of lung cancer for
130 more than 40 years. The radiosensitivity of normal
131
tissues in the thorax, especially the normal lung and
132 esophagus, has led to efforts to enhance the antitumor
132 effects of radiation while reducing its acute and late
adverse effects on normal tissues. Improving local
133
133
control of medically inoperable or locally advanced
134 unresectable disease (stage III non-small cell lung
134 cancer or limited-stage small cell lung cancer, defined
135 as disease confined to one hemithorax and the
135 ipsilateral supraclavicular lymph nodes) can favor-
ably influence overall survival rates. The therapeutic
136
ratio of radiation for the treatment of lung cancer can
136
138 be improved by increasing the biological dose to
maintain local control while protecting normal
tissues. One way of doing so is through the use of
fractionation, that is, manipulating the time interval
and dose of radiation to optimize the therapeutic ratio.
Topics covered in this chapter include dose escalation
with standard fractionation or hyperfractionation;
large-dose fractionation and stereotactic body radia-
tion therapy; accelerated fractionation; means of
reducing the target volume by using techniques such
as 3-dimensional conformal or intensity-modulated
radiation therapy; proton therapy; the importance of
accounting for tumor motion; and the use of combined
thoracic radiation and concurrent chemotherapy.
Radiation therapy has been an important component
of potentially curative treatment of lung cancer for
more than 40 years. The radiosensitivity of normal
129
130
Table 1 Fractionation definitions for lung cancer
Schedule Dose per No. fractions Intervals between
fraction (Gy) per week fractions (h)
Standard 1.8–2.75 4–6 24
Hypo [3.0 1–4 48–168a
Hyper 0.7–1.3 10–25 2–12
Rapid [2.5 5 24
Accelerated 1.5–2.5 10–21 4–12
Numbers or symbols given assume a dose-rate of 2.0–6.0 Gy/min
; or : indicate decreases or increases relative to values given for standard fractionation schedule; NC indicates no change
a
Intervals longer than 168 h constitute a ‘‘split course.’’
tissues in the thorax, especially the normal lung and
esophagus, has led investigators to seek ways of
enhancing the antitumor effects of radiation while
reducing its acute and late adverse effects on normal
tissues. The focus in this chapter is on medically
inoperable or locally advanced unresectable disease,
specifically non-small cell lung cancer (NSCLC)
classified as stage IIIB (T4 or N3) or stage IIIA that is
unresectable because of bulky tumors or fixed N2
disease (according to the 2010 American Joint
Committee on Cancer staging system) and small cell
lung cancer (SCLC) confined to one hemithorax and
the ipsilateral supraclavicular lymph nodes.
The success of radiation therapy in a particular set-
ting often depends on the endpoints used. The traditional
assumption has been that distant metastasis is the major
cause of death from lung cancer; however, uncontrolled
tumor in the chest is also a major cause of mortality.
Indeed, improvements in thoracic computed tomogra-
phy (CT) scanning and fiberoptic bronchoscopy that
allow better visualization of lung tumors have led to the
recognition that lack of local control is the main cause of
treatment failure in lung cancer (Arriagada et al. 1991a,
1997). Two independent randomized trials have shown
that improving local control, which can be achieved
through two different approaches, can affect the overall
survival rates in both SCLC and NSCLC (Saunders et al.
1997; Schaake-Koning et al. 1992).
The therapeutic ratio of radiation for the treatment
of carcinoma of the lung can be improved by
increasing the biological dose to maintain local con-
trol while protecting normal tissues. One way of
doing so, and our emphasis in this chapter, is through
the use of fractionation, i.e., manipulating the time
interval and dose of irradiation to optimize the ther-
apeutic ratio.
D. Gomez et al.
Total no. Duration of Total dose
fractions treatment (weeks) (Gy)
25–40 5–8 55–75
; NC or ; NC or ;
: (;) NC NC (:)
; ; ;
; ;; ;
1 Non-Small Cell Lung Cancer
Local control of NSCLC, like that of SCLC, is
directly related to survival. The ability to maintain
local control of NSCLC has been far from satisfac-
tory, and hence several attempts have been made to
manipulate fractionation dose and schedule to esca-
late the biologically effective dose to the tumor and
thus improve the outcome. Table 1 gives some defi-
nitions that are useful in reviewing the literature on
time, dose, and fractionation in lung cancer.
1.1 Dose Escalation with Standard
Fractionation
The concept and standardization of dose constraints
for the lungs in the setting of standard fractionated
radiation therapy for lung cancer have changed in
recent decades. With regard to maximum tolerated
doses, studies of fractionated irradiation delivered
either to both lungs or to one lung at a time (Cox et al.
1972) suggested that an appropriate lung dose con-
straint was approximately 20 Gy at 1.5 Gy/fraction.
With regard to the volume of lung subjected to radi-
ation, Graham et al. 1995 used dose–volume histo-
gram analysis to show that the percentage of normal
lung volume receiving a total dose of at least 20 Gy
(V20) in standard daily fractions was strongly related
to the risk of severe or life-threatening pulmonary
toxicity.
The initial landmark study of dose escalation
with standard fractionation was conducted by the
Radiation Therapy Oncology Group (RTOG) (Perez
et al. 1988). Patients were randomly assigned to
Radiation Time, Dose, and Fractionation in the Treatment of Lung Cancer
one of four treatment groups. Three of these treat-
ments involved standard fractionation (2.0 Gy/day
given 5 days/week) to total doses of 40 Gy (in 20
fractions), 50 Gy (in 25 fractions), and 60 Gy
(in 30 fractions); the fourth treatment used large-
dose fractionation given in a split course (4 Gy/day
for 5 days, followed by a 3-week interruption, and a
second course of 4 Gy per day for 5 days) to a total
dose of 40 Gy (in ten fractions over 5 weeks). The
higher total radiation dose led to improved survival
rates, but this effect came at the cost of increased
toxicity. The RTOG investigators’ conclusion that
60 Gy in 30 fractions was the most effective
treatment became the standard for the RTOG, for
other cooperative groups, and for radiation oncolo-
gists throughout the US.
However, since that time, other studies have
corroborated the feasibility of increasing the total
dose while still using standard fractionation. In
RTOG 9311, 177 patients receiving three-
dimensional conformal radiation therapy (3D CRT)
were stratified to receive escalating radiation doses
at levels that depended on the V20. Twenty-five
patients received induction chemotherapy, but no
patient received concurrent chemotherapy. Patients
with a V20 of \25% received successive standard-
fractionation doses of 70.9, 77.4, 83.8 and 90.3 Gy.
Patients with V20 of 25–36% received successive
doses of 70.9 and 77.4 Gy. The investigators found
that radiation dose could be safely escalated with
this technique to 83.8 Gy if the V20 was \25% and
to 77.4 Gy if the V20 was between 25 and 36%
(Bradley et al. 2005).
In the subsequent RTOG 0117 trial, radiation dose
escalation with 3D CRT was studied in a phase I/II
setting with concurrent paclitaxel and carboplatin
chemotherapy. In the initial study design, the radia-
tion dose was to be intensified by increasing the daily
fraction size, starting from a total dose of 75.25 Gy to
be delivered in 35 fractions. However, among the
initial eight patients, two experienced dose-limiting
toxicity and thus, the protocol was revised to
de-escalate the radiation dose. The investigators
reported that the maximum tolerated dose was 74 Gy
in 37 fractions (Bradley et al. 2010). These results
led to an RTOG randomized trial that is currently
ongoing (RTOG 0617) comparing total doses of 60 to
74 Gy with concurrent chemotherapy for local-
regionally advanced NSCLC.
131
1.2 Large-Dose Fractionation
and Stereotactic Body Radiation
Therapy
Advocates of large-dose fractionation emphasize the
usefulness of this form of treatment (also called
hypofractionation) in lessening the overall number of
treatments and the corresponding burden on health
care facilities, reducing the stress on patients to
adhere to a schedule of 5 visits per week over a period
of six weeks, and possibly in increasing the biological
antitumor effect. Thames et al. (1983) documented in
the early 1980s that the use of large-dose fractions
was associated with increased late effects in normal
tissues; a comprehensive review of large-dose frac-
tionation published 2 years later by Cox (1985) con-
firmed the increase in late effects but also drew
attention to the possibility that this practice also had
adverse effects on tumor control because it allowed
repopulation of tumor cells between fractions.
In a subsequent study involving large-dose frac-
tionation, Uematsu et al. (2001) used CT-guided
frameless stereotactic radiation therapy to treat 50
patients with stage I NSCLC. Most of the patients in
this study were given 50–60 Gy in 5–10 fractions for
1–2 weeks, and 18 patients had already undergone
conventional radiation therapy (40–60 Gy in 20–33
fractions) before the stereotactic procedure. At a
median follow-up time of 36 months, 47 patients
(94%) showed no evidence of local progression on
follow-up CT scans, and the 3-year overall survival
rate was 66%. No adverse effects conclusively related
to the stereotactic radiation therapy were noted except
for minor bone fractures (two patients) and temporary
pleural pain (six patients).
During the past decade, the use of stereotactic
body radiation therapy (SBRT) has increased sharply.
Improved imaging techniques such as cone-beam CT
have allowed precise localization of the tumor during
treatment that minimizes treatment margins and sub-
sequent toxicity from normal tissue damage. One of
the initial reports on the safety and efficacy of this
technique for early-stage lung tumors was from the
University of Indiana. In that investigation, 37
patients with T1 or T2 disease received SBRT at an
initial dose of 8 Gy/fraction, with successive dose
escalations of 2 Gy/fraction. A dose of 60 Gy was
achieved for both patients with T1 and those with T2
disease, and no failures were noted among patients
132
who had received at least 18 Gy per fraction
(Timmerman et al. 2003). A subsequent study from
the same institution demonstrated that the rate of
severe toxicity for centrally located tumors, defined as
those within 2 cm of the bronchial tree, approached
50% (Timmerman et al. 2006), prompting recom-
mendations that lower fractionation regimens be used
for tumors in this location.
A recent report of 59 patients with solely periph-
eral tumors treated with 54 Gy in 3 fractions (18 Gy
per fraction) demonstrated a primary tumor control
rate of 97.6% and a local-regional control rate of
87.2% at a median follow-up time of 34.4 months.
Twelve percent of patients experienced grade 3 tox-
icity, and two patients experienced grade 4 toxicity,
but none experienced grade 5 toxicity (Timmerman
et al. 2010). Although this local control rate is
promising, longer follow-up is needed to establish the
effectiveness of SBRT in the long term. In the
meantime, the RTOG is conducting two trials, both of
which were ongoing when this chapter was written.
RTOG 0915 is a randomized phase II study compar-
ing SBRT schedules for patients with stage I periph-
eral NSCLC who are not candidates for surgery.
Patients are randomly assigned to one of two frac-
tionation regimens, either 48 Gy in four once-daily
fractions or 34 Gy in one fraction. The primary end-
point is the rate of grade 3 or higher toxicity at 1 year.
The other study, RTOG 0813, was designed to
identify the maximum tolerated dose for patients with
centrally located, T1/T2N0M0 NSCLC who are not
candidates for surgical resection. Doses are escalated
beginning at 50 Gy in five fractions, with the target
dose being 60 Gy in five fractions. A secondary
endpoint is the local control rate at the maximum
tolerated dose.
1.3 Dose Escalation
with Hyperfractionation
The potential for hyperfractionation to improve the
therapeutic ratio of radiation for many malignant
tumors was recognized in part from the failure of
large-dose fractionation to improve local control and
in part from the observation that use of smaller frac-
tions was associated with fewer late effects in normal
tissues. The RTOG conducted a series of trials of
hyperfractionated radiation therapy in which 1.2-Gy
D. Gomez et al.
fractions were given twice daily and the total doses
were escalated (Diener-West et al. 1991). For cancer of
the lung, the total doses ranged from 60 Gy (in 50
fractions over 5 weeks) to 79.2 Gy (in 66 fractions over
6.5 weeks). Improved survival rates were noted at the
total dose of 69.6 Gy, given in 58 fractions, with no
further improvement at higher doses. This dose frac-
tionation regimen was subsequently investigated in a
prospective trial in comparison with groups given either
standard fractionation or induction chemotherapy
followed by standard fractionation (Sause et al. 1995).
In that trial, use of induction chemotherapy was
associated with improved short-term survival but use
of the hyperfractionated regimen was not.
1.4 Accelerated Fractionation
With its twice-daily doses of 1.2 Gy, the protocol in
the RTOG study cited in the previous paragraph did
involve some acceleration of treatment; however, the
most thorough investigation of a markedly acceler-
ated course of radiation therapy was conducted at
Mount Vernon Hospital in the UK by Saunders et al.
(Saunders et al. 1997; Saunders 2000). Their inves-
tigation of continuous hyperfractionated accelerated
radiation therapy (CHART) involved use of three
1.5 Gy fractions per day for a total of 12 consecutive
treatment days, with no interruptions for weekends.
The total dose for this regimen was 54 Gy, given in
36 fractions over 12 days.
After CHART was found to produce promising
results in comparison with the historical experience at
Mount Vernon Hospital, a prospective randomized
trial was undertaken to compare CHART (total dose
of 54 Gy given in 36 fractions over 12 consecutive
days) to standard fractionation (total dose of 60 Gy in
30 fractions, 5 days per week, for 6 weeks). The
observed improvement in survival in the CHART
group was considered to result largely from the
improved intrathoracic tumor control. A derivative
benefit of this local tumor control was the lesser
incidence of distant metastasis in the CHART group
compared with the standard-fractionation group
(Saunders, 2000). This finding suggests that metas-
tasis from locally advanced lung cancer, like that at
other cancer sites, may arise through secondary
dissemination from residual local-regional tumors
(Arriagada et al. 1995).
Radiation Time, Dose, and Fractionation in the Treatment of Lung Cancer
Several reports have appeared during the past
5 years on the use of hyperfractionation for NSCLC.
Jeremic and Milicic (2008) examined the results of 78
patients with stage I or stage II NSCLC treated with
either conventionally fractionated or hyperfrac-
tionated radiation, and they found that a hyperfrac-
tionated regimen resulted in slightly improved overall
survival with similar toxicity (Jeremic and Milicic
2008). Din et al. (2008) examined 583 patients with
stage I–IV disease who had received CHART from
1997 to 2005 at five centers in the UK and found that
only four cases of grade 4 or 5 toxicity had been
documented. The median survival time, 16.2 months,
was comparable to that in the original study exam-
ining this technique. The current practice at MD
Anderson Cancer Center is to reserve the use of
hyperfractionated regimens for tumors located near
neurologic structures such as the spinal cord and
brachial plexus, because sparing these structures from
late effects after high doses of standard fractionated
radiation is difficult to accomplish. Such tumors are
generally treated with twice-daily 1.2 Gy fractions to
a total dose of 69.6 Gy.
1.5 Reducing the Target Volume with 3D
Conformal Radiation Therapy
Some evidence exists to suggest that very high radia-
tion doses (i.e., in excess of 70 Gy) for medically
inoperable stage I disease can produce acceptable local
control and survival (Qiao et al. 2003). Patients with
small but inoperable tumors may be candidates for 3D
CRT, which can allow dose escalation if the high-dose
radiation volume conforms closely to the size and shape
of the tumor. Essential components of 3D CRT include
the capability for CT simulation, beam’s-eye-view
treatment planning, and multileaf collimators to
maximize conformality around the treatment volume.
The relationship between pulmonary toxicity, espe-
cially symptomatic toxicity, and the volume of irradi-
ated lung is well established, and dose escalation has
been performed successfully in this setting to doses
approaching 85 Gy. Indeed, conformal techniques
have become the standard of care in the treatment of
lung cancer because they can spare structures such as
the lung, esophagus, heart, and spinal cord.
By using 3D CRT techniques, it has been possible
to selectively target lymph nodes that are involved
133
with disease rather than broadly applying nodal irra-
diation. Several investigators have shown that
involved-field irradiation is feasible with failure rates
between 5 and 10% (Rosenzweig et al. 2001, 2007).
The involved-field technique allows doses to be
escalated to regions at risk while minimizing the dose
to normal structures; by avoiding broadly applied
elective nodal irradiation for locally advanced lung
cancer, some investigators have been able to increase
the radiation dose to the tumor above 80 Gy
(Belderbos et al. 2003). A group at the Shandong
Cancer Hospital in China conducted a randomized
trial to compare elective nodal irradiation to involved-
field irradiation as part of definitive chemoradiation
for inoperable stage III NSCLC. These investigators
concluded that use of involved-field irradiation could
increase the overall survival time, improve local
control, and reduce rates of radiation pneumonitis
(Yuan et al. 2007). However, this trial must be
interpreted cautiously because of its single-institution
design and its use of different doses in the two
treatment arms, with the involved-field irradiation
arm receiving a higher tumor dose. A subsequent
editorial on elective nodal irradiation that included
investigators from several institutions highlighted the
fact that achieving effective involved-field irradiation
depends largely on the confidence of the treating
physician in the quality of the diagnostic imaging.
Without the benefit of positron emission tomography
(PET) scanning or appropriate mediastinal staging
methods (bronchoscopy, mediastinoscopy), defining
‘‘involved’’ nodes can be difficult if not impossible.
The authors of the editorial concluded that clinicians
should adopt a ‘‘tailored’’ approach that would reflect
the range of imaging and investigational tools that
are available for assessing an individual patient’s
case such that selective nodal irradiation could be a
possibility in some cases (Belderbos et al. 2009).
1.6 Intensity-Modulated Radiation
Therapy
Development of sophisticated software programs,
combined with improvements in diagnostic imaging
and image reconstruction, have allowed tumors to be
visualized and delineated ever more precisely, which
improves the delivery of 3D CRT and opens the door
for intensity-modulated radiation therapy (IMRT).
134
Two sources of error in IMRT that could prevent the
successful delivery of optimal conformal treatment
result from movement—movement of the patient,
which can be addressed by careful immobilization,
and the internal motion of thoracic tumors caused by
respiration and heartbeats. Indeed, the main challenge
in IMRT is to avoid increasing the integral dose to
organs that lie in the path of the multiple fields that
are focused on the target volume.
In practice, the question to be considered in the
choice of treatment technique for thoracic tumors is
whether IMRT can reduce the V20. Several dosimetric
reports have shown that IMRT can indeed reduce lung
dose compared with 3D CRT for locally advanced
NSCLC (Christian et al. 2007; Grills et al. 2003).
A 2010 report from MD Anderson Cancer Center
compared the outcomes of 496 patients who had been
treated between 1999 and 2006 with concomitant
chemotherapy and either CT-based treatment
planning with 3D CRT or 4D CT-based planning and
IMRT. The comparison showed that both the V20 and
the rate of severe pneumonitis were significantly
lower in the IMRT group. The overall survival was
also improved in the patients who received 4D CT
with IMRT. Rates of disease-free survival and distant
metastases were similar among the two groups (Liao
et al. 2010). These results suggest that if the resources
are available, IMRT should be adopted as the stan-
dard practice for locally advanced NSCLC.
1.7 Accounting for Tumor Motion
That intrathoracic tumors move in concert with respi-
ratory and cardiac cycles has always been known, but
the importance of accounting for this movement has
been magnified with the advent of 3D CRT and IMRT.
Several studies have been performed during the past
decade to characterize the direction and extent of lung
tumor movement. Although tumors can move signifi-
cantly in any direction, the largest movements most
often occur in the superior–inferior direction (Michalski
et al. 2008), and small tumors tend to move more than
larger tumors (Liu et al. 2007). Moreover, because
the location and size of the tumor can change over the
course of radiation therapy that lasts several weeks, the
importance of recognizing and accounting for tumor
motion over the course of radiation therapy is becoming
increasingly apparent. Hence repeated monitoring of
D. Gomez et al.
tumor motion and location may be required to ensure
that tumors remain within the high-dose region
throughout the course of treatment.
At MD Anderson Cancer Center, treatments for all
patients are simulated while the patients hold their arms
over their head to maximize the number of potential
beam arrangements. All patients undergo 4D CT during
which an external fiducial is placed on the abdomen to
assess tumor motion in terms of respiratory excursion.
If the tumor is found to move up to 1 cm in any direc-
tion, the patient is treated with a ‘‘free-breathing’’
technique, in which the extent of tumor motion is
accounted for by using a single expanded target
volume, the internal target volume. However, if the
tumor moves more than 1 cm and the patient is capable
of controlling their breathing, then radiation is deliv-
ered while the patient holds their breath at full inspi-
ration (deep inspiratory breath hold technique), or the
radiation is timed for delivery at a chosen point in
the breathing cycle (ventilator gated technique).
1.8 Proton Therapy
Proton therapy represents a new paradigm in the cate-
gory of conformal therapy. The advantage of proton
beam therapy lies in the dose distribution characteris-
tics of the proton particles; protons deliver nearly all
their energy at the height of the Bragg peak, meaning
that any exit dose past the target is negligible. During
the past 5 years, results from several dosimetric com-
parisons of proton therapy with other techniques have
been published, and early clinical outcomes after
proton therapy for lung cancer are becoming available.
Chang et al. (2006) published dosimetric results of
patients with stage I or III NSCLC treated with 3D
CRT, IMRT, or proton therapy. The authors found that
all three techniques could provide excellent target
coverage, but doses to the lung, spinal cord, esophagus,
and integral dose were all lower with proton therapy
than with the other two techniques (Chang et al. 2006).
These dosimetric advantages seem to be translating
improved clinical outcomes. Sejpal et al. (2011) com-
pared the toxicity of three radiation therapy techniques,
all in combination with concurrent chemotherapy, for
NSCLC. At a median follow-up time of approximately
16 months, the median radiation dose from proton
therapy was found to be higher than the doses delivered
by IMRT or 3D CRT (74 Gy (RBE) vs. 63 Gy,
Radiation Time, Dose, and Fractionation in the Treatment of Lung Cancer
respectively), but the proton therapy produced lower
rates of severe pneumonitis and esophagitis than did
IMRT or 3D CRT (Sejpal et al. 2011). Chang et al.
(2011) published early results of a prospective phase I/II
trial examining the efficacy of high-dose, slightly
hypofractionated proton therapy for medically inopera-
ble T1N0 or T2-T3N0 NSCLC. All patients received a
dose of 87.5 Gy in 2-Gy fractions. At a median follow-
up time of 16.3 months, the rate of local control was
88.9%, and no patient had experienced any grade 4 or
grade 5 toxicity. Notably, no patient had experienced
grade 3 or higher pneumonitis (Chang et al. 2011). A
meta-analysis comparing the effectiveness of photons,
protons, and carbon-ion therapy for NSCLC showed that
survival rates for the patients treated with protons or
carbon ions were higher than those for patients who
underwent photon therapy when standard fractionation
schemes were used. Survival rates were similar to those
obtained from SBRT with photons (Grutters et al. 2010).
Virtually all studies that have been published on
proton therapy for NSCLC have involved the use of a
passive scattering technique. However, some evi-
dence exists to suggest the feasibility of modulating
proton fluence, akin to the modulation of photons in
IMRT. A dose–volume histogram analysis of treat-
ment plans generated for intensity-modulated proton
therapy, for IMRT, or for passive scattering proton
therapy of locally advanced NSCLC indicated that
intensity-modulated proton therapy spared the lung,
heart, spinal cord, and esophagus to a great extent
than did IMRT. Intensity-modulated proton therapy
further allowed an increase in the maximum tolerated
dose from 74 Gy with passive scattering proton
therapy to 84.4 Gy without significant compromise in
normal tissue doses (Zhang et al. 2010). If intensity
modulation of proton therapy could be successfully
achieved in clinical practice, this planning technique
would offer an additional advantage over IMRT by
allowing range modulation as well, which cannot be
done with photon techniques. Future studies will offer
further information on the clinical applicability of
intensity-modulated proton therapy.
1.9 Concurrent Chemotherapy
The use of concurrent weekly or daily cisplatin with
radiation therapy has been based mainly on the
results of a large randomized trial by the European
135
Organisation for Research and Treatment of Cancer
(Schaake-Koning et al. 1992) that showed improved
local control and overall survival from the use of
concurrent chemotherapy and radiation. However,
this trial was based on a fractionation scheme that
may have been less than optimal, in that 3-Gy frac-
tions were given daily for 10 days, followed by an
interruption of 4 weeks and then daily 2.5-Gy frac-
tions for 10 days. Randomized studies of fractionated
radiation for locally advanced carcinomas of the
upper respiratory and digestive tract (Fu et al. 2000)
suggest that interruptions such as this are quite likely
to have allowed the proliferation of surviving clono-
gens, not only in normal tissues but also in the tumor.
Also, a recent meta-analysis based on individual
patient data raised some doubts about the magnitude
of benefit (Auperin and Le Pechoux 2003) from
concurrent chemotherapy and radiation therapy and
suggested that additional randomized evidence was
needed to support use of the combined approach.
The most extensive experience with using altered
fractionation with concurrent chemotherapy for
NSCLC comes from MD Anderson Cancer Center
and the RTOG. Results from randomized phase II
trials of a fractionation scheme developed by the
RTOG (58 twice-daily 1.2-Gy fractions for a total
dose of 69.6 Gy) used with concurrent chemotherapy
seemed promising (Komaki et al. 1997). However,
the most favorable outcomes seemed to be associated
with a learning curve; specifically, institutions at
which five or more patients received concurrent
chemotherapy and twice-daily irradiation showed
significantly better survival rates than institutions
with less experience in this form of treatment (Lee
et al. 2002). At MD Anderson Cancer Center, long-
term follow-up of patients given 1.2-Gy fractions
twice a day with concurrent cisplatin and etoposide
showed a 5-year survival rate of 26%—the most
favorable such rate reported to date (Liao et al. 2002).
2 Small Cell Lung Cancer
The current treatment strategy for limited-stage SCLC
involves the use of chemotherapy, thoracic radiation
therapy (Turrisi et al. 1999), and, for those who
achieve a complete response, prophylactic cranial
irradiation (PCI) (Auperin et al. 1999). Comparisons
of chemotherapy plus thoracic radiation therapy with
136
chemotherapy alone have shown that use of combi-
nation therapy improves survival rates; other trials
have shown that concurrent chemotherapy and tho-
racic radiation therapy is superior to sequential or
alternating chemotherapy and thoracic radiation
therapy with regard to local-regional control and
survival for patients with limited-stage SCLC.
2.1 Use of Combined Chemotherapy
and Thoracic Radiation Therapy
Because even initially localized SCLC tends to
metastasize early in the course of the disease,
chemotherapy is an essential component of the
treatment regimen; intrathoracic failure becomes
more important after distant metastases are con-
trolled. Two separate meta-analyses have confirmed
the value of adding thoracic radiation therapy to
chemotherapy for SCLC in terms of decreasing the
rate of local recurrence and improving survival.
Warde and Payne (1992) analyzed results from 11
prospective randomized trials of chemotherapy with
or without thoracic radiation therapy for patients with
limited-stage SCLC and found that the addition of
thoracic radiation therapy conferred an absolute
increase of 5.4% in the overall survival rate at 2 years
(from 15 to 20.4%) and an absolute increase of 25%
in the local control rate at 2 years (from 15 to 40%).
Pignon et al. (1992), in their analysis of data from
2,140 patients in 13 randomized trials of chemother-
apy alone versus chemotherapy plus thoracic radia-
tion therapy, found an absolute increase of 5.4% in
the overall survival rate at 3 years.
2.2 Concurrent Therapy
Potential advantages of delivering chemotherapy and
radiation therapy concurrently are the ability to apply
both modalities early in the course of treatment; the
possible induction of synergistic effects; the enhanced
accuracy of treatment planning (because induction
chemotherapy may obscure the original tumor volume);
and the short overall treatment time (high dose-
intensity), which prevents the proliferation of clono-
gens. Potential disadvantages of concurrent therapy are
enhanced toxicity to normal tissues, which could
necessitate dose modification or treatment breaks; the
D. Gomez et al.
inability to assess response to either modality; and
possibly sensitization of normal tissues.
In 1990, McCracken et al. (1990) reported the
results of a phase II trial of the Southwest Oncology
Group in which two courses of cisplatin, etoposide,
and vincristine were given concurrently with radiation
therapy consisting of once-daily 1.8 Gy fractions
given 5 days/week to a total dose of 45 Gy. The
concurrent therapy was followed by additional
chemotherapy with vincristine, methotrexate, and
etoposide alternating with doxorubicin and cyclo-
phosphamide for 12 weeks. This study evaluated 154
patients. With a minimum observation period of
3 years, the 2-year survival rate was 42% and the
4-year survival rate was 30%. An updated analysis
(Janaki et al. 1994) after a longer observation period
showed a 5-year survival rate of 26%.
In 1999, the RTOG and the Eastern Cooperative
Oncology Group (ECOG) (Turrisi et al. 1999)
reported the results of a US nationwide randomized
study of limited-stage SCLC treated with concurrent
chemotherapy (etoposide and cisplatin) and thoracic
radiation therapy (45 Gy given in twice-daily 1.5-Gy
fractions or once-daily 1.8 Gy fractions); radiation
was begun on the first day of the chemotherapy cycle.
The 2-year survival rate for the entire group was 44%.
The 5-year survival rate was 16% for those given
once-daily radiation and 26% for those given twice-
daily radiation—a remarkable improvement over
previously reported 5-year survival rates.
The Japanese Clinical Oncology Group (Goto et al.
1999) conducted a phase III study of concurrent
versus sequential thoracic radiotherapy, given in
combination with cisplatin and etoposide chemo-
therapy, for patients with limited-stage SCLC.
Chemotherapy was given in either a 28-day cycle (the
concurrent group) or a 21-day cycle (the sequential
group). Thoracic radiation therapy was begun either
on day 2 of the first cycle of chemotherapy in the
concurrent group or after the fourth cycle of chemo-
therapy in the sequential group. The radiation therapy
consisted of 45 Gy delivered to the thorax in twice-
daily 1.5-Gy fractions over 3 weeks. PCI was given to
patients who showed a complete or a near-complete
response; the PCI consisted of 24 Gy given in twice-
daily 1.5-Gy fractions given 5 days a week. The inci-
dence of grade 3 or 4 leukopenia was significantly
higher in the concurrent-therapy group (86.8 vs. 51.3%,
P \ 0.001), but the incidence of non-hematologic side
Radiation Time, Dose, and Fractionation in the Treatment of Lung Cancer
effects was no different in the two groups. The 2- and
3-year survival rates in the sequential-therapy group
were 35.4 and 20.7%, respectively, as compared
with 55.3 and 30.9% in the concurrent-therapy group.
Overall survival seemed to be superior in the
concurrent group, but this apparent trend was not
statistically significant.
Arriagada et al. (1991a, b) reported the results of
two protocols involving 72 consecutive patients with
limited-stage SCLC. Patients were given two cycles
of induction chemotherapy followed by three 2-week
cycles of thoracic radiation therapy that included
chemotherapy with the same regimen as that used for
the induction. Cisplatin and etoposide were used in
the first trial, and cisplatin, etoposide, cyclophospha-
mide, and doxorubicin were used in the second trial.
The results of this trial are among the most favorable
reported in terms of long-term survival. The complete
response rate was 87% and the overall survival rate
was 26% at 3 years; the overall survival of patients
who showed a complete response to the interdigitated
therapy was 26% at 5 years.
Whether thoracic radiation therapy should be
delivered early or late in the treatment course remains
controversial. The National Cancer Institute of Canada
Clinical Trials Group studied this issue in a randomized
trial (Murray et al. 1993). In that trial, 308 patients were
given six cycles of chemotherapy with cyclophospha-
mide, doxorubicin, and vincristine alternating with
etoposide and cisplatin (CAV/PE). Patients were ran-
domly assigned to receive thoracic radiation therapy
(40 Gy to the primary tumor site in 15 fractions over
3 weeks given concurrently with etoposide and cis-
platin) beginning either at week 3 (the early group) or at
week 15 (the late group). Those who showed a com-
plete response were then given PCI (25 Gy in ten
fractions over 2 weeks) after the completion of all
chemotherapy and thoracic irradiation. Although the
complete response rates were no different in the two
groups, progression-free survival (P = 0.036) and
overall survival (P = 0.008) were significantly better
in the early-radiation group. Patients in the late-
radiation group also had a significantly higher rate of
brain metastasis (P = 0.006). This study indicated that
early use of thoracic radiation therapy with concurrent
chemotherapy improved survival, possibly by elimi-
nating the clonogens in the primary tumor.
However, this study was essentially repeated by
investigators in the UK with conflicting results. In that
137
study, patients with limited-stage SCLC received six
cycles of the same alternating CAV/PE chemotherapy
and were then assigned to receive radiation either
early (at the second chemotherapy cycle) or late
(at the sixth chemotherapy cycle). The radiation reg-
imen was also the same as that in the Canadian trial,
40 Gy in 15 fractions, and patients with a response
were offered PCI, also 25 Gy in ten fractions. The
authors found no difference in survival between the
groups given radiation early or late in the course of
chemotherapy (Spiro et al. 2006).
To reconcile the results of randomized trials such
as these, a meta-analysis was published in 2007
comparing early versus late radiation therapy.
‘‘Early’’ was defined as within 30 days after the start
of chemotherapy, and the results were analyzed
according to the treatment time and the use of plati-
num-based chemotherapy regimens. When all seven
randomized trials were examined, no clear benefit was
found regarding early versus late radiation. However,
when only those trials were included in which patients
received chest radiation over a period lasting less than
30 days, a statistically significant improvement was
noted in the overall survival. Similarly, when only
those studies involving platinum chemotherapy regi-
mens were included, a slight benefit in the 5-year
overall survival rate was found with early RT
(Pijls-Johannesma et al. 2007). Based on results such
as these, the standard practice at MD Anderson
Cancer Center is to begin thoracic radiation during the
first or second cycle of chemotherapy. This practice
is also supported by the National Comprehensive
Cancer Network.
2.2.1 Fractionation
Three fractionation regimens have been shown to be
effective for limited-stage SCLC. First, in the widely
cited Intergroup study 0096 (Turrisi et al. 1999)
conducted with the ECOG and RTOG, investigators
compared once-daily versus twice-daily radiation
therapy in combination with concurrent cisplatin and
etoposide. All patients received four 21-day cycles of
chemotherapy. The once-daily fractionation group
received a single 1.8-Gy fraction each day, to a total
dose of 45 Gy in 25 fractions over 5 weeks. The
twice-daily fractionation group received two 1.5-Gy
fractions each day, with a 4- to 6-h interval between
fractions, to a total dose of 45 Gy in 30 fractions
over 3 weeks. Irradiation began during the first
138
chemotherapy cycle. Patients who achieved a com-
plete response then were offered PCI (ten 2.5-Gy
fractions). Although accelerating the radiation
improved median survival time (from 19 months for
the standard fractionation group to 23 months for the
twice-daily group) and 2-year survival rates (41 vs.
47%), a statistically significant difference in survival
was not apparent until 5 years (16 vs. 26%;
P = 0.04). The accelerated regimen also produced
acute grade 3 esophagitis in 27% of cases as
compared with 11% of those in the once-daily
fractionation group.
The second regimen was tested by the Cancer and
Leukemia Group B (CALGB), which studied 63
patients with limited-SCLC who received induc-
tion chemotherapy with paclitaxel and topotecan,
followed by three cycles of carboplatin and etoposide
concurrent with thoracic radiation to 70 Gy in 2-Gy
fractions. PCI was offered to patients experiencing a
complete or partial response. The 2-year overall sur-
vival rate in this study was 48%, and the progression-
free survival rate was 31%. Thus the rates of overall
survival and disease-free survival as well as those of
hematologic and esophageal toxicity were similar in
the CALGB and INT 0096 trials (Bogart et al. 2004).
The third regimen, evaluated in RTOG 0239,
consisted of 61.2 Gy delivered in 5 weeks delivered
with the first two of four cycles of etoposide and
cisplatin. The first 16 fractions were given once daily,
and after 16 fractions a field reduction was made
based on an adaptive treatment simulation, at which
time the regimen was changed to twice daily. The
findings from that trial have yet to be published,
although this regimen is currently being compared
with the first two in a joint study (CALGB 30610/
RTOG 0538) (Fig. 1). PCI is offered in all patients
with a complete or near-complete response. The pri-
mary endpoint is overall survival, and secondary
endpoints are complete response rates, progression-
free survival, and tumor progression.
2.3 Radiation Dose to the Thorax
Arriagada et al. (1990) at the Institut Gustave-Roussy
conducted three consecutive trials of 173 patients
with limited-stage SCLC treated with different
thoracic radiation doses. All thoracic radiation was
given in split courses alternating with chemotherapy;
D. Gomez et al.
Fig. 1 Treatment Arms in CALGB 30610/RTOG 0538:
BID = twice daily, fx = fraction
the total doses given were 45 Gy (i.e., doses split
15–15–15), 55 Gy (20–20–15), and 65 Gy (20–20–
25). The corresponding 3-year local control rates were
66% for the group given 45 Gy and 70% for the two
higherdose groups; the 5-year survival rates were 16%
for the 45-Gy group, 16% for the 55-Gy group, and
20% for the 65-Gy group. None of these apparent
differences were statistically significant among the
three groups. The overall incidence of lethal toxicity
was 10%, and this rate was no different among any of
the three radiation dose groups.
Choi et al. (1998) conducted a phase I study to
determine the maximum tolerated dose of radiation
given either in standard daily fractionation or
in hyperfractionated-accelerated twice-daily radiation
schedules with concurrent chemotherapy for limited-
stage SCLC. The maximum tolerated dose of hyper-
fractionated radiation therapy was 45 Gy given in
30 fractions over 19 days. However, in daily fraction-
ation, the maximum tolerated dose was not reached at
66 Gy given in 33 fractions over 45 days, and thus
patients were accrued for a third group to receive 70 Gy
in 35 fractions over 47 days. The tumor response rates
varied from 78 to 100%, and no difference was found
among dose levels. Doses above 40 Gy did not
significantly improve the local control rate. Esophagitis
and granulocytopenia of grade 3 or higher were more
common among patients given the hyperfractionated
and accelerated-fractionation treatments.
To clarify the maximum tolerated dose of thoracic
radiation (in terms of acute esophagitis and pneu-
monitis) that could be given in combination with
Radiation Time, Dose, and Fractionation in the Treatment of Lung Cancer
Table 2 Intergroup Study 0096 versus RTOG 9712
Intergroup
Group 1
Thoracic radiation dose 45 Gy
Duration of radiation 5 weeks
Median survival time 19 months
Survival rates
1-year 63%
2-years 44%
5-years 16%
Local failure rate 52%
Incidence of grade 3 esophagitis 11%
*Significantly different from Group 1 (P = 0.01)
cisplatin and etoposide chemotherapy for patients with
limited-stage SCLC, the RTOG conducted trial 9712
(Table 2) (Komaki et al. 2003). The findings of this
phase I trial indicated that doses could be escalated to
61.2 Gy over 5 weeks through the use of a concomi-
tant boost technique without more than 40% of patients
developing esophagitis of grade 3 or higher. This total
dose was given as follows. Eleven 1.8-Gy fractions
were given to large fields once daily for 5 days a week,
followed by 4 days of twice-daily radiation therapy in
which one 1.8-Gy fraction was given in the morning to
large fields and another 1.8-Gy fraction was delivered
to boost fields 6 h later; for the final 5 days, twice-
daily 1.8-Gy fractions were given to the boost fields.
This regimen is currently being compared to two
alternative regimens in the protocol CALGB 30610/
RTOG 0538, as described above.
Acknowledgment Supported in part by National Cancer
Institute grants CA 16672 and 06294 and the Texas Tobacco
Settlement.
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 3D Radiation Treatment Planning
and Execution
Mary K. Martel
Contents
1 Introduction.............................................................. 143
2 Treatment Planning Process ..................................
2.1 Introduction................................................................
2.2 Immobilization and Simulation.................................
2.3 Planning Target Volume ...........................................
3 Radiation Beam Design and Delivery ................... 148
3.1 Standard Beam Arrangements................................... 148
3.2 3D Conformal Treatment Techniques ...................... 150
4 Normal Tissue Tolerance and Treatment
Planning Objectives................................................. 151
5 Dose Calculation Issues........................................... 153
5.1 Effects of Lung Density ............................................ 153
5.2 Calculation Algorithms ............................................. 154
6 Summary................................................................... 155
References.......................................................................... 155
M. K. Martel (&)
Department of Radiation Physics,
Division of Radiation Oncology,
University of Texas MD Anderson Cancer Center,
1515 Holcombe BLVD, Houston, TX 77030, USA
e-mail: mmartel@mdanderson.org
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_302, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
Technological advances have become commer-
cially available and widely implemented. In par-
144 ticular, 3D conformal therapy has become the first
144 step in improving the targeting of dose to the
145 tumor while sparing dose to normal tissue. The
145
treatment planning process including beam design,
treatment planning objectives, and dose calculation
issues for 3D radiation treatment planning will be
reviewed. Topics such as target volume definition,
use of imaging, set-up uncertainties, respiration
control, and normal tissue tolerance are briefly
introduced.
1 Introduction
The goal of radiotherapy is to deliver therapeutic dose
in a precise and accurate manner to the target volume
while minimizing dose to surrounding normal tissue.
Advancement in technology over the past several
decades has brought highly developed means to reach
this objective. Planning and delivery of radiation
therapy has evolved to a multi-step process which is
individualized for each patient. This process includes
anatomy definition (including tumor and important
normal structures), radiation beam design, delivery of
the treatment plan, and verification of delivery. The
complexity of the treatment process depends on many
factors; of paramount importance is the level of dose
prescription and whether the ultimate clinical intent is
curative.
143
144
For treatment of non-small cell lung cancer
(NSCLC), radiation therapy (RT) dose prescriptions
with standard dose per fraction range from 60 to
70 Gy at 1.8 to 2 Gy per fraction. However, it appears
from clinical data that 70 Gy may translate to a tumor
control probability (or local progression-free survival)
of approximately 30% (Martel et al. 1999; Hazuka
et al. 1993). Supporting this outcome data are results
from other single institution trials (using standard
doses) which show overall survival rates of 33–43%
(Armstrong et al. 1995; Graham et al. 1995; Sibley
et al. 1995). In addition, however, several of these
trials, along with the multi-institutional RTOG 8301
altered fractionation trial (Cox et al. 1990), saw an
elevated incidence of high grade pneumonitis. These
modest local control and survival rates coupled with
undesired normal lung toxicity led to a rethinking of
the radiotherapy treatment approach. Interest in RT
dose escalation beyond 70 Gy launched a series of
phase I trials aimed to determine the maximum tol-
erated dose (Robertson et al. 1997; Armstrong et al.
1997; Rosenzweig et al. 2000; Belderbos et al. 2003),
with secondary endpoints to determine impact on
local control and survival. However, given the dose-
volume relationship for normal lung with toxicity,
(Martel et al. 1994; Oetzel et al. 1995; Graham
et al. 1999; Marks et al. 1997; Kwa et al. 1998;
Sepenwoolde et al. 2003) a novel dose escalation
scheme (Ten Haken et al. 1993) was designed so that
the prescribed dose would depend on the amount of
normal lung volume irradiated, rather than escalate in
the standard fashion. A normal tissue complication
probability (NTCP) model for the calculation of risk
of pneumonitis was used to set the dose levels so that,
as the dose was escalated, the risk of toxicity
increased in a predictable manner. Using this design,
doses were escalated well above standard doses,
achieving 84–102.9 Gy for many patients (Kong et al.
2006) without the development of pneumonitis. For
the subgroup of patients receiving doses greater than
92.4 Gy (Narayan et al. 2004), survival rates
improved. However, local control remained prob-
lematic, with progression occurring for many of the
patients.
It has been hypothesized that one source of failure
of high doses to control all tumors is due to the
possible accelerated repopulation late in the treatment
course of 8–10 weeks needed to deliver doses in
excess of 80 Gy. Estimates predict a 1.6% loss of
M. K. Martel
survival rate per day for treatment prolongation
beyond 6 weeks (Fowler and Chaell 2000). Accord-
ingly, dose escalation schemes that limit overall
treatment time to 6 weeks or less provide a potential
‘‘radiobiological’’ avenue to explore for improvement
of outcome. Several trials are already under-
way (Mehta et al. 2001; Belderbos et al. 2003;
Timmerman et al. 2003). The subject of time, dose
and fractionation of radiation therapy is explored in
depth (Cox) elsewhere in this book.
Another major source of failure is geographic miss
of the tumor target volume by the planned radiation
fields. This is mainly due to effects related to the
anatomical site of the tumor in the lung, namely,
respiration effects causing tumor movement, and the
uncertainties of the radiation dose calculation due to
the lower density of the lung. Also as well, the
treatment planning phase is highly dependent on how
target volumes are determined for a given patient.
Inadequate tumor definition from imaging studies
leads to a target volume that does not cover the full
extent of the disease, and geographic miss will occur.
The solutions to minimize geographic miss are tech-
nological in nature and will be briefly discussed in
this chapter. The basic and advanced technical aspects
of treatment planning for radiation therapy will be
covered, which will serve as an introduction to later
chapters that describe target volume definition, nor-
mal tissue toxicity, respiration control, and advanced
delivery techniques such as stereotactic radiotherapy
and intensity modulated radiation therapy in greater
detail.
2 Treatment Planning Process
2.1 Introduction
In simple terms, radiotherapy treatment planning can
be defined as the process of arrangement of beams to
irradiate a defined target volume to the prescribed
dose. The accuracy of beam targeting improved in the
1980s with the advent of computerized image-based
treatment planning which allowed the widespread use
of dose calculations in three dimensions (3D) based
on patient-specific 3D anatomy. For the anatomical
site of the thorax, treatment planning is complicated
by the number of normal organs (spinal cord, normal
lung, esophagus and heart) located close to the tumor,
3D Radiation Treatment Planning and Execution
which have limited tolerance to radiation. However,
‘‘3D’’ technology has allowed reduced irradiation of
normal tissues by design of field shapes with the
‘‘beam’s eye view’’ and arrangement of multiple non-
coplanar, non-axial beam angles with 3D visualiza-
tion tools (McShan et al. 1990). This allows dose to
‘‘conform’’ to the tumor/target volume while maxi-
mizing sparing of dose to surrounding normal tissue;
this technique is called ‘‘conformal’’ therapy. Dose
distributions calculated in 3D can be evaluated
throughout the 3D patient volume, allowing for
detailed analysis to facilitate achievement of the
optimal plan. The intricacies of the treatment plan-
ning process for both standard and conformal radio-
therapy techniques for lung cancer will be reviewed
here. In addition, Senan et al. (2004) have an excel-
lent review of literature-based recommendations for
treatment planning for the lung.
2.2 Immobilization and Simulation
3D planning begins with the acquisition of an imaging
volume data set with the patient in the treatment
position. First, the patient is placed on a support table
in a position that can be easily reproduced during
treatment setup. For patients with lung cancer, opti-
mally the arms are positioned above their head so as
not to restrict selection of beam angles and prevent
treatment through the arms. A positioning (otherwise
known as ‘‘immobilization’’) device is used to help
duplicate the same position for each day of treatment.
It is now common to make custom devices to fit
individual patients. Custom foam cradles are used for
immobilization of thorax region. A foam mixture fills
the space between a styrofoam form and the patient,
forming to the body shape, which is then attached
with pegs to the treatment table. Well made immo-
bilization devices will reduce the magnitude of daily
set-up uncertainty.
Localization of patient anatomy is performed using
imaging studies. The simplest method is the use of a
machine called a simulator that has the same geo-
metrical features of a linear accelerator (identical
isocentric gantry design and position of treatment b),
but has a diagnostic X-ray generator in the head of the
machine. It produces radiographs in two dimensional
planes that visualize the intended anatomic area of
treatment, but often using bony landmarks to
145
approximate the location of soft tissue target volumes.
Computed tomography (CT) scan information sup-
plements, and, now more commonly, replaces the
simulator X-rays for soft tissue volume delineation.
Axial images are acquired with thin slices (3–5 mm)
through the target area and adjacent normal struc-
tures, usually from vertebral bodies C4 to L1 at a
minimum, and to include the entire volume of both
lungs. A coordinate system must be established
between the imaging studies and the treatment
machine. This is accomplished through the use of an
alignment system common to the simulator, CT
scanner, and treatment rooms. Wall mounted lasers
project lines in three planes (axial, sagittal and coro-
nal) and intersect at the isocenter, defined as the focal
point of the treatment linear accelerator’s rotation at a
point in space. In an X-ray simulator or CT simulator
(a CT scanner with a laser system and localization
software), the patient is aligned so that the approxi-
mate center of the tumor is positioned at the isocenter.
An example of the placement of the isocenter during
the CT simulation process is given in Fig. 1. The field
center and border can be display by the simulation
software and the isocenter can be placed via software
tools to the center of the tumor, using the coronal
(left) and axial (right) reconstructed CT images as
guidance. Since the lasers are aligned to point to the
isocenter, the intersection of the lasers with the
patient’s skin surface is then marked in the simulator.
These reference marks are used to re-align the
patients at the time of daily treatment at the linear
accelerator.
2.3 Planning Target Volume
2.3.1 ICRU Guidelines
The imaging studies are used to construct a target
volume, the first crucial step in the planning process.
To promote systematic target volume definition, the
International Commission on Radiation Units and
Measurements (ICRU) has published nomenclature
and guidelines (ICRU 1993, 1999). For target volume
delineation, several concentric volumes are described.
First, the extant of malignant cells visible on imaging
studies, including any involved nodes, is called the
gross tumor volume (GTV). Next, a margin around
the GTV is added to account for potential local–
regional subclinical extension, and is called the
146
Fig. 1 Coronal digital reconstructed radiograph (DRR) (left) showing placement of an anterior field isocenter; and an axial CT
slice with placement of the isocenter at depth in the patient
clinical target volume (CTV). The GTV and the CTV
are based solely on anatomic and biological consid-
erations. The final volume is the planning target
volume (PTV). This volumetric expansion accounts
for the uncertainties of the geographic position of the
CTV from day-to-day. Specifically, a margin is added
to compensate for physiologic changes in the size,
shape, and position of internal anatomy. Additional
margins are added to account for patient movement
(e.g., breathing) and differences in patient positioning
from day to day (set-up uncertainty). The construction
of the PTV is discussed below. In addition, Armstrong
(1998), and Senan, Kepka and Videtic in later chap-
ters discuss target volume definition.
2.3.2 Use of CT for Gross Tumor Volume
Delineation
CT imaging is the most common modality used for
treatment planning. However, distinguishing tumor
from surrounding normal lung and soft tissue is often
not straightforward, even with the use of contrast, and
there can be large variations in contoured volumes
among clinicians and institutions (Senan et al. 1999;
Bowden et al. 2002). Bowden et al. (2002) found that
despite input from radiologists, significant variation
up to 42% (on average 20%) occurred in the delin-
eation of the 3D gross tumor volumes of NSCLC
among oncologists. The authors propose standardi-
zation of the approach and give guidelines, which
M. K. Martel
when followed, resulted in a reduction in the variation
to 7–22% (average 13%). Reduction of the contouring
variation on CT is important since studies often relate
clinical outcome to tumor size or volume. The
recommended guidelines are given below, which are
adapted from the procedure for the measurement of
the volume of the primary tumor and involved lymph
nodes from the TROG 99-05 study (Bowden et al.
2002): Preparation: Volume measurements will be
based on planning CT images, which should be con-
trast-enhanced. If the planning image does not have
contrast, a recent (within 2 weeks of planning) diag-
nostic contrast-enhanced CT scan should be available
for viewing alongside the planning CT scan. The
planning CT scan should include all known tumor and
all enlarged intrathoracic lymph nodes. Steps: (1)
Identification of tumor and nodes: The contour should
therefore closely hug the surface of the tumor and
should not include a margin for suspected or micro-
scopic spread. Opacities thought unlikely to represent
tumor, but that a prudent radiation oncologist might
include in the CTV because of lack of absolute cer-
tainty, should be excluded. The tumor, plus all hilar
and mediastinal nodes with a diameter [1 cm, should
be identified and outlined with a fine-tip felt pen by a
diagnostic radiologist on the hard copy. (2) Initially
the volume is contoured using mediastinal window
(MW) settings (width 400 HU and level +20 HU).
Because the density scale on commercial planning
3D Radiation Treatment Planning and Execution
systems does not always correspond with Hounsfield
units, it is recommended that the window settings be
standardized for each individual department and that
the same settings be used on every occasion. It is
suggested that a diagnostic radiologist be asked to
establish which settings most closely correspond with
the range of Hounsfield units for both MWs and lung
window (LW), as described in the report by (Harris
et al. 1993). For disease involving the mediastinum,
the tumor/node edge should be defined by the inter-
face between the tumor/node and fat or contrast-
enhanced vessel using MW settings. (3) In practice, it
is easiest to determine the tumor volume using the
MW settings and then to enlarge this volume as
required after changing to the LW settings. The LW
should most closely correspond with a level of -750
HU and a window width of 850 HU. With these set-
tings, the volume can only be contoured at the lung/
tumor interface, because all mediastinal definition is
lost. The maximal cross-sectional dimension of the
tumor should be measured and recorded using the LW
window image. Special situations (1) Spicules: Only
the solid portion of the tumor should be contoured.
Fine spicules radiating into the surrounding lung
should not be included, because the interpretation of
their size and significance varies considerably among
observers. (2) Cavitating tumor: If the tumor is cav-
itating, its volume will be taken to be that volume if
no cavitation were present. (3) Atelectasis: Patients
with adjoining atelectasis represent a special case.
Sometimes the radiologist is able to distinguish ate-
lectatic lung from tumor, especially if liver window
settings are used (window width 150 HU, level 50
HU).
2.3.3 Addition of PET Scans
18-FDG-positron emission tomography (PET) has
had a large impact on the delineation of the gross
tumor volume for lung cancer because it images
metabolically active tumor cells. In particular, PET
has several advantages over CT in distinguishing
tumor from collapsed lung or mediastinal structures,
and benign from malignant lymph node enlargement.
A detailed discussion on the use of PET in lung
cancer is given in a later chapter (MacManus). The
PET (or other image datasets, such as MRI) infor-
mation needs to be correlated to CT scans through the
use of image registration software. Image data in
the PET transmission/emission or PET/CT dataset can
147
be aligned with the CT set by transforming the PET
coordinate system to match the planning CT. Several
types of algorithms exist to achieve this transforma-
tion (Pelizzari 1998). For example, one of the sim-
plest techniques is to identify anatomical landmarks
in each dataset and ‘‘tie’’ the two image sets together.
A more complex registration method uses the entire
volume of image data (i.e., intensities of the image
voxels) for matching of ‘‘mutual information’’. Once
the different image series are registered, image fusion
software is used to display the two modalities
simultaneously.
2.3.4 Microscopic Margin
Generally, the size of margin added to the GTV to
account for microscopic extent (ME) has been
somewhat arbitrary (i.e., 5 mm), or not used at all.
However, Giraud et al. (2000) examined NSCLC
surgical specimens with adenocarcinoma (ADC) and
squamous cell carcinoma (SCC) histology. The mean
value of ME was 2.69 mm for ADC and 1.48 mm for
SCC. The usual 5 mm margin covers 80% of the ME
for ADC and 91% for SCC. To have 95% confidence
that all tumor is included in the clinical target volume,
a margin of 8 and 6 mm must be chosen for ADC and
SCC, respectively.
2.3.5 Setup Uncertainties
2.3.5.1 Sources of Error
Patient orientation at treatment may be different from
the planned position. This is due in large part to
random variation, but some systematic effects are
present. Some sources of error are given below. For
one, the location of the lasers used to indicate the
isocenter may differ between the simulation and
treatment room. Also, the patient may not be marked
on the setup points in an exact manner in the CT
simulation room. The patient may be imaged on the
treatment machine before radiation is applied, which
quantifies setup error, but there are limitations in the
ability to visually reading the portal image, as
opposed to utilizing computer-aided graphical align-
ment tools. Also, based on the portal image, it is
common to correct the position of the patient only
when the needed shift exceeds 5 mm or greater.
Further, there may be limitations in the ability to
make the proper shift in patient position. Finally, the
patient may move on the table after imaging but
148
before treatment commences. Studies to measure
patient setup errors should be carried out to estimate
the margin to be used for the planning target volume
definition. Study results will be dependent on the
immobilization, simulation and treatment techniques
used at each individual institution. Portal imaging
everyday (instead of the current once-per-week) will
certainly decrease the setup uncertainty. An alternate
method would be to image every day during the first
week of treatment to determine an individualized
margin for use during the remainder of the treatment.
However, it is clear that regular observation and
correction for patient setup is a necessity.
2.3.5.2 Accounting for Respiratory Motion
Tumor motion due to respiration must be included in
the planning target volume definition, and can be
determined at the time of imaging. Simulator X-ray
films or planning CTs represent a ‘‘snapshot’’ of a
point in time during the respiration cycle, which may
not be at the same point under treatment conditions.
The use of CT simulators is now common place, and
CT images may be acquired during different phases of
the respiratory cycle (4D-CT). Incorporation of a
margin for motion will increase the planning target
volume, and consequently, increase the amount of
normal lung that is irradiated. Alternately, respiration
can be suspended during the planning CT and treat-
ment, as described by Wong et al. (1999), through the
use of a device called active breathing control (ABC)
or through respiratory gated therapy (Kubo et al.
2000), where radiation is delivered only at a certain
phase of the respiration cycle when the target is in a
known position. Respiration control and 4D-CT is
discussed in detail in a later chapter (Senan).
3 Radiation Beam Design
and Delivery
3.1 Standard Beam Arrangements
After imaging data is complete for a given patient, the
target volumes and normal anatomic structures must
be defined. Each structure is circled or contoured on
individual axial images, using image display work-
stations. The contouring process segments the image
data into separate structures, each uniquely identified.
Semi-automated and automated algorithms are
M. K. Martel
available that will contour structures having the same
density, allowing rapid definition of an entire 3D
region. For example, lungs have one-third of the
density of soft tissue and can be easily differentiated
from surrounding tissue. Surfaces for each structure
are generated from the segmented contours, and can
be viewed in any plane that is generated through the
surface. In Fig. 2, the planning target volume in green
and the spinal cord volume in yellow are displayed as
overlays on several reconstructed CT plans, such as
the axial, sagittal and coronal planes in the left panels.
This type of display is useful during treatment beam
design.
The next step in the planning process is the design
of radiation beam field or aperture. In the treatment of
lung cancer, relatively simple beam arrangements
have been traditionally used. This is due in large part
to the prophylactic treatment of hilar, mediastinal and
in some cases, supraclavicular lymph nodes which
may be at risk for harboring microscopic disease,
which is called ‘‘elective’’ nodal irradiation (ENI).
Though the ENI volume is determined by anatomical
landmarks located on simulator X-ray images or
reconstructed coronal CT planes, it is rarely (if ever)
contoured by the radiation oncologist as a separate
structure. It is common to treat the ‘‘approximated’’
ENI volume, along with the contoured primary GTV/
PTV, in large fields aimed from the anterior and
posterior (AP/PA) direction of the patient in parallel-
opposed fashion (see 2). Since the spinal cord is
irradiated by the AP/PA fields, this beam arrangement
can only be used until the tolerance dose of the cord is
reached, generally 45–50 Gy at 1.8–2 Gy/fraction.
Fields are then arranged ‘‘off-cord’’ to treat only the
primary PTV. An example design of off-cord fields is
shown in Fig. 3. Here, beam apertures are planned
using 3D treatment planning software, called ‘‘virtual
simulation’’. Initially the radiation field borders are
set in a rectangular fashion. Then, beam directions are
selected by the use of the beam’s eye view (BEV)
tool. Target and normal structures are viewed from
different directions in planes perpendicular to the
beam’s central axis using BEV (see Figs. 2 and 3).
Structures are distinguished from each other by use of
different colors. In Fig. 3, the beam direction is
angled away from the normal structure to separate the
PTV structure from the spinal cord. The beam shape
is then modified by designing a block that will
allow full dose to the PTV but minimize dose to
3D Radiation Treatment Planning and Execution 149

Fig. 2 Gross tumor volume

(GTV) contours shown in
green and spinal cord
contours in yellow are
overlaid on the coronal DRR
(upper right), and on axial,
sagittal and coronal CT slices.
The projection of the field
borders on the patient is
shown in yellow in each panel

Fig. 3 To avoid delivering dose to the spinal cord (yellow ‘‘separation’’ of the cord from the tumor volume (outlined in
contours) with the anterior field (left), the head of the machine blue) (middle). Blocks to shield normal tissue are then drawn
must be rotated until the virtual simulation software shows (outside blue line) (right)

surrounding normal tissue. The block shape is repre-
sented by the outermost shape in the BEV in Fig. 3.
Blocks consist of heavy metallic material mounted on
a tray which is placed in the head of the machine, or a
block substitute called a multileaf collimator (MLC).
The MLC consists of a number of small leaves that
move independent of each other to form the planned
shape (displayed in the BEV in Fig. 4).
Once beam angles and shapes are designed, dose
calculations are performed. Since it is not possible or
150
Fig. 4 Beam’s eye view
planning with non-coplanar
and non-axial beams to avoid
normal structures for an upper
lobe tumor (University of
Michigan UMPlan)
practical to measure a 3D dose distribution for each
patient situation, a general dose calculation system
must be used to ‘‘predict’’ the dose in the patient.
These calculations incorporate basic data that char-
acterize the radiation beam energy and geometry,
such as depth dose curves and isodose information for
standard field sizes. The deposition of dose from
photon irradiation results from the generation of
secondary electrons. In the case of photon energies in
the therapeutic range, electrons are primarily set in
forward motion by Compton interactions (in which
energy is both absorbed and scattered), which then
penetrate deeper into tissue. Energy is deposited into
tissue as these electrons slow down. Computerized
algorithms have been developed to combine the dose
distributions generated by combinations of beams,
using individual patient information such as depth of
the point of calculation, external body contour, and
various densities of anatomical structures. Dose dis-
tributions are displayed with concentric curves for
chosen dose levels (isodoses) which are displayed as
overlays on anatomic structures. These curves are
normalized to a reference dose, either at isocenter or
to the lowest isodose curve that encompasses the
PTV. Ideally, the 95% isodose curve will cover the
planning target volume, or adjustments will be made
M. K. Martel
in the field angles after evaluation of the dose
distribution.
3.2 3D Conformal Treatment Techniques
The fundamental rule of treatment planning is the use
of multiple beams to concentrate the high isodose
region at the isocenter and in the PTV. Two opposed
beams, such as the AP/PA fields described above, will
produce a more uniform dose distribution throughout
the volume when compared to the use of a single beam.
However, when more than two beams are used, the
dose is further concentrated in the PTV and dose to
normal tissues can be further reduced. An ideal treat-
ment plan is both conformal (high dose wraps closely
around the PTV with rapid falloff to low doses) and
homogeneous (± 5% variability of dose within the
PTV). Two example cases of conformal beam
arrangements are given below. Shown in Fig. 4 is a
tumor of the upper lobe. Normal tissue structures such
as lungs, heart, esophagus and spinal cord are con-
toured on CT, and are displayed as solid surfaces in 3D
in a variety of BEV displays. The PTV, in red, is tar-
geted by beams directed from five different machine
gantry angles, and several different couch angles.
3D Radiation Treatment Planning and Execution
Fig. 5 Dose-volume histograms for treatment plan shown in
Fig. 4
These angles were chosen so that each normal structure
is irradiated by only several, but not all, of the beams.
For example, the spinal cord, in green, is contained
within two of the 6 BEV fields. If the dose distribution
for the PTV is not homogeneous, segments of fields
may be placed to ‘‘boost’’ the dose; one such segment is
shown in the lower right of Fig. 4.
The treatment plan can be evaluated as to whether
it meets objectives of PTV coverage and normal tis-
sue avoidance. A set of criteria for normal tissue
tolerances (discussed in the next section) must be
given to guide the treatment planner. Dose distribu-
tions for 3D volumes can be displayed and analyzed
graphically with dose-volume histograms (DVH),
generated for each structure. The cumulative form of
the DVH is a plot of the volume of a given structure
receiving a certain dose or higher as a function of
dose. DVHs for the beam arrangement in Fig. 4 are
displayed in Fig. 5. The dose-volume histogram for
normal lung is the addition of the dose distributions of
both lungs but minus the dose distribution in the
GTV. The GTV is selected instead of the PTV, since
the PTV contains normal lung receiving high dose
which influences the normal tissue toxicity rate.
The second case is shown in Fig. 6. The tumor is
centrally located and in the lower lobe. Though the
PTV is located near the spinal cord, dose to the cord is
kept below tolerance by shielding the structure in two
of the four fields. However, the PTV is also blocked,
and the dose is boosted by adding a field segment,
151
shown in the lower left panel. The dose-volume
histograms are shown in Fig. 7.
If the treatment plan does not meet the given
dose-volume objectives, beam arrangements or other
parameters are adjusted. This can include a change of
beam energy, beam angle, or adjustment of the beam
intensity. For ‘‘forward-planned’’ conformal therapy,
these adjustments are carried out manually, with chan-
ges made in an iterative fashion by the treatment planner.
Normally the beam intensity is uniform across the beam
width and length. The simplest modification of the
intensity is a wedged shape filter placed in the machine
head. A more complex method is to break the field
aperture into segments with varying beam-on times.
Currently the most intricate form of intensity modulation
achieves a checkerboard pattern with each square of a
varying intensity. The delivery of this type of pattern is
with a compensator or with a device called a multileaf
collimator, which can move under computer control to
shape segments of the field to deliver the intensity pat-
tern. This is called intensity modulated radiation therapy
(IMRT) and with this technique, there is potentially a
high degree of control over the shaping of the dose dis-
tribution. IMRT for treatment of lung cancer is described
in detail in a later chapter (Grills et al. 2003).
Once the final beams are designed, X-ray images in
the form of digitally reconstructed radiographs (DRRs)
are generated from the treatment planning CT to
enhance the bony anatomy with high contrast, and are
in the beam’s eye view plane. An example of a DRR of
the lung is shown in Fig. 3. DRRs are used to compare
to portal images taken before treatment, which are
either films placed in the beam exiting the patient or
with an electronic portal device. Verification of the
radiation beam placement vis-à-vis the patient is car-
ried out pre-treatment so that patient position can be
adjusted accordingly. Beam delivery is carried out with
use of beam modifiers such as blocks, multileaf colli-
mators, wedges, compensators, or IMRT.
4 Normal Tissue Tolerance
and Treatment Planning Objectives
Three dimensional conformal therapy is now a mature
technology in widespread use. However, it is still
difficult to design the ‘‘best’’ plan, defined as a bal-
ance of achieving high dose delivery to the tumor
with a low rate of normal tissue toxicity. A set of criteria
152 M. K. Martel

Fig. 6 Beam’s eye view

planning with non-coplanar
and non-axial beams to avoid
normal structures for an lower
lobe tumor (University of
Michigan UMPlan)

for normal tissue tolerances should be established from

published studies and adapted for local clinical use. A
good starting point is the report by a National Cancer
Institute-sponsored task force which carried out an
extensive literature search and presented updated
information on tolerance of normal tissues, with
emphasis on partial volume effects (Emami et al. 1991).
For uniform irradiation of normal lung, tolerance
doses for a 5% chance of pneumonitis occurring within
5 years for uniform irradiation of 1/3 of the lung was
45 Gy, 2/3 was 30 Gy and whole lung was 17.5 Gy.
For the esophagus, the corresponding doses are: 60 Gy
(1/3), 58 Gy (2/3) and 55 Gy (whole) for an endpoint
of clinical stricture/perforation. For the heart: 60 Gy
(1/3), 45 Gy (2/3) and 40 Gy (whole) for the endpoint of
pericarditis. The 50% chance of a complication occur-
ring in 5 years was also given for each organ. These Fig. 7 Dose-volume histograms for treatment plan shown in
Fig. 6
tolerance data show that the complication probability
may be a function of irradiated volume and dose.
The Emami tolerance data summary was one of the doses given were based on limited volumetric dose
early efforts towards the use of objective criteria in data publications and on ‘‘guesstimates’’ based on
evaluating treatment plans. However, the tolerance clinical experience. As 3D dose distributions for
3D Radiation Treatment Planning and Execution
Fig. 8 The incidence of radiation pneumonitis as a function of
the mean normalized total dose (NTDmean), representing mean
lung dose (Kwa et al. 1998)
normal lung became available, dosimetric parameters
could be correlated with complication data. Martel
et al. (1994), Oetzel et al. (1995), Marks et al. (1997),
Graham et al. (1999) related dose-volume metrics to
the risk of developing pneumonitis. Kwa et al. (1998)
found a relationship between the incidence of radia-
tion pneumonitis and the mean lung dose in an anal-
ysis of pooled data of 540 patients from five
institutions of the previously listed studies. Increasing
mean lung dose correlated well with increasing
pneumonitis rate. Figure 8 illustrates this relationship
and can be used to reliably predict the risk of pneu-
monitis when mean lung dose is evaluated from a
treatment plan DVH. Each of these studies provides
dosimetric parameters that can be extracted from the
3D dose distribution to give the clinician a guide for
safe treatment. The Emami data have been recently
updated by an AAPM/ASTRO/NCI group called
‘‘Quantitative Analyses of Normal Tissue Effects in
the Clinic’’ (QUANTEC) (Bentzen et al. 2010).
Updated treatment related toxicity information is
given in detail in later chapters.
Complication data such as those discussed above
have helped in the design of dose escalation trials.
As discussed in the introduction, one of the first
trials in the 3D treatment planning era used a novel
dose escalation scheme (Ten Haken et al. 1993;
153
Hayman et al. 2001) at the University of Michigan.
Because of the observed dose-volume relationship
for normal lung with toxicity, the prescribed dose
depended on the volume of lung irradiated by the
plan, rather than escalate in the standard fashion
with all patients regardless of the amount of lung
irradiated receiving the same level of dose. A normal
tissue complication probability (NTCP) model was
used to set the dose levels so that, as the dose was
escalated, the risk of pneumonitis increased in a
predictable manner. The Netherlands Cancer Insti-
tute (Belderbos et al. 2003) has a similar approach
but use mean lung dose to stratify patients into dose
groups. The Radiation Therapy Oncology Group’s
(RTOG) trial (RTOG 1993) has three levels of
stratification according to V20. The use of 3D con-
formal therapy is a requirement for these studies.
Dose escalation will be discussed in a later chapter
(Rosenzweig).
5 Dose Calculation Issues
5.1 Effects of Lung Density
It is generally recommended to use density correc-
tions and low energy photon beam for treatment
planning of lung cancer. When density is not taken
into account in computer calculations, lungs are
assigned a density of one, which is equivalent to
water, instead of approximately 0.2–0.4 that is reality.
This means that the attenuation of photons per unit
length is lower in low density lung tissue compared
with unit density water-equivalent tissue. When dose
was measured in a benchmark test phantom to a point
in between two lungs, there was increased dose ran-
ging from 5 to 14% relative to a phantom of unit
density. The effect decreases as the photon energy
increases. The use of high energy beams could be
used to minimize the dose correction discrepancies.
However, studies (Mackie et al. 1985; Rice et al.
1988) have shown that higher energy beams tend to
‘‘spare’’ the surface of the tumor when traversing
through the lung. Too, higher energies will have an
increased range of secondary electrons in lung tissue,
which further spreads out the low isodoses relative to
a water-equivalent tissue (Ekstrand and Barnes 1990).
When a clinically relevant phantom study was per-
formed (Klein et al. 1997), dose delivered to the PTV
154
Fig. 9 Isodose distributions in transverse and coronal views
through the dose specification point of a five-field plan of a
treatment of a right hilar NSCLC, computed using (left) the
EPL algorithm and (right) the CS algorithm. The isodose levels
displayed are: blue, 95%; pink, 90%; yellow, 80%; green, 50%;
with 6 MV was within 5% of predicted, but low by
11% with use of 18 MV.
5.2 Calculation Algorithms
Current treatment-planning computer systems have the
capability of incorporating the effect of lower lung
density into the dose calculation, and there are several
density-correction algorithms. However, because of
the variety of treatment situations for lung cancer, it is
difficult to take into account all effects, such the build-
up and scattering of secondary electrons. Such effects
depend on, for example, how much lung is traversed,
beam energy, and beam field size. Correction-based
algorithms such as the equivalent-pathlength (EPL)
model, the generalized Batho and equivalent-tissue-air
ratio (ETAR) methods are available commercially.
M. K. Martel
white, 20%. The colorwashes in red and blue represent the
GTV and the PTV, respectively. Note the difference in the
computations of the 95% isodose line in the PTV (De Jaeger
et al. 2003)
The limitation of these algorithms is that the increased
lateral electron scatter in lung tissue is not accounted
for. Calculation algorithms have become more
sophisticated in the past decade and practical to use
with the increase in computer calculation power. For
example, the convolution-superposition (CS) method
can predict the lack of lateral electron transport in the
calculation. The effect of the more accurate CS algo-
rithm versus the EPL algorithm is shown in Fig. 9
(De Jaeger et al. 2003). The patient’s original plan
using EPL shows that the 95% isodose line is enclosing
the PTV (left panels). Recalculation of the dose dis-
tributions with the CS model shows that the 95% iso-
dose line constricts into the PTV, causing a reduction
of dose particularly in the region of the PTV that is
embedded in lung, due to the penumbra broadening in
the low-density lung tissue. This effect is less at the
mediastinal boundary with the PTV. Overall, the mean
3D Radiation Treatment Planning and Execution
lung dose as determined by the CS and EPL algorithms
differed on average 17%, and the V20 differed on
average by 12% (De Jaeger et al. 2003).
Model-based calculation techniques, such as the
convolution-superposition and more recently, Monte
Carlo methods, offers a physics-based approach found
to be more accurate than correction-based methods
for calculating the dose in inhomogeneous media. The
Monte Carlo method is the only method that explicitly
transports photons and electrons within a material and
is therefore likely to provide more accurate results at
material interfaces and within lower density material
(Chetty et al. 2003). A wide range of experiments
have been conducted in both unit density and low
density geometries to validate user-specific Monte
Carlo codes developed for clinical treatment plan-
ning. When Monte Carlo was used to recalculate
patient cases (Wang et al. 2002) the calculated dose
distributions were again characterized by reduced
penetration and increased penumbra due to larger
secondary electron range in the low-density media,
not as accurately accounted for in the pencil beam
algorithm compared to Monte Carlo. It was concluded
that it would be optimal to either use a Monte Carlo
once fast algorithms are developed.
6 Summary
Technological advances have become commercially
available in the past decade. In particular, 3D con-
formal therapy has become the first step in improving
the targeting of dose to the tumor while sparing dose
to normal tissue, and has facilitated radiation dose
escalation. Though local control and survival has not
yet dramatically improved with recent dose escalation
trials, this may possibly due to geographical misses
because of poor target definition, movement of the
tumor due to respiration, and dose/fractionation lev-
els. Improved construction of the planning target
volume is an important first step in improving the
treatment planning process. Further improvements
can be gained by sophisticated beam arrangement
planning, made possible with intelligent choice of
clinically relevant normal tissue tolerance criteria.
Finally, algorithms to account for the effects of lower
lung density have become available and will facilitate
the accurate and realistic calculation of dose to the
PTV and the lung. The next step in the coming
155
decades is to determine the impact of new technology
on treatment outcome.
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 Four-dimensional Radiation Therapy
for Non-Small Cell Lung Cancer:
A Clinical Perspective
Max Dahele, Johan Cuijpers, and Suresh Senan
Contents
1 Introduction.............................................................. 157
2 What is Four-Dimensional Radiotherapy?........... 159
2.1 How Much Do Lung Tumors and Mediastinal
Lymph Nodes Move? ................................................ 161
3 What Is the Evidence to Support the Use
of 4DRT in Lung Cancer?...................................... 163
4 An Institutional Approach to 4DRT ..................... 165
5 Can I Still Perform Image Guided 4DRT
without a 4DCT or Cone Beam CT? .................... 167
6 Strategies to Facilitate Knowledge Transfer
and 4DRT Implementation..................................... 168
7 Conclusion ................................................................ 168
References.......................................................................... 168
M. Dahele (&)
J. Cuijpers
S. Senan
Department of Radiation Oncology,
VU University Medical Center, De Boelelaan 1117,
1081 HV, Amsterdam, The Netherlands
e-mail: m.dahele@vumc.nl
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_284, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
The purpose of this chapter is to review 4-dimen-
sional radiotherapy (4DRT) for lung cancer in a
way that supports the wider adoption of existing
technologies and effective treatment strategies.
4DRT is defined, the components of a 4DRT
program are identified, resource-sensitive 4DRT
strategies are addressed and our own institution’s
approach to 4D lung RT is discussed.
1 Introduction
Translating existing knowledge and techniques into
routine clinical use can present significant chal-
lenges, but is essential for improving the effective-
ness of radiotherapy (RT) and improving local
control and survival (Palma et al. 2010). Over the
last two decades a convergence of technologies has
helped to shape modern day four-dimensional
radiotherapy (4DRT) for lung cancer. Several of
these are highlighted in Table 1. However, at a time
when the prognosis for many patients with lung
cancer remains poor, many technical advances
have failed to enter routine clinical use, even
after the available technology has been acquired
(Mayles 2010; Routsis et al. 2010; Whitton et al.
2009). Although the explanations for this will likely
vary between healthcare systems, one possible rea-
son is that useful developments in RT are sometimes
seen as difficult to implement, or perceived as
too complex or time consuming for day to day
use. Frequently, a lack of resources is implicated
(Mayles 2010) however, all too often a systematic
157
158
Table 1 Over the last two decades a variety of technologies have contributed to modern day four-dimensional radiotherapy
(4DRT) several are highlighted here
Advances
Three-dimensional conformal
radiotherapy (3DCRT)
Stereotactic lung RT
Intensity modulated RT (IMRT)
Respiratory gated RT (RGRT)
Cone beam CT (CBCT)
Use of external markers to track lung
tumor motion
Computed tomography (CT) for
imaging tumor motion
M. Dahele et al.
Comments
3DCRT introduced about 20 years ago helped by computerized planning systems and multi-leaf
collimators. Dose–volume histograms and multi-planar dose displays highlighted by Emami et al.
(1991). It was anticipated that ‘major progress towards uncomplicated local regional control of lung
cancer may be forthcoming’
Planning studies suggested 3DCRT could improve the therapeutic ratio for high-dose lung RT
(Armstrong et al. 1993)
Seminal report from Blomgren et al. (1995), over 15 years ago, described extracranial stereotactic RT
for targets in various locations including lung. With follow-up of 1.5–38 months local control was 80%
Reports of IMRT for lung tumors appeared almost 15 years ago. In an early planning study, Derycke
et al. (1997) used non-coplanar intensity modulated beams to escalate the dose to central stage III
tumors
Concepts for current day tomotherapy and intensity modulated arc therapy techniques were described
in 1993 and 1995, respectively (Mackie et al. 1993; Yu 1995)
Moving beam treatments capable of rotation/arc delivery in any plane were being used over 50 years
ago to deliver doses comparable to the present time (Clarkson et al. 1959)
Concept of gated radiation therapy demonstrated over 20 years ago (Ohara et al. 1989)
In mid-1999 Minohara et al. reported treatment of over 150 patients with lung or liver tumors using a
gated heavy-ion technique that incorporated an external infrared sensor to determine the respiratory
signal and digitized fluoroscopic images to assess organ motion (Minohara et al. 2000). The same
group reported the use of in-room CT for positional verification 12 years ago (Kamada et al. 1999)
Active breathing control (ABC) for temporarily suspending breathing and reducing tumor motion in
the thorax and abdomen described by Wong et al. (1999) and initial experience with deep inspiratory
breath hold RT for lung cancer by Rosenzweig et al. (2000), who also reported verbal commands could
increase the regularity of breathing and therefore improve the performance of respiratory gating
(Mageras et al. 2001)
CBCT for radiotherapy described over 15 years ago (Cho et al. 1995). Jaffray et al. (2002) reported the
development of a high-resolution gantry mounted flat panel CBCT unit suitable for high-precision
image guided RT (IGRT)
Sonke et al. (2005) described 4D, respiratory correlated CBCT in 2005
Early studies seeking to characterize breathing induced tumor motion and its relationship to external
markers were reported a decade ago and highlighted the challenges of phase discordance between
target and surrogate (Chen et al. 2001)
Dosimetric problems associated with free breathing CT studies incorrectly localizing the position and
volume of critical structures described in the mid-1990s (Balter et al. 1996)
Six ‘fast’ CT scans may underestimate motion in early-stage tumors compared to 4DCT (Underberg
et al. 2004)
Slow CT described around 10 years ago. Without 4DCT tumor motion can be approximated using the
contour (plus a margin) from a single ‘slow’ CT scan limited to the region of interest (in combination
with a fast CT of the whole thorax for treatment planning) (Lagerwaard et al. 2001; Nakamura et al.
2008)
Slow CT is feasible with present-day scanners (Chinneck et al. 2010)
Two-phase shallow inspiration and expiration breath hold imaging can also be used when 4DCT is not
available (Ritchie et al. 1994; Yamada et al. 2002). This strategy was described over 15 years ago
4DCT has been in clinical use for close to a decade and workflows describing its use in patients with
early stage lung cancer have been published (Underberg et al. 2005). It has become the preferred CT
technique for routine imaging of mobile structures
Recent data from Riegel et al. (2009) suggest that cine CT may be an alternative to 4DCT—they
observed that it identified more motion than 4DCT in phantom studies
A new generation of 256- and 320-slice CT scanners is well suited to volumetric cine CT (Mori et al.
2007; Coolens et al. 2009)
(continued)
Four-dimensional Radiation Therapy 159

Table 1 (continued)
Advances
Positron emission tomography
Heterogeneity corrected treatment
planning systems
Multi-modal image fusion for
treatment planning
Uncertainty margins
Comments
4D PET-CT may provide more complete information than 3D PET-CT about the motion of a
metabolically active region and result in less blurring (Aristophanous et al. 2011)
‘Optimal gating’ may quantify the maximum standardized uptake value (SUVmax) better than 3D PET
and produce images with less noise than 4D PET (van Elmpt et al. 2011)
Several studies have now evaluated the correlation between PET and pathology reaching various
conclusions about the optimum metric for target volume segmentation (Wanet et al. 2011; Devic et al.
2010) (note when evaluating such studies that the tumor is moving in vivo, but not ex vivo)
Radiation treatment planning systems (RTP) with heterogeneity correction (HC) are now standard
(Elmpt et al. 2008). While they can better model the dose distribution in lung tumors and organs at risk
(OAR) no improvement in outcome has been directly attributed to their use
Caution with respect to tumor and OAR doses is needed when comparing non-HC and HC treatment
schedules or converting from non-HC to HC RTP systems (Franks et al. 2010; Hurkmans et al. 2009)
In a 2009 survey of American radiation oncologists (36% responded), 95% reported using some form
of advanced imaging in RTP for example PET (76%) and 4DCT (44%), most often for lung tumors
(Simpson et al. 2009)
Clear guidelines needed to support the optimum use of multi-modal imaging in RTP
Stereotactic lung RT typically uses reduced margins to minimize normal tissue toxicity. The high doses
immediately around the gross tumor volume (GTV) may permit this (Arvidson et al. 2008)
In the early phase of our own stereotactic lung practice local control was high with GTV–PTV margins
of only 3 mm, while at the same time setting up patients on the spine (Lagerwaard et al. 2008)
Clarity is needed before attributing improvements in outcome to technology rather than effective dose-
fractionation schedules in appropriately selected patients

and focused approach to change and implementation

may be lacking (Kotter 1995; Spear 2004). Under
such conditions the risk is high that technology imple-
mentation projects will fail, deliver below expectation,
or take a very long time to complete. Ultimately this
adversely affects their ability to impact positively on
patient outcomes.
Against this background, this chapter addresses the
following practical issues: (1) key concepts in 4DRT,
(2) existing technical and educational resources, (3)
components of a modern day lung RT program, (4)
the impact of 4DRT technologies, (5) our institution’s
approach to the routine clinical use of 4DRT, (6)
resources required for different 4DRT strategies, and
(7) strategies to promote knowledge transfer and the
implementation of 4DRT. Throughout this chapter we
focus on what can be achieved in everyday clinical
practice using standard commercial equipment. This
does not currently include true 4D dose computation,
which has lead some to suggest that full 4DRT has yet
to arrive. We have elected to focus on techniques and
technologies that reflect our institutional practice, but
additional references describing other approaches to
4DRT are provided. No liability is assumed and
techniques are subject to change.
2 What is Four-Dimensional
Radiotherapy?
Four-dimensional lung RT makes it possible to
identify and account for breathing related tumor and
(OAR) motion during radiation treatment plan-
ning and delivery. This concept is not new as the
movement of lung tumors and surrounding struc-
tures was also appreciated during treatment simu-
lation in the 2DRT era. Indeed many of the
goals of 2D lung RT mirror those in 4DRT. For
example,
1. Identify target motion during imaging: 2DRT =
fluoroscopy at the simulator, 4DRT = 4D (retro-
spective) respiratory- correlated computed tomog-
raphy (4DCT)
2. Account for motion during treatment planning
while trying to spare normal tissues: 2DRT =
asymmetric margins to reflect typical tumor
motion (largest in the cranio-caudal direction) and
respect normal tissues, 4DRT = individualized
target volume incorporating respiratory motion,
one example of which is a motion encompass-
ing internal target volume (ITV) with isotropic
160 M. Dahele et al.

Table 2 Selected resources that address important aspects of four-dimensional radiotherapy

Resources References (years)
EORTC recommendations for high-dose, high precision lung cancer RT De Ruysscher et al. (2010)
AAPM report on the management of respiratory motion Keall et al. (2006)
Tumor and normal tissue motion during breathing Weiss et al. (2007)
Review of 4D (computed tomography, CT) imaging and treatment planning Keall (2004)
Motion management of thoracic tumors during treatment planning and delivery Verellen et al. (2010)
Challenges in quality assurance for 4DRT Jiang et al. (2008)
4DCT quality assurance Hurkmans et al. (2011)
Clinical implementation of respiratory gated intensity modulated RT Keall et al. (2006)
Four-dimensional radiotherapy for lung cancer Lagerwaard and Senan (2007)
Review that links 4D and adaptive RT for lung cancer Sonke and Belderbos (2010)
Strategies to increase the conformity of lung RT, including 4DRT Chang and Cox (2010)
AAPM American Association of Physicists in Medicine, 4DRT Four-dimensional radiotherapy, 4DCT Four-dimensional computed
tomography, IMRT Intensity-modulated radiotherapy, 4DCBCT Four-cone beam computed tomography

expansion to create the planning target volume
(PTV)
3. Verify that initial RT fields are appropriate:
2DRT = visual check prior to treatment using
fluoroscopy at the simulator, 4DRT = volumetric
on board imaging, for example 4D-cone beam CT
(4DCBCT) or non-4DCBCT (may not completely
image motion)
4. Verifying motion during a course of treatment:
2DRT = check fluoroscopy on the simulator,
4DRT = range of approaches from no regular
check, to some form of intermittent or daily online
imaging such as non-4D/4DCBCT or fluoroscopy.
In 3D conformal RT (3DCRT), the use of con-
ventional CT scans allowed for direct imaging of the
tumor and organs at risk, and led to improvements
over 2DRT in target coverage and OAR sparing
(Graham et al. 1994; Ragan and Perez 1978). How-
ever, conventional CT scans may contain substantial
motion artifact and they provide no information
about tumor displacement which risks both a geo-
graphic target miss and the irradiation of excessive
amounts of normal tissue (Shih et al. 2004). The last
decade or so has resulted in the development of
various commercial imaging solutions including
4DCT that address this shortcoming (Slotman et al.
2006). These make it possible to routinely combine
motion and detailed anatomical information in
order to create motion encompassing target volumes
(e.g., ITV) that can form the basis for treatment
planning. Commercial onboard volumetric imaging
(e.g., CBCT) can also provide information about
tumor motion, including a time-averaged volume that
approximates the tumor as seen on the average
intensity projection (Ave-IP) of the 4DCT or full
4DCBCT, which allows for 4D image guided RT
(IGRT) delivery. CBCT can also provide information
about changes in tumor and OAR anatomy and
location that underpin adaptive radiotherapy (ART).
Again it is the name ART and the technology that is
new, not the concept, which was also practiced
during the 2D era, for example a new immobilization
mask and treatment plan might be made when a head
and neck tumor was clinically responding. A more
detailed discussion of technical issues and the theory
of 4DRT and ART is found in recent publications
(Table 2).
From the preceding discussion, it can be appreci-
ated that the availability of 4DCT, a radiation treat-
ment planning system (RTP)—preferably one with
type B heterogeneity correction that adequately
models photon and electron transport in low density
tissues (e.g., convolution/superposition, Monte Carlo,
or the Analytical Anisotropic Agorithm, ‘AAA’)
(Hurkmans et al. 2009), and a CBCT mounted on a
standard linear accelerator fitted with a multi-leaf
collimator represents one common equipment con-
figuration that provides all the physical building
blocks for a fully-fledged 4D-adaptive lung RT pro-
gram. Figure 1 puts 4D lung RT into the wider con-
text of a comprehensive conventional and stereotactic
lung RT program.
Four-dimensional Radiation Therapy
Fig. 1 Elements of a contemporary lung cancer radiation
therapy program including Four-dimensional radiotherapy
(4DRT)
2.1 How Much Do Lung Tumors
and Mediastinal Lymph Nodes
Move?
Four-dimensional radiotherapy for lung cancer is
predicated on the fact that lung tumors move.
A number of studies have investigated the magnitude
of this motion and two of these using 4DCT are
summarized in Table 3. In short, many tumors move
less than might be expected, usually less than 1 cm in
any direction. Clinical challenges include identifying
those tumors that move so much, or so erratically, that
they risk compromising the effectiveness of treatment,
161
and in developing efficient workflows that allow for
the incorporation of essential 4D routines into daily
clinical practice. The practical question of whether a
single 4DCT is sufficient to identify tumor motion has
been addressed by several authors including Under-
berg et al. (2004) who compared a single ten-phase
4DCT with six fast multi-slice CT scans, Gucken-
berger et al. (2007) who evaluated repeated 4DCT
scans taken at 10 min-intervals and Redmond et al.
(2009) who compared initial 4DCT scans with two
subsequent rescans. The overall message from these
studies is that for most patients a single 4DCT is
probably acceptable although there are individual
patients with irregular breathing for whom this is not
the case (Fig. 2). 4DCT remains prone to artifact with
one retrospective study finding at least one artifact in
90% of patients (45/50) and 30% (6/20) of lung or
mediastinal tumors (Yamamoto et al. 2008). This
highlights that 4DCT scans must be carefully
reviewed at the time of acquisition (Fig. 3).
It is also clear that mediastinal lymph nodes move
(Fig. 4) although often to a different degree than the
primary tumor and not necessarily in the same phase.
Pantarotto et al. (2009) used 4DCT to study the motion
of 100 lymph nodes in 41 patients with either stages I or
III non-small cell lung cancer (NSCLC). They found
that 10% of nodes moved more than 1 cm, with those in
the lower mediastinum moving the most. Assessment
of the motion of 16 locally advanced tumors revealed
no association between primary tumor and nodal
motion, and phase offsets of at least 20 or 30% were
seen in 33 and 12% of nodes, respectively. In 11/16
patients at least one exhaustively trial primary tumor. In
an ideal world, this argues for the inclusion of infor-
mation about both lymph nodes and the primary tumor
in adaptive radiotherapy strategies, especially when
using highly conformal plans. However, mediastinal
structures are typically poorly visualized on cone beam
computed tomography (CBCT). Donnelly et al. (2007)
have reported similar findings and Sher et al. (2007)
quantified mediastinal and hilar node motion using
4DCT in 24 patients and reported mean peak-to-peak
cranial-caudal motion in paratracheal, subcarinal, and
hilar locations of 4, 6, and 7 mm, respectively . The
routine use of 4DCT to contour nodal motion allows an
ITV to be created for individual nodes during the
planning process.
Once a treatment plan has been derived using
patient-specific motion information, delivery may be
162 M. Dahele et al.

Table 3 Lung tumor motion evaluated with four-dimensional computed tomography (4DCT)
Author Institutions Comments
(Refs.)
Liu (2007) MD 166 tumors, 152 patients (57.2% stage III/IV) 4DCT normal respiration
Anderson 39.2, 1.8, 5.4% of tumors moved [0.5 cm along superior–inferior (SI), lateral and anterior–
posterior (AP) axes, respectively
95% of tumors moved \1.34, 0.4 and 0.59 cm along these axes
10.8% of tumors moved [1 cm along SI axis
Small tumors in lower half of lung more mobile
Motion driven mainly by movement of the diaphragm
Redmond Johns 20 patients
(2009) Hopkins Mean GTV excursion in SI, lateral and AP directions was 0.67, 0.21 and 0.29 cm, respectively

Fig. 2 Four-dimensional computed tomography for stereotac-
tic lung radiotherapy (RT). The upper and lower panels (left)
each show a blended image comprising the end-inspiration and
end-expiration phases of separate 4DCT scans from the same
patient taken at one imaging session. In the first (upper) study
of the whole thorax the cranio-caudal extent of tumor motion
was approximately 2 cm. A second limited 4DCT of the tumor
region revealed cranio-caudal motion of 1.2 cm (lower). This
variation is also reflected in different breathing patterns/
amplitudes as shown by the traces on the right: pink 4DCT1,
blue 4DCT2 (generally smaller amplitude and in this case also
less tumor motion), yellow fraction 1 (even smaller amplitude).
This illustrates some of the challenges of 4DCT and shows that
for selected patients with variable breathing, one 4DCT may
not be representative. In this situation relative uncertainty
increases. In selected cases we have constructed an initial ITV
with information from both 4DCT studies, followed by online
monitoring of breathing using Real-time Position Management
(RPM) system, (Varian Medical Systems Inc.) ± repeat 4DCT
and re-planning as indicated

compromised in several ways, for example if there is
an excessive change in the magnitude and direction of
motion, or if the tumor position changes systemati-
cally in relation to the planned location due to
anatomical changes and baseline drift. An awareness
of changes in tumor position relative to critical
structures is important when performing online
target-based image-guidance, since a change in the
co-location of the target and a critical structure may
result in unintended dose being delivered to the OAR.
Although there are now several strategies for assess-
ing tumor motion and location before treatment
delivery, it is not yet the standard practice to evaluate
these parameters during beam-on, or to obtain a
dynamic online evaluation of the dosimetric conse-
quences of such changes.
Four-dimensional Radiation Therapy
Fig. 3 The upper image illustrates multi-level 4DCT artifact
(arrows). When there is artifact in the region of the tumor or an
adjacent critical structure we typically acquire a second short
4DCT that can be used for contouring these volumes (lower
image shows superimposed full thorax and limited volume
scans). Although at times a 4DCT study of the full thorax may
need to be repeated, the initial average intensity projection
(Ave-IP) is frequently acceptable to be used for dose calcula-
tion and contouring the remaining organs at risk
3 What Is the Evidence to Support
the Use of 4DRT in Lung Cancer?
The pragmatic view is that one of the main aims of
RT is to hit the target whilst avoiding as much normal
tissue damage as possible in the process. Nonetheless,
even when a technology provides better information
about the target (e.g., 4DRT, IGRT) there have been
calls for high-level evidence to support its use. On
one level this seems similar to asking a surgeon to
operate with inferior equipment that compromises
their chance of performing a complete excision of the
163
Fig. 4 In this illustration, the mediastinum contains extensive
lymphadenopathy. On four-dimensional computed tomography
(4DCT) imaging the lateral border of the lymphadenopathy is
seen to move a maximum of approximately 1 cm in the medio-
lateral plane
tumor, in order to study any differences in patient
outcomes that might arise and determine efficacy and
cost-effectiveness. Specialists in other disciplines
might reasonably object to such a scenario. Further-
more, it is important that the resources required for a
clinical trial and the altruism of patients are used to
address the most appropriate clinical questions in
such a way that an answer is likely to be forthcoming,
and to consider that clinical trials may not always be
the most appropriate way of using scarce resources
that in this case might perhaps be better deployed to
implement effective treatments like stereotactic body
radiotherapy (SBRT) for lung cancer (Palma et al.
2010; De Ruysscher et al. 2010) or to make full use of
expensive equipment that has already been purchased.
There is a risk that studies designed to look at the
benefit of a specific technology will be expensive,
underpowered, deliver out of date results, and deflect
attention and resources away from day-to-day priori-
ties and other major barriers to implementing effec-
tive treatments in under-resourced environments
(Nagata et al. 2011). The idea that not to exhaustively
trial technologies means a market free for all does not
stand up to scrutiny. As we have illustrated, basic
equipment that has been commercially available for
the best part of 5–10 years is what is required to do
4D-adaptive lung RT, and if acquiring such equip-
ment is not possible, less sophisticated variants of
4DRT may still be possible.
164 M. Dahele et al.

Table 4 Outcomes for locally advanced non-small cell lung cancer (NSCLC) treated with today’s advanced technologies are
comparable to those reported in the preceding era, as are the delivered doses
Study (Refs.)
RTOG 9410 (three-arm phase III
study) (Curran et al. 2003)
SWOG 9504 (single arm phase II
study) (Gandara et al. 2003)
Sura et al. (2008) (retrospective
institutional review)
Liao et al. (2010) (retrospective
institutional review comparing
CT ? 3DCRT with
4DCT ? IMRT)
Years Radiation arm of interest Outcomes
1994–1998 63 Gy/34fr (1.8 Gy 9 25, Median survival (MS) 17 m with
then 2 Gy 9 9) minimum and median ‘potential’
follow-up (FU) times of 4 and 6 years
Concurrent chemo-RT 21% 4 year survival
Stages II and III Total of 595 evaluable patients in
Two-phase (boost) three arms
technique
CT-based treatment
planning whenever possible
1996–1998 61 Gy/33fr (1.8 Gy 9 25, MS of 26 m for 83 eligible patients
then 2 Gy 9 8) with median FU 32 m
Two phase RT using post- 1, 2, and 3 year survival rates 76, 54
induction volume for phase and 37%
two)
Concurrent chemo-RT
Proven stage IIIB
2 dimensional planning
2001–2005 Stages I–IIIB inoperable MS 25 m for stage III, with median
Patients CT-planned and FU 26 m among survivors
treated with IMRT using
1.8–2 Gy/fr
Minimum dose 60 Gy, 2 year overall survival 58%
mean 69.5 Gy for stage III
23/39 stage III pts had
sequential chemo-RT and
13/39 concurrent chemo-
RT
1999–2006, Concurrent chemo-RT Mean FU 3DCRT = 2.1 years, mean
4DCT ? IMRT FU 4DCT/IMRT = 1.3 years
introduced 2004 3DCRT = 318pts, 4DCT/ Median survival 0.85 years (10.2 m)
IMRT = 91pts for 3DCRT and 1.4 years (16.8 m)
for 4DCT/IMRT
Both groups median dose Reduced grade C3 radiation
63 Gy pneumonitis with 4DCT/IMRT
Percentage of N2/3 in
3DCRT group 60/27% and
4DCT/IMRT group 48/32%
Percentage with PET
staging 3DCRT 49 versus
82% in 4DCT/IMRT

The growing availability of advanced technologies
including 4DRT (Table 1) raises the issue of whether
it is having a discernible effect in the clinic. If we look
at locally advanced lung cancer one conclusion might
be that although techniques have changed this is not
reflected in the prescribed dose or clinical outcomes,
despite evidence of a dose-response relationship and a
trend to reduced target volumes brought about by a
shift away from elective nodal irradiation (Table 4)
(De Ruysscher et al. 2010; Dillman et al. 1990, 1996;
Kong et al. 2005). One study in Table 4 deserves
more attention (Liao et al. 2010). Liao et al. (2010)
have suggested that for patients treated with chemo-
radiation, a more recent cohort whose radiotherapy
Four-dimensional Radiation Therapy
incorporated a combination of 4DCT and IMRT did
better than a group treated with 3DCRT both in terms
of overall survival and reduced lung toxicity. Whilst
these intriguing data allow for hypothesis generation,
when they are interpreted in the context of other
available studies they perhaps raise at least as many
questions as they answer (Gandara et al. 2003; Inoue
et al. 2001; Bentzen 2008; Yom et al. 2007; Albain
et al. 2002; Phernambucq et al. 2011). Indeed, it
remains to be seen whether the inference that
advanced technologies per se caused the gain in sur-
vival is supported, or whether they were one factor
associated with it.
So where does this leave things? Our own depart-
ment, which operates within the constraints of a
public healthcare system, aims to create an environ-
ment that is receptive to the rapid adoption of new
technologies and techniques that can make a specific
treatment possible (Lagerwaard et al. 2008), permit
the delivery of potentially toxic treatment with a
lower predicted risk (Verbakel et al. 2010), or enable
greater efficiency (Verbakel et al. 2009). Technology
is an enabler but the most important component of the
treatment chain remains the radiation and how it is
used. For example, during the first 5 years of our
department’s stereotactic lung RT program, early-
stage peripheral lung tumors were treated using
4DCT-based imaging in combination with patient
setup on the spine (Lagerwaard et al. 2008). This
produced results comparable to that reported by
groups using 4DCT with online CBCT for localiza-
tion based on the tumor position (Taremi et al. 2011).
We currently use non-4DCBCT-based online setup,
and have changed our delivery technique from 8–12
non co-planar fixed beams to volumetric modulated
arc therapy (RapidArcÒ, Varian Medical Systems
Inc., Palo Alto, CA, USA).
4 An Institutional Approach to 4DRT
4DCT imaging was introduced into our department in
2003, and all patients with early stage and locally
advanced tumors are planned using this technique.
There are alternative strategies, but Fig. 5 illustrates
the key steps that are currently used for both groups of
patients. The present dose/fractionation schedules are
based upon a ‘risk-adapted’ philosophy for stereo-
tactic RT: 3 9 18, 5 9 11 and 8 9 7.5 Gy using
165
the Varian ‘AAA’ algorithm for dose calculation
(EclipseTM TPS, Varian Medical Systems Inc.). For
conventional chemo-radiotherapy, a dose of 66 Gy in
33 fractions of 2 Gy is delivered in eligible patients
with locally advanced tumors (Lagerwaard et al.
2008; Phernambucq et al. 2011).
For 4DCT imaging, patients enter the scanner and
are settled by the technologist who explains the pro-
cedure. Both groups of patients lie on a thin mattress
placed on top of the treatment couch, with a foam
cushion under the knees and an adjustable support to
comfortably place the arms above the head. If this is
not possible, an alternative position has to be used,
such as one arm up, and one arm down, or both arms
down. Patients to be treated with stereotactic lung RT
have infrared surface markers placed on their thorax
(ExacTracÒ, Brainlab AG, Feldkirchen, Germany).
Once the patient is breathing comfortably, a ten-phase
free-breathing 4DCT is acquired using a 16-slice
wide-bore CT scanner (GE DiscoveryTM CT590 RT,
GE Healthcare, Waukesha, WI, USA) and the Varian
Real-time Position ManagementTM (RPM) system
(Varian Medical Systems Inc.) (Underberg et al.
2004). After 4DCT acquisition the online recon-
structed 4D scan is reviewed by the technologists for
artifacts and the patient’s respiratory trace is analyzed
for reproducibility. During this time the patient
remains in the treatment position on the couch. If an
imaging artifact is observed in the tumor region, or
the CT has been acquired at an unrepresentative point
in the breathing trace, then the scan is repeated, either
a complete scan of the thorax or a shorter one that
includes the target lesion with a cranio-caudal margin
of several centimeters (Fig. 3) (Guckenberger et al.
2007; Yamamoto et al. 2008). In the latter scenario,
the long scan that encompasses the whole thorax will
be used for dose calculation and lung volumes and the
shorter scan for target delineation (± adjacent critical
structures). Skin marks are made to guide initial
patient positioning prior to treatment delivery.
For 4D lung SBRT, ITV is defined using the maxi-
mum intensity projection (MIP), modified as necessary
using information from the individual phases (modified
MIP ITV) (Underberg et al. 2005; Lagerwaard
et al. 2008). If the MIP is considered unreliable, for
example, when the tumor is in close proximity to the
chest wall or other solid structures, then individual
phases are relied upon. Mediastinal and lung window
settings are used to aid the contouring process. Either
166 M. Dahele et al.

Fig. 5 Flowchart illustrating

the approach to four-
dimensional radiotherapy
(4DRT) for stereotactic
(left hand images) and
conventional (right hand
images) lung radiotherapy in
our institution. Row 1 =
four-dimensional computed
tomography (4DCT) imaging,
Row 2 = target volume
delineation, Row 3 =
low- dose region (5 Gy), Row
4 = high-dose region (95%),
Row 5 = online cone beam
CT (CBCT) target and planar
kilovoltage (kV) spine
imaging. Individual steps
are described further and
referenced in the text

all ten phases can be used or only those phases that
represent the extremes of motion in each translational
direction can be selected by viewing the moving tumor
on an appropriate 4D workstation. If contouring is
performed using a system other than the RTP, then it
should be verified as being correct after transfer to the
RTP, as changes in the position of the original contours
of up to several millimeters have occasionally been
identified. For routine cases a 5 mm isotropic ITV–
PTV margin is currently used. A dosimetric margin is in
the process of being introduced for tumors with a
motion amplitude [15 mm (Cuijpers et al. 2010). All
contours are attached to the Ave-IP dataset that is used
for dose calculation and normal structure delineation
(Admiraal et al. 2008). Where necessary certain mobile
organs are also contoured using 4DCT (e.g., the
esophagus, or for some lower zone tumors the stomach
or bowel) (Dieleman et al. 2007). Automated contour
propagation is not yet in routine use (van Dam et al.
2010) and experience so far suggests such tools require
careful visual inspection ± manual adjustment.
Motion suppression, gating, tracking, and implan-
ted fiducials are not currently used for stereotactic
lung RT at our center. Patients are treated under free
Four-dimensional Radiation Therapy
breathing conditions. Initial positioning is using
skin marks with ExacTracÒ markers ± stereoscopic
X-rays with 6D robotic table corrections (e.g. for
tumors close to the spine). A non-gated CBCT
(On-Board ImagerÒ, Varian Medical Systems Inc.) is
acquired and an automatic target match is performed
using the Ave-IP planning CT as the reference data
set, followed by visual verification of target alignment
in all three planes and manual adjustment as neces-
sary. For selected tumors very close to the spine the
patient may be set up to the spine, to ensure that the
spinal cord dose is as planned. The position of
the target and critical structures is verified using the
ITV/PTV and critical structure contours, and where
necessary the relevant critical structure isodose (e.g.,
the dose limit for the spinal cord). Infrared ExacTracÒ
markers are used for intra-fraction motion monitoring.
All patients are now treated with RapidArcÒ volu-
metric modulated RT, routinely consisting of two arcs
(Verbakel et al. 2009). Initial work has not demon-
strated a clinically significant interplay effect between
tissue motion and dynamic MLC movements (Ong
et al. 2011). Individual patient dosimetric quality
assurance is performed using a commercial digital
2D ionization chamber array (MatriXX Evolu-
tion ± Gantry Angle Sensor, IBA Dosimetry GmbH,
Schwarzenbruck, Germany). Prior to being approved
by the radiation oncologist, all treatment plans are
checked by one technologist and one physicist, who
are independent of the team that created the plan.
In locally advanced non-small cell lung cancer, an
ITV consisting of the primary tumor and lymph nodes
are contoured using the extremes of motion identified
as above. The MIP data set is not used because the
ability to discriminate the boundary between tumor
and normal structures is typically lost in the medias-
tinal and hilar regions. Once again the Ave-IP is used
as the primary data set and contouring is performed
on the phase bins representing the extreme positions
of the tumor and lymph nodes, using mediastinal and
lung window settings. An isotropic 10 mm ITV–PTV
expansion is typically used and most patients are
treated under free breathing conditions. If gating is
used it is typically phase gating at end-inspiration
with audio coaching. An increasing number of
plans are made using a hybrid conventional-IMRT
technique that has enabled a reduction in lung
doses (Verbakel et al. 2010). Daily online setup
is performed on the spine using expiration-gated
167
orthogonal X-ray imaging and intermittent CBCT.
At the minimum, CBCT imaging is acquired at the
beginning of weeks 1, 3, and 5 (of a 33 fraction
schedule, treating with five daily fractions per week)
however, this may be increased depending for
example on the presence of atelectasis or other fea-
tures. It is important to note that certain changes in
normal anatomy and tumor position can be detected
using planar imaging provided that the team is aware
of what to look for (e.g., tracheal shift, aided by the
trachea contour, or the development of consolidation).
Daily IGRT can help to control systematic and ran-
dom errors and allow a reduction in setup margins
(Higgins et al. 2010; Yeung et al. 2010). After treat-
ment the CBCT scans are visible in the treatment
planning system (EclipseTM, Varian Medical Systems
Inc.) where they have been automatically registered
with the planning CT. This means that as long as that
was the position in which the patient was treated in
and provided that the anatomy is stable and no sig-
nificant new clinical changes have developed, it is
possible to estimate dose coverage of the target and
selected other structures. Certain isodoses (e.g., 95%)
are also exported to the treatment unit for this purpose
(their use is subject to the same conditions). When
target volume coverage appears to be unsatisfactory,
the radiation oncologist and physicist review the
treatment plan and dosimetric coverage before
deciding on whether to acquire a new 4DCT and
replan the patient. In some cases a plan is calculated
on the CBCT as part of the decision- making process.
5 Can I Still Perform Image Guided
4DRT without a 4DCT or Cone
Beam CT?
In appropriately selected patients, alternatives to
4DCT for identifying tumor motion include limited
volume slow CT, breath-hold imaging at normal end
expiratory/inspiratory positions and repeated fast CT
(Underberg et al. 2004; Lagerwaard et al. 2001;
Nakamura et al. 2008; Chinneck et al. 2010; Ritchie
et al. 1994; Yamada et al. 2002). An additional fast
CT of the full thorax is also acquired with either of
the first two strategies to be used for treatment plan-
ning. Whilst the slow CT strategy can be used for
stereotactic lung RT it is not suited to locally
advanced tumors, however, expiratory/inspiratory
168
breath-hold imaging remains an option. A motion
encompassing ITV can be created from the CT
information with a further expansion to generate the
PTV. If there is no access to CT then conventional
simulator techniques can also be used to estimate
visible tumor motion. In suitable patients with
peripheral lesions stereotactic lung treatment can be
delivered under free-breathing conditions using pla-
nar image-guidance [e.g., orthogonal kilovoltage (kV)
or megavoltage (MV) images] with patient setup on
the spine. Note that prior to commencing CBCT-
based tumor matching in 2008 for stereotactic RT of
peripheral lung tumors, we used stereoscopic kilo-
voltage imaging to set up the patient on the spine and
achieved high rates of local control (Lagerwaard et al.
2008), which have stood the test of longer follow up.
Furthermore, the ITV was defined using an uncoached
free breathing 4DCT, and a 3 mm ITV–PTV expan-
sion was used, patients were treated in free breathing
with multiple non-coplanar beams, calculated using
the pencil beam algorithm with simple heterogeneity
corrections (Lagerwaard et al. 2008). For patients
with locally advanced lung cancer and an appropriate
PTV, daily planar imaging with setup on the spine
appears to be acceptable, again treating without
respiratory coaching or gating (Table 4, Phernambucq
et al. 2011).
6 Strategies to Facilitate Knowledge
Transfer and 4DRT Implementation
Technology adoption and healthcare innovation pre-
sents real challenges (Herzlinger 2006). It involves
individual factors as diverse as beliefs, ambition, and
ability to teamwork, and institutional factors such as
leadership, vision, focus, and people—who you hire,
how they are deployed, and how hard they work for the
group. At a departmental level, it requires clarity of
thought and purpose to identify and prioritize key
technologies and techniques that will result in the
ability to deliver the best treatments to patients, and
strategies to acquire essential knowledge and expertise,
demystify outwardly complex techniques, and gain the
confidence to use them (Dahele and Slotman 2011).
When it comes to implementation and change there are
helpful resources that can provide practical guidance
and motivation (Kotter 1995; Spear 2004; Sirkin et al.
2005). This may be complemented by regional and
M. Dahele et al.
national efforts such as those being rolled out in Canada
and the UK with the aim of increasing the uptake of
specific technologies, in this case IMRT. Such pro-
grams typically have several components including the
development of standards, summaries of the available
evidence, mentorship schemes, and targets (Whitton
et al. 2009; Williams et al. 2010). How effective various
strategies turn out to be will be of great interest.
7 Conclusion
4DRT is an improvement on conventional 3DRT per-
formed without patient-specific motion information.
The essential components of 4D lung RT can be
implemented into routine clinical workflows and per-
formed using standard linear accelerators with a mini-
mum of additional equipment. Although the
contribution that 4DRT per se is making to clinical
outcomes is unresolved we feel that this is not a reason
to delay the implementation of logical and welcome
advances in radiotherapy, especially if they can assist
the development and delivery of more effective treat-
ment schedules to more patients. Responsible and
effective purchasing of equipment and strategies to
ensure that new equipment is brought quickly into
routine clinical use and used to facilitate the delivery of
the most effective treatments to as many patients as
possible are an important part of ensuring the maximum
impact on patient care, return on investment, and the
efficient use of available resources.
Conflicts of interest The Department of Radiation Oncology,
VU University Medical Center has research collaborations with
Varian Medical Systems Inc. (Palo Alto, CA, USA), Brainlab
AG (Feldkirchen, Germany), Velocity Medical Solutions
(Atlanta, GA, USA).
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 PET and PET/CT in Treatment Planning
Michael P. Mac Manus and Rodney J. Hicks
Contents
1 Introduction.............................................................. 173
2 Lessons for the Radiation Oncologist From
Preoperative PET Staging in Potentially
Resectable NSCLC .................................................. 174
2.1 Intra-Thoracic Lymph Node Evaluation................... 174
2.2 Evaluation for Distant Metastasis ............................. 174
3 Role of PET in Selecting Patients for
Radiotherapy/Chemoradiotherapy in NSCLC..... 175
4 Use of PET and PET/CT for Radiotherapy
Treatment Planning................................................. 177
5 Tumor Contouring .................................................. 178
6 Role PET in Restaging After Definitive Radical
Radiotherapy/Chemoradiotherapy for NSCLC ... 179
7 The Future of PET in NSCLC ..............................
7.1 Use of PET Tracers Other Than FDG in Staging
and Treatment Response Assessment in Lung
Cancer ........................................................................
7.2 Respiratory Gating of PET Data...............................
7.3 Response Adapted Radiotherapy: Targeting Tumor
Subvolumes During a Course of Radiotherapy........
8 Conclusions ............................................................... 184
References.......................................................................... 184
M. P. Mac Manus (&)
Department of Radiation Oncology,
Peter MacCallum Cancer Centre,
St Andrew’s Place, East Melbourne,
VIC 3002, Australia
e-mail: Michael.macmanus@petermac.org
R. J. Hicks
Centre for Molecular Imaging,
Peter MacCallum Cancer Centre,
St Andrew’s Place, East Melbourne,
VIC 3002, Australia
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_300, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
Positron emission tomography (PET) is a major
advance in lung cancer imaging and is having an
increasing impact on the management of patients
with non-small cell lung cancer who are candidates
for potentially-curative treatment with radiother-
apy. PET imaging, using 18F-flurodeoxyglucose as
the tracer, and more recently in the form of FDG-
PET/CT is now the most important single imaging
modality for staging, patient selection and radio-
therapy planning in NSCLC. If scans are acquired
under appropriate conditions and the patient is
positioned for radiotherapy, a single scan can be
used for all of these purposes. In this chapter the
role of PET and PET/CT in staging, patient
181 selection and radiotherapy planning are discussed.
Additionally, the use of FDG-PET for response
assessment is described and finally the potential
181
value of PET tracers other than FDG is considered.
183
183
1 Introduction
The advent of positron emission tomography (PET)
has been the most significant advance in cancer
imaging since the introduction of computed tomog-
raphy (CT) (Stroobants et al 2003) and is having an
increasing impact on the management of patients with
lung cancer, especially those being considered for
radiotherapy (Hicks and Mac Manus 2003). The
problems caused by separate acquisition of PET and
CT images are becoming increasingly rare as hybrid
PET/CT scanners supersede older stand-alone PET
173
174
scanners (Townsend and Beyer 2002). PET/CT has
become an essential investigation for the radiation
oncologist, both helping to exclude from radical
radiotherapy those patients who cannot benefit because
they have extensive thoracic or distant metastatic dis-
ease and serving as the primary tool for target volume
definition, based on a growing literature of prospective
studies and expert reviews. PET/CT can minimize
the risk of a geographic miss while on average reducing
the unnecessary irradiation of normal tissues and
demonstrating a higher degree of reproducibility
compared to CT-based planning. Since the last edition
of this book, the evidence base for the use of PET-based
staging and radiotherapy planning has further
strengthened and, despite the absence of randomized
trials in radiotherapy patients, PET/CT is widely con-
sidered to be a mandatory investigation for patients
with non-small cell lung cancer (NSCLC) who are
candidates for potentially curative radiotherapy.
The literature supporting use of FDG PET and
PET/CT in small cell lung cancer (SCLC) is still sparse,
although PET can frequently influence management
decisions (Bradley et al. 2004; Blum et al. 2004).
Accordingly, most of the literature on the value of PET
scanning in lung cancer relates to NSCLC. The role of
PET and PET/CT in evaluation of patients who are
planned to receive radical radiotherapy will be dis-
cussed in this chapter. A single PET/CT scan can per-
form dual roles for the radiation oncologist; (1) staging
for patient selection for radiotherapy and (2) determi-
nation of the gross tumor volume (GTV) for treatment
planning. These roles are inseparable because the
staging information used in patient selection is also
employed for target volume definition and therefore
both will be considered together in this chapter.
2 Lessons for the Radiation
Oncologist From Preoperative PET
Staging in Potentially Resectable
NSCLC
2.1 Intra-Thoracic Lymph Node
Evaluation
When CT is used to stage the mediastinum, node
size is the only significant parameter to be consid-
ered, commonly using a short axis diameter of 1 cm
to indicate malignancy. Accordingly CT has poor
M. P. Mac Manus and R. J. Hicks
sensitivity and specificity for the detection of lymph
node involvement by tumor (Toloza et al. 2003).
Numerous clinicopathological studies and meta-
analyses have proven the superior accuracy of PET
staging for mediastinal involvement compared to CT
based staging. In the Gould meta-analysis of 39
studies with surgical confirmation of imaging results,
median sensitivity and specificity for PET were 85
and 90%, respectively (Gould et al. 2003). By con-
trast, sensitivity of 57% and specificity of 82% were
reported for CT (Toloza et al. 2003). Mediastinal CT
is falsely negative in the approximately 20% of
patients with non-enlarged lymph nodes but approx-
imately 80% of patients with pathologically positive
normal-sized nodes had positive PET findings in those
nodes. This information is very useful for planning
radiotherapy with PET/CT. Nevertheless, both tech-
niques can miss small volume nodal deposits that can
only be identified by pathological examination. Sur-
vival in NSCLC is powerfully correlated with lymph
node staging and drops precipitously when mediasti-
nal nodes contain tumor. Dunagan and colleagues
reported that survival was more strongly correlated
with PET stage than CT based stage in a large group
of patients, who were mostly surgical candidates
(Dunagan et al. 2001). We have found similarly
superior prognostic stratification by FDG PET in a
group of patients with more advanced conventional
stage, many of which were only candidates for
radiotherapy (Hicks et al. 2001).
2.2 Evaluation for Distant Metastasis
PET can typically detect unsuspected distant metastasis
in 5–10% of patients with potentially-resectable stages
I–II disease but the rate of detection is higher in those
with more loco-regionally advanced disease. Both PET
and PET/CT are capable of accurately detecting disease
in the adrenals. PET is also more specific than radio-
nuclide bone scanning in the detection of bone
metastasis in lung cancer. In a study from Peter
MacCallum Cancer Institute of 42 patients with
PET-detected distant metastasis before planned surgery
(n = 7) or radical radiotherapy (RT)/chemoradiother-
apy (n = 35) for NSCLC, survival was investigated as
the principal endpoint (MacManus et al. 2003). The
influence of metastasis number and other prognostic
factors was investigated using Cox regression analysis.
PET and PET/CT in Treatment Planning
All but four patients had died by last follow up.
Median survival was 9 months overall, 12 months for
27 patients with single PET-detected metastasis
and 5 months for 15 patients with [1 metastasis
(p = 0.009). ECOG performance status (p = 0.027) but
not pre-PET stage, weight loss or metastasis site corre-
lated with survival. Dual modality PET/CT staging is
more accurate for detection of distant metastasis in
NSCLC than either PET or CT as single modalities.
Accurate localization of FDG avid regions on fused CT
and PET images reduces the risk of false positives.
3 Role of PET in Selecting Patients
for Radiotherapy/
Chemoradiotherapy in NSCLC
Radical radiotherapy or chemoradiotherapy is offered
predominantly to suitable patients who have stage IIIA
or IIIB disease. Patients with stages I–II disease who
cannot undergo resection because of significant co-
morbidity may also be treated with radical radiother-
apy. The factors that make these patients unsuitable for
surgery (advanced disease or significant comorbidi-
ties), militate against confirmation of their intratho-
racic lymph node status at thoracotomy. These factors
consequently necessitate accurate non-invasive meth-
ods of staging. For pragmatic reasons, the literature
evaluating the diagnostic performance of FDG PET
has primarily focused on staging prior to surgery in
cohorts of patients with predominantly stages I–II
disease since histopathologic staging provides an
accepted reference standard for staging accuracy. As
detailed above, such studies have consistently indi-
cated the superiority of PET and PET/CT compared to
CT. However, there is no reason to suppose that FDG
PET or PET/CT are any less reliable in stage III dis-
ease, despite the relative paucity of studies in which
rigorous pathological confirmation has been per-
formed in this setting. Because it is generally neither
ethical or feasible to subject such patients to compre-
hensive biopsy of all PET and CT detected lesions
simply to assess diagnostic accuracy, the only practical
means to compare diagnostic performance is to per-
form detailed follow-up using serial imaging and sur-
vival as reference standards. Based on these standards,
FDG-PET is clearly the most reliable non-invasive
staging test, and justifies its use in the staging of
patients who are candidates for radical radiotherapy.
175
Prognostic stratification is an important, albeit
indirect, means of assessing the relative diagnostic
performance of different staging procedures. At Peter
MacCallum Cancer Centre, a prospective study was
instituted in 1996 in which 153 consecutive patients
with NSCLC who were candidates for radical radio-
therapy, in most cases given with concurrent che-
motherapy, underwent both conventional staging and
FDG-PET prior to therapy (Mac Manus et al. 2001).
After PET, 30% of patients were denied radical
radiotherapy because of unexpected distant metastasis
(Fig. 1) or because of PET-detected intrathoracic
disease that was too extensive for safe radical irradi-
ation. In the 107 patients who actually underwent
radical therapies, PET stage powerfully correlated
with survival (p = 0.0041) whereas conventional
stage correlated rather poorly with survival
(p = 0.19). Early in this study, PET findings of
extensive disease that were unsupported by review of
conventional imaging were not judged to be sufficient
reason to deny a patient an attempt at radical therapy.
However, it soon became clear that early progression
occurred at all untreated metastatic sites detected by
PET. In separate study from Peter MacCallum, it was
reported that conventional T and N stage assessment
in patients treated with radical radiotherapy is a
relatively poor predictor of outcome (Ball et al. 2002),
which is in contrast to the situation surgically treated
patients who are better served by the current staging
system. Our experience using PET/CT for staging
radiotherapy patients over the past decade suggests
that approximately a third of patients being consid-
ered for radical treatment are unsuitable for this
treatment. Similar experience has been recently
reported by a Polish group who found that only 75 of
100 patients with NSCLC being considered for radi-
cal RT actually went on to receive this treatment after
PET/CT imaging (Kolodziejczyk et al. 2011). In
particular, detection of distant metastatic disease is
critical to avoiding futile attempts at curative radio-
therapy, which involves considerable expense,
resource utilization and toxicity. As expected on
Bayesian principles, the likelihood of metastatic
disease increases with increasing conventional stage.
In a cohort of 167 patients, the rate of PET-detected
metastasis increased significantly (p = 0.016) with
increasing pre-PET stage from I (7.5%) through II
(18%) to III (24%), and, in particular, was signifi-
cantly higher in stage III (p = 0.039) than I–II.
176 M. P. Mac Manus and R. J. Hicks

Fig. 1 Following diagnostic

CT and evaluation of
pulmonary function tests this
patient was considered to be a
radical radiotherapy candidate
and therefore underwent FDG
PET/CT scanning on a flat
palette in treatment position.
Although mediastinal nodes
were mildly enlarged, only
similar size nodes in the
superior right hilum had
significant FDG-avidity.
However, intense focal
abnormality in the L-3
vertebra (fused PET/CT in
right upper panel and PET
in left lower panel) without
corresponding CT
abnormality (left middle
panel) indicated metastatic
bone disease. There were also
several other metabolically-
active bone marrow
abnormalities including
lesions in the left posterior
iliac crest, right lesser
trochanter and right ischium
(arrowed on the maximum
intensity pixel (MIP)
projection image in the lower
left panel) and a volume
rendered image (right upper
panel). Accordingly, the
patient was considered to
have stage IV disease and the
treatment plan was changed
to palliative radiotherapy

Eschmann and colleagues reported a similarly high
rate of detection of distant metastases in apparent
stage III disease (Eschmann et al. 2007). These data
have significant implications for radiotherapy patients
in whom conventional stage is generally more
advanced than in surgical cohorts and also limits the
ability to directly extrapolate data of diagnostic
accuracy of FDG PET and PET/CT from surgical
series to impute potential costs and benefits in
radiotherapy settings although this is often attempted
(Buck et al. 2010).
The impact of PET selection on survival of
patients treated with radical radiotherapy has been
illustrated by a further study from Peter MacCallum
Cancer Centre in which two prospective cohorts with
and without access to PET staging were compared
(Mac Manus et al. 2002). Cohort 1 consisted of all
participants in an Australian randomized trial from
our center given 60 Gy conventionally fractionated
radical radiotherapy with or without concurrent car-
boplatin from 1989 to 1995. Eligible patients had
Stages I–III, Eastern Cooperative Oncology Group
PET and PET/CT in Treatment Planning
status 0 or 1, \10% weight loss, and had not under-
gone PET. Cohort 2 included all radical radiotherapy
candidates between November 1996 and April 1999
who received RRT after PET staging and fulfilled the
same criteria for stage, Eastern Cooperative Oncology
Group status, and weight loss. Eighty and seventy
seven eligible patients comprised the PET and
non-PET groups, respectively. The median survival
was 31 months for PET patients and 16 months for
non-PET patients. Mortality from NSCLC in the first
year was 17% for PET patients and 32% for non-PET
patients, respectively. The hazard ratio for NSCLC
mortality for PET versus non-PET patients was 0.49
(p = 0.0016) on unifactorial analysis and was 0.55
(p = 0.0075) after adjusting for chemotherapy, which
significantly improved survival. This study suggests
that, by using PET to exclude unsuitable patients with
advanced disease and by integrating it within the
radiotherapy treatment planning process, previously
unattainable survival results can be obtained.
As the central importance of PET in selecting
patients for radical radiotherapy for NSCLC becomes
established, it is becomes important to consider the
timeliness of the scans used for radiotherapy plan-
ning. In some countries with restricted access to
radiotherapy services, a significant period may elapse
between FDG-PET scanning and initiation of RT. In a
prospective study at our centre, we reported a very
high rate of disease progression between initial stag-
ing PET scans and RT planning images performed a
median of 3 weeks later. Approximately 39% of scans
showed progressive disease at loco-regional or distant
metastatic sites, which in 29% of cases caused a
change to from radical palliative therapy (Everitt et al.
2010). Thus, if there is any significant delay between
FDG PET/CT and delivery of radiotherapy, it is likely
that progression of disease may invalidate either the
treatment plan or intent.
4 Use of PET and PET/CT
for Radiotherapy Treatment
Planning
The intention behind radical or ‘‘definitive’’ radio-
therapy in NSCLC is cure but with acceptable toxic-
ity. An ideal radiotherapy plan would deliver
sufficient radiation to control the tumor whilst
depositing less than tolerance dose to surrounding
177
normal tissues. Although this ideal is usually unat-
tainable, because the RT dose needed to control the
majority of lung cancers is greater than the dose that
can be given while maintaining the function of sur-
rounding normal tissues, complementary advances in
molecular imaging and radiotherapy delivery mean
that significant improvements in locoregional disease
control are possible. PET/CT based planning is an
exciting development that will help maximize the
benefit from advanced radiotherapy techniques, which
are often associated with tight margins around tumors,
by ensuring that the treatment accurately targets all
sites of gross disease.
The burgeoning PET and PET/CT literature clearly
shows that an estimate of disease extent based on
FDG-PET is very frequently different from and is
usually more accurate than an estimate made using
CT alone. Because pathological confirmation of the
truth of either PET/CT or CT based staging is rarely
available in stage III NSCLC patients treated with
radical radiotherapy, it is reasonable to employ PET/
CT information as a de facto ‘‘gold standard’’ for
radiotherapy planning. In a growing number of
studies in the literature, PET or PET/CT based
radiotherapy planning has been compared with CT
alone plans, using each patient as their own control.
Comparisons between RT treatment plans or tumor
volumes made with and without the assistance of PET
have been made.
PET based radiotherapy planning has been shown to
have an especially high impact on patients with
atelectasis. On CT scans, atelectatic lung and tumor
tissues typically have similar densities. The lack of
contrast makes it impossible for the radiation oncolo-
gist to do anything other than guess where the bound-
ary between tumor and lung lies. However, when CT
information is supplemented by FDG PET informa-
tion, especially in the form of a fused PET/CT image, it
is often very easy to determine the boundary between
normal tissue and tumor, thereby attaining tumor
coverage with the least exposure of uninvolved lung.
Prospective and retrospective trials in which PET
and PET/CT have been used for RT planning in lung
cancer are listed in Table 1. All reports have shown a
clinically significant impact of PET, although most
studies were small. The effect of PET on radiotherapy
planning varied between studies, at least in part
because of variations in sample size and treatment
practices at the various institutions. In cases with
178 M. P. Mac Manus and R. J. Hicks

Table 1 Studies of PET or PET/CT in RT planning with [20 patients

Author/year Patients Parameter studied Change in RT parameter
Munley et al. (1999) 35 RT field [34%
Nestle et al. (1999) 34 RT field 35%
Vanuytsel et al. (2000) 73 GTV 62%
Caldwell et al. (2001) 30 GTV 100%
Mac Manus et al. (2001) 102 GTV 38%
Mah et al. (2002) 23 PTV 100%
Bradley et al. (2004) 24 GTV 58%
Van Der Wel et al. (2005) 21 GTV 100%
RT field 100%
De Ruysscher et al. (2005) 21 RT dose deliverable with equal toxicity 55.2 Gy RT
68.9 Gy PET
Deniaud-Alexandre et al. (2005) 92 GTV 48%
Van Loon et al. (2008) 21 Change in RT plan (SCLC) 24%
Pommier et al. (2010) 119 Change in RT plan 31%
Kolodziejczyk et al. (2011) 75 Geographic miss 27% if PET not used
Abbreviations: RT Radiotherapy, GTV gross tumour volume, PTV planning target volume, SCLC small cell lung cancer

atelactasis (Nestle et al. 1999) the target volume was

often reduced because non-cancerous atelectatic lung
was excluded from the treatment volume. In cases
with more extensive nodal involvement than sus-
pected on CT, PET could lead to an increase in target
volume (Mac Manus et al. 2001). At some centers,
including our own, enlarged but FDG negative nodes
are routinely excluded from the GTV, unless there are
clear features on CT that the nodes are largely
necrotic. Other centers regard such nodes as suspi-
cious based only on size criteria and irradiate them.
Different planning policies can therefore have a large
influence on the impact of PET.
Despite differences in methodology, all published
studies of PET and PET/CT in radiotherapy planning
show that this new technology has a very significant
impact on treatment volumes. It is currently impos-
sible to quantify the benefit of PET based planning,
but it is reasonable to assume that a treatment plan
made using a more accurate estimate of tumor extent
is going to be a better one. One significant conse-
quence of the use of PET and PET/CT for radio-
therapy planning is the need for the PET suite to be
considered as part of the chain of radiotherapy quality
control. Technical aspects of the use of PET and PET/
CT in radiotherapy planning were considered in detail
in the IAEA expert report (MacManus et al. 2009).
5 Tumor Contouring
The topic of tumor contouring (definition of the
margin of the tumor in 3 dimensional (3D) space) in
NSCLC is a complex one. Early studies of the use of
CT images to define target volumes for RT in lung
cancer were characterized by poor agreement between
observers when they were asked to contour the same
tumors (van de Steene et al. 2002). There was both
very wide inter- and intra- observer variability
because the CT scans contained insufficient data to
allow a clear delineation of tumor extent. However, it
is possible to improve upon this by ensuring that
observers adhere to a defined contouring protocol
(Bowden et al. 2002). Fused PET and CT images are
much more suitable for contouring tumors because
they provide greater contrast between tumor and
normal tissues. Nevertheless, even with PET/CT
images significant variation between observers can
occur if steps are not taken to ensure that a stan-
dardized contouring process is used. One cause of
difficulty is the relative low resolution of PET com-
pared to CT, leading to blurring of the margins of
structures apparent on PET scans. At our own centre,
we adapted our established CT contouring protocol to
apply it to PET/CT based planning and found that a
PET and PET/CT in Treatment Planning
detailed visual contouring protocol could achieve a
high level of reproducibility between observers
(Bayne et al. 2010). This process gave the observers
consistent instructions for window settings and image
display and provided rules for contouring nodes and
determining tumor margins. It relied upon the spatial
abilities of the human brain to synthesize information
from the PET and CT components of the images and
all other clinical information.
Other groups have used automated contouring
software approaches that rely upon mathematical
functions to objectively determine the tumor margins.
These methods use only the FDG PET data and do not
take into account the CT information but have the
advantage that they should give identical results each
time they are used on a particular imaging dataset.
The wide range of automated methods available is an
indication that the problems raised by this approach
have not been solved. The same tumor (Nestle et al.
2005) may appear to vary greatly in size depending
upon which method is used there is no consistently
effective method that can reliably account for tumor
movement, even in phantoms (Yaremko et al. 2005)
All of the automated methods require editing by a
human observer, but because of their reproducibility
they may provide an excellent starting point for sub-
sequent editing and thereby reduce variation between
observers. Some centers have used simple SUV cut-
offs but these are especially unreliable (Biehl et al.
2006) and will give very different results depending
upon the level of SUV selected (Hong et al. 2007).
More complex methods such as tumor to background
ratio analysis are to be preferred (Nestle et al. 2006).
Nevertheless the location of a moving tumor in 3D
space cannot be verified independently so no reliable
gold standard exists. Histopathological analysis of
resected lung specimens (van Baardwijk et al. 2007)
and subsequent comparison with preoperative imag-
ing are plagued by inevitable distortions and con-
tractions that occur when tissues are processed for
pathological examination (Dahele et al. 2008). Anal-
ysis of patterns of failure may ultimately provide the
only clinically relevant measure of the accuracy of
PET based radiotherapy planning.
The primary step in radiotherapy planning is to
contour all gross tumor deposits. Because of the
effects of movement with respiration the process of
GTV definition aims to describe not just the location
of tumor at a particular instant, but to delineate the
179
space within which it moves. Effectively a 3D space
that contains all of the tumor, all or most of the time is
produced. Margins are added for microscopic disease
(clinical target volume or CTV) and this is used to
define a larger planning target volume (PTV) which is
actually treated. The volume enclosed by a moving
tumor with an additional margin has been referred to
as an ‘‘internal target volume’’ or ITV. The prolonged
acquisition time of PET provides a more accurate
estimate of the average location of the tumor over
time than a single CT image.
6 Role PET in Restaging After
Definitive Radical Radiotherapy/
Chemoradiotherapy for NSCLC
Response to therapy could potentially determine the
further management of patients with lung cancer after
radical radiotherapy, including consideration for sal-
vage or consolidation therapies in incomplete or
complete responders. Three-dimensional structural
imaging modalities, such as CT and MRI have long
been the most important investigations for assessment
of response to non-surgical therapies such as radiation
therapy or chemotherapy. World Health Organization
or RECIST criteria are applied to measurements of
tumor dimensions made before and after therapy and
responses are categorized as complete response (CR),
partial response (PR), no response (NR) or progres-
sive disease but are recognized to have significant
limitations (Jaffe 2006). In NSCLC in particular,
tumors may be obscured by atelectasis before or after
therapy and may be obscured by radiation pneumo-
nitis or fibrosis in the post treatment period (Lever
et al. 1984). As discussed above, lymph node size
measured on CT is an unreliable measure of lymph
node involvement by tumor. Tumors often regress
gradually over several months, mandating serial
measurements to assess response. Lesions may
never regress radiologically despite having been
controlled by treatment. FDG-PET may facilitate
more accurate early assessment of response to treat-
ment of NSCLC than structural imaging. Preliminary
evidence in patients that PET scanning may be useful
after radiation therapy and it is probably superior to
CT for detecting both the presence and the extent of
recurrent disease irrespective of the primary treatment
modality.
180
Prospective data from Peter MacCallum Cancer
Centre (Mac Manus et al. 2003), show that a visually
read PET response is much more powerfully corre-
lated with survival than response measured by CT
scanning. Seventy-three patients with NSCLC
underwent PET and CT scans before and after radical
radiotherapy (n = 10) or chemoradiotherapy
(n = 63). Follow-up PET scans were performed at a
median of 70 days post radiotherapy. Each patient
had prospective determinations of response to therapy
made with PET and CT. In this study a visual
assessment was made to determine PET-response
while WHO criteria were used for CT response. PET-
response categories were defined as follows;
(1) CMR (complete metabolic response)—no abnor-
mal tumor FDG uptake; activity in the tumor
absent or similar to mediastinum.
(2) PMR (partial metabolic response)—any appre-
ciable reduction in intensity of tumor FDG uptake
or tumor volume. No disease progression at other
sites.
(3) SMD (stable metabolic disease)—no appreciable
change in intensity of tumor FDG uptake or
tumor volume. No new sites of disease.
(4) PMD (progressive metabolic disease)—apprecia-
ble increase in tumor FDG uptake or volume of
known tumor sites or evidence of disease pro-
gression at other intrathoracic or distant meta-
static sites.
Responses were correlated with subsequent sur-
vival. Median survival after follow-up PET was
24 months. There was poor agreement between PET
and CT responses (weighted kappa = 0.35), which
were identical in only 40% of patients. An example
of PET response after radical chemoradiation is
shown in Fig. 2. There were significantly more
complete responders on PET (n = 34) than CT
(n = 10) while fewer patients were judged to be
non-responders (12 vs. 20) or non-evaluable (0 vs.
6) by PET. Both CT and PET responses were
individually significantly associated with survival
duration, but on multifactor analysis including the
known prognostic factors CT response, performance
status, weight loss and stage, only PET metabolic
response was significantly associated with survival
duration (p \ 0.0001).
The best method for response assessment after
therapy has not yet been determined (Wahl et al.
2009), whether visual or quantitative approaches.
M. P. Mac Manus and R. J. Hicks
Although there is scientific appeal in the absolute
evaluation of glucose metabolic rate in tumors, fully
quantitative approaches using arterial blood analysis
are probably too invasive and complex for routine
clinical use. In clinical trials of novel therapeutic
agents, semi-quantitative measures based on the
change in standardized uptake (SUV) in lesions can
be reasonably well standardized if attention is paid to
study acquisition parameters (Binns et al. 2011).
Whichever approach has been chosen, a reduction in
FDG uptake generally predicts patient benefit in
patients treated for lung cancer (Hicks 2009). Chan-
ges in SUV have been shown to have prognostic
significance after neoadjuvant chemotherapy prior to
surgery and after palliative chemotherapy for incur-
able NSCLC. Use of SUV-based assessment follow-
ing radiotherapy may be compromised by a number of
factors, including the commonly observed and
sometimes intense inflammatory reaction to radio-
therapy in normal tissues. These changes may have a
measured SUV in the ‘‘malignant’’ range but can
usually be identified as such on qualitative assess-
ment. Post-radiotherapy changes conform to the vol-
ume of aerated lung in the radiation treatment
volume, are of a geographic rather than segmental or
anatomical distribution and are non-congruent with
the biodistribution of uptake in tumoral sites on
baseline scanning. Residual disease, on the other
hand, conforms to the position of initial tumor
allowing for anatomical distortion relating to further
collapse or re-expansion of lung parenchyma and
tends to maintain a lobular shape. Similarly, tumoral
uptake tends to respect and follow natural tissue
barriers such as the pleura of the oblique fissure
whereas radiation changes are not influenced by such
boundaries. The presence of FDG uptake in previ-
ously normal lung after radiotherapy has a strong
correlation with the presence of radiation pneumonitis
(Mac Manus et al. 2010).
Thus, PET appears to be far superior to CT scan-
ning for predicting survival after radical radiation
therapy. The powerful prognostic information avail-
able from post-treatment PET may encourage the
development of investigational ‘‘response-adapted’’
therapeutic approaches. It also raises the possibility
that early PET response, during a course of radio-
therapy could provide early prognostic information
and provide a basis for modifying therapy during the
treatment course.
PET and PET/CT in Treatment Planning 181

Fig. 2 Coronal images at

baseline FDG PET/CT before
(left upper panel) and after
chemoradiotherapy (post-
CRT, right upper panel)
reveal high activity in the
mid-zone of the left lung.
Evaluation of the sagittal
projection images (middle
panels) clearly demonstrate
that the site of the primary
tumour (blue arrow) losing its
metabolic signal following
treatment whereas new
abnormality with sharply
demarcated superior and
inferior borders (red arrows),
conforming to the cranio-
caudal extent of the radiation
treatment volume, became
apparent. The fused FDG
PET/CT images (lower
panels) confirmed loss of
metabolic abnormality (blue
arrows) in the primary lesion
between the baseline (left) and
post-treatment (right) scans,
which also revealed a sharply
demarcated abnormality (red
arrows) crossing the oblique
fissure and corresponding the
lateral margin of the treatment
volume

false positives related to inflammatory conditions.

7 The Future of PET in NSCLC
7.1 Use of PET Tracers Other Than FDG
in Staging and Treatment Response
Assessment in Lung Cancer
One of the theoretical limitations of FDG as a tracer
for the evaluation of lung cancer is the presence of
The excellent clinical performance of FDG PET
suggests that this is not a major practical limitation in
countries with a relatively low prevalence of granu-
lomatous lung disease. Even where diseases such as
tuberculosis and histoplasmosis are more common,
the combination of the intensity and pattern of uptake,
combined with consideration of the pre-test proba-
bility of disease enables many potential false positive
182
results based purely on the intensity of uptake (SUV)
to be prospectively identified. Even when this cannot
be achieved, most conditions that cause false positive
results represent important pathologies that benefit
from specific diagnosis and therapy. Nevertheless,
there has been interest in assessing alternative tracers
for tumor imaging that may be less prone to uptake in
inflammatory diseases. Early studies included com-
parison between FDG PET and 201Tl, a tumor imag-
ing agent commonly used in conventional nuclear
medicine. The hope that 201Tl SPECT might prove
more specific than FDG was not realized. The lower
spatial and contrast resolution generally achieved
with SPECT limits its ability to detect disease in non-
enlarged mediastinal nodes and beyond the thorax,
which, as shown above, accounts for the major
incremental value of FDG PET compared to CT and
much of its clinical impact.
Recognizing the instrumentation advantages of
PET, comparison with other PET tracers is probably
more important. One of the first PET agents to be
compared was the amino acid tracer, 11C-methionine.
In a study looking at the accuracy of 11C-methionine
for mediastinal nodal staging, superior accuracy
compared to CT was demonstrated using histopa-
thological validation with results comparable to those
reported using FDG PET. However, this study did not
directly compare the 11C-methionine results with
those from FDG PET. In a small series from Sweden
that did compare FDG and 11C-methionine, all pri-
mary tumors were equally well visualized by both
tracers and since there were no false positive FDG
results, the possibility that amino acid imaging may
have a lower propensity for false positive results
could not be evaluated. A larger study from Japan
found that the performance of both tracers was similar
with a marginally higher specificity and accuracy with
11
C methionine but did not reach statistical signifi-
cance (Sasaki et al. 2001). A more recent, but rela-
tively small study evaluating 15 solitary pulmonary
nodules suggested that 11C methionine may be both
more sensitive for some malignancies, such as gastric
and thyroid cancer, known to sometimes have rela-
tively low FDG-avidity and more specific with lack of
significant uptake into inflammatory lesions, such as
tuberculosis. In the restaging setting, where inflam-
matory changes may pose difficulties in determining
nature of increased FDG activity, the MD Anderson
Cancer Center group found that 11C-methionine and
M. P. Mac Manus and R. J. Hicks
FDG had similar diagnostic performance although
FDG yielded significantly higher SUV’s than
11
C-methionine.
Enhanced production of cell membranes in cancer
cells requires uptake of choline to form phosphatidyl-
choline. Accordingly, radiolabeled choline analogs
have been investigated as a potential cancer imaging
agents. Initial studies focused on 11C-choline and
involved comparison with FDG PET in 29 patients with
biopsy proven NSCLC. This study demonstrated
superior sensitivity of 11C-choline for detection of
mediastinal nodes. These results were not however
confirmed by a subsequent study from the Netherlands,
which found that this tracer has lower sensitivity
for mediastinal nodal involvement. An important
observation in this study was the ability of 11C-choline
to detect brain metastases that are not seen on FDG PET
due to high uptake in normal cerebral structures. This
observation is pertinent to other tracers that also have
low accumulation in the brain, including 11C-methio-
nine. Fluorinated choline analogs have recently been
described. Preliminary studies of one of these tracers
for evaluation of lung cancer were, however, not
encouraging (Pauleit et al. 2005).
Another potential imaging target of lung cancer cells
is their high proliferation. Proliferative rate may also
provide insights into the biological activity and prog-
nosis of lung cancers. Although there does appear to be
a relationship between FDG uptake and proliferation in
NSCLC (Higashi et al. 2000), there are factors other
than proliferation that potentially drive FDG uptake in
cancer cells. One of these factors is hypoxia, which
increases expression of glucose transporters and
glycolytic enzymes but decreases cell proliferation.
Hence, tracers that more directly reflect cell prolifera-
tion, such as tracers of DNA synthesis are attractive.
Various thymidine analogs have been developed for
PET imaging. These include 11C-thymidine and the
fluorinated analog FLT. Studies in lung tumors have
demonstrated the feasibility of FLT for evaluating cell
proliferation but this tracer does not appear to be
superior to FDG for lung cancer staging.
A number of studies are now evaluating the utility
of FLT for therapeutic monitoring of radiotherapy and
molecular targeted therapies. Although promising for
the evaluation of molecular targeted agents that may
lead to cell stasis rather than death, a preliminary
study comparing early FDG and FLT response sug-
gested that both were predictive of progression-free
PET and PET/CT in Treatment Planning
survival but only early (day 14) FDG response pre-
dicted overall survival (Mileshkin et al. 2011). These
results have also been confirmed in a study from
Germany.
The ability of FLT to assess the extent and activity
of bone marrow could provide a useful diagnostic tool
in assessing the risk of radiotherapy in heavily pre-
treated patients with recurrent disease. It has also
recently been used to understand the effects of novel
forms of radiotherapy, such as carbon ion therapy, on
bone marrow function (Koizumi et al. 2011).
7.2 Respiratory Gating of PET Data
The acquisition of the emission data used to recon-
struct PET images occurs over several minutes and
therefore integrates the effects of respiratory move-
ment. This has the effect of increasing the apparent
supero-inferior size of lesions near the base of the
lungs that move predominantly in the coronal plane
during respiration and the antero-posterior dimensions
of lesions in the anterior aspect of the lungs that move
mainly in the axial plane. In both circumstances,
apparent activity in slightly reduced by this move-
ment due to partial volume effects. CT scanning,
however, is acquired very rapidly and multi-slice
scanners can acquire images sufficiently fast to
effectively ‘‘freeze’’ respiratory motion. Alternatively,
CT scan images can be acquired during breath hold-
ing at a given phase of respiration. Being derived
from instantaneous images of the relative position of
organs, the location of lesions on CT planning images
does not necessarily correspond to the averaged or
integrated position of lesions detected by emission
scanning. It is clear that respiratory movement can
lead to misregistration of PET and CT lesions on
fused PET and CT images, whether acquired on stand
alone or combined devices. Although this is not a
particularly frequent diagnostic problem, it may pose
difficulties when determining the GTV and PTV for
radiotherapy. The approach at Peter MacCallum
Cancer Centre has been to assume that, since the PET
data represents the integrated position throughout the
respiratory cycle and the average position likely to
also apply during a radiotherapy treatment episode,
PET should be used to plan the GTV. An alternative
approach would be to perform respiratory gating of
both the PET, CT and radiotherapy delivery. This is
183
an extremely complex undertaking. Efforts to develop
methodology for respiratory gated PET have been
reported (Nehmeh et al. 2002) and offer the potential
for highly sophisticated treatment planning and
delivery (Wurm et al. 2006). Whether the resource
implications of such an approach make it practical
and affordable for routine clinical application remains
to be seen but for patients in whom lung function is
marginal for radical therapy, these highly targeted
approaches may be critical to outcome.
7.3 Response Adapted Radiotherapy:
Targeting Tumor Subvolumes
During a Course of Radiotherapy
One of the most promising areas in radiotherapy
research is the use of PET to study changes that occur
in the tumor during a course of therapy. We know that
FDG PET is superior to CT for definitive assessment
of treatment response after chemoradiotherapy for
NSCLC but tumor imaging during therapy may allow
for modification of the treatment course in real time.
Different regions of the target contain different den-
sities of tumor cells and these densities change during
therapy. Serial PET imaging during a course of RT
could potentially provide prognostic information and
more importantly could provide an opportunity to
give a higher RT dose to regions of tumor that show
the poorest metabolic or proliferative response during
therapy. Kong et al. at University of Michigan studied
the correlation between FDG PET scans performed
during RT with the definitive response on a post
treatment PET scan several months later. FDG-PET/
CT scans were acquired before, during, and after RT.
Tumor and lung metabolic responses were assessed
qualitatively by physicians and quantitatively by
normalized peak FDG activity. Of 15 patients, 11 had
PMR, two patients had CMR, and two patients had
stable disease at approximately 45 Gy during RT. The
qualitative metabolic response during RT correlated
with the overall response post-RT (p = 0.03). At our
own centre we are exploring PET imaging with both
FDG and the proliferation marker 18F-30 -deoxy-30 -
fluoro-l-thymidine (FLT) to assess tumor response
during therapy. Pilot data show that significant
reductions in tumor and bone marrow FLT uptake
occur during radiotherapy (Everitt et al. 2009). Tumor
responses vary widely between patients but it is too
184
early to determine how these interim responses are
correlated with eventual outcome and too early to
employ them in modifying target volumes outside of a
clinical trial.
The availability of PET tracers that can evaluate
biological processes relevant to radiotherapy offers
the prospect of biologically-adapted radiotherapy
(Gregoire et al. 2007). For example, dose-painting of
regions of hypoxia could be facilitated by PET imaging
with a range of tracers that are suitable for detection of
hypoxia (Reischl et al. 2007). Radiolabeled mono-
clonal antibodies, such as 89Zr-bevacizumab, may
help to identify patients who could benefit from
inclusion of such agents into combination therapies
with radiotherapy.
8 Conclusions
PET scanning is vastly superior to conventional
methods used in staging lung cancer and with the
widespread adoption of PET/CT this superiority has
only increased. PET/CT should now be considered a
standard tool for radiotherapy planning in NSCLC
because it provides the most accurate estimate of the
true disease extent currently available. The use of
PET to exclude patients with extensive and, currently,
generally incurable disease from potentially toxic
radical radiotherapy will significantly improve the
overall results of treatment with this modality and
early diagnosis of limited recurrent disease could
potentially facilitate salvage therapies. Furthermore,
by decreasing futile attempts at curative treatment,
expensive radical radiotherapy resources can be more
effectively used. The evidence base for PET and PET/
CT for staging and radiotherapy planning in NSCLC
is becoming so compelling that it is difficult to
imagine treating a patient with radical radiotherapy
without access to this technology. Nevertheless, fur-
ther study is necessary to define the cost effectiveness
of this very useful but expensive modality.
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 Target Volume Definition in Non-Small Cell
Lung Cancer
Lucyna Kepka and Milena Kolodziejczyk
Contents
1 Introduction.............................................................. 187
2 Gross Tumor Volume Definition ...........................
2.1 GTV for Tumor .........................................................
2.2 GTV for Nodes..........................................................
2.3 Problems Related to the Use
of PET-CT for GTV Definition ................................
2.4 Definition of GTV After Chemotherapy ..................
3 Clinical Target Volume Definition ........................
3.1 Microscopic Spread Around Primary Tumor
and Pathologic Lymph Nodes...................................
3.2 Elective Nodal Irradiation .........................................
3.3 Lymph Node Stations Delineation for ENI Issues...
3.4 Postoperative Radiotherapy Target Volume.............
4 Planning Target Volume Definition ...................... 196
4.1 Internal Target Volume: Respiratory Motion
Management............................................................... 196
4.2 Margins for Set-up .................................................... 197
References.......................................................................... 197
L. Kepka (&)  M. Kolodziejczyk
M. Sklodowska-Curie Memorial Cancer and Institute
of Oncology, Warsaw, Poland
e-mail: lucynak@coi.waw.pl
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_231,  Springer-Verlag Berlin Heidelberg 2011
Abstract
Proper target volume delineation is a crucial stage
of treatment planning, so any error introduced in
188 this process is a systematic error and cannot be
188 quantified and/or detected by modern treatment
189 technologies, unlike other sources of geometrical
uncertainties. All steps of target definition should
189
190 be standardized. In non-small cell lung cancer
radiotherapy, there are specific problems related to
191
the definition of all three consecutive target
191 volumes recommended by ICRU: gross tumor
192 volume (GTV), clinical target volume (CTV), and
193 planning target volume (PTV). In GTV delinea-
194
tion, the proper imaging, e.g., standardized way of
the use of CT and PET-CT, and continuous
radiological training of radiation oncologists are
emphasized. For CTV, we still lack robust data on
the margin which is necessary to expand around
GTV of the tumor and pathologic lymph nodes to
adequately account for microscopic spread. Addi-
tionally, elective nodal irradiation is still a source
of controversies. For PTV definition, major
increase in technologies is involved. It leads in
some cases to improvement of the tumor coverage
and sparing of organs at risk, but as this process is
expensive and time consuming, it might not be
always beneficial.
1 Introduction
Target volume delineation is the most important step
in the radiation therapy planning. While set-up and
respiratory motion displacements can be quantified
187
188
Table 1 The International Commission on Radiation Units
and Measurements (ICRU 1993, 1999) definitions of target
volumes
Gross tumor Macroscopic extent of the malignant
volume (GTV) growth, e.g., clinically palpable and/or
visualized by the imaging
Clinical target Anatomical-clinical concept that needs
volume (CTV) to be defined before delineation. It
contains GTV and/or subclinical
microscopic disease which should be
eliminated
Planning target Geometrical concept. A 3D-expansion
volume (PTV) of the CTV to account for all
geometrical uncertainties (for target
and organ at risk motion, set-up error,
delineation, anatomical changes during
treatment)
Internal target A component of PTV specified by
volume (ITV) Report 62 (ICRU 1999), e.g.,
CTV ? margin for motion
and corrected at the individualized basis with the
modern technologies, target contouring is still prone
to the risk of introducing human error. The important
inter-observer variability in the target definition, also
for lung cancer, has been documented extensively
(Bowden et al. 2002; Giraud et al. 2002; Steenbakkers
et al. 2005, 2006; Kepka et al. 2007). The error
introduced in the target definition is a systematic error
so it impacts the tumor coverage heavily (van Herk
et al. 2000). Consequently, a continuous education
and training of the radiation oncologists in this field is
needed.
In this chapter, the issues pertinent to the three
stages of the target volume definition in radiotherapy
of non-small cell lung cancer (NSCLC) will be dis-
cussed. Those three stages of target volume definition
follow the recommendation of the International
Commission on Radiation Units (ICRU) and Mea-
surements Report 50 (ICRU 1993) and Report 62
(ICRU 1999). The ICRU recommends the consecu-
tive definition of the gross tumor volume (GTV),
clinical target volume (CTV), and Planning Target
Volume (PTV). Report 62 recommends additional
definition within PTV called the Internal Target
Volume (ITV). The ICRU definitions of respective
target volumes are summarized in Table 1. Thus the
specific issues related to the target definition in
NSCLC radiotherapy will be presented in the light of
the ICRU recommendations.
L. Kepka and M. Kolodziejczyk
2 Gross Tumor Volume Definition
All the steps of gross tumor volume (GTV) definition
should be standardized. Inter-observer variability in
the contouring of the GTV is a major source of the
uncertainty in radiotherapy planning. Reported dif-
ferences in the contouring varied between 12 and 60%
on average (Bowden et al. 2002; van de Steene et al.
2002; Giraud et al. 2002; Steenbakkers et al. 2005).
The numerous measures to overcome this problem are
recommended. The first one is the formulation and
obedience of the departmental contouring guidelines.
The definition of appropriate windows setting for
computerized tomography (CT), appropriate training
in radiology and cooperation with radiologist, and the
use of information from PET-CT (in a standardized
way) are also related to better reproducibility of the
delineated targets (Bowden et al. 2002; Steenbakkers
et al. 2005, 2006; Greco et al. 2007).
2.1 GTV for Tumor
In the era of the three-dimensional conformal radio-
therapy (3D-CRT), the definition of the GTV is based
on the CT. The CT performed for planning purposes
is executed in the treatment position; the consider-
ation of the respiratory motion is crucial for radio-
therapy planning. The CT is not done at the breath
hold as for diagnostic purposes. Slow scanning which
allows for consideration of the tumor movement in
different breathing phases leads to the image blurring.
Currently, the 4D-imaging prevents this inconve-
nience. It records a respiratory signal during image
acquisition and enables retrospective reconstruction
of a dataset from multiple phases of respiratory cycle.
A choice of appropriate window setting for delinea-
tion is of crucial value. For delineation of tumors
located within pulmonary tissue, it is recommended to
use so-called ‘‘pulmonary window’’ setting. The best
concordance between the radiological image and the
actual dimensions of the parenchymal tumor has been
established at the window width 1,600 and level
-600. For tumors located centrally, it is useful to use
also mediastinal window setting with recommended
window width of 400 and level of 20 (de Ruysscher
et al. 2010). However, the ‘‘in house’’ measurements
of appropriate window setting should be done in each
Target Volume Definition in Non-Small Cell Lung Cancer
department, as calibration of CT may differ between
centers. The contrast injection for planning CT may
be useful in case of tumors localized in the hilar
region for the purpose of distinguishing of vessels in
this region.
For central locations of tumor with endobronchial
component, the bronchoscopy findings should be
considered, because even high resolution CT does not
visualize this component and the FDG-PET sensitiv-
ity and specificity is estimated at 73 and 85%,
respectively (Pasic et al. 2005). The special clinical
case for such setting represents a roentgenographi-
cally occult carcinoma, a rare entity treated usually
with combination of external-beam and endobron-
chial brachytherapy. Currently, we do not have clear
guidelines for GTV delineation in those cases,
because series reported so far started with CTV for
delineation which may represent a reasonable solution
in case of the poor tumor visualization (Saito et al.
2000).
2.2 GTV for Nodes
This component of GTV is delineated on the CT
scans; however, the PET-CT is currently quite rou-
tinely used for diagnosis of metastases of NSCLC to
the mediastinal and hilar lymph nodes. It is due to the
higher accuracy of the mediastinal staging in PET
than in CT. In an overview done by Silvestri et al.
(2007), the PET scanning sensitivity and specificity
for mediastinal staging was 0.74 and 0.85 compared
to respective values of 0.51 and 0.85 for CT scanning.
Thus the PET-CT improves the mediastinal staging in
comparison with CT alone, however, it is far from
being perfect. The findings from both examinations
should be considered carefully in the definition of
the nodal GTV. If radiotherapy planning was based
on the CT only, the usual policy would be to include
in the GTV, all mediastinal lymph nodes with a
diameter at short axis of higher than 1.0 cm. With the
use of the PET-CT, we know that for 1.0–1.5 cm
FDG-PET negative lymph nodes, the probability of
metastatic involvement is below 5%. However, for
FDG-PET negative lymph nodes measuring in short
axis [1.5 cm, the probability of metastatic involve-
ment is 21% (de Langen et al. 2006). So the formu-
lation of the guidelines may indicate that we should
include all FDG-PET positive lymph nodes (unless
189
pathologically excluded) and the FDG-PET negative
lymph nodes with a diameter that exceeds 1.5 cm in
the nodal GTV. However, there are also more strict
guidelines for definition of the nodal GTV which
were traditionally used within Radiation Therapy
Oncology Group (RTOG). According to those
guidelines, all FDG-PET positive lymph nodes and all
lymph nodes with a diameter in short axis [1.0 cm
were contoured as nodal GTV (Bradley et al. 2010).
Lymph nodes should be contoured on the mediastinal
window as defined above for central components of
tumors.
2.3 Problems Related to the Use
of PET-CT for GTV Definition
The value of the use of PET-CT for radiotherapy of
NSCLC is described in detail in another chapter of
this book. Only some specific problems for GTV
definition will be overviewed in this paragraph. The
overview of studies on treatment planning of lung
cancer with PET-CT showed 5–64 and 0–70% of
increase and decrease of radiation volumes defined in
the CT alone, respectively (Macmanus et al. 2009).
For the nodal GTV, those changes are related to
higher accuracy of PET-CT than CT alone in the
mediastinal staging discussed above. For the tumor, it
is mainly related to the superior value of the PET in
the distinction of the tumor from atelectasis (Nestle
et al. 2006). However, we should be cautious of the
uncritical interpretation of those changes that result
from PET use. The outcomes of those studies may
differ because of the variability in methodology
across centers. Therefore, to unify PET-CT scan
procedure in treatment planning, the European
Association of Nuclear Medicine (EANM) published
the guidelines for tumor PET imaging (Boellard et al.
2010). The recommendations for the use of PET-CT
in lung cancer radiotherapy were also recently pub-
lished (de Ruysscher et al. 2010). The GTV generated
from functional imaging with poor image resolution
cannot be surrogate for a definition of the GTV
defined by the CT which is able to better visualize the
tumor. It is only an additional source of information
which should be taken into account when contouring
targets. For contouring, the key question is the
method of outlining of the GTV on the FDG-PET
190 L. Kepka and M. Kolodziejczyk

based images. The methods for outlining were used: Table 2 Phase III clinical studies which had in one of arms
(1) the qualitative visual method, (2) the GTV 2.5 radiotherapy delivered after induction chemotherapy and rec-
ommended the use of pre-chemotherapy volumes for target
standardized uptake value (SUV) units, (3) the linear definition
adaptive SUV threshold function method, and (4) the
Trial, year Design of the study
use of any threshold of local maximal uptake value in
which the threshold of 41–42% established in the Le Chevalier Radiotherapy alone versus sequential
et al. 1991 radiochemotherapy
phantoms studies (Boellard et al. 2010; Black et al.
Dillman et al. Radiotherapy alone versus sequential
2004) is commonly used. Despite the fact that
1996 radiochemotherapy
thresholds of 42 (van Loon et al. 2010) and 50% (Wu
Furuse et al. Sequential radiochemotherapy versus
et al. 2010) were seen as fitting the best for the 1999 concurrent radiochemotherapy
diameter of the tumor reported on the pathology
Sause et al. 2000 Radiotherapy alone versus sequential
examination, the use of predefined thresholds is a radiochemotherapy
source of potential errors. It was proven that due to Curran et al. Sequential radiochemotherapy versus
the heterogeneity of the FDG uptake in the lung tumor 2003 concurrent radiochemotherapy
and poor spatial resolution of the PET leading to the Zatloukal et al. Sequential radiochemotherapy versus
partial volume effect, the automatic delineation with 2004 concurrent radiochemotherapy
any predefined threshold cannot provide the reliable Fournel et al. Sequential radiochemotherapy versus
GTV definition (Devic et al. 2010). The recom- 2005 concurrent radiochemotherapy
mended approach of contouring of the FDG-PET Huber et al. 2006 Induction chemotherapy followed by
images is the qualitative visual method (de Ruysscher radiotherapy or concurrent
et al. 2010). It is also not a perfect solution, as it radiochemotherapy
is related to the risk of inter-observer variability. Vokes et al. 2007 Concurrent radiochemotherapy versus
To overcome this problem, the contouring should be induction chemotherapy followed by
concurrent radiochemotherapy
held in close cooperation of the radiation oncologist
van Meerbeeck Induction chemotherapy followed by
and the nuclear medicine physician in experienced et al. 2007 surgery or definitive radiotherapy
centers.
Belderbos et al. Sequential radiochemotherapy versus
2007 concurrent radiochemotherapy
Thomas et al. Induction chemotherapy followed by
2.4 Definition of GTV After 2008 radiochemotherapy and surgery versus
Chemotherapy surgery and postoperative radiotherapy

When radiotherapy is used in case of tumor regression

after induction chemotherapy, the question is raised as
to which pre-, or post-chemotherapy volumes, should
be considered for GTV creation. All phase III clinical
studies (Table 2) which had in one of arms radio-
therapy delivered after induction chemotherapy rec-
ommended the use of pre-chemotherapy volumes for
target definition. Thus we should use a pre-
chemotherapy volume for GTV definition except in
cases where such approach would lead to an unac-
ceptable risk of pneumonitis. Opposite approach may
not be safe, because we lack evidence which indicates
that its outcome in terms of local control is not
inferior. Despite a lack of evidence, the clinical
practice in this field varies considerably. Canadian
patterns of care survey showed that 42% of radio-
therapists used post-chemotherapy target volumes and
the differences in this regard were seen even among
physicians working in the same institution (Tai et al.
2004). It reflects a need for recommendations and
education on this very pertinent issue. The use of pre-
chemotherapy volumes may be an additional source
of uncertainty and errors in radiotherapy planning,
especially, if only the visual inspection for compari-
son of images is used. The co-registration and fusion
of pre- and post-chemotherapy imaging is a recom-
mended approach for adequate consideration of the
initial disease status (Lagerwaard et al. 2002). In case
of the use of PET-CT for radiotherapy planning, a
minimum of 10 days should be taken after the last
chemotherapy dose and planning or it might be even
be better to do the examination as close to the next
chemotherapy as possible (Boellard et al. 2010).
Target Volume Definition in Non-Small Cell Lung Cancer
3 Clinical Target Volume Definition
3.1 Microscopic Spread Around Primary
Tumor and Pathologic Lymph Nodes
The International Commission on Radiation Units
(ICRU) and measurement reports 50 (ICRU 1993)
and 62 (ICRU 1999) recommend the addition of
margin to the GTV for microscopic disease extension
to create the clinical target volume (CTV). There are
three distinct types of CTV margins in lung cancer
radiotherapy, each one causing separate problems,
namely, margin within pulmonary parenchyma, mar-
gin for endobronchial spread, and margin for extra-
capsular extension in mediastinal and hilar lymph
nodes. Obviously, as it is a microscopic spread, we
have no imaging which can detect it. Our current
knowledge on this issue is based on the correlation of
imaging with pathologic data.
For microscopic disease spread of NSCLC within
the pulmonary parenchyma, the seminal work was
performed by Giraud et al. (2000) in which the
pathologic findings were correlated with pre-opera-
tive CT images. It was found that for covering 95% of
microscopic disease around pulmonary GTV, the
margin of 8 and 6 mm is needed, respectively, for
adenocarcinoma and squamous cell carcinoma. The
usual margin of 5 mm would cover 91% of squamous
cell carcinoma, but only in 80% of adenocarcinoma
cases. When the microscopic spread was evaluated for
35 patients with adenocarcinoma, the margin required
for covering 90% of cases was 9 mm, if appropriate
pulmonary window was used for GTV definition
(Grills et al. 2007). Correlation of images with path-
ologic data may be biased by tissue deformations of
resected lung. It has been shown that if the tissue
deformations are not taken into account, the under-
estimation of the microscopic disease extension in
vivo may occur up to factor of 2 (Stroom et al. 2007).
van Loon et al. (2010) evaluated the CTV margins
around GTV defined with CT alone or PET-CT with
tissue deformations taken rigorously into account and
they found that the necessary margin to cover 90% of
cases was as large as 26 mm, even if 50% of 34
evaluated specimens had no microscopic disease
extension at all. It shows that the CTV margin still
represents the big uncertainty in the radiation oncol-
ogy. For this reason, it is crucial to identify the factors
191
related to the presence of the microscopic spread
around pulmonary mass. Giraud et al. (2000) indi-
cated that adenocarcinoma histology requires larger
CTV margins than squamous cell carcinoma. This
was not confirmed in a study done by van Loon et al.
(2010); however, a small sample group (34 cases)
would preclude such a finding. On the other hand,
larger GTV and higher tumor density on the CT scan
revealed to be the predictors of risk of the occurrence
of microscopic disease spread in this study. Of note,
neither the use of CT nor PET-CT had superior value
in the visualization of the CTV and its covering.
Higher differentiation (lower grade) of adenocarci-
noma was related to significantly larger microscopic
disease extension (Grills et al. 2007); it was rather
related to the increased frequency of bronchioalveolar
histology in lower grade tumors. Summarizing, the
CTV around GTV located within lung tissue is still a
source of uncertainty, as our knowledge on the pre-
diction of the risk of microscopic spread is very
limited. In the meantime, we should be aware of this
phenomenon and be particularly cautious about this
margin if the radiation with sharp penumbra or tech-
niques with rapid dose fall-off are used. The lung
tumor should be defined on the pulmonary window,
because its use led to the reduction (but not elimi-
nation) of the potential error of omission of the CTV
margin (Giraud et al. 2000; Grills et al. 2007; van
Loon et al. 2010).
Endobronchial tumor spread may be seen as in-
tramucosal, submucosal or intraparietal microscopic
tumor extension. This is largely discussed in surgical
series and endobronchial brachytherapy. For surgical
specimen, the usual proximal safety margin from the
visible tumor on the bronchial level is 1.5–2.0 cm
(Kara et al. 2000). For external-beam radiotherapy,
we have no clear recommendations for use of margin
for endobronchial microscopic tumor extension. It is
quite surprising, because we have data for central
tumors which shows that the proximal microscopic
tumor extension occurs in 30% of cases and its mean
dimension is about 10 mm (Kara et al. 2001). In the
absence of recommendations on the CTV contouring
within broncho-tracheal tract, it is wise to take this
data into consideration for central tumors and addi-
tionally incorporate the bronchoscopy findings into a
target definition.
Clinical target volume around involved lymph
nodes was not as extensively studied as the extent of
192
margin around pulmonary tumor. In one study (Yuan
et al. 2007a) the margin of 3 mm for lymph nodes
was determined for lymph nodes of size up to 20 mm.
However, for lymph nodes of 21–30 mm, the extra-
capsular microscopic extension might have reached
up to 12 mm. Mediastinal lymph nodes larger than
30 mm were not included in the study. So this indi-
cates another source of uncertainty in the radiation
target planning. In the absence of the robust data on
this issue, different measures are taken to overcome
such a potential source of errors. One of these is the
inclusion of the whole lymph node station that con-
tains the involved lymph node(s) in the CTV
(de Ruysscher et al. 2008; Kepka et al. 2009b). If such
an approach is justified, the further studies are
warranted.
3.2 Elective Nodal Irradiation
Elective nodal irradiation (ENI) in lung cancer means
that CTV includes the volume of uninvolved areas of
hilum and mediastinum, and sometimes supraclavicu-
lar region, in view of eradication of probable
micrometastases within this field. The ENI volume, as
a part of the CTV, remains an anatomic-clinical con-
cept. The mediastinal ENI volume could appear as a
result of clinical compromise between the need of
eradication of subclinical disease and acceptable tox-
icity. The diagnostic possibilities and technical facili-
ties also contribute to the choice of the extent of ENI.
This concept has been historically changing. From the
70s to the 90s, its position was growing which resulted
in the following recommendations ‘‘…for upper and
middle lobe lesions, the mediastinal field should
include 5 cm below the carina and supra-clavicular
areas. For lower lobe lesions, the lower margin of the
field is the diaphragm. Irradiation of contralateral
hilum remains controversial’’ (Rocmans et al. 1991).
However, advances in the technology which enabled
better imaging, dose comparisons which indicated
potential toxicity of ENI, and substantial evidence
about a low risk of isolated nodal failures defined as
regional nodal failures outside radiation field led to the
recommendations to abandon ENI, first in early stages
(Rowell and Williams 2001) and later on for stage III
disease (de Ruysscher et al. 2010).
However, the body of evidence for the use of only
involved field in NSCLC is weak, because only one
L. Kepka and M. Kolodziejczyk
randomized trial addressed this issue specifically
(Yuan et al. 2007b). In this trial, a total of 200 patients
were randomized between involved-field radiotherapy
to 68–74 Gy or ENI to 60–64 Gy. Patients in the
involved-field arm achieved better overall response
rate (90 vs. 79%, p = 0.032) and better 5-year local
control rate (51%) than those in the ENI arm (36%),
p = 0.03. It resulted in the borderline significant
improvement of overall survival at two years
(p = 0.05), but not at five years. Since there were
differences in ENI use and in a total dose between two
arms, it remains unclear if the poorer outcome from
ENI was due to the lower radiation dose used in the
ENI arm or the use of ENI itself.
The opponents of ENI argue that, the low risk of
isolated nodal failure, below 10% in most retrospec-
tive studies does not justify the use of ENI (de
Ruysscher et al. 2010). The planning studies (Grills
et al. 2003) suggested a benefit of omission of ENI for
reduction of pulmonary and esophageal toxicity. This
was partially confirmed in the randomized study of
Yuan et al. (2007b), in which the patients receiving
involved fields concurrent with chemotherapy had
less radiation pneumonitis (p = 0.04) than patients
treated with concurrent radiochemotherapy with ENI.
There was no difference for esophagitis. The retro-
spective analysis by Fernandes et al. (2010) on 108
patients (60 receiving ENI and 48 treated with
involved fields) showed that ENI was related to an
increased, but manageable esophageal toxicity
(p = 0.04). It is also postulated that better staging
with PET-CT use allows for the use of more tailored
fields. Additionally, we can argue that incidental
irradiation (defined as radiation delivered outside of
the defined targets volumes not intentionally, but just
as a result of beams configuration in areas of steeper
or more protracted dose fall-off) may also contribute
to the sterilization of the potential micrometastases in
the neighboring lymph nodes.
All of opponent’s arguments are debatable. First of
all, the so-called ‘‘low risk’’ of isolated nodal failures,
usually between 5 and 9%, does not seem to be really
negligible. If only half of these recurrences would be
prevented by ENI, the survival improvement would
be detectable (Kelsey et al. 2009). It is more than the
benefit from addition of chemotherapy to radiother-
apy in NSCLC which changed the clinical practice.
The toxicity of ENI has not been documented con-
vincingly enough up to now. PET-CT is more
Target Volume Definition in Non-Small Cell Lung Cancer
powerful tool than CT alone for detection of nodal
metastases; however, it has no value for detection of
micrometastases. It was recently demonstrated by
Videtic et al. (2008) that more than 30% of stage III
NSCLC patients had nodal metastases in mediasti-
noscopy which were undetected in PET-CT.
Recently, the prospective study evaluated the value of
ENI in the reduction of risk of potential geographical
miss with radiotherapy planned without PET-CT. In
75 patients for whom curative radiotherapy was
maintained after PET-CT, there were 20 cases of
potential (without pathologic confirmation) geo-
graphical misses on the CT-alone based plans. Thir-
teen patients from this group had ENI initially
planned on CT-alone. For seven patients judged as
less advanced, the ENI was abandoned. It was dem-
onstrated that 90% isodose did cover entirely the
PET-based GTV only in 2 out of 13 patients with ENI
use. On the other hand, for 13 patients receiving ENI,
the mean of minimum dose within missed GTV was
55% of prescribed total dose for gross disease while
for 7 patients without ENI it was 10%, p = 0.006. It
suggests that if PET-CT is unavailable, ENI may to
some extent compensate for an inadequate dose
coverage resulting from diagnostic uncertainties
(Kołodziejczyk et al. 2010).
A recent review (Belderbos et al. 2008) concluded
that the use of ENI depends on many variables which
can be divided into tumor-, patient-, staging-, and
treatment-related. There is clinical situation, as, for
example, in advanced nodal stage when the use of
ENI may be of value due to higher risk of isolated
nodal failure in radiologically uninvolved lymph
nodes and demonstrated poorer sensitivity of PET-
CT. In case of bulky mediastinal disease, the risk of
occurrence of isolated nodal failure exceeded 20%
(Kepka et al. 2008). Another issue to be considered is
a poor staging (imaging) or radiotherapy used as the
only treatment modality for more advanced cases
where toxicity added by ENI may be not so mean-
ingful and potential for dose escalation is limited.
3.3 Lymph Node Stations Delineation
for ENI Issues
If one decides to use some form of ENI, regardless of
purpose, whether for definitive radiotherapy or post-
operative radiotherapy (PORT), the issue of proper
193
delineation of lymph node stations (LNS) appears. In
the era of 3D-CRT, the recommendations for delinea-
tion of LNS using CT imaging were published as late as
in 2005 (Chapet et al. 2005). This was related to the
controversies around ENI and its gradual abandon-
ment. However, there was a need for such guidelines,
for many purposes, out of which postoperative radio-
therapy was one of the most pertinent. Those recom-
mendations, known as the Atlas of Michigan, whose
name comes from the institution where the steps for
this important work had been taken, met with an urgent
need in lung cancer radiotherapy for providing the
guidelines allowing for the introduction of standards
and generation of consensus in the delineation of
uninvolved nodal areas. Atlas of Michigan provided
recommendations for delineation of hilar and medias-
tinal LNS on the CT scans, providing detailed
description of borders of each LNS based on the
structures visible on the CT axial images. It was based
on the N descriptors of the Mountain and Dressler
modification of the American Thoracic Society (MD-
ATS) LNS map (Mountain and Dressler 1997). This
work needed clinical validation about reproducibility
of guidelines and feasibility of treatment plans done
with nodal targets that were defined accordingly. In a
study by Kepka et al. (2007), it was found that varia-
tions of delineation of LNS according to those guide-
lines were similar to all other studies on the variability
in targets definition with a significant difference among
physicians of about 36–60%. However, physicians
working together in this field had fewer differences
which indicate the need for a continuous training in the
proper use of those complex guidelines. This study also
demonstrated that the strict following of these guide-
lines in the setting of the slow scanning techniques led
to some pitfalls and difficulties in interpretation. Using
this technique, the placement of the inferior limit of the
LNS 7 at the origin of the right middle lobe bronchus
according to the Atlas led to the unusually distal
delineation of this LNS, which was due to the relatively
large hilar mobility. The authors then modified this rule
to meet their needs and to meet the normal lung con-
straints limiting the delineation of LNS7 in the space
between the right and left main bronchi. The users of
the Atlas should also be aware that a strict following of
those guidelines in delineation of LNS with addition of
appropriate margins according to the ICRU 62 rec-
ommendations leads to the creation of the elective
fields larger than traditionally defined in the 2D
194 L. Kepka and M. Kolodziejczyk

guidelines (Rocmans et al. 1991, RTOG 9410). This

phenomenon was demonstrated in the planning study
by Kepka et al. (2009a). One solution for this would be
to include fewer LNS in the elective field, e.g., only the
LNS with the highest probability of microscopic
invasion according to the histological type and location
(side and lobe) of the tumor. One of the propositions of
using such more selective ENI is software proposed by
Giraud et al. (2006) that evaluates the risk of medias-
tinal lymph node involvement from easily accessible
individual pretreatment parameters.
Recently, a new LNS map for the seventh edition of
TNM classification of lung cancer effective as of
January 1st, 2010 was published (Rusch et al. 2009).
This new LNS map is a consensus of the International
Association for the Study of Lung Cancer (IASLC)
experts and it reconciles differences among two LNS
maps and nomenclatures, the first one MD-ATS map
adopted by UICC (International Union against Cancer)
in the TNM classification and the Naruke map (Naruke
et al. 1978) used commonly in Japan. The borders of
LNS were specified in the way that allows users to
apply these definitions to clinical practice by CT, as the
appropriate CT illustrations were generated. There are
a number of changes for LNS delineation in compari-
son with MD-ATS map and consequently the Atlas of
Michigan guidelines provided for radiotherapists.
Figure 1 illustrates examples of differences in the LNS
delineation between Atlas of Michigan and a new map
proposed by IASLC. The most important changes
involve: description of supraclavicular and sternal
notch lymph nodes as level 1; shift of the left border of
level 2R and 4R from midline to the left wall of the
trachea; and precise description using anatomical
landmarks borders between LNS 4R and 10, 5 and 10,
10 and 11 bilaterally. Obviously, those differences
between two maps should be taken into account in Fig. 1 Difference in delineation of lymph node stations for
radiation oncology planning. The guidelines used for guidelines of Atlas of Michigan (Chapet et al. 2005) and
International Association of the Study for Lung Cancer
LNS delineation should be specified and reported in all (IASLC) staging committee of a new lymph node map for
treatment protocols involving the LNS delineation. 7th TNM classification of lung cancer (Rusch et al. 2009). a, b
Difference for lymph node stations 2R and 2L. It is a change in
the division between 2R and 2L (midline in the Atlas of
Michigan and left border of trachea in IASLC). a Delineation
3.4 Postoperative Radiotherapy Target according to the Atlas of Michigan (2R in red and 2L in
Volume orange). b Delineation according to the IASLC map (2R in blue
and 2L in green). c Difference in left hilar lymph node station—
Clinical target volume definition for postoperative 10L. In the IASLC map, 10L is delineated around main
bronchus (marked red in the picture), while in the Atlas of
radiotherapy (PORT) represents another source of Michigan, the medial border of 10L is the arbitrary imaginary
controversies, as no clear consensus and evidence line drawn between a lateral border of the pulmonary trunk and
exist in this field. It is related to the controversies with aorta descendens (marked light green in the picture)
Target Volume Definition in Non-Small Cell Lung Cancer
the use of PORT itself. The value of PORT for NSCLC
was questioned by the results of the PORT meta-anal-
ysis (1998) which included 2128 patients from nine
randomized trials in which PORT was compared with
surgery alone. This meta-analysis showed that there is
an increased relative risk of death of 21% with the use
of PORT. This deleterious effect was detected in
patients with pN0-1 disease. The detrimental effect of
PORT on survival was related to the excess of cardiac
and pulmonary deaths. No effect was detected in
patients with pN2 disease. It is now expected that for
the latter category, the benefit of PORT will be dis-
closed in the setting of use of adjuvant chemotherapy.
Improvement of survival with chemotherapy via
reduction or delay of distant metastases may lead to the
disclosure of further benefit in overall survival by
improvement of loco-regional control by the use of
PORT. Such trials are ongoing or in preparation.
Recently, the experts from Lung Adjuvant Radio-
therapy Trial (Lung ART) Investigators Group that
prepared the randomized trial of PORT for pN2 NSCLC
patients demonstrated a large variability of CTV defi-
nition for PORT volumes up to threefold among experts
form EORTC. When the detailed protocol of CTV for
PORT was provided, clear improvement was seen for
contouring of the lymph node stations (LNS) specified
by protocol. Only upper paratracheal lymph nodes (sta-
tions 2R and 2L according to Mountain and Dressler
(1997) nomenclature) were still subject to large varia-
tions of the contouring. This was related to the unclear
definition of the upper border of those LNS. Recom-
mended PORT CTV in this study included: bronchial
stump, any possible extension to the mediastinal pleura
adjacent to the tumour bed, any involved LNS; and
(regardless of involvement) ipsilateral hilum, subcarinal
(LNS 7), lower paratracheal (4R and 4R) LNS. For left
side, subaortic (5) and paraaortic (6) LNS had to be
included. All LNS located between two non-contiguous
involved LNS had also to be included in the CTV
(Spoelstra et al. 2010). Independently of this study,
recently published prospective trial that evaluated pro-
spectively the quality of life and cardiopulmonary mor-
bidity of pN2 patients receiving PORT in comparison
with pN1 patients in whom PORT was not given used
very similar PORT volume definition. CTV included
bronchial stump and LNS with presence of metastases in
pathologic examination. Additionally, the uninvolved
LNS with the highest probability of microscopic
involvement, namely ipsilateral hilum, subcarinal nodes
195
Fig. 2 Target volume for postoperative radiotherapy (PORT)
representing a limited elective nodal irradiation—a coronal
view. CTV (in green) for the right side includes bronchial
stump, ipsilateral hilar region, right/left paratracheal (4R/4L),
and subcarinal lymph nodes. PTV (in red) represents
CTV ? 1 cm margin
(LNS 7), lower paratracheal lymph nodes (4R and 4L),
3A up to top of aortic arch, and LNS 5 (for left side), were
included in the CTV. Decision about inclusion of ipsi-
lateral supraclavicular region in the CTV in case of
invasion of the lymph nodes above aortic arch was left at
the discretion of treating centres. For such defined CTV,
the margin of 1 cm was added to create PTV (Fig. 2). No
increase in the cardiopulmonary toxicity and difference
in quality of life two years after treatment in comparison
with non-irradiated patients were demonstrated in this
study (Kepka et al. 2011). We probably need more data
on the safety of such reduced elective fields for PORT, as
well as more data on the possibility of further reduction
of this volume. In the meantime, it is probably reasonable
option for those who treat pN2 patients with PORT to use
the volumes as proposed above.
For pN0 and pN1 patients, PORT is not used, as its
deleterious effect on the survival has been demon-
strated before. However, if one is using PORT, pos-
sibly in case of microscopically incomplete (R1)
resection, the results of randomized trial published by
Trodella et al. (2002) may be considered. In this
study, only bronchial stump and ipsilateral hilar
region were included in the CTV of pN0 completely
resected patients. The irradiated patients had 2% of
local failure compared to 23% at five years for control
group, and it was related to the border-line significant
5-year survival improvement (p = 0.048).
196
The use of PORT after incomplete resection (R1 or
R2) in subject to fewer controversies, as it is a com-
mon belief, that additional local treatment may pre-
vent or delay recurrence. It is beyond the scope of this
chapter to discuss the efficacy of PORT in such case
scenario. However, we do not have clear and evi-
dence-based guidelines for such indications. The
experts of the International Association for the Study
of Lung Cancer (IASLC) (Rami-Porta et al. 2005)
provided a definition of incomplete resection after
resection of lung cancer carried out with curative
intent. It contains not only the cases of R1 resection
with involvement of resection margins (bronchial,
vascular, parenchymal, or parietal), but also a positive
lymph node that was not removed, extracapsular
nodal extension, and positive pleural or pericardial
effusion. It is hardly conceivable to conduct and plan
any radiation volume for the last indication of dis-
semination of cancer to the visceral cavities. How-
ever, all other indications may be divided in cases of
non-radical (R1) tumor and non-radical (R1) lymph
node resections; and PORT represents the conceiv-
able therapeutic option for both types. For R1 and N0
disease, it is not formally recommended to use ENI,
as its use is controversial. In such cases, the CTV
volume should include the area of the positive mar-
gin. However, thoughtful clinical judgment should be
used when making a decision about a possible
inclusion of the nodal area in the CTV, taking into
account, the predictable toxicity of such an approach,
quality of surgical staging, and imaging studies per-
formed. This caution is based on the findings that the
proximal microscopic tumor extension related to the
R1 resection on the bronchial wall is associated with
an increased risk of lymph node invasion (Kara et al.
2002). For extracapsular nodal extension, the irradi-
ation of mediastinum is a reasonable option according
to the rules described above with the dose boost (up to
60 Gy) done to the LNS with R1 findings. The rules
and controversies described in the paragraph on the
contouring of particular LNS apply here.
4 Planning Target Volume Definition
Margins added to the CTV for creation of the plan-
ning target volume (PTV) in NSCLC have two main
components: (1) for motion (mainly respiratory, but
also cardiac beats) of tumor and organs at risk and (2)
L. Kepka and M. Kolodziejczyk
for set-up errors. We will briefly report on how to deal
with both of these issues in the target definition.
4.1 Internal Target Volume: Respiratory
Motion Management
The extent of lung tumor mobility varies individually and
depends on many factors. Therefore, it should be esti-
mated individually and done separately for both tumor
and lymph nodes (van Sornsen de Koste et al. 2002,
2003). The ‘‘population-based’’ margins should be
replaced by the ‘‘patient-based’’ margins. Numerous
approaches have been used for determination of the
extent of respiratory motion, including the fluoroscopy,
slow CT scans, multiple planning scans, CT scans gen-
erated at maximal inspiration and expiration, and
recently one approach that superseded all former meth-
ods—respiratory-correlated four-dimensional (4D)-CT
scanning approach (Slotman et al. 2006). The estimation
of the tumor motion at the fluoroscopy is definitely an
outdated approach, as this method does not lead to the
three-dimensional display of the extent and shape of the
tumor displacement. Slow CT scanning with time of the
acquisition of one scan of about 4 s (average time of
respiratory cycle) allowed capturing a respiratory
movement of the tumor, but it led to a ‘‘blurred’’ image,
which was a big inconvenience for contouring. Approa-
ches based on multiple scanning are currently replaced by
commercially available 4D-CT scanning. In this method,
a respiratory signal is synchronously recorded during
image acquisition. The imaging data is retrospectively
sorted to create a 4D dataset which contains 3D datasets
for 10 phase bins within a respiratory cycle. It leads to the
construction of the internal target volume (ITV) that
encompasses all motion and shape changes over the
respiratory cycle. Such construction of the ITV may be a
laborious process that requires a delineation of the GTV
on the 10 separate datasets for 10 captured bins of the
respiratory cycle. There are several ways to overcome
this major drawback of the 4D techniques which repre-
sents an increase in the workload at the radiation oncol-
ogy department. One solution is to only use of two
extreme phases of the respiratory cycle, i.e., the end-
expiration and the end-inspiration (Rietzel et al. 2006).
This method speeds up the work of radiation oncology
staff, however; it may introduce errors such as underes-
timation of the changes of the shape of the tumor between
delineated phases (possible ignorance of the hysteresis
Target Volume Definition in Non-Small Cell Lung Cancer 197

effect) and introduction of artifacts by interpolation together with tumor/lymph nodes mobility and (at
(Persson et al. 2010). Another help in contouring on the lesser extent) anatomical changes during treatment.
4D-CT dataset is using the post-processing tool of max- To account for those uncertainities, the population-
imum intensity projection-MIP (the use of the maximum based recipes for margins between CTV and PTV were
density in Hounsfield units on all CT scans for automatic formulatd, from which the Van Herk et al. (2000) for-
generation of the target) for rapid computation of the mula has become the standard for margins definition
ITV. However, this method is far from being perfect and (Sonke and Beldernos 2010). In order to deliver at least
is only suitable for tumors surrounded by pulmonary 95% of dose to the CTV for 90% of patients the margin
parenchyma, and even in those cases, the careful visual should be calculated according to the formula:
inspection of the GTV on all datasets of respiratory cycle X p 2 
M ¼ 2:5 þb r þ r2p  brp
should be done (Rietzel et al. 2008). The ITV computed
from 4D-CT including all tumor motion leads to the P
where M is the CTV to PTV margin; the total standard
inclusion of the large volume of lung tissue in the PTV.
deviation (SD) of the systematic errors; r the total SD of
Thus—in case of the major tumor mobility—the gated
the random errors; rp the width of the penumbra mod-
radiotherapy techniques are in use, as, for example, the
eled by a cumulative Gaussian, and b is the value of the
irradiation at the end of expiration. In such scenario, GTV
inverse cumulative standard normal distribution at the
is delineated in the dataset corresponding to the needed
prescribed PTV minimum dose level (van Herk et al.
respiratory phase.
2000). It shows that systemtic error (that occurs at the
It was shown that the impact of the respiratory
planning stage) impacts much more than random errors
induced motion on the accumulated GTV dose is rel-
occurring at the treatment delivery. For lung cancer, the
atively small, providing that the time-averaged mean
one SD for systematic and random set-up error is up to
position of the GTV is correctly positioned. Wolthaus
4–5 mm (Hurkmans et al. 2001 and Borst et al. 2007);
et al. (2006) have developed a concept of mid-venti-
the one SD for systematic and random respiratory
lation scan, which is extracted from 4D-CT dataset and
motion displacement is up to 7 mm (Sonke and
represents an average position of the tumor during a
Beldernos 2010). For calculation of the margin, the all
respiratory cycle. On such chosen 3D CT frame, the
components of the inaccuracies should be considered.
GTV and subsequent CTV are delineated. The appro-
However, the set-up and motion errors are generally
priate margins for tumor motion and other uncertainties
uncorrelated, and a linear addition of these two com-
margins are calculated. Such constructed final PTV is
ponents is not correct (van Herk et al. 2000). Thus the
smaller than ITV computed from a whole the 4D-CT
different sources of geometrical uncertainities should be
dataset and it still adequately accounts for motion.
added in quadrature not in a linear fashion. It is common
Those considerations of the tumor mobility require
to add the margin directly to the CTV without separating
the use of complex equipment which, even if it is com-
two components (for ITV and set-up). In most clinical
mercially available, may be too expensive and/or too
scenarios of lung cancer, the margin for PTV does not
time consuming for use in all cases. When such equip-
exceed 1 cm. At the planning stage, the population-
ment is not available, at least an estimation of the tumor
based margins should be established. The repetitive
mobility for tumors located in the lower lobes and/or for
imaging during treatment, using multiple available
patients with restricted pulmonary reserves is needed.
technologies of image-guided radiotherapy, may lead to
The recognized mobility of lymph nodes of about
the individualization of the margins by individual
0.5 cm (for most) and about 1.0 cm for subcarinal nodes
quantification of the inter- and intrafractional errors
should be considered (van Sornsen de Koste et al. 2002).
which has now become a new emerging standard.

4.2 Margins for Set-up

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 The Radiation Target in Small-Cell
Lung Cancer
Gregory M. M. Videtic

Contents Abstract
What constitutes the appropriate target in the
1 Introduction to the Role of Radiotherapy treatment of small-cell lung cancer is an area of
in SCLC .................................................................... 201 active investigation. Advances in the last 30 years
2 Historic Trends in Lung Cancer in radiologic and nuclear imaging as well as in
Target Definition...................................................... 202 radiotherapy delivery have prompted revision of
3 SCLC Target Definition and the Impact the classically defined target which was designed
of CHT ...................................................................... 203 to be ‘‘tolerable’’ and encompass visible tumor
4 SCLC Target Definition and ENI.......................... 206 and potential areas of microscopic disease. Cur-
rent trends are to minimize normal tissue irradi-
5 SCLC Target Definition and FDG-PET ............... 208
ation and more precisely define the extent of
6 SCLC Target Definition in Extensive Disease ..... 208 potential microscopic spread in order to optimize
7 SCLC Target Definition in Current Trials .......... 209 target volume. This chapter will review historic
8 Conclusions ............................................................... 209 trials and ongoing studies to provide a compre-
hensive understanding on the evolution of the
References.......................................................................... 209
radiotherapy target in small-cell lung cancer.

1 Introduction to the Role

of Radiotherapy in SCLC

Thoracic radiotherapy (TRT) is an integral com-

ponent in the standard management of patients
presenting with small-cell lung cancer (SCLC). Its
role in improving survival and local control in the
treatment of limited stage disease (LS-SCLC) has
been confirmed in randomized clinical trials over
the past 25 years and in subsequent meta-analyses
(Cooper and Spiro 2006; Lee et al. 2006; Faivre-
Finn et al. 2005a, b; Socinski and Bogart 2007;
G. M. M. Videtic (&) Curran 2001; de Ruysscher and Vansteenkiste
Department of Radiation Oncology/T28, 2000). These reports have shown that the addition
Taussig Cancer Institute, Cleveland Clinic Foundation,
of TRT to combination chemotherapy (CHT) sig-
9500 Euclid Avenue, Cleveland, OH 44195, USA
e-mail: videtig@ccf.org nificantly reduces the risk of loco-regional failure

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 201
DOI: 10.1007/174_2011_251,  Springer-Verlag Berlin Heidelberg 2011
202
(Bleehen et al. 1983; Bunn et al. 1987; Mira et al.
1982; Perez et al. 1984; Perry et al. 1987), and two
meta-analyses have shown an absolute long-term
survival gain of 5% (Pignon et al. 1992; Warde
and Payne 1992). The role of TRT in extensive
stage disease (ES-SCLC) is well established as an
important palliative modality but less so for
potentially influencing overall survival. In that
respect, a provocative phase III study published in
1997 showed that the addition of TRT improved
survival in patients selected by response to che-
motherapy (Jeremic et al. 1999). Prophylactic
cranial irradiation (PCI) has a well-defined role in
LS-SCLC, with evidence showing a *50%
reduction in brain metastasis rates and an absolute
improvement in overall survival of approximately
5% (Auperin et al. 1999). More recently, favorable
results for PCI with respect to survival and pre-
vention of symptomatic brain disease were
observed in a phase III study of ES-SCLC patients
receiving this therapy after demonstrating any
response to chemotherapy (Slotman et al. 2007).
How to best deliver potentially curative radio-
therapy (RT) remains an active area of investigation
and debate. For example, in the setting of LS-SCLC,
there is evidence to support early versus later initia-
tion of TRT with concurrent CHT because of a
favorable impact on survival, but this is not without
controversy (Samson et al. 2007; Fried et al. 2004;
Huncharek and McGarry 2004; Pijls-Johannesma
et al. 2007; Spiro et al. 2006; Jeremic 2006). The
optimal dose of TRT to deliver also remains strongly
debated and is currently the subject of two ongoing
randomized studies, but the most current standard is
based on a pivotal phase III study that demonstrated
survival benefits using 45 Gy over a 3-week course of
hyperfractionated (twice-daily) TRT (Turrisi et al.
1999). Lastly, what exactly constitutes the appropriate
target volume to be irradiated in LS-SCLC within a
given radiochemotherapy program also has not been
clearly defined. There is no doubt that questions on
target definition are dependent in some fashion on
other components of RT for SCLC, such as total dose,
fractionation, and timing of administration with
respect to CHT. That said, the purpose of this chapter
is to summarize perspectives on target delineation in
TRT for SCLC and make reference to prospective and
retrospective reports that may inform current practice
in the management of SCLC.
G. M. M. Videtic
2 Historic Trends in Lung Cancer
Target Definition
In principle, when planning curative RT for lung
cancer (whether NSCLC or SCLC) the target volume
of tissue irradiated to a high-dose should only
encompass the entire tumor and any microscopic
extension of disease, and be kept as small as possible
to minimize damage to normal tissues. From 1960s to
1990s, lung cancer volumes typically encompassed
the definable lung tumor and any overtly involved
lymph nodes (LNs) as discernable from chest radio-
graphs and also included all the regional nodes con-
sidered at risk, which were generally those in the
mediastinum and the bilateral hilar and supraclavic-
ular (SCF) regions. This approach assumed that all the
regional LNs, even if seeming clinically uninvolved,
should be irradiated in order to treat potential
microscopic spread since imaging-based definition of
disease extent was crude. This target often involved a
fairly large volume of the chest being irradiated,
which was usually done with relatively static, ‘‘for-
mulaic’’ field arrangements such as opposed anterior–
posterior fields, followed by a boost to involve tumor
and nodes using oblique fields sparing the spinal cord
(Videtic et al. 2008).
The rapid evolution of radiologic imaging over the
past 20–30 years has allowed clinicians to move away
from the limitations of the chest radiograph to highly
sophisticated means of tumor definition, whether by
computed tomography (CT) scans of the chest or
more recently, by positron emission tomography
(PET) scan. This had triggered a parallel shift in
radiation practice because these technological
advances have permitted improved and potentially
more accurate definition of the lung and LNs clini-
cally involved in tumor. Such refinements in RT
planning have been matched by standardization of
dose reporting criteria, target definitions, and normal
structure labeling by keeping with updates from the
International Commission on Radiation Units and
Measurements (International Commission on Radia-
tion Units and Measurements 1993; International
Commission on Radiation Units and Measurements
1999). Terms such as gross tumor volume (GTV)
indicating detectable or visible disease; clinical target
volume (CTV), containing the GTV with sufficient
margins to account for subclinical disease extension;
The Radiation Target in Small-Cell Lung Cancer
and planning target volume (PTV), a geometrical
parameter obtained by adding adequate margins
around the CTV to account for uncertainties linked to
set-up errors and organ motion, are now routinely
assigned to structures during RT target delineation.
Even more recently, accounting for organ-motion-
associated geometric uncertainties and daily set-up
errors have become more sophisticated. An internal
target volume (ITV) reflecting potential tumor dis-
placements in space is now regularly defined to
minimize PTV expansions for motion. Refinements in
the means of verification imaging before and during
RT delivery are now being accomplished by sophis-
ticated means of image-guided RT (IGRT) systems.
IGRT may permit real time adjustment of RT as
needed on the basis of and according to therapy-
induced tumor changes (Aristei et al. 2010).
On the clinical front, evolving concepts in target
definition for lung cancer have been especially
focused on the issue of mediastinal (regional) lymph
node (MLN) irradiation. As noted above, radiation
oncologists historically defined the lung cancer portal
so that there was comprehensive inclusion of all MLN
stations irrespective of disease status [‘‘elective nodal
irradiation’’ (ENI)] (Emami 1996). However, it is now
becoming common to see omission of ENI in con-
temporary clinical trials and routine treatment (Senan
and de Ruysscher 2005), despite the fact that there are
only very limited prospective data outcomes to sup-
port this practice. A recently completed survey of 800
radiation oncologists reveals in that regard in that 31,
51, and 18% of respondents chose extensive, selective
or no ENI for SCLC, respectively (Kong et al. 2007).
The rationale underpinning omission of ENI has been
the need to improve on the recognized high relapse
rates at the site of the initial tumor after conventional
TRT. Thus, the required dose escalation to potentially
improve local control has been judged to be feasible
only if clinicians were to treat gross disease only, i.e.,
the primary and any involved nodes, termed an
involved-field, or non-ENI, approach. The expecta-
tion is that by reducing the treated volume, one could
reduce the toxicity to the critical normal structures
and therefore allow delivery of higher TRT doses.
With these clinical goals in mind, at the time of SCLC
diagnosis the distinction between primary tumor and
mediastinal disease is nonetheless sometimes difficult
to establish, because the disease can appear as a
conglomerate, relatively indistinct central tumor mass
203
involving parenchyma and MLNs, and surrounding
normal structures. This explains in part why the
specific question of nodal irradiation was often not a
question to be separated out from defining treatment
to the primary disease (Videtic et al. 2008).
With these historical trends in mind, it will be
noted that this chapter reflects results from fact clin-
ically oriented questions with respect to target defi-
nition since they have been the common ones
addressed in prospective studies of TRT. As refer-
ence, Table 1 provides a comprehensive list of com-
pleted or ongoing clinical trials over the last 30 years
and their respective definitions of the target. Not-
withstanding the range of technological innovations
in imaging and RT delivery and their rapid imple-
mentation with respect to modifying target definition,
there are very few studies reported on in this chapter
showing the impact that technology has had on SCLC
TRT. To date, evidence is lacking for survival bene-
fits by adopting these advances, although for many
authors their impact on normal tissues has been as
critical as on tumor outcomes.
3 SCLC Target Definition
and the Impact of CHT
The earliest questions relative to defining the optimal
treatment volume for SCLC were related to the use of
induction CHT prior to the start of TRT. Since sig-
nificant tumor shrinkage can often occur with a
number of CHT cycles, this prompted the question of
what should be designated as the appropriate TRT
volume to be treated: the pre- or the post-CHT vol-
ume. It is interesting to note that it is in this setting
that the only randomized clinical trial to date
addressing the specific question of TRT treatment
volume in SCLC has been conducted. This study,
performed by the Southwest Oncology Group
(SWOG) and published in 1987 (Kies et al. 1987),
involved 466 patients and had a complex randomi-
zation schema based on response; in short, patients
with a partial response or stable disease after four
cycles of CHT (non-platinum based) were random-
ized to RT fields based either on the pre- or the post-
CHT volume of disease. No statistical differences in
survival or recurrence patterns were noted as a func-
tion of volume treated: for complete responders, with
local recurrence rates of 50% with RT, and 72%
Table 1 Target volume definitions from completed and ongoing prospective studies in limited stage SCLC
204

Publication Author (ref.) Study type Planning Pre- or post- Overall target definition
year (2D, 3D) CHT primary
target
Ongoing CALGB30610/ Phase III 3D With cycle GTV by CT, and PET if available
RTOG0538 1 or 2 ITV for motion
CTV1-GTV ? ipsilateral hilum; CTV2-revised; GTV after CHT; otherwise no ENI
PTV 1 and 2- non-ITV or ITV based margins, between 15 and 5 mm, respectively
Ongoing EORTC- Phase III 3D With cycle 2 GTV by CT, and PET if available
CONVERT CTV = GTV ? 5 mm
PTV = 10 mm sup/inf; 8 mm lat
No ENI
2010 van Loon et al. Phase II 3D Post-CHT GTV and PTV defined by PET and CT
(2010) (median of If induction CHT, post-CHT volume considered GTV of primary tumor but for
18 days) MLNs, pre-CHT used
If PET negative in mdtsnm and CT positive, mdstnm not included in GTV.
Margin from GTV to CTV = 5 mm, from CTV to PTV = 5 mm for MLNs and
10 mm for primary
No. ENI
2007 Schild et al. Phase II 2D Post-CHT cycle Split course: cycle 4-primary tumor with ipsilateral hilar, mediastinal, and SCF
(2007) 4/5 of 6 nodes; cycle 5-cone-down to ‘‘reduced’’ mdstnm and only involved SCF
2006 Spiro et al. Phase III 2D Pre-CHT Arms 1, 2: primary
(2006) Tumor with margin ? entire mdstnm; SCF if involved
2006 Baas et al. Phase II 3D After cycle 1 Primary tumor ? all clinical and radiological involved lymph nodes with a short-
(2006) CHT axis diameter of [1 cm
2006 de Ruysscher Phase II 3D CT during the GTV = primary tumor and MLNs with a short-axis diameter of [1 cm
et al. (2006) first cycle of PTV = GTV ? margin
CHT
2004 Bogart et al. Phase II 2D or 3D After cycle 2 GTV = post induction lung tumor and involved MLN (pre- AND post-CHT)
(2004) CHT CTV1 [to 44 Gy] = GTV ? ipsilateral non-involved MLNs ? margin
CTV2 [to 70 Gy] = GTV ? ispilateral hilum
(continued)
G. M. M. Videtic
Table 1 (continued)
Publication Author (ref.) Study type Planning Pre- or post- Overall target definition
year (2D, 3D) CHT primary
target
2002 Takada et al. Phase III Not specified Pre-CHT Arm 1: RT with CHT cycle 1-primary disease with margin, ipsilateral hilum, entire
(2002) mdstnm, SCF if involved
Arm 2: RT after 4 cycles CHT-‘‘pretreatment tumor volume’’
2001 Skarlos et al. Randomized 2D Pre-CHT Arm 1: to 30 Gy-primary tumor ? entire mdtsnm ? bilateral hila; SCF if involved
(2001) phase II To 45 Gy-primary tumor
Arm 2: ‘‘initial tumor volume’’
1999 Turrisi et al. Phase III 2D Pre-CHT Primary tumor, bilateral mediastinal and ipsilateral hilar lymph nodes, SCF only if
(1999) involved, specifically: ‘‘inferior border … 5 cm below the carina or to a level
including ipsilateral hilar structures, whichever was lower’’.
1997 Jeremic et al. Phase III 2D Pre-CHT Arm 1: primary tumor, ipsilateral hilum, entire mdstnm, SCF only if involved
The Radiation Target in Small-Cell Lung Cancer

(1997) Arm 2: initial tumor volume

1997 Work et al. Phase III 2D (rare 3D) Pre-CHT Primary tumor, ipsilateral hilum, entire mdstnm, SCF only if involved
(1997)
1993 Murray et al. Phase III 2D (‘‘CT- Pre-CHT Arms 1, 2: Primary tumor with margin ? entire mdstm, SCF if involved
(1993) planning not
mandatory’’)
1987 Perry et al. Phase III 2D Pre-CHT Arms 1, 2: to 40 Gy-primary tumor with margin ? entire mdstnm, bilateral hila,
(1987) bilateral SCF
Boost to 50 Gy-residual disease on a mid-course CXR
1987 Kies et al. Phase III 2D Arm ‘‘wide- Primary tumor, ‘‘abnormal appearing lung’’, mdstnm, ‘‘low’’ SCF
(1987) field’’: pre-CHT
Arm ‘‘reduced
field’’: post-
CHT
1981 Perez et al. Phase III 2D Pre-CHT Arms 1, 2: primary tumor with margin ? entire mdstnm, bilateral hila, bilateral
(1981) SCF
CT computed tomography, PTV planning target volume, GTV gross tumor volume, CTV clinical target volume, ITV internal target volume, CHT chemotherapy, MLN mediastinal
lymph node, RT radiotherapy; SCF supraclavicular fossa, mdstnm mediastinum
205
206
without RT, and for partial responders or those with
stable disease, local recurrences were 32% for pre-
CHT volumes versus 28% for post-CHT volumes.
Thus post-CHT volumes were judged reasonable for
target delineation. The details of the portals used in
this protocol are relevant. As stated by the authors, the
volume as determined from a chest X-ray included:
the primary tumor, the surrounding abnormal lung,
the low supraclavicular area, ‘‘which gave a very
large portal in some patients’’ (Kies et al. 1987). In
the pre-CHT arm, the X-ray was taken before the
induction chemotherapy; in the reduced-field arm, the
post-induction X-ray served for planning.
Several retrospective analyses have assessed pre-
versus post-CHT tumor volumes in the setting of TRT
for SCLC. Mira and Livingston (Mira and Livingston
1980) assessed 17 LS-SCLC patients treated with
post-CHT volumes and found that the majority who
failed in the chest also failed at the lung periphery
(intrathoracic but outside the field) or with a malig-
nant pleural effusion but not nodal structures, sug-
gesting that pre-CHT volumes would provide
improved local control rates. In contrast, an influential
study by Liengswangwong et al. at Mayo Clinic
supported the use of post-CHT volumes
(Liengswangwong et al. 1994). Of 59 patients studied,
28 were treated with field sizes that encompassed
post-CHT tumor volumes and 31 with fields that
encompassed pre-CHT tumor volumes (defined as a
volume that included at least a 1.5 cm margin on the
pre-CHT tumor volume). Nineteen patients had
intrathoracic recurrence of disease as in-field failures
stratified as follows: 10 of 31 patients treated with RT
fields that encompassed pre-CHT tumor volumes and
9 of 28 patients treated with RT fields that encom-
passed post-CHT tumor volumes, suggesting no dif-
ference between choice of volume for TRT.
Tada et al. looked at the patterns of recurrence in
117 patients treated between 1986 and 1993 (Tada
et al. 1998). Patients were treated with a range of RT
doses and all with systemic CHT. There appeared to
be more regional relapses in the upper mediastinum
and supraclavicular fossae in those patients with
clinical N2 and N3 disease, prompting the authors to
recommend extended upper borders for N2 or N3
disease for unsuspected microscopic disease. Other
means of understanding the impact that target defi-
nition may have on TRT fields have included retro-
spective studies looking at patterns of failure.
G. M. M. Videtic
This includes a series of studies looking at the impact
clinical trial violations on relapse patterns. Impaired
local control and survival were found in trial patients
in whom major RT protocol violations occurred
(‘‘inadequate treatment portals’’), as reported both by
Perez et al. (1981) and by White et al. (1982) in their
analyses of outcomes for SCLC patients enrolled on
clinical trials in the 1970s. In contrast, in trials from
the 1980s when more sophisticated simulation tech-
niques became commonplace, especially CT-based
planning, Arriagada et al. (1991) and Brodin et al.
(1990) each found that tumor recurrences predomi-
nated within the radiation port (i.e., the post-CHT
volume), suggesting that the dose delivered was more
critical than target delineated.
In summary, the only Phase III study ever con-
ducted in target definition for LS-SCLC, a (partially)
randomized trial by SWOG from the pre-platinum
CHT era, suggests that, in SCLC, the radiation target
can be limited sufficiently to the residual gross tumor
as defined clinically after administration of CHT.
Retrospective studies, on the other hand, have shown
mixed results on the selection of the appropriate
treatment volume for TRT. There is, however, a trend
supporting target volumes limited to clinically defined
disease only post-CHT.
4 SCLC Target Definition and ENI
In as much as post-CHT pattern-of-failure data have
suggested that the TRT target could be limited to the
clinically definable disease (without specifically
addressing the ENI question), the trends in LS-SCLC
management were increasingly to: (1) initiate TRT
with the earliest, if not the first cycle of CHT, using
therefore a pre-CHT volume, and (2) work toward RT
dose escalation. These goals were reflected in how
trials decided on the amount of MLN inclusion in the
target as opposed to changing the primary tumor’s
volume. As seen in Table 1, published studies as early
as 1981 started to show modest reductions in nodal
sites included in the target volume by changing the
extent of LN inclusion. In the absence of supportive
clinical data, such changes were effectively empirical
as TRT dose escalation was being attempted.
Study of Perez et al. (1981) and the randomized
Cancer and Leukemia Group B (CALGB) study
published by Perry et al. (1987), volumes included the
The Radiation Target in Small-Cell Lung Cancer
gross tumor, ipsilateral hilum, bilateral mediastinal
nodal chains, and both supraclavicular fossae (SCF).
A shift away from elective SCF inclusion was seen in
Murray et al. (1993) Phase III LS-SCLC trial, where
the target allowed only involved SCF, as did the
Aarhus trial by Work et al. (1997), in which the target
was defined by the pretherapy radiograph. Jeremic
et al. (1997) described therapy by anteroposterior-
posteroanterior fields to the gross tumor, ipsilateral
hilum, entire mediastinum, and involved SCF. In the
landmark 1999 publication from Turrisi et al. (1999),
the target which was defined as gross tumor by CT
scanning, included full mediastinum and ipsilateral
hilum, but no elective irradiation of the SCFs.
A Phase III studied by Skarlos et al. (2001) described
treatment to gross tumor, hilum, mediastinum, and
involved SCF, as did the Japan Clinical Oncology
Group Phase III study published by Takada et al.
(2002) with the initial field in the sequential arm
based on the pre-CHT tumor volume. In 2006, the
most recent Phase III study in LS-SCLC was pub-
lished and was a replication of the early versus late
initiation of RT with CHT by Murray et al. (1993).
The field size described by Spiro et al. (2006) was
based on the pre-CHT tumor and used the target
definitions of the Murray trial.
Relatively recent trials have remained conservative
in their approach to MLN inclusion in the target. In
Bogart et al. (2004) phase II trial of dose escalation in
SCLC planning was based on volumes from the
restaging chest CT obtained after induction CHT, with
the GTV including residual lung tumor after induction
CHT, but with involved lymph node regions (both pre-
CHT and post-CHT) (Bogart et al. 2004). A 2007 report
by Schild et al. on the results of a Phase II study of high-
dose radiotherapy with concurrent chemotherapy
(Schild et al. 2007) had the target initially treated with
anteroposterior-posteroanterior fields that included
primary tumor with ipsilateral hilar, mediastinal, and
SCF nodes. Oblique fields were then tailored to include
primary tumor, ipsilateral hilum, and SCF nodes if
initially involved, and a ‘‘reduced’’ volume of the
mediastinum, although the parameters for reduction
were unspecified. Achieving small treatment portals
was a study goal and so fields were designed after the
fourth and fifth cycles of CHT.
Studies specifically addressing ENI issues have
been relatively recent and have come from extensive
work in the Netherlands. The first clinical study to
207
date directly addressing the issue of ENI in SCLC was
a phase II trial published by de Ruysscher et al.
(2006). The authors explicitly wished to evaluate the
patterns of recurrence when ENI was omitted in
patients with LS-SCLC. Twenty-seven patients
received TRT with 45 Gy/30 fractions (1.5 Gy twice-
daily) concurrent with carboplatin and etoposide
(CbE). Only the primary tumor and the positive nodal
areas on the pretreatment CT scan were irradiated.
A PET scan was not performed. After a median time
of 18 months post-RT, 7 patients developed a local
recurrence. Three patients (11%) developed an iso-
lated nodal failure, all of them in the ipsilateral SCF.
The authors concluded that the sample size limited
their results, but cautioned that omission of ENI on
the basis of CT scans in patients with LS-SCLC
resulted in a higher than expected rate of isolated
nodal failures in the ipsilateral SCF. In the 2006
Phase II study by Baas et al. (2006) the TRT target
volume for irradiation was planned to start within one
week after the start of the second cycle of CHT and
included the primary tumor and all clinical and
radiologically involved lymph nodes with a short axis
diameter of [1 cm; this was termed ‘‘involved field
irradiation’’ (Baas et al. 2006). A PET scan was not
performed. The authors reported an in-feld recurrence
rate of 24%. Out-of-field failures were only seen in 2
patients. Belderbos et al. (2007) compared the failure
patterns in this work by Baas et al. (2006) with those
of de Ruysscher study (2006) and noted that isolated
SCF failures were seen in both studies. Since it had
been reported that routine ultrasound of the supra-
clavicular area has improved the clinical (CT) staging
of SCLC patients (van Overhagen et al. 2004),
Belderbos et al. (2007) suggested that this test be
incorporated in the assessment of LS-SCLC in whom
non-ENI RT fields are being contemplated. van Loon
et al. (vl e 42) provided results from a planning study
incorporating FDG-PET in the TRT planning for
target definition and reported 24% of treatment plans
were changed compared to CT-based planning, with
both increases and decreases observed in GTV. More
recently, van Loon and her colleagues published
results from a series of 60 patients treated with con-
current CHT and hyperfractionated TRT [45 Gy],
with PET scan based selective nodal irradiation
(van Loon et al. 2010). They observed a low rate of
isolated nodal failures (3%). This was in contrast
with the findings from their aforementioned study of
208
CT-based selective nodal irradiation, which resulted
in a higher percentage of isolated nodal failures (11%)
(de Ruysscher et al. 2006). A recent (2010) retro-
spective study from the US by Watkins et al. (2010)
of 52 patients treated with hyperfractionated TRT
starting at CHT cycle 1 or 2 and with involved MLNs
defined by CT and/or PET criteria, showed that
involved-field TRT did not appear to have an adverse
impact on anticipated patterns of failure or survival
(Watkins et al. 2010).
5 SCLC Target Definition
and FDG-PET
The previously noted Phase II studies of ENI in
LS-SCLC distinguished the use of CT imaging for
defining abnormal MLNs from that obtained from
PET imaging. In NSCLC, it has been shown that PET
has a higher sensitivity, specificity, and accuracy for
detecting tumor involvement in MLNs than CT
imaging (van Baardwijk et al. 2006). However, the
gold standard for defining the presence and extent of
MLN metastases in NSCLC has long been, and
remains, mediastinoscopy (Rusch 2005). Validation
of PET-defined nodal targets in RT planning for
NSCLC against the pathologic standard, however, is a
little-investigated area. The question of PET based
imaging and pathologic validation in SCLC as it
applies to RT planning has not been studied.
There are a number of recent publications report-
ing on the utility of PET in the staging of SCLC. Two
studies are of interest with respect to RT planning.
Bradley et al. (2004) prospectively performed PET
scanning on 24 patients determined by conventional
staging to have LS-SCLC. PET identified unsuspected
regional nodal metastases in 6 (25%) of 24 patients
compared with CT: 1 patient with N1 disease on CT
was found to have N2 disease by PET; 5 patients with
clinical N2 disease on CT were found to have N3
disease. As in other studies, none of the PET findings
was confirmed histologically. The RT plan, however,
was significantly altered to include the PET-positive/
CT-negative nodes within the high-dose region in
each of these patients. In a retrospective study by
Kamel et al. (2003), PET scans had an impact on RT
in 8 patients (19%). In 5 patients (12%), PET scans
resulted in a change of RT field and volume after
identifying additional active tumor foci, which were
G. M. M. Videtic
not identified by the conventional staging methods.
In 5 patients with limited disease, PET detected
additional metastatic foci: ipsilateral pulmonary
metastasis (n = 1) and contralateral mediastinal
(n = 1), contralateral supraclavicular (n = 2), and
contralateral cervical (n = 1) lymph node metastases.
Several prospective and retrospective studies have
noted the improved sensitivity and specificity of PET
over CT with respect to identifying mediastinal nodal
abnormalities, but most of these reports did not vali-
date clinical results with pathologic sampling, nor did
they discuss implications for therapy.
In summary, PET imaging contributes substan-
tially to better identification of tumor burden, and can
definitely influence RT treatment plans. A major
weakness of all these studies is the absence of histo-
logic verification of PET and CT findings and none of
the cited studies were correlated with failure patterns.
However, it remains a powerful tool for more accu-
rately staging and defining gross tumor.
6 SCLC Target Definition
in Extensive Disease
Most clinicians conventionally consider the role of
RT in ES-SCLC as essentially palliative. However,
the role of RT in ES-SCLC has regained interest
because of a recent randomized study of PCI by
Slotman et al. (2007) in ES-SCLC patients with a
response after CHT that showed a clear benefit in
terms of lower brain relapses and higher overall sur-
vival. These data recall a not-yet-replicated phase III
study on the role of thoracic RT in favorable ES-
SCLC patients by Jeremic et al. (1999). In that study,
accelerated hyperfractionated RT and concurrent low-
dose daily CHT were instituted after three induction
cycles of cisplatin-etoposide (PE) and compared with
CHT alone. PCI was offered to responders in both
groups. The target volume in the TRT group included
all gross disease and the ipsilateral hilum with a 2 cm
margin and the entire mediastinum with a 1 cm
margin. Both SCF were routinely irradiated. Although
TRT improved local control and survival, there was
no difference between combined RT-CHT and CHT
alone group in terms of bronchopulmonary toxicity.
This important study merits replication, employing
contemporary RT technologies and concepts for tar-
get delineation.
The Radiation Target in Small-Cell Lung Cancer
7 SCLC Target Definition in Current
Trials
The European Organization for Research and Treat-
ment of Cancer (EORTC) is currently running a
Phase III trial in LS-SCLC comparing two RT doses
(European Organisation for Research and Treatment
of Cancer (EORTC) trial 2011). CONVERT (Con-
current once-daily VErsus twice-daily RadioTherapy)
is a Phase III trial in which patients with LS-SCLC
are randomized to either twice-daily thoracic radio-
therapy (45 Gy in 30 fractions starting with the sec-
ond cycle of PE) or to a higher dose of conventional
radiation (66 Gy in 33 daily fractions over 6.5 weeks
starting with the second cycle of PE). The primary
end point is overall survival. ENI is explicitly not
employed. TRT is to be started within 3 weeks of
planning. The GTV is defined as all identifiable tumor
and involved LNs (defined on CT as nodes [1 cm in
short axis). The CTV comprises the GTV with a
0.5 cm margin. The PTV includes the CTV with a
1.5 cm margin superiorly and inferiorly and 1 cm
margin laterally. If PET scans are available for stag-
ing, the GTV is required to include PET-positive LNs.
Also currently ongoing is a randomized three-arm
dose comparison trial in LS-SCLC initiated by the
major North American collaborative groups (CALGB
30610/RTOG 0538) (Phase III randomized study of
three different thoracic radiotherapy regimens in
patients with limited-stage small-cell lung cancer
receiving cisplatin and etoposide. 2011). The primary
objective of this study is to determine whether
administering concurrent PE starting at cycle 1 or 2
with high-dose TRT as 70 Gy (2 Gy once-daily over
7 weeks) or 61.2 Gy (1.8 Gy once-daily for 16 days
followed by 1.8 Gy twice-daily for 9 days), will
improve median and 2-year survival compared with
45 Gy (1.5 Gy twice-daily over 3 weeks) in patients
with LS-SCLC. In this study, the GTV is defined as
the primary tumor and clinically positive LNs seen
either on the pretreatment CT ([1 cm short axis
diameter) or on pretreatment PET scan (SUV [ 3).
There will be two CTVs, 1 or 2, which will be used as
a function of the arm to which the patient is ran-
domized. CTV-1 will include the GTV and the ipsi-
lateral hilum and CTV-2 will consist of a revised
GTV-only based on CHT response. Thus CONVERT
and the US Intergroup study are employing slightly
209
different approaches to target delineation, with the
former having a more rigorous non-ENI approach and
each having an impact factor from the timing of CHT
administration.
8 Conclusions
The criteria for defining the appropriate target when
treating a SCLC patient remains an active area of
investigation. Two ongoing large randomized clinical
trials should provide the most up-to-date evidence to
guide radiation oncologists in optimal planning of RT
delivery to the tumor. It is likely that technological
advances in RT delivery may have their greatest
impact with respect to normal tissue toxicities. In the
absence of strong evidence supporting omission of
ENI, clinicians must use thoughtful clinical judgment,
integrating a number of tools such as PET imaging
along with appropriate interpretation of the evidence
to guide their treatment planning, with an emphasis
on a balance between increase of failure risk and
maximal reduction of treatment-related toxicities to
support improvements in outcomes.
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 Radiation Sensitizers
Anthony M. Brade and Zishan Allibhai
Contents
1 Radiation Sensitizers ............................................... 213
2 Oxygen ......................................................................
2.1 Hyperbaric Oxygen....................................................
2.2 Carbogen ....................................................................
2.3 Efaproxiral .................................................................
2.4 Red Blood Cell Transfusion .....................................
2.5 Erythropoietin ............................................................
3 Targeting Hypoxic Cells ......................................... 216
3.1 Hypoxic Cell Radiosensitizers .................................. 216
3.2 Bioreductive Drugs (Hypoxic Cell Cytotoxins) ....... 217
4 Boron Neutron Capture Theory ............................ 217
5 DNA Repair Inhibitors ...........................................
5.1 AKT Pathway Inhibition ...........................................
5.2 Mitogen-Activated Protein Kinase Inhibition ..........
5.3 HDAC-Inhibitors .......................................................
6 Apoptosis Modulating Agents ................................ 219
6.1 Bcl-2 Inhibitors.......................................................... 219
6.2 Cyclooxygenase COX-2-Inhibitors ........................... 219
References.......................................................................... 219
A. M. Brade (&)
Z. Allibhai
Department of Radiation Oncology,
Princess Margaret Hospital,
5-912 610 University Avenue, Toronto,
ON M5G 2M9, Canada
e-mail: Anthony.brade@rmp.uhn.on.ca
A. M. Brade
University of Toronto, Toronto, Canada
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_278, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
Discovery of effective radiosensitization strategies
that improve the therapeutic ratio for patients with
214 lung cancer has been a goal of researchers and an
214 area of vigorous investigation for the past several
215 decades. A pure radiosensitizer is a drug, a
215
modality of therapy or an intervention that, on its
215
216 own, lacks direct anti-tumor activity but enhances
the cytotoxicity of radiotherapy when employed in
combination. In this chapter we outline the previ-
ous and ongoing attempts to radiosensitize lung
cancers through improved tumor oxygenation,
augmentation of the effectiveness of radiotherapy
217 in hypoxic tumor cells, and use of drugs that
217
218 modulate with DNA repair and apoptosis. To date,
218 no pure radiosensitization strategy has established
itself in standard practice but the current research
suggests that this field continues to hold great
promise for the improvement of outcome in
patients with lung cancer.
1 Radiation Sensitizers
Although radiotherapy has traditionally played a
major role in the treatment of non-small cell lung
cancers (NSCLC), its effectiveness had been limited
by an unfavourable therapeutic ratio, whereby it is
challenging to deliver optimal doses of radiation to
tumors without excessive normal tissue toxicity.
Recently, a number of technological advances in
both imaging and radiation delivery have further
improved our ability to spare normal tissue. A further
approach to enhancing the therapeutic ratio is to
213
214
selectively increase the radiosensitivity of the target
tumor. The advantages of this approach are poten-
tially significant given that the presumed radioresis-
tance of NSCLC has long been a major obstacle to the
efficacy of RT.
A pure radiosensitizer is a drug, a modality of
therapy or an intervention that on its own lacks direct
anti-tumor activity but enhances the cytotoxicity of
radiotherapy when employed in combination. Many
chemotherapeutic agents (e.g. platins, taxanes, and
topoisomerase modulators) enhance the cytotoxicity of
radiotherapy when the two modalities are combined but
as they generally effect some degree of anti-tumor
activity when administered as single agents, they
are therefore not considered true radiosensitizers.
Similarly, newer classes of drugs have been developed
to exploit tumor-specific mutations or target-specific
molecular-based alterations within the tumor or its
microenvironment. Some of these also augment the
efficacy of radiotherapy and have single agent efficacy
against lung cancer and are thus not pure radiosensi-
tizers. For example, tyrosine kinase inhibitors of the
epidermal growth factor receptor such as erlotinib and
gefitinib have shown impressive enhancement in tumor
models when combined with radiation treatment
(Chinnaiyan et al. 2005; Tanaka et al. 2008; Park et al.
2010) in addition to improving outcome as single
agents in patients with NSCLC (Tsao et al. 2005),
particularly in patients bearing specific mutations in the
EGFR gene (Mok et al. 2009). Other examples include
the use of agents that inhibit vascular endothelial
growth factor (VEGF) (Manegold et al. 2008), inhibi-
tors of anaplastic lymphoma kinase (ALK), and
inhibitors of mammalian target of rapamycin (mTOR)
(Nagata et al. 2010). Combinations of radiotherapy
with chemotherapy or molecularly-targeted drugs in
lung cancer are detailed elsewhere in this volume. This
chapter will focus on pure-radiosensitizing strategies
and their potential relevance to the treatment of lung
cancer.
2 Oxygen
One of the earliest radiosensitizers to be identified and
studied was oxygen. Its presence increases the yield,
variety, and lifetime of the radical species formed
secondary to tumor/tissue irradiation. The impact of
oxygen on radiation effect is mathematically
A. M. Brade and Z. Allibhai
described by the oxygen-enhancement ratio (OER)
which quantifies the relative dose required to produce
a certain biologic effect under hypoxic conditions
versus that required to achieve the same effect under
aerobic conditions.
The presence of a hypoxic cell subpopulation is
a common feature of solid tumors, and although the
extent of hypoxia varies widely from tumor to
tumor and within tumors, it contributes significantly
to radioresistance. While the clinical effect of
hypoxia on cancer outcomes has been best dem-
onstrated in the setting of head and neck cancers
(Becker et al. 1998), cervical cancer (Hockel et al.
1993), and soft tissue sarcomas (Brizel et al. 1995),
it has also been shown in NSCLC. For example,
mean hemoglobin levels were associated with the
degree of pathologic response seen following neo-
adjuvant chemoradiation (Robnett et al. 2002)
while low (Laurie et al. 2006) or declining
(MacRae et al. 2002) hemoglobin levels during the
course of chemoradiation have been correlated with
worse overall survival. Tumor hypoxia in NSCLC
has also been correlated with an increased inci-
dence of distant metastasis (Le et al. 2007) and
poorer overall prognosis (Eschmann et al. 2005).
Hypoxia has been demonstrated to trigger the
downregulation of key DNA repair pathways,
leading to genetic instability. Thus, tumor hypoxia
is a key driver of metastatic spread and treatment
resistance (Brizel et al. 1996; Brown and Gaccia
1998).
Considerable effort has been focused on discov-
ering interventions by which tumor hypoxia can be
reduced. These have included artificial means of
increasing hemoglobin oxygenation levels as well
as measures to optimize the hemoglobin levels
themselves.
2.1 Hyperbaric Oxygen
A hyperbaric environment allows greater solubility of
oxygen within plasma and hemoglobin saturation,
thus maximizing oxygen delivery to hypoxic tumor
cells. While randomized studies conducted in patients
with head and neck cancers (Henk et al. 1977) as well
as cervical cancer (Watson et al. 1978) had shown
improvements in local control and/or survival, a
number of trials studying HBO in various other
cancer sites failed to show a benefit. Furthermore,
Radiation Sensitizers
there exist a number of logistical issues in both the
availability and administration of HBO during a
standard course of fractionated radiotherapy. As a
result, the role of HBO in clinical practice has been
limited to the repair of damaged tissues following RT
where it has been shown to limit and in some cases
reverse the process of radiation damage (Bennett et al.
2005; Bui et al. 2004).
2.2 Carbogen
Carbogen is a mixture of oxygen and carbon dioxide
(typically 95% O2 to 5% CO2) and it has a theoretical
advantage over pure oxygen since the increased level
of carbon dioxide triggers a rightward shift of the
oxyhemoglobin curve, thus facilitating the release of
O2 into areas of hypoxia (Rubin et al. 1979).
Carbogen has also been used in combination
with agents that enhance tumor blood flow, for e.g.
nicotinamide, thus providing a synergistic effect.
This combination of agents was studied in a phase
II trial from the Netherlands which found that the
use of ARCON (accelerated radiotherapy with
carbogen and nicotinamide) yielded high control
rates in laryngeal cancer (Kaanders et al. 1998).
While data regarding late toxicity and outcome data
are not yet mature, the subsequent phase III study
comparing ARCON versus accelerated radiation
only demonstrated a mild increase in confluent
mucositis (Janssens et al. 2011). This is consistent
with the results from a phase III study in locally
advanced bladder cancer where the addition of
ARCON to RT improved both local control and
overall survival without significantly increasing late
morbidity (Hoskin et al. 2010).
In regard to lung cancer, a similar phase I/II study
was launched in Switzerland to investigate the effects
of adding carbogen and/or nicotinamide to acceler-
ated radiation for locally advanced NSCLC staged
IIIA or IIIB. There was no difference in radiologic
response or time to progression between the three
groups, and no increase in radiotherapy related
adverse events. However, a significant proportion of
patients in the two groups that received nicotinamide
developed significant (CG2) emesis which was shown
to adversely affect their quality of life (Bernier et al.
1999), thus this strategy is unlikely to be pursued
further in this disease.
215
2.3 Efaproxiral
Efaproxiral (RSR-13) is an allosteric effector of
hemoglobin which enhances its oxygen-carrying
capacity, effectively increasing the delivery of oxygen
to otherwise hypoxic regions. Phases I and II studies
demonstrated that this compound is safe and effective
in improving tumor oxygenation and potentiating
radiation effect. The radiation enhancing allosteric
compounds of hypoxic brain metastases (REACH)
trial was a phase III study designed to evaluate the
addition of efaproxiral to whole brain radiotherapy in
patients with brain metastasis (Suh et al. 2006). No
difference in overall survival was found for the entire
group, over half of whom had metastatic NSCLC. An
unplanned subset analysis did however show that in
the subset of patients with metastatic breast cancer
(20% of patients), the addition of efaproxiral
improved survival as well as quality of life (Scott
et al. 2007).
A phase II trial was designed to test the efficacy
and safety of efaproxiral given concurrently with
radiation following induction chemotherapy for
locally advanced NSCLC. This combination yielded
an overall response rate of 75% and a very encour-
aging median survival of 20.6 months, while the rates
of severe toxicity were relatively low (Choy et al.
2005). These encouraging results prompted the pro-
posal of a phase III study, however, this trial was
never launched (Choy, personal correspondence).
2.4 Red Blood Cell Transfusion
Transfusion represents a potentially direct means of
improving oxygen delivery to tumors in anemic
patients. An important study evaluating transfusion to
counter anemia was undertaken in cervical cancer
patients at Princess Margaret Hospital. This trial
suggested that transfusions might improve outcomes
in patients who were anemic while undergoing
definitive radiotherapy (Fyles et al. 1998).
The systemic administration of hemoglobin vesicle
(HbV), which serves as an artificial oxygen carrier,
represents a recently developed alternative to red cell
transfusion. Animal studies of HbV have demon-
strated that it increases oxygen tension within tumor
tissue and that this positively affects the tumor’s
response to radiation (Yamamoto et al. 2009).
216
This was the first study to test tumor oxygenation
using a liposome-type artificial oxygen carrier, and
further studies are anticipated.
2.5 Erythropoietin
Erythropoietin (EPO) is a glycoprotein hormone that
controls erythropoiesis through its interactions with
the erythropoietin receptor (EpoR) found on bone
marrow stem cells. Human recombinant erythropoie-
tin (and similar exogenous agents) represent another
method by which hemoglobin levels may be increased,
and a number of trials have studied the effect of EPO
in the management of anemic cancer patients.
Although encouraging results were found in anemic
lung cancer patients undergoing chemotherapy
(Vansteenkiste et al. 2002), subsequent trials in breast
and head and neck cancer patients actually suggested
that these agents worsened outcomes (Henke et al.
2003; Leyland-Jones 2003). A subsequent meta-
analysis of 9,353 patients from 53 studies studying the
effects of epoetin or darbopoetin demonstrated an
increased risk of thrombo-embolic events as well as
increased mortality from the use of these agents
(Bohlius et al. 2009).
3 Targeting Hypoxic Cells
3.1 Hypoxic Cell Radiosensitizers
Hypoxic cell radiosensitizers are compounds with
strong electron affinity that mimic the radiosensitizing
effect of oxygen by virtue of their ability to ‘‘fix’’
damage produced by free radicals. As with oxygen,
their strong electron affinity can fix radiation damage.
Analogous to the aforementioned OER metric, the
efficacy of a hypoxic-cell radiosensitizer is expressed
numerically as a sensitizer enhancement ratio (SER).
Misonidazole, a nitroimidazole compound was
found to be a potent radiosensitizer of cells in culture,
activity which was subsequently confirmed in animal
studies. However, in the clinical setting, it caused
severe, dose-limiting peripheral neuropathy. Newer
generation nitroimidazole compounds such as etani-
dazole and pimonidazole were subsequently devel-
oped to improve the pharmacokinetic profile of this
class of drugs and reduce toxicity. Unfortunately,
A. M. Brade and Z. Allibhai
their SERs were also reduced and the two large phase
III trials studying etanidazole in locally advanced
head and neck carcinomas did not yield any
improvements in outcome over conventionally frac-
tionated radiation alone (Lee et al. 1995; Eschwège
et al. 1997).
Nimorazole was also found to have a lower SER
than misonidazole, however, significantly greater
doses could be tolerated since it was far less toxic
than any of its predecessors (Overgaard 1994). This
agent was subsequently evaluated in the Danish Head
and Neck Cancer (DAHANCA) 5 study. This phase
III trial included 422 patients with supraglottic and
pharyngeal carcinomas. The addition of nimorazole
improved 5 year locoregional control from 33 to 49%
(P \ 0.002) and cancer-specific survival improved
from 41 to 52% (P = 0.01). Importantly, there was no
increase in severe late radiation morbidity (Overgaard
et al. 1998). This study has resulted in nimorazole
being incorporated into standard practice in Denmark.
However, the routine use of radiosensitizers for head
and neck cancer has not generally been adopted out-
side Denmark, likely due to the fact that other phase
III trials yielded negative or inconclusive results.
It should be noted that many of these other studies
were underpowered and used earlier generations of
radiosensitizing agents that were less effective and
more toxic (Ang 2010).
A meta-analysis of 82 different trials involving
HBO and hypoxic-cell radiosensitizers showed a
4.6% improvement in local tumor control (Kaanders
et al. 2004). Although few of these trials focused on
lung cancer, some early work with a novel nitroimi-
dazole compound called doranidazole (PR-350) has
shown promise in both NSCLC and SCLC. Preclini-
cal and early clinical trials have demonstrated a rel-
atively high SER in NSCLC, and a recent Japanese
phase I/II trial in patients with locally advanced
NSCLC demonstrated promising efficacy. Patients
receiving 21–30 doses of doranidzole over the course
of the 30 fractions had a median survival of
20.9 months and a 2-year survival rate of 33%
(Nishimura et al. 2007). Furthermore, PR-350 has
also been shown to effectively radiosensitize SCLC
in vivo, and further studies are awaited.
Modeling parameters suggest that hypoxic cell
radiosensitizers would be of particular benefit in
patients being treated with stereotactic body radiation
therapy (SBRT) (Brown et al. 2010) since the delivery
Radiation Sensitizers
of large fractions of radiation over a very short period
of time may not allow for sufficient tumor re-oxy-
genation. This hypothesis however has not yet been
formally tested.
3.2 Bioreductive Drugs (Hypoxic Cell
Cytotoxins)
Bioreductive drugs are agents that undergo metabolic
reduction to generate cytotoxic radical species. This
process is facilitated by bioreductive enzymes and the
lower oxygen conditions present in tumors compared
to normal tissues. While it should be mentioned that
bioreductive drugs are not radiosensitizers per sé, they
do however act in a complementary fashion with
radiation by selectively targeting and killing hypoxic
cells that would otherwise be radioresistant. The most
well-studied of these compounds is tirapazamine, and
early lab studies suggested a supra-additive effect
when combined with ionizing radiation (Wilson et al.
1996). Unfortunately, efforts to use this compound in
clinical trials have been hampered by unpleasant side
effects associated with this agent such as nausea and
muscle cramping. Furthermore, the recently com-
pleted phase III TROG 02.02/HeadSTART trial
adding tirapazamine to chemoradiation in locally
advanced head and neck carcinoma did not demon-
strate improved overall survival (Rischin et al. 2010).
Tirapazamine has also been evaluated in a recently
completed phase II SWOG study for patients with
limited stage SCLC. A median survival of 21 months
was observed in this study (Le et al. 2009). As similar
survival rates have been observed with chemoradio-
therapy alone (Turrisi et al. 1999), it is not clear
whether this compound has merit in SCLC.
4 Boron Neutron Capture Theory
Boron neutron capture theory (BNCT) involves the
injection of a boron-10 tagged chemical (one that
preferentially binds to tumor cells) followed by irra-
diation of the tumor target with a neutron beam. The
interaction of the neutrons with the boron nuclei
produces densely ionizing radiation within the cell
(secondary to production of (Nagata et al. 2010) Li
and an alpha particle). This modality has primarily
been investigated in the treatment of malignant
217
gliomas and head and neck cancers, where the ability
to avoid immediately adjacent critical structures is of
particular importance. Although its use in the treat-
ment of lung cancer has not yet been well-studied,
early animal models have confirmed that metastatic
lung lesions have increased uptake of boronated
compounds in comparison to healthy lung tissue,
suggesting a possible therapeutic role in this setting
(Bortolussi et al. 2011).
5 DNA Repair Inhibitors
Radiation therapy functions through its ability to
damage DNA, directly or indirectly. One mechanism
of therapeutic resistance therefore is the ability of
cancer cells to identify and repair DNA damage. The
use of pharmacological agents that can inhibit DNA
repair pathways in cancer cells has the potential to
counter the phenomenon of therapeutic resistance,
thus enhancing the cytotoxicity of radiation. Impor-
tant DNA repair pathways including homologous
recombination repair (HRR), non-homologous end-
joining (NHEJ), base-excision repair (BER), nucleo-
tide-excision repair (NER), mismatch repair (MMR)
and translesion DNA synthesis (TLS) (Helleday et al.
2008). The development of novel agents that can
inhibit or modulate these pathways is an area of
intense ongoing study. Here, we outline some of the
major classes of drugs that modulate DNA repair.
5.1 AKT Pathway Inhibition
Non-small-cell lung cancers often display amplifica-
tion of EGFR (Ohsaki et al. 2000) which stimulates
the phosphatidylinositol 3-kinase (PI3K)/AKT path-
way as well as the Ras-Raf-Mek-ERK signaling cas-
cade, both of which induce radioresistance through
the promotion of DNA repair. For this reason, agents
such as EGFR-inhibitors (Kriegs et al. 2010; Tanaka
et al. 2008) or AKT-inhibitors (Toulany et al. 2008a)
have the potential to interfere with DNA repair, and
thus may enhance radiation sensitivity through this
mechanism.
Interestingly, statins, a commonly prescribed class
of medications used primarily as anti-cholesterol
agents, have also been shown to interfere with AKT
signaling. In addition to inhibiting cholesterol
218
biosynthesis, they might also have chemopreventative
and cytostatic properties. For example, simvastatin
has been shown to inhibit growth in both NSCLC
(Bellini et al. 2003) and SCLC (Khanzada et al.
2006). In laboratory studies they have also demon-
strated the ability to enhance radiosensitivity in cer-
vical cancer and more recently NSCLC. These agents
drive apoptosis following exposure to ionizing radi-
ation by simultaneously inhibiting and activating the
Akt- and AMPK-signaling pathways respectively.
In comparison to control cells exposed to either 2 or
8 Gy, the use of lovastatin significantly reduced
proliferation of NSCLC by 63 and 90% respectively
(Sanli et al. 2011). Direct inhibition of AKT1 has
been shown to downregulate radiation-induced DNA-
PKcs activity suggesting a potential link between
statins and DNA DSB repair (Toulany et al. 2008a).
5.2 Mitogen-Activated Protein Kinase
Inhibition
The mitogen-activated protein (MAP) kinase cascade
is involved in cancer cell proliferation, survival, and
metastases, thus playing an important role in the
progression and maintenance of cancer (Shannon
et al. 2009). This pathway (which is often upregu-
lated in tumors), is activated following exposure to
ionizing radiation, and can modulate DNA-DSB
repair, through its role in the upregulation of X-ray
repair cross-complementing group I protein
(XRCC1) expression (Toulany et al. 2008b; Wood
et al. 2009). Inhibition of the MAP kinase pathway
has been shown to enhance the radiosensitivity of
non-small-cell lung cancer cells. AZD6244 is one
such MAP-kinase inhibitor, and an in vivo study of
this agent in NSCLC demonstrated an impressive
SER of 3.38 (Chung et al. 2009). Interestingly, the
radiosensitization observed using EGFR inhibitors
may stem, at least in part from inhibition of DNA-
DSB repair mediated by MAP kinase. Both erlotinib
and cetuximab have been shown to downregulate
NHEJ repair of DSBs with erlotinib interfering with
signaling through both AKT and MAPK but cetux-
imab functioning through MAPK in human NSCLC
cell lines (Kriegs et al. 2010). This confirmed a
similar finding reported previously by Tanaka using
A. M. Brade and Z. Allibhai
gefitinib, again in human NSCLC lines (Tanaka
et al. 2008).
5.3 HDAC-Inhibitors
Histone deacetylases (HDAC) modulate the acetyla-
tion status of histones, thus affecting the gene tran-
scription. HDAC overactivity has been associated with
tumorigenesis, presumably through transcriptional
repression of tumor suppressor genes (Zhang et al.
2004). HDAC-Inhibitors (HDACIs) have been shown
to suppress the ability of cancer cells to repair DSBs in
response to ionizing radiation (Marks et al. 2000).
Laboratory studies evaluating different HDACIs
have demonstrated that co-treatment with these agents
increases the radiosensitivity in NSCLC cells (Zhang
et al. 2009; Geng et al. 2006; Cuneo et al. 2007).
Vorinostat, a first generation HCADi does not appear
to have single agent activity in lung cancer suggesting
that HDACIs may function as true radiosenstizers
(Vansteenkiste et al. 2008). Ongoing and future
studies will help to determine whether this promising
strategy can provide meaningful clinical benefit.
Histone acetyltransferase (HAT) works in con-
junction with HDAC to regulate transcription.
Interestingly, recent studies have shown that HAT-
inhibitors may also have potent radiosensitizing
effects (Bandyopadhyay et al. 2009), and further
studies are ongoing.
PARP-Inhibitors Poly(ADP-ribose) polymerase
(PARP) is a nuclear enzyme that plays an important
role in sensing and repairing DNA damage via the
modification of a number of key proteins, particularly
those involved in single-strand break repair via BER
(de Murcia et al. 1997; Dantzer et al. 2000). With
continuous PARP inhibition, single-strand breaks are
converted to double-strand breaks, and thus PARP-
inhibitors demonstrate synthetic lethality in tumors
that are reliant on NHEJ and BER (such as those
affected by BRCA-1 or BRCA-2 mutations) (Chalmers
et al. 2010). Various PARP inhibitors have been shown
to potentiate the effect of radiation, particularly in
hypoxic cells whose radiosensitivity is enhanced to a
similar degree as oxic cells (Liu et al. 2008). Preclin-
ical studies of PARP inhibitors in lung cancer models
have been encouraging (Albert et al. 2007).
Radiation Sensitizers
6 Apoptosis Modulating Agents
6.1 Bcl-2 Inhibitors
The Bcl-2 gene family of proteins is fundamentally
involved in regulation of the apoptotic pathway with
some family members effecting pro-apoptotic sig-
naling and others functioning as anti-apoptotic mod-
ulators. While the relative importance of apoptosis (as
opposed to mitotic catastrophe) in radiation-induced
cytotoxicity in solid tumors is debatable, there is
some evidence that drugs modulating the apoptotic
response may be relevant to radiosensitivity in lung
cancer. For example, radioresistant cells have been
demonstrated to have higher levels of Bcl-2 (Roa
et al. 2005). Preclinical studies have suggested that
certain Bcl-2 inhibitors may enhance radiosensitivity
in both NSCLC (Moretti et al. 2010) and SCLC (Hann
et al. 2008; Loriot et al. 2010). In the case of NSCLC,
both radiosensitive and radioresistant cell lines had
increased response to RT when given with one of
these agents.
6.2 Cyclooxygenase COX-2-Inhibitors
COX-2 mediates prostaglandin synthesis in response
to various stimuli such as inflammation and exposure
to carcinogens. This enzyme has been found to be
upregulated in many tumors including cancer of the
lung (Komaki et al. 2004) where it serves to inhibit
apoptosis and modulate cell proliferation (Sobolewski
et al. 2010). Several preclinical models and Phase I
studies have demonstrated that COX-2 inhibitors
and other non-steroidal anti-inflammatory drugs
(NSAIDs) increase radiosensitivity of tumors without
significantly increasing toxicity. For example, ni-
mesulide (Kim et al. 2009; Grimes et al. 2006) has
been studied in xenograft models, demonstrating
significantly delayed tumor growth compared to
tumors receiving radiation alone. The in vitro com-
ponent of the study showed significantly decreased
clonogenic survival with the addition of nimesulide
(P \ 0.001).
Celecoxib is another COX-2 inhibitor studied for
its radiosensitizing properties. This agent had shown
promise in preclinical and early clinical studies for
both primary (Liu et al. 2003) and metastatic
219
(Cerchietti et al. 2005; Klenke et al. 2011) NSCLC
lesions. These led to the development of a random-
ized phase II trial comparing RT +/- concurrent
celecoxib in patients with stages II–III disease (De
Ruysscher et al. 2007). Unfortunately, this study
closed due to poor accrual, and thus it remains unclear
as to whether or not this strategy has merit in the
clinical setting.
In conclusion, to date, no clear benefit has been
established for pure radiosensitization strategies in
lung cancer. Many novel approaches in this field have
shown recent promise, however. The ability to
selectively enhance the radiosensitivity of tumor cells
continues to hold appeal, particularly when combined
with recent technological advances that enable
delivery of radiation with increased accuracy and
precision. Along with improvements in cytotoxic
chemotherapy and targeted agents, this field remains a
potentially fruitful area for research in the quest to
further increase the therapeutic ratio and improve
outcome in patients with lung cancer.
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 Radioprotectors and Chemoprotectors
in the Management of Lung Cancer
Ritsuko Komaki, Zhongxing Liao, James D. Cox,
Kathy A. Mason, and Luka Milas

Contents 12 Concluding Remarks ............................................... 238

1 Introduction.............................................................. 224
2 Thiols as Radioprotective Agents ..........................
2.1 Amifostine: Preclinical Findings...............................
2.2 Amifostine: Clinical Studies .....................................
2.3 Amifostine: Meta-Analyses of Clinical Studies .......
2.4 Amifostine: Route of Administration .......................
2.5 Amifostine: Quality of Life Studies .........................
3 Prostanoids, COX-2 and COX-2 Inhibitors ......... 231
3.1 Clinical Trials of COX-2 Inhibitors
for Lung Cancer ........................................................ 232
4 Growth Factors and Cytokines..............................
4.1 Basic Fibroblast Growth Factor ................................
4.2 Keratinocyte Growth Factor......................................
4.3 Interleukin-11.............................................................
4.4 Epidermal Growth Factor Receptor..........................
5 Pentoxifylline ............................................................ 234
6 Angiotensin-Converting Enzyme Inhibitors ......... 235
7 Flavopiridol .............................................................. 236
8 Poly(ADP-Ribose) Polymerase Inhibitors............. 236
9 Bcl-2 Inhibitors ........................................................ 237
10 Efaproxaril................................................................ 237
11 Radioprotective Gene Therapy/Antioxidant
Therapy: Superoxide Dismutase............................ 238
R. Komaki (&)
Z. Liao
J. D. Cox
Department of Radiation Oncology, Unit 97,
The University of Texas MD Anderson Cancer Center,
1515 Holcombe Blvd, Houston, TX 77030-4009, USA
e-mail: rkomaki@mdanderson.org
K. A. Mason
L. Milas
Department of Experimental Radiation Oncology,
The University of Texas MD Anderson Cancer Center,
Houston, TX, USA
References.......................................................................... 239
225
Abstract
226
227 Lung cancer is the leading cause of cancer death in
229 most developed countries. The prognosis remains
230 poor with an overall survival rate at 5 years of only
231
about 15%. Between 70 and 85% of all cases are
histologically classified as non-small cell lung
carcinoma (NSCLC). Radiation therapy has tradi-
tionally been the treatment of choice for locally
233 advanced disease and medically inoperable early
233
233
stage NSCLC. However radiation therapy alone
234 was not effective treatment for patients with
234 locally advanced NSCLC. The addition of cyto-
toxic drugs to radiotherapy considerably improves
treatment outcome, and the combination of
chemotherapy with radiotherapy has become com-
mon practice for the treatment of locally advanced
lung cancer. The addition of chemotherapy to
radiotherapy has two principal objectives: one, to
increase the chance of local tumor control and two,
to eliminate metastatic disease outside of the
radiation field. Several randomized trials have
shown improvement of local control and survival
by application of concurrent chemotherapy rather
than sequential chemotherapy followed by radia-
tion treatment. This combined treatment approach
results in median survival times of 13 to 14 months
and survival rates at 5 years as high as 15 to 20%.
These improvements have been achieved by using
standard chemotherapeutic agents, primarily cis-
platin-based drug combinations. However, concur-
rent chemoradiotherapy has increased significant

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 223
DOI: 10.1007/174_2011_288, Ó Springer-Verlag Berlin Heidelberg 2011
224
normal tissue toxicity such as esophagitis and
pneumonitis. Therefore normal tissue protectors
without protective cancer cells became necessary to
improve therapeutic ratio. We will discuss mecha-
nism and efficacy of Amifostine to protect normal
tissue followed by other normal tissue protectors or
molecular targeted treatment without increasing
normal tissue damage e.g., prostanoids (COX-2)
inhibitors, Growth factor and Cytokines inhibitors,
Basic and other inhibitors targeting Fibroblast
Growth Factor, Karatinocyte Growth Factors,
Epidermoid Growth Factor Receptor, Pentoxifyl-
line, Angiotensin-Converting Enzyme Flavopiridol
Poly(ADP-Ribose) Polymerase, Bcl-2 , and Efa-
proxaril, as well as Radioprotective Gene Therapy/
Antioxidant Therapy: and Superoxide Dismutase
1 Introduction
Lung cancer is the leading cause of cancer death in
most developed countries. An estimated 1.6 million
new cases of lung cancer were diagnosed in 2008, and
the prognosis remains poor with an overall survival
rate at 5 years of only about 15% (Jemal et al. 2004;
American Cancer Society 2011). Between 70 and
85% of all cases are histologically classified as non-
small cell lung carcinoma (NSCLC), which comprises
squamous cell, adenocarcinoma, large cell, or undif-
ferentiated histologic subtypes; the remainder of the
cases are of small cell histology. At the time of
diagnosis most patients present with locally advanced
disease and many have overt metastatic dissemina-
tion. Radiation therapy has traditionally been the
treatment of choice for locally advanced disease but
has provided limited benefits both in terms of local
tumor control and patient survival, with 2- to 5-year
survival rates of 10% or less (Dillman et al. 1996).
The addition of cytotoxic drugs to radiotherapy con-
siderably improves the treatment outcome, and the
combination of chemotherapy with radiotherapy has
become the common practice for the treatment of
advanced lung cancer (O’Rourke et al. 2010). The
addition of chemotherapy to radiotherapy has two
principal objectives: one, to increase the chance of
local tumor control and two, to eliminate metastatic
disease outside the radiation field. The former can be
R. Komaki et al.
achieved by reducing cell burden in tumors under-
going radiotherapy or by interfering with tumor cell
radioresistance factors, thereby rendering tumor cells
more susceptible to destruction by radiation. Factors
that contribute to tumor radioresistance include the
failure of tumor cells to undergo cell death after
radiation, the cells’ ability to efficiently repair DNA
damage, continued cell proliferation during the course
of radiotherapy, cell radioresistance secondary to the
hypoxia that commonly develops in solid tumors, and
the presence in tumor cells of various abnormal
molecular structures or with dysregulated processes
linked to cellular radioresistance (Milas et al. 2003a).
The addition of induction (neoadjuvant) chemo-
therapy to radiotherapy results in an increase in
median survival time of approximately 4 months, and
the overall survival rates at 2 years range from 10 to
15% (Milas et al. 2003a; Dillman et al. 1990;
LeChevalier et al. 1991). These modest therapeutic
gains can be improved upon still further by using
concurrent chemoradiotherapy, i.e., by administering
cytotoxic drugs during the course of radiation treat-
ment (Milas et al. 2003a; Komaki et al. 2002; Turrisi
et al. 1999; Schaake-Konig et al. 1992; Curran et al.
2003). This combined treatment approach results in
median survival times of 13 and 14 months and sur-
vival rates at 5 years as high as 15 to 20%. These
improvements have been achieved by using standard
chemotherapeutic agents, primarily cisplatin-based
drug combinations. Since the completion of trials that
directly compared induction with concurrent chemo-
radiotherapy and clearly demonstrated the therapeutic
superiority of the latter approach (Schaake-Konig
et al. 1992; Curran et al. 2003), concurrent chemo-
radiotherapy can be regarded as the current standard
of care for local-regionally advanced lung cancer.
Yet, the low overall survival rates among patients
with lung cancer necessitates the introduction of
treatment strategies that would further improve local
tumor control, survival rates, and quality of life.
Many factors, known and unknown, limit thera-
peutic success of radiotherapy or chemoradiotherapy
for lung cancer, with one major factor being the level
of tolerance of normal tissues to the damage by these
agents. Toxicities associated with chemotherapy and
radiotherapy can limit the dose and duration of the
treatment, adversely affect both short- and long-term
quality of life of the patient, be life-threatening, and
increase the costs of patient care. Normal tissue
Radioprotectors and Chemoprotectors in the Management of Lung Cancer 225

Table 1 Radioprotective thiols and phosphorothioates

Compound CAS register number Structure
Thiols
Dithiothreitol (DTT) [27565-41-9] HSCH2CH(OH)CH(OH)CH2SH
2-Mercaptoethanol (WR-15504) [60-24-2] HOCH2CH2SH
Cysteamine (MEA, WR-347) [156-57-0] H2NCH2CH2SH
2-((Aminopropyl)amino)ethanethiol (WR-1065) [31098-42-7] H2N(CH2)3NHCH2CH2SH
WR-255591 [117062-90-5] CH3NH(CH2)3NHCH2CH2SH
WR-151326 [120119-18-8] CH3NH(CH2)3NH(CH2)3SH
Phosphorothioates
WR-638 [3724-89-8] H2NCH2CH2SPO3H2
WR-2721 [20537-88-6] H2N(CH2)3NHCH2CH2SPO3H2
WR-3689 [20751-90-0] CH3NH(CH2)3NHCH2CH2SPO3H2
WR-151327 [82147-31-7] CH3NH(CH2)3NH(CH2)3SPO3H2
WR Walter Reed Army Institute of Research
Reprinted from Murray and McBride (1996) with permission

toxicities are more common and more serious after
chemoradiotherapy than after radiotherapy alone, and
these toxicities can be particularly severe with con-
current (as opposed to sequential) chemoradiotherapy.
Because of the risk of severe toxicity, the dose of
chemotherapeutic agents in the setting of concurrent
chemoradiotherapy must be significantly reduced,
which may reduce the ability of the drugs to control
both local-regional tumor and disseminated disease.
Because normal tissue toxicity is a major barrier to
radiotherapy and chemoradiotherapy for lung cancer,
every effort must be taken to avert or minimize
potential injury to critical normal tissues or other side
effects of these treatments. Improvements are being
sought primarily through more precise delivery of
radiation therapy or the use of chemical or bio-
logical radioprotective or chemoprotective agents.
Technical improvements in radiotherapy include
three-dimensional treatment planning, conformational
radiotherapy techniques such as intensity-modulated
radiotherapy, or the use of proton beam therapy.
These normal tissue-sparing strategies may allow
higher doses of radiation, chemotherapeutic drugs, or
both to be given, with the hope of achieving superior
treatment outcome.
This chapter is intended as an overview of selected
relevant preclinical and clinical findings on the use of
radio- and chemo-protective agents to prevent or
reduce injury to normal tissues that limit the use
of cytotoxic doses of radiotherapy for lung cancer.
The first part of the discussion focuses on the radio-
protective effects of amifostine. Additional informa-
tion can be found in other reviews on this topic
(Kouvaris et al. 2007; Weiss and Landauer 2009).
Other radioprotective agents and potential strategies
discussed include prostanoids, growth factors and
cytokines, pentoxifylline, angiotensin-converting
enzyme inhibitors, and gene therapy focused on
superoxide dismutase.
2 Thiols as Radioprotective Agents
Both preclinical and clinical investigations on chem-
ical protectors in radiotherapy have predominantly
focused on thiols. The most effective compounds have
those with a sulfhydryl, SH, group at one terminus
and a strong basic function, an amino group, at the
other terminus. Some important radioprotective
thiols are listed in Table 1. The general structure of
these aminothiols is H2N(CH2) x NH(CH2)y SH;
among these, phosphorothiaotes (such as WR 2721,
WR-3689, WR-151327) are the most effective and
least toxic (Murray and McBride 1996). Various
mechanisms have been proposed for the thiol-medi-
ated radiation protection of normal tissues. Thiols
(RSH) and their anions (RS-) rapidly bind to free
radicals such as OH and prevent them from reacting
with cellular DNA. This type of protection from DNA
damage by scavenging free radicals is oxygen-
226
dependent (Travis 1984). Another mode of protec-
tion occurs via H-atom donation (the fixation–repair
model). Thiols compete with oxygen for radiation-
induced DNA radicals. DNA radicals are ‘‘fixed’’
(not repaired) by reacting with oxygen and poten-
tially harmful hydroxyperoxides may be generated.
However, DNA radicals can be chemically repaired
when they react with thiols by donation of hydro-
gen (Durand 1983). Further, intracellular oxygen
can be depleted as a result of thiol oxidation
(Durand and Olive 1989), which would decrease the
rate of oxygen-mediated DNA damage fixation.
Finally, thiols induce DNA packaging that may
decrease the accessibility of DNA sites to radiolytic
attack. This mechanism may be oxygen-independent
and may explain the protection from densely ion-
izing radiation such as neutrons (Savoye et al.
1997).
2.1 Amifostine: Preclinical Findings
Amifostine (Ethyol) is a thiol-containing compound
that has long been recognized for its strong radio-
protective properties and has been used in clinical
trials (Brizel 2003, 2007; Movsas et al. 2005).
Amifostine does not readily cross the cell membrane
because of its hydrophilicity. The drug is rapidly
dephosphorylated to its active metabolite WR-1065
and cleared from plasma with a half-life of 1 to 3 min
after intravenous administration (Shaw et al. 1999).
In contrast to its brief systemic half-life, the drug is
retained for prolonged periods in normal tissues
(Yuhas 1980). During the first 30 min after adminis-
tration, drug uptake into normal tissues such as the
salivary gland, liver, kidney, heart, and bone marrow
has been demonstrated to be up to 100-fold greater
than in tumor tissues (Yuhas 1980). Biodistribution
studies show that the highest tissue levels of amifos-
tine and its metabolites are found in salivary glands
(Rasey et al. 1986).
During the 1970s and 1980s extensive animal
studies explored the ability of amifostine to protect a
variety of normal tissues against acute and late
radiation injury and whether the drug improves
therapeutic ratio of radiotherapy. A radioprotective
effect was observed for acute injury of the bone
marrow, esophagus, jejunum, colon, hair follicles,
testis, and immune system (Murray and McBride
R. Komaki et al.
1996; Milas et al. 1988). Amifostine was also a
potent radioprotector of late-responding tissues such
as lung and subcutaneous tissues (Milas et al. 1988;
Travis et al. 1985; Vujaskovic et al. 2002a, 2002b;
Lockhart 1990; Hunter and Milas 1983). Protection
of the lung was achieved against both single and
fractionated radiation, and was assessed by bio-
chemical testing such as reduction in hydroxyproline
content of lung tissue and functional assays such as
breathing frequency (Travis et al. 1985; Vujaskovic
et al. 2002a). Amifostine treatment was associated
with reduction in accumulation of macrophages in
irradiated lung and profibrogenic cytokine activity
(Vujaskovic et al. 2002b). Interestingly, systemic
application of amifostine was radioprotective for the
lung tissue (Travis et al. 1985; Vujaskovic et al.
2002a, b), but inhaled amifostine was ineffective
(Lockhart 1990). In contrast to the near- universal
protection of acutely responding tissues and lung,
amifostine was not effective in protecting the brain
from radiation injury, which was attributed to the
inability of the hydrophylic drug to cross the blood-
brain barrier (Utley et al. 1984). Wide variation in
the degree of radioprotection was noted among
various tissues, with protection factors for murine
normal tissues ranging from 1.2 for hair follicles to
greater than two for jejunum and bone marrow
(Murray and McBride 1996; Milas et al. 1988). The
degree of radioprotection depended on the drug dose
and time of administration in relation to radiation
exposure. In general, higher doses of amifostine
produced better protection up to a maximum dose of
about 400 mg/kg (Murray and McBride 1996; Milas
et al. 1982, 1988). Maximum radioprotection was
achieved when amifostine was given 10 to 30 min
before radiotherapy (Murray and McBride 1996;
Milas et al. 1988, 1982). In addition to normal tissue
radioprotection, several studies have examined
whether amifostine protects tumors as well.
Although some studies documented a small degree
of tumor radioprotection, primarily of microscopic
tumor foci, most studies showed no tumor protection
(Murray and McBride 1996; Milas et al. 1982, 1988;
Wasserman et al. 1981). Therefore, preclinical
studies support the notion of selective or preferential
normal tissue protection resulting in increased ther-
apeutic gain of radiotherapy.
The mechanism of amifostine’s selective or pref-
erential protection of normal tissues is related to
Radioprotectors and Chemoprotectors in the Management of Lung Cancer
several factors. Amifostine undergoes preferential
rapid uptake into normal tissues but negligible or
slower uptake into tumor tissues. Whereas normal
tissues actively concentrate amifostine against the
concentration gradient, solid tumors generally absorb
amifostine passively (Yuhas 1980). This selectivity
results, in part, from differences in pH and alkaline
phosphatase at the level of the capillary endothelium,
both being higher in normal tissues than in tumors
(Yuhas 1980; Rasey et al. 1985, 1986). The acidic
tumor microenvironment inhibits the alkaline phos-
phatase necessary for uptake and conversion of ami-
fostine to the active protective thiol WR-1065
(Calabro-Jones et al. 1985), a condition absent in
normal tissues. Once inside the cell, WR-1065 acts as
a scavenger of oxygen free radicals (Marzatico et al.
2000), which is reduced under hypoxic conditions
commonly present in solid tumors. In addition, ami-
fostine may be less available to tumors because of
their defective vascular network.
Overall, a large body of preclinical data shows that
amifostine preferentially protects most normal tissues,
including the lung, from the effects of DNA-damag-
ing agents such as radiation. In addition to inter-
acting with radiation, amifostine has been shown to
exert independent antimetastatic and antiangiogenic
activity (Grdina et al. 2002; Giannopoulou and
Papadimitriou 2003). Thus, these preclinical data
provide a strong rationale for the clinical development
of combined modality cancer treatment with amifos-
tine and radiotherapy.
2.2 Amifostine: Clinical Studies
Clinical trials with amifostine began in the 1980s and
showed that the drug is generally well tolerated. Its
administration is associated with several transient side
effects including nausea, vomiting, sneezing, mild
somnolence, hypotension, a metallic taste during
infusion, and occasional allergic reactions (Kligerman
et al. 1988; Schuchter and Glick 1993). Hypotension
seemed to be the most clinically significant side effect
that could curtail treatment. Several subsequent trials
showed that amifostine reduces the severity of
toxicity of radiotherapy or chemotherapy (Kligerman
et al. 1988; Brizel et al. 2000; Kemp et al. 1996).
Brizel et al. (2000) reported a randomized trial
showing that amifostine reduces both severity and
227
duration of xerostomia in head and neck cancer
patients treated with radiotherapy. The findings from
that study led the US Food and Drug Administration
to approve the use of amifostine for this clinical
indication.
Several clinical trials have been performed using
amifostine in combination with chemoradiotherapy
for lung cancer (Koukourakis et al. 2000; Antonadou
et al. 2001, 2003, Senzer 2002; Leong et al. 2003;
Komaki et al. 2004a; Movsas et al. 2005). Results are
summarized in Table 2. Antonadou et al. (2001,
2003) conducted a randomized phase III trial of
concurrent chemotherapy (either paclitaxel or carbo-
platin) and radiation treatment plus/minus daily ami-
fostine given iv at 300 mg/m2 15 to 20 min before
each fraction of radiotherapy and before chemother-
apy in patients with locally advanced lung cancer.
The results showed that amifostine significantly
reduced the incidence of severe (grade C3) radiation-
induced pneumonitis (from 56.3 to 19.4%, P \ 0.002)
and (grade C3) esophagitis (from 84.4 to 38.9%,
P \ 0.001) without compromising antitumor efficacy
(Antonadou et al. 2003).
Komaki et al. (2004a) reported findings from a
prospective randomized comparative study of whe-
ther amifostine could reduce the incidence and
severity of acute toxicity associated with concurrent
cisplatin-based chemotherapy with radiation therapy
for NSCLC. In that study, 62 evaluable patients (of 64
total) received 69.6 Gy of thoracic radiation at
1.2 Gy/fraction, 2 fractions/day for 5 days/week;
chemotherapy consisted of oral etoposide, 50 mg
twice a day for a total of 20 days plus four doses of
cisplatin 50 mg/m2 iv. The experimental group
received amifostine, 500 mg iv, twice weekly before
chemoradiation, and the control group received
chemoradiation without amifostine. At a minimum
follow-up time of 24 months (median 31 months for
living patients), amifostine increased the incidence of
mild esophageal toxicity (from 23 to 48%), but con-
versely it reduced the incidence of severe esophageal
toxicity (from 35 to 16%) (P = 0.021) (Fig. 1).
Amifostine significantly reduced the incidence of
constipation, pneumonitis, and neutropenic fever
(Fig. 2). Notably, severe (grade 3) pneumonitis
occurred in 16% of patients treated with chemora-
diotherapy alone but in no patients that received
amifostine in addition to chemoradiotherapy. Con-
sistent with findings from other studies, hypotension
228 R. Komaki et al.

Table 2 Randomized trials of amifostine for lung cancer

Reference No. of Radiation dose Chemotherapy Amifostine dose Comments
patients
Movsas 242 69.6 Gy at Induction P ? C 9 2; 500 mg iv 4 9 per No difference in
et al. 1.2 Gy twice concurrent weekly C week between twice- esophagitis but improved
(2005) daily, days daily RT fractions self-reported swallowing
43–78 and weight loss
Median survival, 15.6
months with versus 17.9
months without amifostine
Antonadou 146 55–60 Gy at None 340 mg/m2 daily ; pneumonitis
et al. 2.0 Gy once before RT ; esophagitis
(2001) daily
(no survival data)
2
Antonadou 73 55–60 Gy at Concurrent weekly P or C 300 mg/m daily ; esophagitis (P \ 0.001)
et al. 2.0 Gy once before chemoRT and ; pneumonitis (P = 0.009)
(2003) daily RT
(no survival data)
Senzer 63 64.8 Gy at Concurrent P ? C q week 500 mg iv before No difference in toxicity,
(2002) 1.8 Gy once 9 7; gemcitabine and weekly chemo; no survival data (ongoing
daily, beginning cisplatin 9 3 after 200 mg iv daily trial)
on day 1 chemoradiation before RT
Komaki 62 69.6 Gy at Concurrent iv cisplatin 500 mg iv day 1 and ; degree of esophagitis
et al. 1.2 Gy twice day 1, 8, 29, 36 2 each week before ; pneumonitis
(2004a) daily, beginning chemo and first RT
on day 1 fraction ; neutropenic fever
Etoposide po days 1–5 Median survival, 19
8–12, 29–33, 36–40 months with versus 20
months without
amifostine)
Leong et al. 60 60–66 Gy at Induction P ? C 9 2; 740 mg/m2 with each Esophagitis grade 2–3
(2003) 2.0 Gy once concurrent weekly P chemo (day 1, 22, 43, 43% in amifostine group,
daily, beginning 50, 57, 64, 71, 78) 70% in control group (not
on day 43 significant)
Median survival, 12.5
months with versus 14.5
months without amifostine
P paclitaxel, C carboplatin; RT radiation therapy
Adapted from Komaki et al. (2004a), with permission

was the most common adverse effect, occurring in
65% of patients. Importantly, amifostine did not affect
tumor response to chemoradiotherapy, as demon-
strated by rates of local-regional control, distant
metastases-free survival, and overall survival (Fig. 3).
Other investigations from MD Anderson showed that
amifostine can partially reverse the reduction of lung
diffusion capacity caused by chemotherapy or radio-
therapy (Gopal et al. 2003), further documenting
amifostine-induced radioprotection of normal tissues
during thoracic radiotherapy.
In another important clinical trial, the phase III
Radiation Therapy Oncology Group (RTOG) 98-01
(Movsas et al. 2005), 243 patients with stages
II–IIIA/B NSCLC were treated with paclitaxel
and carboplatin as induction chemotherapy followed
by concurrent chemotherapy and hyperfractionated
radiotherapy (69.6 with 1.2 Gy/fraction, twice a day).
Patients received either no-amifostine or amifostine
500 mg iv four times/week. The amifostine group
experienced higher rates of acute nausea, vomiting,
cardiovascular toxicity, and infection or febrile neu-
tropenia, but interestingly patient self-assessments
indicated that amifostine was associated with clini-
cally meaningful improvements in swallowing and
pain. Amifostine did not reduce the rates of severe
Radioprotectors and Chemoprotectors in the Management of Lung Cancer 229

50 to having protective effects on normal tissues, would

Percent Experiencing Toxicity

also have protective effects on tumors, thereby affect-

40
ing the efficacy of therapy. To date, three meta-analyses
have been conducted to address this question. In the
30
Control first of these analyses (Sasse et al. 2006), the investi-
Amifostine gators reviewed 14 randomized trials (1451 patients)
20
that compared radiation with or without amifostine for
10
treatment of a variety of types of cancer. They found
that the use of amifostine significantly reduced the risk
0
of developing mucositis, esophagitis, acute xerosto-
Mild Moderate Severe mia, late xerostomia, dysphagia, acute pneumonitis,
Degree of Esophageal Toxicity and cystitis. Although no difference in the overall
response rate was noted between the amifostine and
Fig. 1 Effect of amifostine on the severity of esophageal
toxicity induced by chemoradiotherapy in patients with non- no-amifostine groups, the complete response rate was
small cell lung cancer (modified from Komaki et al. 2004a, thought to be superior for patients using amifostine.
with permission) The next meta-analysis focused specifically on
patients with locally advanced NSCLC who had been
Percent Experiencing Toxicity

100
80
60
40
20
0 response in locally advanced NSCLC.
Constipation Pneumonitis
Fig. 2 Effect of amifostine on the incidence of constipation,
pneumonitis, and neutropenic fever caused by chemoradiother-
apy in patients with non-small cell lung cancer (modified from
Komaki et al. 2004a, with permission.)
esophagitis, but it also did not affect median survival
time. These investigators concluded that other, less
toxic routes of administration of amifostine should be
explored, as well as other means of minimizing
esophagitis such as reducing esophageal exposure
with more conformal radiation techniques and
exploring various biological therapies.
2.3 Amifostine: Meta-Analyses of Clinical
Studies
Although the findings from clinical studies of amifos-
tine are intriguing, the median follow-up times have
been relatively short and none of the randomized con-
trolled trials conducted to date has been powered to
address the question of whether amifostine, in addition
treated with radiation or chemoradiation with or
without amifostine or a placebo (Mell et al. 2007).
This analysis of six studies (552 patients) revealed
Control
that amifostine was associated with slightly improved
Amifostine response rates, with pooled relative risk estimates
ranging from 0.99 to 1.21, leading the investigators to
conclude that amifostine has no effect on tumor
Neutropenic fever
A third meta-analysis (Bourhis et al. 2011) was
undertaken with the rationale that neither of the first
two analyses had access to survival data. This meta-
analysis, which involved updating individual patient
data from the surveyed trials, was intended to
evaluate the effect of amifostine on overall and
progression-free survival. Ultimately 12 trials (1,119
patients) were analyzed; 431 patients (3 trials) were
treated with radiation only and 688 (9 trials)
received chemoradiation. About one-third of the
patients had lung cancer; most of the others had
head and neck cancer. The vast majority of patients
(91%) had locally advanced disease. The median
follow-up time was 5.2 years. The results showed
that amifostine did not reduce overall or progression-
free survival in patients treated with radiation or
chemoradiation therapy—in other words, that ami-
fostine had no tumor-protective effect. They did note
that any benefit in terms of reduced radiation-
induced toxicity from amifostine must be weighed
against the costs and side effects of this agent, par-
ticularly given the ongoing improvements in tech-
nologies that allow better sparing of normal tissues
(Brizel 2007).
230 R. Komaki et al.

Fig. 3 Kaplan–Meier A. 100

survival curves showing the
75 P=0.99
effect of amifostine on

% Survival
a overall survival rate, 50 Amifostine
b local-regional (LR) tumor
25
control, and c distant- Control
metastasis (DM)-free survival 0
among patients with non- 0 1 2 3
small cell lung cancer after
B. 100
chemoradiotherapy (modified

% LR Control
from Komaki et al. 2004a, 75
P=0.39
with permission) Control
50
25
Amifostine
0
0 1 2 3
C.
% DM-Free Survival

100
P=0.77
75
Control
50
25 Amifostine
0
0 1 2 3

2.4 Amifostine: Route of Administration
Although most of the larger clinical trials of amifos-
tine conducted to date have involved intravenous
administration, its associated adverse effects (e.g.,
Movsas et al. 2005) as well as logistic issues have led
to exploration of alternative routes of administration
(Praetorius and Mandal 2008; Bensadoun et al. 2006).
Of the three routes tested in clinical settings to date
(oral, subcutaneous, and intrarectal), most studies
have focused on subcutaneous delivery. A phase I
study to compare the relative bioavailability of ami-
fostine administered subcutaneously (at a fixed dose
of 500 mg) and intravenously (200 mg/m2) (Bonner
and Shaw 2002) suggested that the bioavailability of
the product is greater when injected subcutaneously
rather than intravenously. In a randomized phase II
study of 140 patients to assess the feasibility, toler-
ance, and cytoprotective efficacy of subcutaneous
amifostine after radiation therapy (Koukourakis et al.
2000), 70 patients received 500 mg of amifostine as a
single subcutaneous injection 20 min before each
radiotherapy fraction. The regimen was well toler-
ated, effectively reduced the early toxicity of radio-
therapy, and prevented treatment-induced delays.
Patients reported a reduction in hypotension and
nausea as compared with intravenous administration.
Another study by the same group showed that sub-
cutaneous amifostine given before chemotherapy
was better tolerated than the intravenous form
(Koukourakis et al. 2003). A French randomized study
conducted by the GORTEC group (Bardet et al. 2002)
compared amifostine given in intravenous doses of
200 mg/m2 and subcutaneous doses of 500 mg in 305
patients with head and neck carcinoma. The results of
this study, completed in December 2004, suggest that
subcutaneous injection is feasible, only mildly toxic,
reduces treatment-related side effects relative to other
published series, and does not diminish antitumor
efficacy. A phase II study of the efficacy of subcuta-
neous administration of amifostine in patients with
surgically resected NSCLC undergoing postoperative
radiotherapy is ongoing at MD Anderson. Other
studies are being conducted at Kaiser Permanente in
California (Wang et al. 2004) and at Dana Farber in
Boston (Haddad et al. 2003) to evaluate the safety and
efficacy of subcutaneous amifostine during chemora-
diation for head and neck cancer. Finally, a recent
report of a study of patients with small cell lung cancer
from Korea (Han et al. 2008) suggested that subcuta-
neous amifostine (500 mg, 3 times a week during
concurrent chemoradiation therapy) was tolerated
with manageable adverse effects but did not reduce
severe treatment-related toxicities.
Radioprotectors and Chemoprotectors in the Management of Lung Cancer
2.5 Amifostine: Quality of Life Studies
The 2008 American Society of Clinical Oncology
practice guidelines (Hensley et al. 2009) recommend
that amifostine not be used to prevent esophagitis
during concurrent chemoradiotherapy for NSCLC
given the lack of consistent benefit found to date.
However, at least one group maintains that amifostine
may produce clinically meaningful improvement in
patient-reported symptoms (Movsas et al. 2005, 2009;
Dest 2006; Sarna et al. 2008). In one such analysis,
quality of life among 138 participants in RTOG 98-01
was evaluated before and again 6 weeks after treat-
ment for stages II–III NSCLC. Patients who had
received amifostine reported greater pain reduction
after treatment, less difficulty swallowing during
treatment, and less weight loss than patients who had
not received amifostine. Interestingly, physician-rated
assessments of dysphagia were no different between
the two groups. The authors of this report concluded
that patient evaluations of difficulty in swallowing
and pain suggest benefits from amifostine that differ
from clinician-rated assessments.
3 Prostanoids, COX-2 and COX-2
Inhibitors
In response to physiological signals, stress, or injury
including radiation injury, cells produce prostanoids
(prostaglandins and thromboxanes), a family of
diverse, highly biologically active lipids derived from
the enzymatic metabolism of arachidonic acid by
cyclo-oxygenase (COX)-1 or COX-2. COX-1 is
ubiquitous and responsible for prostanoid production
in normal tissues, where prostanoids exert numerous
homeostatic physiological functions. In contrast,
COX-2 is an inducible enzyme involved in prosta-
glandin production in pathologic states, particularly in
inflammatory processes and cancer. COX-2 is
induced by various factors including inflammatory
cytokines (such as tumor necrosis factor [TNF]-a,
interleukin [IL]-1b, and platelet activity factors),
oncogenes, growth factors, and hypoxia. Prostanoids
participate in the pathogenesis of various pathologic
states including inflammation; prostaglandin E2
(PGE2), a potent vasodilator and an immunosuppres-
sive substance, is the major prostaglandin involved.
PGE2 is produced in abundance by pro-inflammatory
231
mononuclear cells such as macrophages and mediates
the typical symptoms of inflammation through its
vasodilatory action. This augments the edema caused
by substances that increase vascular permeability
such as histamine. PGE2 is also involved in the
development of erythema and heat at the site of
inflammation. Because radiation-induced-lung injury
is characterized by inflammatory tissue reactions,
PGE2 and other prostaglandins as well as pro-
inflammatory cytokines are produced in injured tissue
in abundance. Because different prostanoids have
complementary or antagonistic activities, the final
biological effect on tissues depends on the balance of
similar and opposing actions of the prostanoids
involved.
Production of PGE2 and other pro-inflammatory
prostanoids can be suppressed by non-steroidal anti-
inflammatory drugs (NSAIDs), which inhibit both
isoforms of COX enzyme, or by selective COX-2
inhibitors. Because selective COX-2 inhibitors do not
inhibit prostanoid production in normal tissues, they
are less toxic than commonly used NSAIDs. Inter-
estingly, both prostanoids and their inhibitors have
been reported to exert radioprotective actions on
normal tissues. Exogenous administration of PGE2,
other prostaglandins, or prostaglandin analogs before
irradiation of mice was shown to protect a variety of
tissues including hematopoietic tissue, jejunal
mucosa, dermis, and testis (reviewed in Hanson 1998;
Milas and Hanson 1995). Prostaglandins vary widely
in their radioprotective ability; however, the prosta-
glandin analog misoprostol is amongst the most
effective. Paradoxically, using NSAIDs to inhibit
prostaglandins has also been shown to protect many
tissues, including the lung, against radiation injury
(Milas and Hanson 1995; Michalowski 1994; Lee and
Stupans 2002). For example, Milas et al. (1992)
reported that the NSAID indomethacin can protect
mouse lung from radiation damage, but the protection
was limited to the early pneumonitis phase of injury.
Preliminary investigations of the selective COX-2
inhibitor SC-236 did not demonstrate significant
protection from radiation-induced pneumonitis when
the drug was administered a few days before and after
lung irradiation. Subsequent experiments using a
different COX-2 inhibitor, celecoxib, provided sug-
gestive evidence that giving the inhibitor during the
development phase of acute pneumonitis may reduce
either the latency or severity of lung injury. It should
232
be emphasized that even in the absence of lung
radioprotection by COX-2 inhibitors, their adminis-
tration can provide therapeutic benefit because of
their potent enhancement of tumor radioresponse. The
ability of COX-2 inhibitors to selectively enhance
tumor radioresponse has been reviewed in detail
elsewhere (Milas 2001, 2003b; Choy and Milas
2003).
3.1 Clinical Trials of COX-2 Inhibitors
for Lung Cancer
Clinical and experimental findings have demonstrated
conclusively that COX-2 overexpression correlates
with reduced survival among patients with NSCLC
(Khuri et al. 2001), that radiation treatment is asso-
ciated with an increase in COX-2 expression in
tumors (Steinauer et al. 2000), and that inhibiting
COX-2 activity in tumors is associated with an
improved response to radiation (Choy and Milas
2003). Experimental evidence further indicates that
selective COX-2 inhibitors can enhance tumor
response to radiation without substantially enhancing
the radiosensitivity of normal tissues (Kishi et al.
2000). These findings have prompted several clinical
trials combining selective COX-2 inhibitors with
radiation for cancer treatment. These trials, results of
which were mostly unpublished when this chapter
was updated (Choy and Milas 2003; Baumann et al.
2004; Komaki et al. 2004b), are discussed briefly
below.
The RTOG is conducting two trials using the
selective COX-2 inhibitor celecoxib with radiation,
one a phase II study of postoperative celecoxib
(400 mg twice daily) with radiation (50.4 Gy) for
patients with completely resected stages I/II NSCLC
and the other a phase I/II trial of the same treatment
for patients with stage IIB/III NSCLC treated with
fractionated radiation (66 Gy) and twice-daily cele-
coxib for up to 2 years. Objectives in both studies
include assessing the tolerability of celecoxib at this
dose, evaluating the role of biomarkers as predictors
of celecoxib activity, and seeing if celecoxib
improves the response and survival rates.
Another phase II trial conducted at Vanderbilt
Cancer Center involved the addition of celecoxib to
standard chemoradiation with paclitaxel and carbo-
platin for previously untreated stage III NSCLC
R. Komaki et al.
(Mutter et al. 2009). This study was stopped early
because it did not meet the predetermined goal of an
80% response rate; findings from the evaluable
patients suggested that adding celecoxib to concurrent
chemoradiation did not improve survival. However,
the findings did indicate that urinary levels of PGE-M,
the major urinary metabolite of PGE2, may be useful
as a marker for predicting response to celecoxib.
Another phase II study at the same institution com-
bining celecoxib with docetaxel chemotherapy for
recurrent NSCLC (Csiki et al. 2005) produced an
overall response rate of 11% and a median survival
time of 6 months, similar to those observed after
docetaxel alone. The authors concluded that com-
bining celecoxib with docetaxel at the doses and
schedules used did not improve survival in unselected
patients with recurrent previously treated NSCLC.
This disappointing finding was unexpected given
ample preclinical evidence that celecoxib was highly
effective at enhancing tumor response to docetaxel
(Nakata et al. 2004). A related clinical study, also
underway at Vanderbilt, assessed celecoxib with
radiation and taxane therapy for recurrent NSCLC;
this combination produced two partial responses and
three disease stabilizations among 13 evaluable
patients, none of whom had responded to previous
therapy. A fourth study at Vanderbilt is evaluating the
benefit of radiation (62.5 Gy) combined with daily
celecoxib for inoperable stages I/II NSCLC. A phase I
study at MD Anderson Cancer Center (Liao et al.
2005) evaluated the tolerability of celecoxib at doses
ranging from 200 to 800 mg/day given in combina-
tion with radiation for poor-prognosis NSCLC.
Among 47 enrolled patients, the main toxicities were
found to be grade 1 or 2 nausea and esophagitis, and
these were independent of the celecoxib dose or
radiation schedule. Two patients, one given celecoxib
200 mg/day and the other at 400 mg/day, developed
severe (grade 3) pneumonitis. Of 37 patients evalu-
able for tumor response, 14 had complete response,
13 had partial responses, and 10 had stable or pro-
gressive disease. Actuarial local progression-free
survival rates of 66% at 1 year and 42% at 2 years
were considered promising and worthy of further
assessment in a phase II/III trial.
Corticosteroids are highly potent anti-inflamma-
tory drugs used for symptomatic treatment of radia-
tion-induced pneumonitis. They inhibit production of
all prostanoids because, in addition to their ability to
Radioprotectors and Chemoprotectors in the Management of Lung Cancer
inhibit COX enzymes, they prevent release of
arachidonic acid from membrane phospholipids by
stimulating the generation and secretion of lipocor-
tins. (Ward et al. 1992a) showed that giving steroids
to rats at the time of radiation delivery protected rats
from lung interstitial edema, delayed or suppressed
radiation-induced alveolitis, but did not affect devel-
opment of pulmonary fibrosis.
4 Growth Factors and Cytokines
Growth factors and cytokines have critical roles in the
pathogenesis of radiation injury, including that to the
lung. Radiation alters the magnitude and dynamic
activity of factors already present in affected tissues.
Response to radiation occurs within minutes or hours
after irradiation and can persist for days and months,
influencing the pathogenesis of both early and late
radiation damage. Growth factors and cytokines
principally act on cell and tissue proliferation, as well
as cell loss. Hence, growth factors affect all the major
determinants of cell and tissue radioresponse: total
number of clonogenic cells, cell cycle redistribution,
cell repopulation, cellular repair mechanisms, and
tissue microenvironment such as tumor hypoxia and
acidity. Many growth factors may be affected upon
tissue irradiation, those that have cytotoxic actions
and those that have cytoprotective ability, so that the
extent of tissue damage depends on the interaction
of cytokines with similar or opposing activities.
Involvement of growth factors and cytokines in the
pathogenesis of lung radiation damage is discussed in
more detail elsewhere in this volume.
4.1 Basic Fibroblast Growth Factor
Because some growth factors and cytokines may have
protective effects, attempts have been made to protect
tissues that are at risk from lung cancer radiotherapy.
Basic fibroblast growth factor (b-FGF) was found
to protect endothelial cells from radiation both in
vitro (Haimovitz-Friedman et al. 1991) and in vivo
(Haimovitz-Friedman et al. 1991; Fuks et al. 1994).
To confer radiation resistance in vitro, b-FGF had to
be present at the time of radiation exposure or within
several hours afterward. This protective effect was
abolished by treatment with anti-b-FGF antibodies.
233
The radioprotective effect of b-FGF was attributed to
its ability to increase cellular repair. A subsequent
study by the same group (Fuks et al. 1994) showed
that mice could be protected from lethal doses of
whole lung irradiation if given intravenous b-FGF
immediately before or within 2 h after irradiation.
The effect was attributed to the protection of endo-
thelial cells against radiation-induced apoptosis. His-
tologic analysis of irradiated lung tissue, but not of
lungs exposed to both b-FGF and radiation, showed
apoptotic changes in the endothelial cell lining of the
pulmonary microvasculature within 6 to 8 h after
radiation exposure. Also, histologic features of radi-
ation-induced pneumonitis were absent in mice trea-
ted with b-FGF. These results were not confirmed in a
subsequent study by Tee and Travis (1995) that
assessed the radioprotective action of b-FGF in two
strains of mice having different susceptibilities to
radiation-induced lung injury. The reasons for the
discrepancy are unclear, but some differences in
experimental conditions such as radiation dose, field
size of radiation, and mouse strain could have
accounted for this disparity.
4.2 Keratinocyte Growth Factor
Keratinocyte growth factor (KGF) is another cell
growth factor that has been investigated for its ability
to protect against radiation-induced lung damage.
Although a member of the FGF family (FGF-7),
KGF’s cell growth stimulatory activity is confined to
epithelial cells (Rubin et al. 1989; Miki et al. 1992).
KGF was shown to be a good stimulator of the pro-
liferation of type II pneumocytes in vitro and in vivo
(Panos et al. 1993; Ulich et al. 1994), a type of cells
considered to play an important role in repair of
injured lung tissue. Yi et al. (1996) showed that
intratracheal administration of KGF to rats 3 or
2 days before the rats were exposed to 18 Gy
of bilateral thoracic irradiation reduced the severity of
radiation-induced pneumonitis and fibrosis observed
histologically. However, no significant improvement
was noted in rat survival. In contrast, KGF was highly
effective both in preventing development of bleomy-
cin-induced fibrosis and in improving the survival of
treated animals. Significant protection was also ren-
dered against the damage inflicted by the combination
of bleomycin plus radiation treatment. A more recent
234
study (Terry et al. 2004) showed that a single intra-
tracheal administration of recombinant human KGF
to normal mice increased the proliferation of alveolar
epithelial cells 3 to 7 days later. This treatment
afforded significant protection against lethality from
radiation-induced pneumonitis when the mice were
irradiated at day 7 after administration of the growth
factor.
4.3 Interleukin-11
Regarding the radioprotective abilities of cytokines, it
is worth mentioning that subcutaneous administration
of recombinant interleukin-11 (rIL-11) rendered
significant protection to mice from fatal thoracic
irradiation (Redlich et al. 1996). The observed
radioprotection was attributed to the rIL-11-induced
inhibition of radiation-induced expression of TNF
mRNA as well as TNF production by macrophages.
4.4 Epidermal Growth Factor Receptor
The epidermal growth factor receptor (EGFR) pathway
is associated with resistance to both cytotoxic chemo-
therapy and radiation therapy in cancer cell lines and is
a validated therapeutic target in NSCLC (Benhar et al.
2002; Sumitomo et al. 2004; Liang et al. 2003; Goel
et al. 2007; Shepherd et al. 2005). Cetuximab is an anti-
EGFR immunoglobulin G1 monoclonal antibody that
targets the extracellular domain of the EGFR, binding
to it with a higher affinity than with the natural ligand
(Marshall 2006). Preclinical data indicate that cetux-
imab can amplify the response to chemotherapy and has
radio sensitizing properties (Bruns et al. 2000; Baselga
et al. 1993, 2000; Ciardiello et al. 1999; Raben et al.
2005; Saleh et al. 1999; Bianco et al. 2000; Milas
et al. 2000). Combinations of cetuximab with various
types of chemotherapy for metastatic NSCLC have
shown that cetuximab is effective and tolerable with a
manageable toxicity profile (Robert et al. 2005; Rosell
et al. 2008; Lynch et al. 2010; Thienelt et al. 2005;
Pirker et al. 2009). These findings, in combination with
promising results from the concomitant use of cetux-
imab with radiation for head and neck cancer (Bonner
et al. 2006) led to the initiation of a randomized
trial of cetuximab with chemoradiation for locally
advanced stage III NSCLC (Blumenschein et al. 2011).
R. Komaki et al.
That study, which involved 93 patients (87 evaluable)
with unresectable NSCLC and good performance status
receiving 63 Gy in combination with weekly carbo-
platin and paclitaxel chemotherapy and 250 mg/m2 of
cetuximab, showed promising activity and median and
overall survival times (22 and 24 months), longer than
any that have been previously reported by the RTOG.
The efficacy of radiation may be further improved
by the concomitant administration of EGFR tyrosine
kinase inhibitors such as gefitinib and erlotinib with
radiation (Kim and Choy 2004). Combinations of
antiangiogenic agents such as bevacizumab with radi-
ation and chemotherapy have also produced encour-
aging results in glioma (Lai et al. 2011) and rectal
cancer (Willett et al. 2010). Combinations of agents
that target both angiogenesis and EGFR signaling
pathways, such as anti-VEGF antibodies (e.g., bev-
acizumab) plus EGFR tyrosine kinase inhibitors, are
being tested in clinical trials (Raben et al. 2004; Kerbel
2004). Currently, little evidence is available regarding
the synergy of molecular targeted drugs in combination
with radiation or chemoradiation for lung cancer, nor
can definitive conclusions be drawn as to whether
adding a third agent (even a molecular targeted drug)
improves the results compared with a standard two-
drug regimen together with radiation (Eberhardt et al.
2006). Local-regional control might be improved,
however, by further dose intensification of radiation in
this context (Bradley et al. 2005; Socinski et al. 2004).
5 Pentoxifylline
Pentoxifylline (Trental), a methylxanthine derivative,
is hemorrheologic agent that can reduce or ameliorate
late radiation sequelae. In humans, pentoxifylline is
used to treat persistent soft tissue ulcerations and
necrosis. It has a variety of physiological activities
including inhibition of platelet aggregation, regula-
tion of tissue-damaging cytokines such as TNFa, and
enhancement of blood flow in injured microvascula-
ture. The drug may increase radioresponse of solid
tumors by increasing tumor oxygenation (Lee et al.
2000), and as such was tested in a clinical phase III
trial in combination with radiotherapy for NSCLC
(Kwon et al. 2000). That study showed that pentox-
ifylline was modestly effective, increasing the median
time to relapse by 2 months and the median survival
time from 7 to 18 months. Although pentoxifylline
Radioprotectors and Chemoprotectors in the Management of Lung Cancer
can modestly improve tumor radioresponse, it has
been used most often to reduce radiation injury to
normal tissues. Preclinical studies in experimental
animals have generally shown pentoxifylline to be
radioprotective, but the degree of protection varies
considerably. As an illustration, Lefaix et al. (1999)
reported striking regression of subcutaneous fibrosis
induced by radiation to the skin surface of pigs using
a combination of pentoxifylline and alpha-tocopherol
(vitamin E). On the other hand, pentoxifylline seems
to have little or no effect on acute skin or lung injuries
(Dion et al. 1989; Koh et al. 1995; Rube et al. 2002;
Ward et al. 1992b). With respect to lung injury,
pentoxifylline inhibited the radiation-induced
increase in TNFa mRNA during the acute phase of
radiation injury, pneumonitis, but the impact of this
biochemical change on lung injury was unclear (Rube
et al. 2002). In another study (Ward et al. 1992b),
pentoxifylline was found to further increase the
radiation-induced production of prostanoids (PGI2
and TXA2) while decreasing endothelial dysfunction
accompanied by increases in lung wet weight, protein
and hydroxyproline content in the irradiated lung.
A randomized clinical trial, however, using prophy-
lactic pentoxifylline showed a significant reduction in
both early and late radiation-induced lung toxicities in
patients with breast or lung cancer (Ozturk et al.
2004). A subsequent study of pentoxifylline with
alpha-tocopherol given daily during and after radia-
tion therapy for lung cancer reduced the incidence of
radiation-induced lung toxicity in both the subacute
and acute phases (Misirlioglu et al. 2007). The
investigators suggested that this combination might
be especially useful for patients with lung cancer who
receive concurrent chemoradiation therapy or have
poor respiratory function. Other authors, however,
have urged caution in interpreting the results of
clinical trials of pentoxifylline, with or without vita-
min E, as many of those trials were nonrandomized or
had other design flaws (Nieder et al. 2005).
6 Angiotensin-Converting Enzyme
Inhibitors
Angiotensin-converting enzyme (ACE) converts
angiotensin I to angiotensin II, which is a potent
vasoconstrictor and hypertensive factor. Captopril is
an inhibitor of ACE that has been shown to protect
235
against radiation-induced injury of several tissues
including the lung. In addition to inhibition of ACE,
captopril is a free radical scavenger (Chopra et al.
1989) and exhibits superoxide dismutase (SOD)-like
activity (Roberts and Robinson 1995). Captopril
reduces radiation-induced pulmonary endothelial
dysfunction (Ward et al. 1988) and pulmonary fibrosis
(Ward et al. 1990a, 1992c) and may ameliorate or
delay radiation-induced pulmonary arterial hypoper-
fusion in rats (Graham et al. 1988; Ward et al. 1993).
Moreover, the use of ACE inhibitors as prophylaxis in
rats receiving whole lung radiation was found to
reduce the radiation-induced activation of ACE and
plasminogen activator and reduce the production of
prostaglandins and thromboxane (Ward et al. 1988).
Adding captopril to the feed after irradiation led to
reduced early lung reaction in rats receiving frac-
tionated hemithoracic irradiation (Ward et al. 1993).
In addition to pulmonary protection, ACE inhibition
also protects against radiation injury of other tissues
including kidney (Moulder et al. 1993), skin (Ward
et al. 1990b), jejunum (Yoon et al. 1994), and heart
(Yarom et al. 1993). With respect to the heart, Yarom
et al. (1993) showed that captopril ameliorated the
decrease in capillary function, increase in mast cells,
fibrosis, number of atrial granules, and changes in
nerve terminals, but it failed to prevent the progres-
sive functional deterioration of the heart after
irradiation. Mechanisms of captopril-mediated radio-
protection are not fully understood, but they are at
least partially related to its antihypertensive activity
and its thiol-like function. Another study of captopril,
enalopril (another ACE inhibitor), and an angiotensin
II receptor blocker in rats receiving total-body irra-
diation and cyclophosphamide as a model of bone
marrow transplantation has implicated the inflamma-
tory system as well (Molteni et al. 2007).
These promising preclinical observations on
radioprotection by ACE inhibitors have led to several
clinical studies being undertaken. Wang et al. (2000)
reported a retrospective clinical study of ACE inhib-
itors given for the management of hypertension in
patients with lung cancer treated with definitive
radiotherapy. The study showed that ACE inhibitors
given at a dose within the range used to treat hyper-
tension did not reduce the incidence or delay the onset
of symptomatic radiation pneumonitis. A phase II
randomized clinical trial of captopril with radiation
and chemotherapy for lung cancer, RTOG 0123, was
236
closed early because of problems with accrual; the
goal of that study was to see whether giving captopril
after radiotherapy could reduce the incidence or
severity of treatment-related pulmonary damage.
7 Flavopiridol
Flavopiridol (alvocidib) is a synthetic cyclin-dependent
kinase inhibitor that has been shown in preclinical
studies to have both cytostatic and radiosensitizing
effects in a variety of types of tumor cells, including
esophageal cancer (Sato et al. 2004; Raju et al. 2006),
glioma (Newcomb et al. 2006), prostate cancer (Camp-
hausen et al. 2004), and lung cancer (Kim et al. 2004).
Mason and colleagues at MD Anderson showed that
flavopiridol alone led to tumor growth delays in mice
implanted with MCa-29 breast cancer cells, OCa-1
ovarian cancer cells, or Ly-TH lymphoma cells, but
flavopiridol in combination with single-dose or frac-
tionated radiation led to significant radioenhancement,
producing high rates of local tumor control or cure and,
interestingly, antimetastatic activity as well (Mason
et al. 2004). These investigators concluded that thera-
peutic gain was achieved when flavopiridol was initiated
either before or after the start of irradiation and that this
compound showed promising clinical potential admin-
istered alone or in combination with other cytotoxic
agents. Raju et al. (2003, 2006), also at MD Anderson,
found that flavopiridol treatment significantly enhanced
the radiosensitivity of SEG-1 human esophageal ade-
nocarcinoma cells (2006) and ovarian cancer cells
(2003) in vitro and sharply enhanced the radioresponse
of SEG-1 tumor xenografts (2006). Their findings fur-
ther suggest that the mechanisms by which these effects
take place include cell cycle redistribution, apoptosis,
DNA repair, and transcriptional inhibition. Sato et al.
(2004) found that flavopiridol had a similar radiosensi-
tizing effect on three other esophageal squamous cell
carcinoma cell lines and also had dose-dependent effects
on cell cycle distribution and expression of cyclin D1,
Rb, and Bcl-2 protein. Hara et al. (2008) also found
evidence of Bcl-2 involvement in their study of cervical
cancer cells; McAleer et al. (2006), studying a zebrafish
embryo model, found that the radiosensitizing effect of
flavopiridol was attributable to inhibition of cyclin D1.
In addition to its radiosensitizing properties,
flavopiridol has shown promise with regard to
potentiating the antitumor effects of chemotherapeutic
R. Komaki et al.
agents. In a preclinical study (Kim et al. 2004),
treating mice bearing H460 lung carcinoma xeno-
grafts with docetaxel and flavopiridol significantly
enhanced the effects of radiation, with the effects
being greatest when docetaxel was given first, fol-
lowed by radiation, followed by the flavopiridol.
As for clinical trials, most that have been completed
to date have tested flavopiridol as single-agent
therapy or in combination with chemotherapeutic
agents rather than with radiation (McInnes 2008).
Its effectiveness as a single-agent has been largely
disappointing in phase II trials of multiple myeloma
(Dispenzieri et al. 2006), melanoma (Burdette-Radoux
et al. 2004), sarcoma (Morris et al. 2006), and endo-
metrial adenocarcinoma (Grendys et al. 2005). More
encouraging results have been obtained from using
flavopiridol in combination with other drugs for
hematologic malignancies, such as cytarabine and
mitoxantrone for acute myelogenous leukemia (Karp
et al. 2007), fludarabine and rituximab for mantle-cell
lymphoma, indolent B-cell non-Hodgkin’s lympho-
mas, and p53-mutated chronic lymphocytic leukemia
(Lin et al. 2010), and cytosine arabinoside and
mitoxantrone for leukemias (Karp et al. 2007, 2010,
2011). Combinations used to treat various solid tumors
have included flavopiridol with leucovorin, fluoroura-
cil, and oxaliplatin (FOLFOX) (Rathkopf et al. 2009);
with gemcitabine and irinotecan (Fekrazad et al. 2010);
with carboplatin or cisplatin (Bible et al. 2005); with
leucovorin, fluorouracil, and irinotecan (FOLFIRI)
(Dickson et al. 2010); with carboplatin and paclitaxel
(George et al. 2008); and with docetaxel (Carvajal et al.
2009; Fornier et al. 2007; El-Rayes et al. 2006). The
toxicity of flavopiridol is significant, consisting mostly
of diarrhea and myelosuppression. Clearly, much work
remains to be done to identify the most effective and
least toxic regimens combining flavopiridol, radiation,
and other drugs for clinical applications in lung cancer.
8 Poly(ADP-Ribose) Polymerase
Inhibitors
As noted previously in this chapter, the responsive-
ness of tumor-cells to chemotherapy and radiation is
determined by a combination of genetic factors, par-
ticularly those that modify cell cycle arrest, repair of
DNA damage, or cell death, and microenvironmental
factors such as hypoxia. Experimental evidence from
Radioprotectors and Chemoprotectors in the Management of Lung Cancer
preclinical studies suggests that inhibitors to poly
(ADP-ribose) polymerase (PARP), a nuclear enzyme
that recognizes and binds to DNA breaks to facilitate
DNA strand break repair, may potentiate the effects of
radiotherapy and chemotherapy. The radiosensitiza-
tion effect of PARP inhibitors has been demonstrated
in vitro in a broad variety of cancer cell cultures;
moreover, this effect is present under both hypoxic
and euoxic conditions (Liu et al. 2008). PARP
inhibitors have also shown radiosensitization
in vivo in mouse xenograft models of cervical cancer
(Kelland and Tonkin 1989), colon and rectal cancer
(Donawho et al. 2007; Calabresi et al. 2004), head
and neck squamous cell carcinoma (Khan et al. 2010),
glioblastoma (Russo et al. 2009), and lung cancer
(Albert et al. 2007). Although some clinical evidence
is emerging that supports the use of PARP inhibitors
with chemotherapy (Powell et al. 2010), such com-
binations have been associated with severe, dose-
limiting myelosuppression. No data have yet been
published from clinical trials of PARP inhibitors and
radiation therapy. Such trials should be designed with
special care given the substantial toxicity of these
agents in combination with chemotherapy.
9 Bcl-2 Inhibitors
Another potential molecular target for radiosensiti-
zation in lung cancer that has been the subject of
attention is Bcl-2, a key regulator of apoptosis
thought to be responsible in part for the development
of radioresistance in tumor-cells. Moretti et al. (2010)
at Vanderbilt recently reported a preclinical study of
the pan-Bcl-2 inhibitor AT-101 as a radiosensitizing
agent in two lung cancer cell lines: A549, which is
radioresistant, and HCC2429, which is radiorespon-
sive. AT-101 not only enhanced apoptosis in both cell
lines when used alone but also proved to be a potent
radiosensitizer for both radioresistant and radiore-
sponsive cell types. The authors concluded that Bcl-2
family members may serve as effective targets in lung
cancer and that clinical trials are warranted to assess
the potential of AT-101 to enhance the therapeutic
ratio of radiation therapy for lung cancer.
The same group also explored another strategy for
enhancing the radiosensitivity of H460 lung cancer
cells in which apoptosis and autophagy (degradation
of cellular components via lysosomes) were
237
upregulated simultaneously by combining another
Bcl-2 inhibitor, ABT-737, with rapamycin (Kim et al.
2009). The combination of the two agents markedly
enhanced the sensitivity of H460 cells to radiation in
clonogenic assays. Moreover, the combination of
ABT-737 and rapamycin and radiation led to drastic
tumor growth delays in a mouse xenograft model. The
combined treatment was confirmed to increase both
apoptosis and autophagy; it also suppressed tumor-
cell proliferation and vascular density to a greater
extent than radiation alone. These investigators con-
cluded that concurrent induction of apoptosis and
autophagy enhanced the effectiveness of radiation
therapy both in vitro and in lung cancer xenograft
models, and suggested that the clinical potential of
this strategy should be explored for patients with lung
cancer.
10 Efaproxaril
Efaproxaril (also known as RSR13) is a small syn-
thetic molecule that noncovalently binds to hemo-
globin, decreasing its oxygen-binding affinity and
shifting the oxygen dissociation curve to the left
(Viani et al. 2009). The effects of efaproxaril are
based on increased oxygen levels in tumors, and thus
it can circumvent restrictions imposed by the blood–
brain barrier (Shaw et al. 2003; Kavanagh et al. 2001;
Kunert et al. 1996; Suh 2004). Shaw et al. (2003)
conducted a phase II, open-label, multicenter study of
efaproxaril plus whole-brain irradiation for 57
patients with brain metastases and compared the
results with those from the RTOG’s recursive parti-
tioning analysis (RPA) database on brain metastases.
The mean survival time for patients treated with
efaproxaril was slightly but significantly longer than
that for the historical control group from the database
(6.4 vs. 4.1 months, P \ 0.0174). In a subsequent
phase III trial, Suh et al. (2006) also found a reduction
in risk of death and a modest improvement in survival
associated with the use of efaproxaril in patients with
brain metastases from breast or lung cancer, but the
magnitude of the effect seemed more pronounced for
the group with breast cancer. The addition of efa-
proxaril to whole-brain irradiation for patients with
brain metastases from breast cancer was also associ-
ated with improvements in quality of life and quality-
adjusted survival (Scott et al. 2007).
238
11 Radioprotective Gene Therapy/
Antioxidant Therapy: Superoxide
Dismutase
The manganese superoxide dismutase (MnSOD)
located within the mitochondria is one of nature’s
most efficient catalysts. The enzyme protects redox
machinery within the mitochondria from the super-
oxide radicals produced during normal respiration. In
many pathological conditions, such as inflammation
caused by radiation-induced free radical damage,
superoxide is abundantly produced and may over-
whelm the cell’s ability to efficiently remove it,
thereby leading to tissue injury. Via its antioxidant
activity, MnSOD inactivates superoxide and hence
has potential to protect against free radical induced
injury. Early studies showed that systemic adminis-
tration of SOD can prevent radiation injury (Petkau
1987) and can even reduce preexisting radiation-
induced fibrosis (Delanian et al. 1994). When given
before radiation, the activity of SOD has generally
been attributed to its radical scavenging effects,
whereas when given after radiation the effects are
most likely related to its anti-inflammatory and or
immunostimulatory properties (Murray and McBride
1996; Grdina et al. 2009). Another SOD, recombinant
CuZnSOD. was shown to protect the lung of hamsters
from radiation-induced damage as evidenced by the
absence of severe histopathologic tissue changes 4 to
16 weeks after irradiation and the prevention of ele-
vation of total protein content in brochoalveolar
lavage (Breuer et al. 2000).
More recently, a novel approach has been
advanced for radioprotective gene therapy in which
the antioxidant MnSOD is delivered to specific target
organs such as lung and esophagus by gene transfer
vectors such as plasmid/liposomes and adenovirus
(Greenberger et al. 2003; Greenberger and Epperly
2007; Borrelli et al. 2009). Radiation protection by
MnSOD transgene overexpression at the cellular level
is localized to the mitochondrial membrane. Intra-
esophageal administration of MnSOD-PL before
irradiation induces transgene expression for 48–72 h,
with an associated decrease in radiation-induced
expression of inflammatory cytokine mRNA and
protein and esophagitis (Epperly et al. 2001, 2003).
Intratracheal injection of adenovirus containing
MnSOD protected mice against radiation-induced
R. Komaki et al.
organizing alveolitis (Epperly et al. 1999). Intratra-
cheal MnSOD-PL gene therapy also reduced radiation-
induced inflammatory cytokines without rendering
protection to orthotopic Lewis lung cancer models
(Guo et al. 2003). Preclinical animal studies suggested
that radioprotective gene therapy reduces radiation-
induced toxicity and may facilitate dose-escalation
protocols to improve the therapeutic ratio of lung
cancer radiotherapy. However, the efficacy and speci-
ficity of this approach need further investigation.
Application of MnSOD-PL gene therapy in the
setting of fractionated chemoradiotherapy is being
tested in clinical trials for prevention of esophagitis in
patients with NSCLC. The gene therapy approach to
specifically deliver agents to targeted tissues is not
limited to MnSOD but has high potential for delivery
of a wide array of agents including both cytotoxic and
radioprotective agents.
12 Concluding Remarks
Normal tissue damage remains a major limiting factor
in radiotherapy and chemoradiotherapy for cancer, as
improvements in tumor control and survival come at
the cost of more common and more severe treatment-
related toxicity. For many years scientists have
explored various approaches to minimize damage to
tissues, including the use of chemical and biological
radioprotective agents. As elaborated in this chapter,
many of these agents have had significant radiopro-
tective and chemoprotective effects in experimental
animal models and some have been tested in clinical
trials. Amifostine has been the most extensively
investigated, in both preclinical and clinical settings.
Several clinical trials provided encouraging, although
somewhat inconsistent, results with respect to reduc-
tions in the incidence and severity of esophagitis and
pneumonitis. The agents discussed have complex
mechanisms of action and affect a variety of radia-
tion-induced tissue reactions both directly and indi-
rectly. Radiation elicits the release of many
substances, such as growth factors, cytokines, and
prostanoids, that can have both radioprotective and
radioenhancing properties. Because the final outcome
of treatment depends on the balance between these
competing processes, the use of radioprotective
agents may act on only some of the many factors
involved. This is likely one reason for the
Radioprotectors and Chemoprotectors in the Management of Lung Cancer
inconsistency in the literature on radioprotection.
Rapid achievements in recombinant technology and
genetic engineering are opening possibilities to
upregulate or downregulate cellular expression of
diverse factors involved in tissue responses to radia-
tion and to select appropriate factors to achieve a
predetermined response. For example, redirecting the
actions or optimizing the concentrations of a given
response factor may become useful in increasing the
therapeutic ratio of radiotherapy by enhancing tumor
radioresponse, or by reducing damage of normal tis-
sues with radioprotectors.
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 Systemic Therapy for Lung Cancer
for the Radiation Oncologist
Chandra P. Belani
Contents
1 Introduction.............................................................. 248
2 Non-Small Cell Lung Cancer................................. 248
3 Early Stage Resectable Non-Small Cell Lung
Cancer ....................................................................... 249
4 Systemic Chemotherapy for Early Stage Resected
Non-Small Cell Lung Cancer ................................. 249
5 Locally Advanced Unresectable Stage III
Disease ....................................................................... 251
6 Systemic Therapy for Advanced and Metastatic
Non-Small Cell Lung Cancer .................................
6.1 Histology-based treatment of advanced Non-Small
Cell Lung Cancer ......................................................
6.2 Maintenance therapy .................................................
6.3 Epidermal Growth Factor Receptor Tyrosine Kinase
Inhibitors ....................................................................
6.4 Mechanisms of Resistance to Epidermal Growth
Factor Receptor ........................................................
7 Anti-Angiogenic Therapies for Non-Small Cell
Lung Cancer............................................................. 257
8 Bevacizumab............................................................. 257
9 Other Vascular Endothelial Growth Factor
Receptor Inhibitors.................................................. 259
9.1 Other Targeted Approaches for Non-Small Cell
Lung Cancer .............................................................. 259
10 Small Cell Lung Cancer ......................................... 260
11 Future Perspectives ................................................. 260
References.......................................................................... 261
C. P. Belani (&)
Miriam Beckner Distinguished Professor of Medicine,
Penn State Hershey Cancer Institute,
500 University Drive, CH72, Hershey,
PA 17033, USA
e-mail: cbelani@psu.edu
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_307, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
Worldwide, approximately 1.6 million new cases
of lung cancer are diagnosed each year. It contin-
ues to be the leading cause of cancer death. With
the use of systemic therapy in addition to radiation
and surgical resection, the outcome of all lung
cancer patients continues to improve. There is an
absolute improvement not only in overall survival
(OS) but also in the quality of life of these patients,
though modest at best. Non-small cell lung cancer
(NSCLC) accounts for approximately 87% of all
lung cancers, and is subdivided into two major
251
types, nonsquamous carcinoma and squamous cell
252 carcinoma, the former including adenocarcinoma,
252 large cell carcinoma, bronchioloalveolar carci-
noma, and poorly differentiated histological sub-
254
types. Most patients present after NSCLC have
256 spread to regional or distant sites. Patients pre-
senting with advanced, unresectable disease (stage
IIIB or IV) and patients who develop recurrent or
metastatic disease following surgical resection are
candidates for systemic therapy. Even patients
with early stage resected disease have improved
OS with the use of adjuvant therapy. There is an
urgent need to develop novel and effective regi-
mens as the current therapies do not offer a
curative potential and is palliative with benefits
restricted to patients with a good performance
status (Eastern Cooperative Oncology Group 0
or 1). The cisplatin-pemetrexed regimen has
demonstrated preferential activity in patients with
non-squamous histology. Pemetrexed and erlotinib
have recently emerged as an option for mainte-
nance therapy in patients with advanced disease
247
248
following four cycles of combination chemother-
apy leading to a change in treatment paradigm.
Epigenetic alterations have been linked to the
pathogenesis and progression of cancer as they
lead to the inhibition of transcription of key cell
cycle regulatory genes. Vorinostat (SAHA), with
functional effects on histone acetylation attempts
to restore the normal transcription of cell regula-
tory genes. Provocative activity has been noted
with the combination of chemotherapy and
vorinostat in advanced NSCLC. Thus, HDAC
inhibitors are a new class of agents that will
require extensive evaluation in lung cancer.
Bevacizumab, a monoclonal antibody against the
vascular endothelial growth factor (VEGF), was
the first agent to demonstrate improved survival in
combination with chemotherapy (ECOG 4599) in
patients with advanced non-squamous NSCLC.
The increase in toxicity noted with the addition of
bevacizumab with chemotherapy calls for caution
in selecting patients for therapy. The VEGF
tyrosine kinase inhibitors (TKIs) appear promising,
though they have unique toxicities such as hand–
foot syndrome and fatigue in addition to hyper-
tension. It remains to be seen whether the combi-
nation of VEGF TKI and chemotherapy will
surpass the efficacy seen with bevacizumab-che-
motherapy regimens. Identification or predictive
biomarkers for patient selection remains elusive
for anti-angiogenic agents. Molecular markers for
treatment selection of patients with NSCLC are
increasingly being utilized to personalize therapy.
The presence of an activating mutation in the
epidermal growth factor receptor (EGFR) is asso-
ciated with high response rates and improved PFS
with EGFR TKIs. This has already led to the use of
an EGFR TKI as first-line therapy in patients with
a sensitive EGFR mutation. For patients with wild-
type EGFR (or if the EGFR status is unknown)
chemotherapy remains as the ‘standard of care’ for
first-line therapy of advanced NSCLC. The second
generation EGFR inhibitors are currently under
evaluation. The studies to evaluate the definitive
role of an ALK inhibitor in patients with a
translocation in the EML 4- ALK gene are in
progress. Other markers of interest in NSCLC
include: Excision repair cross-complementing
gene 1 (ERCC1), RRM1, thymidylate synthase
(TS), K-ras mutation, c-met expression/mutation,
C. P. Belani
TRAIL R2, IGF-1R, JAK-2 and the list goes on.
Thus the major focus of current research has been
the proper selection of patients for optimizing the
effect of molecularly targeted agents with the
identification and validation of biomarkers.
1 Introduction
Lung cancer continues to be the leading cause of
cancer deaths worldwide (Jemal et al. 2010b).
Approximately, 1.6 million new cases of lung cancer
are diagnosed each year (Jemal et al. 2010a). The
number of cases continues to increase in many places
around the world. The overall cure rate from lung
cancer is modest (approximately 17%) because of the
advanced stage at diagnosis in the majority of
patients. The role of systemic therapies has expanded
in the last 2 decades leading to modest improvements
in overall outcome.
2 Non-Small Cell Lung Cancer
Non-small cell lung cancer (NSCLC), which
accounts for approximately 87% of all cases of lung
cancer, is a biologically heterogeneous disease. It
includes various histological subtypes such as ade-
nocarcinoma, bronchioloalveolar carcinoma, squa-
mous cell, and large cell carcinoma. In approximately
20–30% of the patients, a specific histological subtype
is not identified, primarily related to lack of adequate
tissue from the diagnostic specimen. Presentation
with advanced stage of disease is one of the major
reasons behind the poor overall outcomes for patients
with NSCLC. In recent years, a number of important
advances in therapy have led to improved survival for
patients with all stages of NSCLC. Combination
chemotherapy with platinum-based regimens has led
to improvements in overall survival (OS) and quality
of life in advanced stage disease (Non-small Cell
LUng Cancer Collaborative Group 1995; NSCLC
Meta-Analyses Collaborative Group 2008). For
patients with surgically unresectable, locally
advanced disease, combination of chemotherapy with
external beam radiation is superior to single modality
therapy. Even for patients with early stage disease,
administration of chemotherapy following surgery
Systemic Therapy for Lung Cancer for the Radiation Oncologist
results in improved OS (Arriagada et al. 2004; Winton
et al. 2005). Given the extensive role of chemotherapy
in NSCLC, development of effective systemic treat-
ment regimens is an important priority for physicians
and researchers.
3 Early Stage Resectable Non-Small
Cell Lung Cancer
Surgical resection is the foundation of treatment
for patients with early stage resected NSCLC.
Unfortunately, only 30% of patients have resectable
disease at the time of presentation and 50% of
these have significant co-morbid illness making
them unfit for definitive surgery. For those who are
medically unresectable, external beam radiation
therapy (RT) or stereotactic body radiosurgery
(SBRT) have emerged as promising therapeutic
options (Timmerman et al. 2010). A randomized
study of SBRT versus surgical resection in
medically unresectable patients is in progress.
Lobectomy continues to be the gold standard and
lesser resections e.g., sub-lobar, wedge, segmental
procedures are associated with increased local fail-
ure. Pneumonectomy is associated with increased
morbidity and mortality. Video-assisted thorascopic
surgery (VATS) is increasingly being utilized for
definitive surgical resection (McKenna 1994, 2005;
Scott et al. 2010).
Adjuvant RT for patients with resected NSCLC
was noted to be detrimental in a meta-analysis of a
large number of clinical trials. It is not recommended
in patients who undergo an R0 resection as routine
care. Patients with margin position disease and those
with mediastinal node involvement (PORT Meta-
analysis Trialists Group 1998) postoperative RT may
improve but in addition, these patients benefit from
adjuvant systemic therapy. For patients with early
stage NSCLC that are not candidates for surgery due
to medical co-morbid illness, external beam radiation
is used to treat the tumor. SBRT has emerged as a
highly promising therapeutic option for these patients
and in one of the phase II studies for medically
unresectable patients, 97% primary tumor control sets
was seen at 3 years (Timmerman et al. 2010).
Currently, there is an ongoing European trial
comparing SBRT to surgical resection in medically
resectable NSCLC.
249
4 Systemic Chemotherapy for Early
Stage Resected Non-Small Cell
Lung Cancer
Approximately, 70% of the patients with early stage
resected disease develop recurrence at distant sites.
Therefore, in addition to surgical resection, there is
the need for systemic therapy to eradicate micro-
metastatic disease. Platinum-based chemotherapy
has emerged as an effective adjuvant systemic
therapy post surgical resection. The International
adjuvant lung trial (IALT) with more than 1,700
patients comprising stages I, II, or III NSCLC
(Arriagada et al. 2004) randomized after surgery to
a cisplatin-based two-drug combination versus
observation (Winton et al. 2005) (Table 1) dem-
onstrated a significant but modest 4% improvement
in 5-year survival rate of 4%. The National cancer
institute of Canada (NCIC) trial compared cisplatin
vinorelbine versus observation in patients with
stages IB and II NSCLC (Winton et al. 2005).
There was an overall 15% improvement in 5-year
survival in the adjuvant chemotherapy group.
A meta-analysis of all recent trials with adjuvant
cisplatin-based chemotherapy demonstrated a 5%
improvement in OS (Pignon et al. 2008) leading to
a shift of treatment paradigm.
The role of adjuvant chemotherapy has been lim-
ited to stages II and III resected NSCLC based on the
preferential benefit in these subgroups from the
adjuvant therapy studies. Among those with stage I
disease, there continues to be a controversy and there
are some data to support its use in those with tumors
C4 cm in size (Strauss et al. 2008). For patients with
stage IA disease, adjuvant chemotherapy is not usu-
ally recommended (Pignon et al. 2008).
Cisplatin-based combination therapy is the ‘stan-
dard of care’ in the adjuvant setting. Whether carbo-
platin can be substituted for cisplatin in these
combination regimens when utilized in the adjuvant
setting remains to be a subject of controversy.
The Cancer and Leukemia Group B (CALGB) trial
of carboplatin/paclitaxel combination in patients with
stage 1B disease failed to show a survival benefit,
despite improvement in disease-free survival (Strauss
et al. 2008). The optimal number of cycles of adjuvant
chemotherapy has also not been addressed in
randomized studies. Based on the present evidence,
250 C. P. Belani

Table 1 Adjuvant chemotherapy for early stage resected NSCLC

Adjuvant lung Big lung International JBR 10 National Adjuvant navelbine
project trial(BLT) adjuvant lung Cancer Institute of international trialist
Italy(ALPI) (Stephens trial(IALT) Canada (Winton et al. association (ANITA)
(Scagliotti 2005) et al. 2002) (Arriagada et al. 2005) (Douillard et al. 2006)
2004)
Design MVPa vs. Cisplatin Cisplatin doublet vs. Cisplatin vinorelbine Cisplatin vinorelbine vs.
observation doublet vs. observation vs. observation observation
observation
Median 36.5 vs. 27 vs. – - 36.3 vs. 20.7 months HR
PFS 28.9 months HR 24.7 months 0.8; P = 0.017
0.89; P = 0.128 HR 0.97;
P = 0.81
Median 55.2 vs. 33.9 vs. – 94 vs. 73 months HR 65.7 vs. 43.7 months HR
survival 68 months HR 32.6 months 0.69; P = 0.04 0.8; P = 0.017
0.96; P = 0.589 HR 1.02;
P = 0.9
5-year – – 44.5 vs. 40.4% HR – –
Survival 0.86; P \ 0.03
Comment No benefit No benefit Overall 4.1% Benefit limited to Degree of benefit higher
absolute benefit in stage II patients with stage
survival
a
MVP -Mitomycin, Vindesine, Cisplatin

3–4 cycles of cisplatin-based chemotherapy are
administered in routine practice settings.
Approximately two-thirds of all resected patients
are able to receive adjuvant chemotherapy as others
have co-morbid illness of varying degree and/or
post-operative complications. Neoadjuvant or induc-
tion therapy has also been investigated to improve the
delivery and compliance of chemotherapy. A phase
III study conducted by the Southwest oncology
group demonstrated an improvement in OS with
neoadjuvant chemotherapy followed by surgery ver-
sus surgery alone (Pisters et al. 2010). However,
these differences did not reach statistical significance
and the trial was closed early because adjuvant
chemotherapy became the new ‘standard of care’.
Similar data has also been reported from a European
trial that evaluated pre-operative therapy (Scagliotti
et al. 2008a), neoadjuvant chemotherapy prior to
surgery versus surgery alone versus surgery followed
by adjuvant chemotherapy were compared in the
Spanish study (Felip et al. 2010). The delivery of
chemotherapy was found to be superior in the pre-
operative setting (90 vs. 66%) (Felip et al. 2010).
Neo-adjuvant chemotherapy in this Spanish trial was
associated with a non-significant trend towards
longer disease-free survival compared to surgery
alone. The power of this study was limited and there
was a high proportion of stage I patients who
supposedly do not benefit from systemic therapy.
Neo-adjuvant therapy is an efficacious and safe
approach for patients with early stage NSCLC but
the ‘standard of care’ for patients with R0 resection
is adjuvant chemotherapy. Integration of targeted
therapies and proper patient selection will lead to
tailor-made therapies with resultant improvement in
outcome.
Excision repair cross-complementing gene 1
(ERCC1) is an important mediator of DNA repair and
has been noted in several studies to be a determinant
of sensitivity to platinum-based therapy (Lord et al.
2002; Simon et al. 2007). In a subset analysis of the
IALT study, tumor specimens of patients were eval-
uated by immunohistochemistry for ERCC1 expres-
sion (Olaussen et al. 2006). Patients with high ERCC1
expression did not appear to derive benefit from cis-
platin-based chemotherapy, though the OS for this
group was more favorable. In the ERCC1 negative
group, adjuvant chemotherapy was associated with a
robust survival advantage over observation. This
observation has led to prospective studies that eval-
uate treatment selection based on ERCC1 expression
for patients with early stage NSCLC.
Systemic Therapy for Lung Cancer for the Radiation Oncologist
In the adjuvant setting, epidermal growth factor
receptor (EGFR) inhibitors have also been investi-
gated for patients with resected early stage NSCLC.
Though gefitinib as adjuvant therapy failed to dem-
onstrate a benefit in this group it was not conclusive
as the study was stopped early (Goss et al. 2010).
Erlotinib has been evaluated in a randomized trial in
the adjuvant setting (RADIANT). The trial has com-
pleted accrual and the results are eagerly awaited. A
combination of bevacizumab with standard chemo-
therapy is the subject of evaluation in the Eastern
Cooperative Oncology Group 1505 trial.
5 Locally Advanced Unresectable
Stage III Disease
Combined modality approaches involving systemic
therapy and radiotherapy are the standard of care for
patients with locally advanced unresectable disease.
Tumors that invade the mediastinum, major blood
vessels, heart, or the vertebral body are not considered
surgically amenable, in addition to those with
multi-station N2 disease. The addition of systemic
chemotherapy to radiation therapy has been associated
with improvement in OS compared to radiotherapy
alone in randomized studies (Dillman et al. 1990; Le
Chevalier et al. 1991). Though the sequential of che-
motherapy followed by RT is superior to definitive RT
alone, the concurrent approach has clearly shown to be
more efficacious as compared to the sequential
approach. The role of chemoradiotherapy controver-
sies and consensus regarding the choice of agents and
combination regimens is described elsewhere in this
book. Patients with locally advanced unresectable
disease are in general treated with concurrent or
sequential chemotherapy and definitive RT. These
approaches result in 20–25% overall 5-year survival
(Curran et al. 2000; Furuse et al. 1999).
6 Systemic Therapy for Advanced
and Metastatic Non-Small Cell
Lung Cancer
The overall goals of treatment are to improve symp-
toms, preserve or improve quality of life, and prolong
survival. The performance status of the patient
remains an important determinant of overall
251
prognosis and is a prime consideration in treatment
selection. Recently, gender has also become recog-
nized as an important prognostic factor, with females
experiencing a better survival than males (Siddiqui
et al. 2010; Batevik et al. 2005; Harichand-Herdt and
Ramalingam 2009; Visbal et al. 2004).
Elderly patients (age C70 years) account for
approximately 50% of all cases of NSCLC (Langer
et al. 2002). In contrast, patients with a poor perfor-
mance status (ECOG 2, 3 or 4) have short median
survival duration of approximately 4 months (Ruck-
deschel et al. 1986).
Systemic therapy remains the mainstay or treat-
ment of advanced stage NSCLC. Combination che-
motherapy with a platinum-based regimen has
emerged as the standard therapy for patients with
advanced stage disease (Bunn 2002). Improvements
in OS and quality of life have been demonstrated with
platinum-based regimens over supportive care alone
in randomized clinical trials (Rapp et al. 1988).
Among the platinum compounds, both cisplatin and
carboplatin have been extensively studied for the
treatment of NSCLC. In general, carboplatin-based
regimens have a favorable tolerability profile over
cisplatin-based regimens (Schiller et al. 2002; Kelly
et al. 2001). Despite the marginally higher response
rate with cisplatin-based regimens, considering the
palliative intent of therapy, carboplatin-based regi-
mens have found wide applicability in routine care.
However, recent improvements in anti-emetic therapy
have rendered the use of cisplatin-based regimens
more tolerable.
A number of randomized clinical trials have
established the superiority of a platinum-containing
two-drug combination over single agent therapy
(Wozniak et al. 1998; Sandler et al. 2000; Lilenbaum
et al. 2005). The response rate, progression-free
survival, and OS all appear to be improved with
combination regimens in patients with advanced
NSCLC, though the benefits come with higher
toxicity. Paclitaxel, docetaxel, gemcitabine, vinorel-
bine, irinotecan, and pemetrexed, commonly referred
to as the ‘third generation’ cytotoxic agents, have all
demonstrated efficacy when given in combination
with a platinum compound in patients with advanced
NSCLC (Schiller et al. 2002; Wozniak et al. 1998;
Ohe et al. 2007; Fossella et al. 2003; Scagliotti et al.
2008b; Belani et al. 2005). A large randomized
clinical trial conducted by the ECOG compared the
252
efficacy of four commonly used combination regi-
mens in the treatment of advanced NSCLC (Schiller
et al. 2002). Cisplatin–docetaxel, cisplatin–gemcita-
bine, and carboplatin–paclitaxel were all associated
with comparable efficacy parameters to that of the
control arm of cisplatin–paclitaxel. These observa-
tions, supported by findings of other contemporane-
ous clinical trials, established the notion that an
‘efficacy plateau’ had been reached with two-drug
combinations in advanced stage NSCLC. The use of
three-drug cytotoxic combinations has generally
resulted in higher toxicity without clear evidence of
improvement in efficacy across clinical trials and has
therefore not been pursued subsequently (Alberola
et al. 2003). With the currently available platinum-
based two-drug regimens, the median survival and
1-year survival rate are 8–11 months and 30–40% in
patients with a good performance status (Ramalingam
and Belani 2004).
6.1 Histology-based treatment
of advanced Non-Small Cell Lung
Cancer
Choice of systemic therapy based on the sub-histol-
ogy of NSCLC is a new paradigm. Scagliotti et al.
(2008b) showed that cisplatin-pemetrexed combi-
nation was associated with increased efficacy in the
nonsquamous subset of patients. (Scagliotti et al.
2008b). Over 1700 patients were randomized to the
combination of cisplatin–pemetrexed versus cis-
platin–gemcitabine. The study met its non-inferiority
objective and in all NSCLC patients there was no
difference in survival between the two groups.
The cisplatin–pemetrexed regimen demonstrated
preferential activity in patients with non-squamous
histology. In patients with adenocarcinoma histology,
the median survival with the cisplatin–pemetrexed
regimen was 12.6 m versus 10.9 with cisplatin–
gemcitabine and was statistically significant. Though
the exact reasons behind the histology-interaction and
pemetrexed are not known but the outcome was
significantly improved in the adenocarcinoma subset.
In addition, this regimen was also associated with a
favorable tolerability profile. These results led to the
approval of the cisplatin–pemetrexed regimen for
patients with only non-squamous NSCLC. Improved
efficacy of pemetrexed in adenocarcinoma may in fact
C. P. Belani
be due to low level of expression of thymidylate
synthase (TS), a known target for pemetrexed
(Eismann et al. 2005; Righi et al. 2010) in adeno-
carcinoma compared to squamous or small cell
carcinoma (Scagliotti et al. 2009).
Another novel chemotherapeutic agent, albumin-
bound paclitaxel when combined with carboplatin
showed improved response rate in patients with
advanced NSCLC when compared to the standard
combination of paclitaxel and carboplatin (37 vs.
25%) with a signal of even larger benefit (41 vs. 24%)
in those with squamous cell subset (Socinski et al.
2010). Expression of Secreted Protein Acidic and
Rich in Cysteine (SPARC), which facilitates accu-
mulation of albumin in the tumor and thus increase
intracellular concentrations of the nab-paclitaxel may
be the reason for the increased efficacy but needs
validation (Desai et al. 2009). Survival data from the
trial is awaited before it can be introduced to the
routine care of NSCLC. Thus for now, histology may
represent a harbinger of activity with specific agents
and regimens though eventually there may be a
plausible relationship with a molecular/correlative/
biological marker.
6.2 Maintenance therapy
Until recently, 4–6 cycles of combination chemo-
therapy formed the ‘standard of care’ for patients with
advanced NSCLC (Socinski et al. 2002; Smith et al.
2001) (Table 2). Extension of the same treatment
failed to demonstrate any evidence of benefit. Recent
trials of maintenance therapy in stable/responding
patients to front-line regimen have shifted the treat-
ment paradigm in favor of this approach. Pemetrexed
and erlotinib administered as single agents are
approved by the FDA and EMZA for maintenance
therapy based on the results of randomized trials
(Ciuleanu et al. 2009; Cappuzzo et al. 2010). The
agents are fairly well tolerated and are devoid of
significant cumulative toxicity. Furthermore, benefit
of maintenance therapy is related to the ability to
tolerate an active agent following initial chemother-
apy rather than at the time of recurrence/progression
(Table 3) though the outcome of those who receive
maintenance versus those who are able to receive
treatment at the time of progression may be the same
(Fidias et al. 2009), approximately 35–40% of those
Systemic Therapy for Lung Cancer for the Radiation Oncologist 253

Table 2 Clinical trials of maintenance therapy in advanced NSCLC: prolonged or continuation maintenance
Smith et al. (2001) Socinski et al. (2010) Brodowicz et al. Park et al. (2007) Belani et al. (2010)
(2006)
Design MVP 9 3 cycles vs. PC 9 4 cycles vs. PC GC vs. GC PC 9 4 cycles vs. GC followed by BSC vs.
MVP 9 6 cycles until progression followed by G PC 9 6 cycles GC followed by G
PFS 5 vs. 5 months – 5 vs. 6.2 vs. 4.3 months 7.4 vs. 7.7 months
6.6 months P = 0.001 P = 0.575
P = 0.0001
OS 6 vs. 7 months 8.5 vs. 6.6 P = 0.63 11 vs. 15 vs. 16 months 8 vs. 9.3 months
13 months P = 0.469 P = 0.838
P = 0.469

Table 3 Clinical trials of switch maintenance in advanced NSCLC

Westeel Fidias et al. (2009) SATURN trial ATLAS trial (Miller et al. IFCT-GFPC0502
et al. (Cappuzzo et al. 2009) (Perol et al. 2010)
(2005) 2010)
Design MIC vs. GC followed Platinum doublet Platinum GC followed by BSC
MIC immediately by D vs. followed by doublet ? Bevacizumab vs. G vs. Erlotinib
followed GC followed by D at placebo vs. followed by: Bevacizumab
by V progression Erlotinib vs. Erlotinib ? Bev
PFS 5 vs. 5.7 vs. 2.7 months 11.1 vs. 4.76 vs. 3.75 P = 0.0012 2.9 vs. 1.9 months
3 months P = 0.001 12.3 weeks erlotinib (P = 0.002)
P = 0.32 P = 0.001 3.8 vs. 1.9–G
(P = 0.001)
OS 10.4 vs. 12.3 vs. 9.7 months 12 vs. 11 months 15.9 vs. 13.9 months –
11 months P = 0.853 P = 0.088 P = 0.90

who have initial response are not able to make it to
true second-line intervention. In the intent-to-treat
analysis, pemetrexed demonstrated a 5.3 month
improvement in median survival over placebo main-
tenance in the non-squamous patients with NSCLC
leading to its approval by the FDA. A word of caution
is that those with a poor PS (C2) are not candidates
for maintenance therapy.
Similarly erlotinib, an EGFR TKI, has also shown
improvement in PFS and OS in the maintenance set-
ting in responding and stable patients [progression-
free survival (12.3 vs. 11.1 weeks) and OS (12 vs.
11 months)] (Cappuzzo et al. 2010). The benefit is
more provocative with erlotinib in those with acti-
vating mutations in the EGFR TK domain although it
is modest at best in the overall populations. Both
Pemetrexed and erlotinib have established the foun-
dation for the maintenance therapy paradigm and are
approved by the regulatory agencies both in Europe
and in the USA. The meta-analysis of maintenance
therapy studies demonstrates a significant improve-
ment in progression-free survival and a modest
improvement in OS (Soon et al. 2009).
There is continued controversy among lung cancer
care regarding the optimal patient for the maintenance
therapy, the choice of agent (continuation of the same
agent vs. switch to a new agent). For now ‘‘switch
maintenance’’ has been established until new data
become available and those patients with poor or
declining PS should not be offered maintenance
therapy (Belani et al. 2010). Ongoing studies evalu-
ating maintenance are the paramount trial and the
POINTBREAK STUDIES (Figs. 1, 2). These will
provide further insights into this new treatment par-
adigm. Bevacizumab and Cetuximab were continued
as maintenance therapy in the investigational arms of
ECOG 4599 & FLEX trials (Perol et al. 2010) but the
definite role of these agents in the maintenance setting
254
Fig. 1
Fig. 2
has not been established (Sandler et al. 2006; Pirker
et al. 2009). Prolonged use of the targeted agent fol-
lowing 4–6 cycles of cytotoxic therapy has been
adopted as a quasi ‘standard of care’. ECOG 5508 is
evaluating the role of continuation bevacizumab
versus pemetrexed versus the combination versus the
combination of the two in patients who have stable or
responsive disease after initial treatment with carbo-
platin, paclitaxel, and bevacizumab.
Maintenance therapy paradigm is increasingly
being adopted. It is fair to say for now that despite
chemo follow-up of responding and stable patients,
approximately a third of patients are not able to make
C. P. Belani
it to second-line therapy and lack of crossover to the
‘‘agent’’ is the placebo arm at progression will con-
tinue to pose questions but it is impossible to develop
a design of a trial which would attempt to answer
these questions.
6.3 Epidermal Growth Factor Receptor
Tyrosine Kinase Inhibitors
EGFR pathway has been implicated in driving tumor
growth, proliferation, inhibition of apoptosis, increased
metastatic potential, and initiation of neo-angiogenesis
Systemic Therapy for Lung Cancer for the Radiation Oncologist 255

Table 4 First-line therapy with EGFR TKIs for advanced NSCLC: Randomized studies in enriched patient populations
Trial Selection Design PFS OS
method
(WJTOG3405a Trial) EGFR Gefitinib vs. 9.2 vs. 6.3 months Not reported
(Mitsudomi et al. mutation cisplatin/ P \ 0.0001
2010) docetaxel
Rosell et al. (2009) EGFR Erlotinib 14.0 months (95% 27.0 months (95% CI, 22.7–31.3)
mutation CI, 11.3-16.7)
Maemondo et al. EGFR Gefitinib vs. 10.8 vs. 5.4 months 30.5 months in the gefitinib group and
(2010) mutation carboplatin/ P \ 0.001 23.6 months in the chemotherapy group
paclitaxel (P = 0.31)
Mok et al. (2009) Clinical Gefitinib vs. 5.7 m vs. 5.8, HR 18.6 vs. 17.3 months HR 0.91
characteristics carboplatin/ 0.74, months
paclitaxel P \ 0.001
First Signal Trial Clinical Gefitinib vs. 6.6 vs. 6.1 months 21.3 vs. 23.3 P = 0.420
(Lee et al. 2009) characteristics cisplatin/ P = 0.044
gemcitabine
a
West Japan Thoracic Oncology Group

(Baselga 2001). EGFR is expressed in more than 40%
of NSCLC tumors. EGFR pathway inhibitors gefitinib
and erlotinib were evaluated in patients with refractory
NSCLC. There was evidence of single agent activity in
approximately 10–20% of the (Perez-Soler et al. 2004;
Kris et al. 2003; Fukuoka et al. 2003) with skin rash and
diarrhea as the most common side effects. NCIC-BR21
established the efficacy of erlotinib in patients with
recurrent (second-line) advanced NSCLC (Shepherd
et al. 2005). There was a significant improvement in OS
and progression-free survival leading to the approval of
erlotinib with second-line setting in unselected
patients. Gefitinib, however, failed to show a difference
in OS when compared to placebo (Thatcher et al. 2005)
but the patient population in the Iressa survival evalu-
ation (ISEL) study as they had more aggressive/pro-
gressive disease but the subsets of never-smokers/
Asian ethnicity demonstrated a benefit. Clinical char-
acteristics for response to EGFR TKIs in the early trials
included female sex adenocarcinoma histology, never-
smokers, and those with Asian ethnicity (Paez et al.
2004). Search for a molecular reason for efficacy in
these subsets led to the discovery of EGFR activity
mutations in the tyrosine kinase domain of the receptor
responsible for the selective activity with EGFR TKIs.
Approximately 0–15% of all NSCLC patients were
found to harbor the mutative among the Western pop-
ulation of NSCLC patients while the incidence is much
higher (*40%) in those with Asian ethnicity (Paez
et al. 2004). Prospective randomized and patient
selection studies evaluated the role of gefitinib and
erlotinib (Paz-Ares et al. 2006) resulting in high
response rates to the extent of 80% in the subsets
validating the predictive potential of EGFR mutation
for response to EGFR TKIs (Rosell et al. 2009). The
results of a recent landmark phase III study conducted
in Asia confirmed the role of EGFR mutation as the
main predictor of outcome with EGFR TKIs (Mok et al.
2009) (Table 4). Utilizing a clinical enrichment
strategy (women with adenocarcinoma, and history
of no or light cigarette smoking were randomized to
therapy with either gefitinib or a standard first-line
chemotherapy regimen of carboplatin and paclitaxel.
Gefitinib was better tolerated with overall population
and resulted in a superior PFS, the primary endpoint.
Sixty percent of the patients in whom the tumors
were analyzed had presence of EGFR mutation in
exons 19 and 21. The response rates of 60–80% and
median survival of 24–30 months in this selected
population with EGFR mutations are provocative.
The I-PASS study established in addition that
administration of gefitinib in patients with wild-type
EGFR was not warranted and chemotherapy was the
preferred treatment. The Korean Study (Lee et al.
2009) confirmed these observations. Randomized
phase II studies in patients with documented EGFR
mutation (Maemondo et al. 2010; Mitsudomi et al.
2010) have now shown with gefitinib as compared
to chemotherapy establishing a new paradigm of
treatment in the front-line setting for selected. In
256
Table 5 Irreversible EGFR Drug
TKIs
BIBW 2992
HKI-272
EKB-569
CI-1033
PF00299804
AV-412/MP-412 EGFR/HER2
EGFR epidermal growth factor receptor, TKIs tyrosine kinase inhibitors
addition, thin trials have also established the neces-
sity for evaluation of all adenocarcinomas for EGFR
mutation. The value of adding chemotherapy and
EGFR TKIs in the front-line setting in patients with
tumors harboring the EGFR mutation has not been
established and there is an early indication of no
added benefit in a recently reported randomized trial
(Herbst et al. 2004; Giaccone et al. 2004).
To test whether the combination might be benefi-
cial in selected patients, a recent trial randomized
never or light smokers with advanced NSCLC to
therapy with erlotinib alone or in combination with
carboplatin and paclitaxel (Janne et al. 2010) There
was no difference in the outcomes between the two
groups even in patients with EGFR mutation, thus
excluding a role for combination of EGFR TKIs in
combination with chemotherapy.
A completely different biological basis appears to
be responsible for anti-cancer effects of agents that
target the external domain of the EGFR. Cetuximab,
a chimeric monoclonal antibody against the EGFR,
has minimal activity when given as monotherapy
for patients with advanced stage NSCLC
(Hanna et al. 2006). However, when given in
combination with platinum-based chemotherapy, a
modest improvement in OS was noted (11.3 vs.
10.1 months) over chemotherapy alone (Pirker et al.
2009). However with other combination regimes,
cetuximab has failed to demonstrate significant
improvement in survival (Lynch et al. 2007).
Because of differential efficacy of cetuximab based
on K-ras mutation (Khambata-Ford et al. 2010)
status in patients with colon cancer, molecular
analyzes have been performed in the NSCLC trials
(Pirker et al. 2009; Lynch et al. 2007; Mukohara
et al. 2005). No definitive biological marker has
emerged to define sensitivity to cetuximab including
K-ras mutation.
C. P. Belani
Class Targets Status
EGFR/HRE2 EGFR and HER2 Phase III
EGFR/HER2 EGFR and HER2 Phase II
EGFR/HER2 EGFR and HER2 Phase II
Pan-ErbB EGFR, HER2, and HER4 Phase II
Pan-ErbB EGFR, HER2, and HER4 Phase II
EGFR and HER2 Phase I
6.4 Mechanisms of Resistance
to Epidermal Growth Factor
Receptor
The efficacy of EGFR inhibitors is limited by pri-
mary and acquired resistance. Primary resistance to
erlotinib and gefitinib has been associated with in-
frame insertion mutations in EGFR exon 20 which
reduces sensitivity to these TKIs by about 100-fold
and in rare cases, with the T 790M missense
mutation also located on exon 20 (Kobayashi et al.
2005). Gene amplification of MET, the receptor for
hepatocyte growth factor may provide an alternate
stimulus for promoting survival of NSCLC cells
(Engelman et al. 2007). MET amplification occurs
in 3–7% of patients who are EGFR TKI na. Sec-
ondary acquired resistance in those who have been
treated with EGFR TKIs for a period of time can
also be caused by the missense 7790M mutation and
this emerges during treatment in nearly half the
cases. Other secondary mutations such as D761c
have also been associated with EGFR TKI resis-
tance (Balak et al. 2006). Also, as a result of
genetic heterogeneity the clones with activating
mutation may decrease or disappear during treat-
ment with gefitinib or erlotinib, resulting in a
selective survival of wild-type EGFR clones that are
resistant to these agents (Jiang et al. 2008). MET
amplification is also known to moderate acquired
resistance in 20% of cases (Herbst et al. 2008).
Tumors that undergo epithelial to mesenchymal
transition also exhibit an increase in metastatic
potential and less reliance on EGFR (Barr et al.
2008). Second generation irreversible EGFR inhib-
itors have demonstrated anti-cancer activity in
tumors resistant to reversible TKIs. These include
BIBW 2992, PF-299804 and others (Belani 2010;
Boyer et al. 2010) (Table 5).
Systemic Therapy for Lung Cancer for the Radiation Oncologist
To delay the emergence of resistance involves
combination therapy with inhibitors of the C-MET
and EGFR being utilized in a randomized phase II
study, erlotinib alone or in combination with ARQ-
197, a small molecular C-MET (Schiller et al. 2010)
demonstrated a significant improvement in progres-
sion-free survival and OS and has led to an ongoing
phase III definitive trial.
7 Anti-Angiogenic Therapies
for Non-Small Cell Lung Cancer
Higher microvessel density and vascular endothelial
growth factor (VEGF) concentrations have been
linked with an aggressive NSCLC phenotype by
various investigators (Fontanini et al. 2002). This
provided the rationale to evaluate a variety of anti-
angiogenic agents for the treatment of NSCLC.
Continuing the common trend in clinical investiga-
tions, efforts to develop anti-angiogenic therapies for
NSCLC have mainly focused on patients with
advanced stage disease. Bevacizumab was the first
agent to demonstrate survival advantage in patients
with advanced stage NSCLC and is approved for
routine use in the first-line setting for patients with
metastatic non-squamous NSCLC. A number of
VEGF TKIs have also demonstrated modest anti-
cancer activity as monotherapy in advanced NSCLC,
thus leading to randomized clinical trials that have or
are evaluating novel combination regimens (Socinski
et al. 2008; Blumenschein et al. 2009a).
8 Bevacizumab
Bevacizumab is a monoclonal antibody that binds
to all isoforms of VEGF and inhibits activation of
the receptor (Ramalingam 2007). It was first eval-
uated in NSCLC on a randomized phase II study of
carboplatin and paclitaxel given with or without
bevacizumab (Johnson et al. 2004). This regimen
was administered to patients with previously
untreated advanced stage NSCLC. Bevacizumab
was administered at a dose of either 7.5 or 15 mg/kg.
Patients on the chemotherapy alone were crossed over
to receive bevacizumab as monotherapy upon disease
progression. The response rate, median progression-
free survival and OS were all improved with the
257
addition of 15 mg/kg dose of bevacizumab to che-
motherapy. No objective responses were noted for
patients who received bevacizumab as monotherapy;
4 out of 13 patients with squamous cell histology
developed fatal or life-threatening hemoptysis,
whereas bleeding was uncommon in other histological
sub-types. This observation led to the exclusion of
patients with squamous cell histology in subsequent
clinical trials of bevacizumab in NSCLC. Other
adverse events noted with bevacizumab-based regi-
men included hypertension and proteinuria.
The promising efficacy data from this phase II
study led to a confirmatory phase III study of
carboplatin and paclitaxel with our without
bevacizumab for advanced non-squamous NSCLC
(ECOG 4599) (Sandler et al. 2006). The 15 mg/kg
dose of bevacizumab was given in combination
with standard doses of carboplatin and paclitaxel
for patients in the experimental arm. Following
6 cycles of combination therapy, bevacizumab was
continued as monotherapy for responding patients
or those with stable disease. Patients with brain
metastasis, history of hemoptysis, and predominant
squamous histology were excluded. The study met
its primary endpoint of OS which was superior for
patients treated with bevacizumab (10.3 m, 12.3 m,
P-0.003) (Table 6).
The progression-free survival duration was also
improved with bevacizumab (6.2 vs. 4.5 m,
P \ 0.001). Treatment was tolerated well overall,
with a less than 5% incidence of major bleeding
events. There was a numerically higher incidence of
treatment-related deaths with the addition of
bevacizumab (15 vs. 2). This was the first ran-
domized study to document an improvement in OS
with the addition of a targeted agent to chemo-
therapy for advanced NSCLC and also formed the
basis for approval of this regiment by the FDA. A
second trial conducted outside the USA noted some
similarities with the efficacy data seen in ECOG
4599, though a survival benefit was not evident
(Reck et al. 2009). In this study (AVAiL), patients
were randomized to receive cisplatin and gemcita-
bine with either bevacizumab or placebo. Patients in
the bevacizumab arm were randomized to either the
7.5 mg/kg dose or 15 mg/kg. The eligibility criteria
were similar to those of ECOG 4599. The primary
endpoint of the study was changed from OS to PFS
after nearly two-thirds of the patients had been
258
Table 6 Bevacizumab in combination with chemotherapy for advanced NSCLC
Author Regimen
Sandler et al. Carboplatin, paclitaxel ? Bevacizumab
(2006)
Carboplatin, paclitaxel
Reck et al. Cisplatin, gemcitabine ? Bevacizumab
(2009) (7.5 mg/kg)
Cisplatin, gemcitabine ? Bevacizumab
(15 mg/kg)
Cisplatin, gemcitabine
enrolled. Neither the toxicity nor the efficacy
parameters were significantly different between the
two dose levels of bevacizumab. The median PFS
was improved with the addition of bevacizumab,
though the differences were relatively modest
(6.7 vs. 6.1 m, P = 0.003) for the low dose bev-
acizumab and 6.5 versus 6.1 m, P = 0.03 for high
dose bevacizumab). The median survival was
approximately 13 months in all three arms of the
study (Table 6).
Even though patients with brain metastasis were
not included in both these phase III studies, sub-
sequent non-randomized studies have documented the
safety of bevacizumab-based regimens in patients
with treated brain metastasis (Socinski et al. 2009).
The AVAiL study also noted no increase in incidence
of bleeding when bevacizumab-based regimen was
given to patients on full dose anti-coagulation ther-
apy. The safety of bevacizumab has also been docu-
mented when used in combination with other
commonly used platinum-based doublets used for the
treatment of advanced NSCLC (Patel et al. 2009; Kris
et al. 2009). Notably, when given in combination with
carboplatin and pemetrexed, bevacizumab was asso-
ciated with a median survival of approximately
14 months and a median PFS of 7.8 months (Patel
et al. 2009). Taken together, bevacizumab can be used
safely for the treatment of patients with advanced
non-squamous NSCLC and leads to modest
improvements in efficacy.
The use of bevacizumab has also met with some
challenges in certain patients subsets. An unplanned
subset analysis of the ECOG 4599 study noted a
higher incidence of certain adverse events such as
fever with neutropenia, hypertension, proteinuria, and
C. P. Belani
Phase Response rate Median PFS Median survival
(%) (m) (m)
III 35 6.2 12.3
15 4.5 10.3
III 34 6.7 13.6
30 6.5 13.4
20 6.1 13.1
a trend towards higher treatment-related deaths in
patients C70 years of age (Ramalingam et al. 2008).
This calls for careful evaluation of patient perfor-
mance status, co-morbid illness, and baseline risk
factors for toxicities for elderly patients, before
initiation of bevacizumab-based regimens. Another
setting to exercise caution involves the use of bev-
acizumab with thoracic radiotherapy, since tracheal-
esophageal fistula formation has been noted in some
patients (Spigel et al. 2009a). Therefore, its use
should be avoided in patients receiving concurrent
radiotherapy or in the immediate aftermath of thoracic
radiation outside the setting of carefully controlled
clinical trials.
The documented ability of bevacizumab to
enhance the efficacy of chemotherapy has prompted
an US intergroup study to evaluate its role in the
setting of adjuvant chemotherapy (ECOG 1505). This
ongoing study randomized patients with stage IB, II,
or IIIA NSCLC to treatment with 4 cycles of cis-
platin-based chemotherapy with or without concur-
rent bevacizumab.
Despite promising phase II data, the combination
of bevacizumab with erlotinib, an inhibitor of the
EGFR, failed to improve survival in a randomized
study conducted for second-line therapy of advanced
stage NSCLC (Herbst et al. 2007; Hainsworth 2008).
The same combination used as maintenance
therapy also failed to improve survival compared to
bevacizumab alone (Miller et al. 2009). Thus for
patients who receive chemotherapy in combination
with bevacizumab as first-line therapy, bevacizumab
is used as maintenance monotherapy, though its
utility has not been confirmed in a randomized
clinical trial.
Systemic Therapy for Lung Cancer for the Radiation Oncologist
9 Other Vascular Endothelial Growth advanced NSCLC. However, given the relatively
Factor Receptor Inhibitors modest efficacy, it is unlikely to be useful for routine
A number of novel multi-kinase inhibitors which also
target the VEGF receptor have all been tested for the
treatment of advanced NSCLC. Sorafenib, Sunitinib,
Axitinib, Vandetanib, Vatalanib and Linifanib
(Socinski et al. 2008; Blumenschein et al. 2009a;
Schiller et al. 2009; Natale et al. 2009; Gauler et al.
2007; Tan et al. 2009) have demonstrated evidence of
single agent activity and anticancer effects in NSCLC.
When given in combination with chemotherapy,
Sorafenib failed to show an improvement in survival
(Hanna et al. 2008) and in fact patients with squamous
cell histology, the placebo group fared better. When
combined with erlotinib in the second-line recurrent
NSCLC, sorafenib demonstrated a modest improve-
ment in efficacy in unselected patients when compared
to erlotinib alone (PFS 1.9 vs. 3.1 m and OS 6 vs.
8.1 m) (Spigel et al. 2009b). The results of a recently
completed study of sorafenib versus placebo in heav-
ily treated patients are eagerly awaited. A phase II
study evaluating sunitinib in combination with
erlotinib versus erlotinib and placebo is in progress.
Sunitinib is also being studied in the maintenance
following four cycles of combination chemotherapy
(CALGB study). Vandetanib is a dual inhibitor of the
EGFR and VEGF receptor tyrosine kinases. It has also
been studied in various settings for the treatment of
advanced stage NSCLC. In the front-line treatment of
advanced NSCLC, the combination of carboplatin and
paclitaxel with vandetanib was associated with a
modest improvement in median PFS over that of
the same chemotherapy given without vandetanib
(Heymach et al. 2008). In the second-line setting,
two phase III studies have been completed with
vandetanib. In the first study, docetaxel was given
alone or in combination with vandetanib (100 mg/day
dose) (Herbst et al. 2009). There was a modest and
significant improvement in median PFS, though OS
was not improved. In the second study, vandetanib
was added to pemetrexed for second-line therapy (De
Boer et al. 2009). Though a numerical improvement in
PFS was noted, the differences did not reach statistical
significance. Vandetanib was also compared directly
to erlotinib in a phase III study for advanced NSCLC
ans was noted to have comparable efficacy (Natale
et al. 2009). Taken together, these results suggest that
259
vandetanib is an active agent in the treatment of
clinical care in any of the settings mentioned here. An
ongoing phase III study compares vandetanib to pla-
cebo for patients who progressed following treatment
with erlotinib for advanced NSCLC.
Cediranib, a potent inhibitor of VEGF-R2, was
combined with carboplatin and paclitaxel for first-line
therapy of advanced NSCLC by the NCIC (Laurie
et al. 2008). This randomized phase II study noted
favorable efficacy trends with the addition of cedira-
nib, though the toxicity profile has warranted a
reduction in the dose of cediranib to 20 mg/day for
the subsequent follow-up study. Axitinib is another
well tolerated agent that had demonstrated robust
single agent activity and is currently being developed
in combination with chemotherapy (Schiller et al.
2009). Linifanib (ABT-869) is a potent VEGF-R2
inhibitor that has also demonstrated single agent
activity in advanced NSCLC and is currently being
tested in a randomized phase II study with combina-
tion chemotherapy (Tan et al. 2009). The combination
of motesanib, a VEGF receptor inhibitor, with
carboplatin and paclitaxel was compared to the same
chemotherapy doublet with bevacizumab in a ran-
domized phase II study (Blumenschein et al. 2009b).
The two treatment arms were associated with com-
parable efficacy though there was some distinct
additional toxicity with the oral agent. All of these
agents have varying inhibitory concentrations, bio-
availability, toxicity profile, and anti-cancer activity.
It is hoped that one or more of these agents may
emerge as efficacious in the near future.
9.1 Other Targeted Approaches
for Non-Small Cell Lung Cancer
Echinoderm microtubule-associated protein-like 4
gene and the anaplastic lymphoma kinase fusion gene
(EML4-ALK) has been identified in 4–5% of patients
with NSCLC (Soda et al. 2007). ALK translocations
occur in young never-smokers with adenocarcinoma
(Shaw et al. 2009). NSCLC patients with ALK
translocation appear to have reduced sensitivity to
both standard chemotherapy and EGFR TKIs.
Crizotinib (PF-234066), a small molecule TKI is
known to inhibit ALK kinase. In a single arm study of
260
82 patients with ALK translocation or presence of
EML4-ALK fusion protein (Bang et al. 2010), a
provocative response was noted with crizotinib. The
disease control rate of 87% was noted. A Phase II
study comparing crizotinib to standard chemotherapy
(docetaxel or pemetrexed) in patients w with EML4
ALK-positive second-line patients with recurrent
NSCLC is ongoing. Screening for EML4-ALK
translocation by fluorescence in situ hybridization
(FISH) technique in never/light smokers with adeno-
carcinoma is increasingly being utilized in the clinical
setting. This is one successful example of a targeted
approached in NSCLC.
Other targeted agents in development for NSCLC
include but are not limited to HDAC (histone deace-
tylase) inhibitors (Owonikoko et al. 2010; Ramalingam
et al. 2010a), mTOR inhibitors (Sun et al. 2006; Hudes
et al. 2007), IGF-IR inhibitors (Ramalingam et al.
2010b; Soria et al. 2009).
10 Small Cell Lung Cancer
SCLC cases account for only 13% of all lung cancers
in the Western world and the numbers continue to
shrink (Govindan et al. 2006). Despite a reduction in
the percentage of patients with SCLC in recent times,
it is still a considerable source of morbidity and
mortality with more than 25,000 new cases diagnosed
each year in the USA (Govindan et al. 2006). With the
adoption of the new staging system, the use of the
TNM staging has been recommended over the pre-
vailing categorization of SCLC into limited and
extensive stage disease (Vallieres et al. 2009). This
will allow for an improvement in the ability to
establish prognosis.
Platinum-based chemotherapy continues to be the
cornerstone of treatment for SCLC and very little
progress has been achieved in the past three dec-
ades. Four cycles of combination therapy with a
platinum compound and etoposide remains the
‘standard of care’ for both limited (with thoracic
radiotherapy) and extensive stage SCLC. Irinotecan,
a topoisomerase inhibitor failed to show a survival
advantage (seen in the Japanese study) (Noda et al.
2002) when given in combination with cisplatin and
compared to the gold standard of cisplatin–
etoposide.
C. P. Belani
Recently, targeted agents such as anti-angiogenic
agents, mTOR inhibitors, and Bcl-2 inhibitors have
been studied without much success (Pandya et al.
2007; Rudin et al. 2008). Topotecan, a topoisomerase
inhibitor is the only proven agent in patients that
relapsed following platinum-based chemotherapy,
though its efficacy is restricted to patients with che-
motherapy-sensitive disease (von Pawel et al. 1999).
Higher response rate than that with topotecan has
been noted with amrubicin, an anthracycline deriva-
tive, in phase II studies for refractory SCLC. This is
now being evaluated in a phase III study for second-
line therapy (Onoda et al. 2006).
The use of thoracic radiotherapy and prophylactic
cranial irradiation (PCI) are associated with modest
improvements in survival for patients with limited-
stage disease. Recently, a randomized study in
patients with extensive stage SCLC demonstrated an
improvement in OS with PCI. Though this study was
limited in not staging the brain before initiation of
PCI, the robust survival results have led to the con-
sideration of PCI in patients who experience a good
response to combination chemotherapy.
Ongoing studies are evaluating newer classes of
molecularly targeted agents such as the Hedgehog
inhibitors and the IGF-1R pathway inhibitors.
A greater understanding of mediators of resistance
and sensitivity to platinum is also necessary to
improve the efficacy of combination chemotherapy
for SCLC.
11 Future Perspectives
The treatment options for patients with lung cancer
have improved considerably in recent years with
modest benefit in outcome measures. Adjuvant che-
motherapy for early stage resected disease and
maintenance therapy for advanced stage response
disease have emerged as new treatment paradigms in
the last decade. The success with selective use of
EGFR TKIs in a targeted population has led to per-
sonalized approaches to treatment. Deciphering of the
dominant oncogenic drivers in the tumors from
patients with lung cancer and increase in the know-
ledge of lung cancer biology will be of utmost
importance in guiding various treatment methods and
strategies.
Systemic Therapy for Lung Cancer for the Radiation Oncologist
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 Combined Radiotherapy
and Chemotherapy: Theoretical
Considerations and Biological Premises
Branislav Jeremic, Dusan Milanovic, and Nenad Filipovic

Contents Abstract
Starting point for full realization of clinical
1 Introduction.............................................................. 267 achievements of combined radiation therapy and
2 Exploitable Mechanisms ......................................... 268 chemotherapy in lung cancer is nothing but full
understanding of general theoretical consideration
3 Implications from Clinical Evidence..................... 269
as well as basic radiobiological premises of
4 Future Consideration .............................................. 271 combined radiation and chemotherapy. Both are
References.......................................................................... 272 nowadays considered as mandatory ingredients in
any consideration of combined radiation therapy
and chemotherapy in lung cancer, as well as
cancers in other tumour sites. More than 30 years
ago, four basic mechanisms through which radia-
tion therapy and chemotherapy can interact were
established including spatial cooperation, indepen-
dent cell kill, protection of normal tissues and
enhancement of tumor response, the latter fre-
quently replaced by terms such as radiosensitiza-
tion or radio enhancement. Clinical evidence
supports importance of exploitable mechanisms,
although protection of normal tissue has never
been proven. Novel radiation therapy technologies,
occasionally changing fractionation pattern and
new drugs/compounds will set the stage and scene
for further verification of basic principles of
combined radiation therapy and chemotherapy in
clinical research of lung cancer.

B. Jeremic (&)
Institute of Lung Diseases, Sremska Kamenica, Serbia
e-mail: nebareje@gmail.com 1 Introduction
D. Milanovic
Department of Radiation Oncology, Over the past several decades combined radiation
University of Freiburg, Freiburg, Germany therapy and chemotherapy have been increasingly
N. Filipovic used in many human cancers. Increasing evidence had
Bioengineering Research Centre, Kragujevac, Serbia been mounting in various tumour sites such as head

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 267
DOI: 10.1007/174_2011_297, Ó Springer-Verlag Berlin Heidelberg 2011
268
and neck, cervix, and gastrointestinal cancers, to
name but a few. One of the excellent examples of how
we have progressed as community of oncologists is
also a lung cancer case. Here, combination of radia-
tion and chemotherapy have also been intensively
investigated, particularly in locally advanced stage III
nonsmall cell lung cancer (NSCLC) and limited-
disease small cell lung cancer. The rationale for
combining radiation and chemotherapy in clinic is to
achieve improved treatment outcome. This designa-
tion equals ‘‘an improved therapeutic ratio’’, which, in
turn, should be determined as a function both of
tumour response and normal tissue damage. Starting
point for full realization of clinical achievements of
combined radiation therapy and chemotherapy in lung
cancer is nothing but full understanding of general
theoretical consideration as well as basic radiobio-
logical premises of combined radiation and chemo-
therapy. Both are nowadays considered as mandatory
ingredients in any consideration of combined radia-
tion therapy and chemotherapy in lung cancer, as well
as cancers in other tumour sites.
2 Exploitable Mechanisms
More than 30 years ago, four basic mechanisms
through which radiation therapy and chemotherapy
can interact were established by Steel and Peckham
(1979). The situation in which disease in a particular
anatomical site that is missed by one therapeutic
agent is dealt with adequately by another has been
described as Spatial cooperation. In this scenario,
radiation therapy would act on disease in thorax (or
better said on those parts of the primary tumour and
the lymph nodes within the radiation therapy treat-
ment field), but not on extrathoracic (subclinical)
disease, which should be dealt with by chemotherapy.
This scenario does not request interaction between the
two anticancer agents. The term ‘‘interaction’’ used
here is as it represents the situation in which treatment
with one agent modifies the response of a tissue
(normal or tumour) to the second agent. The situation
which occurs when two partially effective anticancer
agents are combined without having to reduce their
dose levels seriously has been described as Indepen-
dent cell kill (simple addition of anti-tumour effects)
described. With it, an improvement in therapeutic
result is sought. Provided that two anticancer agents
B. Jeremic et al.
do not interact negatively to the extent that the overall
level of tumour cell kill is less than that could be
produced by the best agent, one would expect that two
such agents are more effective than a single agent. In
that scenario, both radiation therapy and chemother-
apy can act on intrathoracic disease independently
leading to cell kill higher than that obtained by the
better treatment (i.e., radiation therapy) given alone.
This scenario also does not require interaction
between radiation therapy and chemotherapy.
Another mechanism of combined radiation therapy
and chemotherapy in which the combination of the
two treatments allows delivery of greater dose of
radiation to be given than would be tolerated other-
wise has been described as Protection of normal tis-
sues which could happen only if tumour cells are not
similarly protected. In lung cancer, this scenario
would mean that a particular chemotherapy (or any
other) agent protects normal tissue (e.g. oesophageal
mucosa) without protecting an intrathoracic tumour.
This mechanism requests interaction between radia-
tion therapy and chemotherapy. Finally, the mecha-
nism of combination of radiation therapy and
chemotherapy that produces a greater antitumor
response than would be expected from the response
achieved with the agents used separately has been
described as enhancement of tumour response is as
with protection of normal tissues, enhancement of
tumour response also requests interaction between
radiation therapy and chemotherapy.
Any one of these mechanisms by itself could give an
improved therapeutic strategy compared with radiation
therapy or chemotherapy used alone. Importantly,
more than one mechanism may be simultaneously
exploited with a particular combination of radiation
therapy and chemotherapy. For example, if one
attempts to achieve enhancement of tumour response
using chemotherapy agents that have no overlapping
toxicity with radiation therapy, there may also be (1) a
benefit from the simple addition of anti-tumor effects
(independent cell kill), while (2) chemotherapy may
also deal with the disease outside the radiation therapy
treatment field (spatial cooperation).
Of all four possible mechanisms of combined
radiation therapy and chemotherapy, enhancement of
tumour response was of particular interest for radia-
tion oncologists over the years. In an attempt to
achieve it, different processes may be exploited:
(a) modification of the initial radiation damage
Combined Radiotherapy and Chemotherapy: Theoretical Considerations and Biological Premises
(modification of the slope of the dose–response
curves), (b) decreased accumulation or inhibition of
repair of radiation damage in tumour cells, (c)
exploitation of induced cell-cycle synchrony (pertur-
bation in cell kinetics), (d) reoxygenation following
drug treatment and before irradiation, (e) improved
drug access following irradiation, (f) decrease of the
tumour bulk by irradiation leading to more rapid
proliferation and greater chemosensitivity of tumour
cells, and (g) decrease of the tumour bulk by drugs,
enabling smaller radiation therapy field-sizes and
higher radiation therapy doses to be used.
The enhancement of tumour response may be
additive, infra-additive, or supra-additive (synergis-
tic). Additive effect is the one in which the effect of
two independent agents is the sum of the effects that
they would have if acting alone (i.e. 3 ? 2 = 5).
Subadditive effect is the effect of two independent
agents which results in a lesser effect than each agent
individually, or the sum of the individual effects (i.e.
3 ? 2 = 4). The presence of one therapy here
diminishes the effects of the second. Finally, supra-
additive (synergistic) effect is the effect of two inde-
pendent agents which results in a greater effect than
each agent individually, or the sum of the individual
effects (i.e. 3 ? 2 = 6). The presence of one therapy
here enhances the effects of the second.
A subset of a supra-additive effect would include
‘‘sensitization’’ or ‘‘potentiation’’, meaning that of
two agents that are combined one has no effect other
than to increase the effect of the other. Good exam-
ples of ‘‘sensitization’’ or ‘‘potentiation’’ include
attempts to overcome tumour hypoxia by using hyp-
oxic cell sensitizers (e.g. Tirapazamine and RSR-13).
3 Implications from Clinical Evidence
Locally advanced non-small cell lung cancer and
limited-disease small cell lung cancer seem to be
good examples for verification of theoretical consid-
erations in daily clinical practice. The vast majority of
studies of combined radiotherapy and chemotherapy
in the two diseases included either induction (upfront,
neoadjuvant) chemotherapy followed by radiotherapy
or concurrent radiation and chemotherapy. Since there
are only a few studies using alternating radiation
therapy and chemotherapy, or consolidation chemo-
therapy (following concurrent radiochemotherapy) in
269
locally advanced non-small cell lung cancer, such
studies will not be included into the consideration for
the sake of simplicity of presentation. Examples of
induction chemotherapy in locally advanced non-
small cell lung cancer include studies of Dillman et al.
(1990) and Sause et al. (1995) in which induction
chemotherapy (two cycles of cisplatin/vinblastine)
was given in a 4 week split followed by radical
radiation therapy (60 Gy in 30 daily fractions) start-
ing on day 50, while in the study of Le Chevalier et al.
(1992), a four-drug regimen was given before and
after radiation therapy (two cycles each). The ratio-
nale for all the induction chemotherapy studies
included decrease of intrathoracic tumour bulk and
treatment of subclinical disease outside the thorax.
Examples of concurrent radiochemotherapy include a
study of Schaake-Koning et al. (1992) and studies of
Jeremic et al. (1995), (1996). While the study of
Schaake-Koning et al. (1992) split-course radiation
therapy was used with a total dose of 55 Gy and either
weekly (30 mg/m2) or daily (5 mg/m2) cisplatin,
Jeremic et al. used hyperfractionated radiation ther-
apy with a total radiation dose of either 64.8 Gy
(Jeremic et al. 1995) or 69.6 Gy (Jeremic et al. 1996)
and concurrent carboplatin/etoposide given either
every other week (Jeremic et al. 1995) or daily
(Jeremic et al. 1996). The rationale for the concurrent
radiochemotherapy is to improve locoregional (intra-
thoracic) tumour control. Although concurrent che-
motherapy may have acted on the disease outside the
radiation therapy treatment field, due to its specifics
(rather low-doses) it was assumed from the onset that
this type of administration would not have a major
effect on systemic disease outside the radiation therapy
treatment field. The aforementioned six studies were
used as examples because they all showed advantages
for combined radiation therapy and chemotherapy over
the same radiation therapy given alone. While the
induction chemotherapy studies showed a significant
survival advantage for the combined approach owing
to significant improvement in the distant metastasis
control, a finding opposite to that of the concurrent
approach studies, which unequivocally showed sig-
nificant improvement in survival owing to significant
improvement in locoregional tumour control.
If one now wants to put these data into the per-
spective of exploitable mechanisms of combined
radiation therapy and chemotherapy, spatial coopera-
tion was the only mechanism enabling the therapeutic
270
benefit of induction regimens. No independent cell
kill can be noted in any of the induction chemo-
therapy regimens because there was no significant
difference in locoregional tumour control, as one
may have expected if such independent cell kill
would have happened. Also, no enhancement of
tumour response can be noted due to the same rea-
son, due to non-existing overlapping (portions) of
the two treatment modalities. Contrary to these
findings, in concurrent studies, spatial cooperation
was not effective, while both independent cell kill
and enhancement of tumour response may have
occurred. In the low-dose (daily) chemotherapy arms
of the concurrent studies, however, it seems highly
unlikely that independent cell kill occurred, due to
its low-doses, which were traditionally considered as
less effective than doses usually given with more
split (e.g. every 3 weeks). Therefore, enhancement
of tumour response could be seen as the only viable
alternative.
If one now focuses on possible processes exploited
in achieving enhancement of tumour response, two of
them could have been attractive for induction regi-
mens, namely (1) shrinking of tumour burden by
drugs enabling smaller radiation therapy treatment
fields and (2) reoxygenation following chemotherapy
and before radiation therapy. None of these two,
however, have actually happened in induction che-
motherapy regimens since there was no significant
difference in locoregional tumour control. In contrast
to induction chemotherapy regimens, several possible
processes seem to have worked well in concurrent
radiochemotherapy regimens, such as modification of
the initial radiation damage or decreased accumula-
tion or inhibition of repair of radiation damage. Of
particular importance is the fact that in all concurrent
radiochemotherapy regimens, the drug was given
either before the only daily radiation therapy fraction
(Schaake-Koning et al. 1992) or in-between the two
daily fractions (Jeremic et al. 1995, 1996). The aim of
these administration modes was to enable drugs to be
present in tumour cells at the time of first or second
radiation therapy fraction. Therefore, it could both
modify the initial radiation damage and decrease/
inhibit the repair of radiation damage. Although no
prospective randomized trial investigated the effect of
induced cell synchrony in NSCLC, a recent study
from Chen et al. (2003) showed excellent results and
promising outcome with radiation therapy and strictly
B. Jeremic et al.
time-scheduled administration of paclitaxel. Their
results proved to be a possible indicator of radiation
therapy and chemotherapy working together towards
enhancement of tumour response. Other two pro-
cesses, which may be of further importance, are
improved drug access after radiation therapy as well
as reducing the tumour bulk with radiation therapy
leading to more rapid proliferation and greater
chemosensitivity of surviving tumour cells. Although
several prospective phase II studies (Lau et al. 2001;
Sekine et al. 2006; Gandara et al. 2006) in which
concurrent radiochemotherapy was followed by
additional (consolidation) chemotherapy showed
promising results, its first verification in a randomized
fashion failed completely. Hanna et al. (2008) showed
no difference in treatment outcome between concur-
rent radiochemotherapy alone and the same concur-
rent radiochemotherapy followed by consolidation
chemotherapy. Their results reconfirmed precious
observations that concurrent radiochemotherapy
without any consolidation chemotherapy (i.e. alone)
offers the best treatment outcome.
These clinical examples obtained through pro-
spective randomized clinical trials show that
exploitable mechanisms of combined radiotherapy
and chemotherapy in locally advanced NSCLC may
be seen as appropriately identified. From the discus-
sion above, one may assume that concurrent radio-
chemotherapy may offer more possibilities for
therapeutic benefit, because of involvement of two
mechanisms, while induction regimens seem to be a
good example of only one (spatial cooperation). It is,
indeed, what we have recently seen when these two
treatment approaches have been compared in a pro-
spective fashion. Albeit of somewhat different study
design, both Japanese study (Furuse et al. 1999, 2000)
and a Radiation Therapy Oncology Group study 9410
(Curran et al. 2000) showed an advantage for con-
current regimens over induction ones due to an
improvement in local tumour control (Furuse et al.
2000; Curran et al. 2000).
Virtually the same was observed with different
hybrid induction chemotherapy regimens such as
those using induction chemotherapy followed by
concurrent radiochemotherapy with or without con-
solidation chemotherapy. Several clinical trials
clearly showed that any intensification of the latter/
major part of the combined treatment approach via
concurrent radiochemotherapy is not effective, once
Combined Radiotherapy and Chemotherapy: Theoretical Considerations and Biological Premises
you have started with induction chemotherapy.
Several studies of Cancer and Leukemia Group B
(Clamon et al. 1999; Vokes et al. 2002; Akerley et al.
2005; Socinski et al. 2008) showed that there is no
compensation for insufficient start (i.e. with chemo-
therapy). Other attempts, such as the use of three daily
fractions of radiation therapy (Belani et al. 2005), also
proved to be ineffective. All in all, whatever you do
after you start with chemotherapy, failure is inevitable
and comes fast. With this approach, you can only
achieve more toxicity (Socinski et al. 2008) and even
if you use the modern radiation therapy tools such as
three-dimensional radiation therapy and attempt
treatment intensification by escalating the total dose,
again, one cannot achieve better outcome. Indeed,
impressive 12% mortality in the most recent Cancer
and Leukemia Group B attempt (Socinski et al. 2008)
to combine induction chemotherapy with subsequent
concurrent radiochemotherapy led investigators to
early stopping of the trial.
Possible success in combining radiation therapy
and chemotherapy must be placed into the context of
another important aspect, that is, normal tissue mor-
bidity (toxicity). Again, sequencing of radiation
therapy and chemotherapy (induction vs. concurrent
regimens) seems to be a dominating factor. While the
toxicity was usually not troublesome with induction
regimens owing to a gap of a few weeks usually
occurring between the end of chemotherapy and
beginning of radiotherapy, this was one of the major
concerns in concurrent regimens. What available
concurrent studies showed is that the type and mag-
nitude of toxicity largely depend on the dose and
sequence of chemotherapy administered. Concurrent
low-dose chemotherapy led to the incidence of 12%
acute grade [3 oesophageal toxicity in pooled data
analysis in patients with stage III NSCLC of Jeremic
et al. (unpublished data) which compares very
favourably to incidence of the same toxicity (and
severity) reported during various studies from the
same era which used high-dose radiation therapy and
high-dose concurrent chemotherapy. In studies of
Radiation Therapy Oncology Group (90-15, 91-06,
92-04) (Byhardt et al. 1995; Lee et al. 1996; Komaki
et al. 1997) when platinum-based doublets were used,
such incidence ranged 24–53%, being 34% when
pooled together (Byhardt et al. 1998). In more con-
temporary studies, using paclitaxel and carboplatin
(LUN-56 and LUN-63) (Choy et al. 1998, 2000) it
271
was 25–26%, and even higher (46%) in very recent
reports of other investigators (Qiao et al. 2005). It is,
therefore, intuitive to identify low-dose daily che-
motherapy as the major factor contributing to much
lower toxicity in contemporary concurrent radioche-
motherapy regimens. Concurrent low-dose chemo-
therapy in the observation of Jeremic et al.
(unpublished data) also led to grade [3 acute (11%)
and late grade [3 (7%) pulmonary toxicity which
compare favourably with those of other series per-
formed at the same time, and using higher doses of
concurrent chemotherapy, especially when late bron-
chopulmonary toxicity is concerned. In the series of
Radiation Therapy Oncology Group, in 170 patients
treated with hyperfractionated radiation therapy and
concurrent chemotherapy, late grade [3 bronchopul-
monary toxicity was observed in 20% (Byhardt et al.
1998).
Due to the lack of uniformity in clinical studies
available numerous questions remain, however,
unanswered. Our reality, unfortunately, includes too
many ‘‘standards’’, too many drugs, and too many
questions asked, all inevitably leading to less-than-
optimal conclusions and, ultimately, very poor
implementation in clinical practice worldwide.
4 Future Consideration
Yet, we have entered the era of strong orientation
towards investigation and application of molecular
biology in this field (Huang and Harari 1999; Brown
2001). The progress and the success in molecular
targeting have formed the basis of many new drug
developments. Some of the mainly investigated
compounds include PARP inhibitors, protease inhib-
itors, HDAC inhibitors, m-TOR inhibitors, IGF-IR
targeting therapies, COX-2 inhibitors, ALK targeted
inhibitors, Aurora kinase and Polo-like kinase inhib-
itors as well as hedgehog pathway inhibitors. In
addition, agents with a specific targeting moiety
coupled to a radionuclide (radiopharmaceuticals)
have been investigated. These approaches have pro-
ven to be effective in ‘‘personalized medicine’’
regarding lung cancer treatment in recent years.
While majority of the compounds mentioned here
have not yet been investigated in combination
with radiation within the context of formal phase
I–II studies, several compounds have undergone
272
laboratory studies in combination with radiation, and
have given interesting results while some have even
entered a phase III life (Kishi et al. 2000; Milas 2001;
Raju et al. 2002).
One of the main limitations of current drug ther-
apies, is their high toxicity, which often leads to
reduction in the administrable dose, and delivery to
the tumour itself, resulting in a diminished therapeutic
effect. One approach considered to circumvent these
limitations, is targeted delivery of the therapeutically
active molecule in the effective concentrations to the
target organ or tissue where it is needed while
reducing systemic exposure and unwanted side-
effects. Due to the advantages that nanotechnology
offers, it is expected that nanotechnology will play an
important role to cancer treatment in the near future.
However, up to now, the oncologists who used
nanoparticles for drug administration usually lacked
important information needed to optimally apply this
therapy. It is expected that further research in opti-
mizing drug/compound delivery using nanotechnol-
ogy offers substantial advantage over current means
of transportation and drug/compound delivery.
If so, this may shed a new light on possible drug-
related issues (e.g. metabolism, excretion, time to
achieve certain plasma level as a surrogate for ther-
apeutic efficiency) or time to achieve certain tumor
concentration (deemed as necessary for certain level
of radio enhancement) as well as various radiobio-
logical considerations when such new scenario occur
with different fractionation regimens, possibly asking
for new consideration of the four existing exploitable
mechanisms of combining radiation therapy and
chemotherapy in not only lung cancer, but other
cancers as well.
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 Radiotherapy and Second Generation Drugs
Michael Geier and Nicolaus Andratschke

Contents
1 Introduction.............................................................. 275
2 Mechanism of Action of Second Generation
Chemotherapeutic Agents and Their Interaction
with Radiotherapy ...................................................
2.1 Platinum Compounds (Cisplatin and
Carboplatin) ...............................................................
2.2 Etoposide....................................................................
2.3 Vincaalkaloide (Vinblastin, Vindesine) ....................
2.4 Ifosfamide ..................................................................
2.5 Mitomycin..................................................................
3 Early Clinical Evaluation ....................................... 277
3.1 Sequential Radiochemotherapy ................................. 278
3.2 Concurrent Radiochemotherapy................................ 279
4 Summary................................................................... 287
References.......................................................................... 288
Abstract
Unsatisfactory outcomes with radiotherapy alone and
the advent of very potent and possibly radiation
enhancing drugs, especially platinum compounds
and vinkaalkaloids, prompted the preclinical and
276 clinical investigation of combinded radiochemother-
apy protocols with second generation chemothera-
276
276 peutic drugs as a definitive treatment in inoperable
277 NSCLC. Not for all substances used unequivocal
277 experimental evidence for a true radiosensitizing
277
effect could be demonstrated. Instead, the effects
may result from independent additive cytotoxicity
crucial for sterilizing clonogenic tumor cells sur-
viving radiotherapy and a different non-overlapping
toxicity profile. This chapter summarizes the pre-
clinical data and early clinical evidence for the
rational of combining second generation drugs with
radiotherapy in advanced stage NSCLC.

1 Introduction

Poor outcomes with radiotherapy alone and the advent

of very potent and possibly radiation enhancing drugs,
especially platinum compounds and vincaalkaloids,
prompted an excited interest in the investigation of
combined radiochemotherapy protocols as a definitive
treatment in inoperable NSCLC. Currently, treatment
of choice in inoperable advanced stage non-small-cell
M. Geier
N. Andratschke (&) lung cancer (NSCLC) in curative intent is combined
Department of Radiation Oncology, radiochemotherapy with platinum-based regimens.
Technical University of Munich, Effective protocols have emerged, though outcomes
Munich, Germany still remain unsatisfactory.
e-mail: n_andratschke@yahoo.de

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 275
DOI: 10.1007/174_2011_272, Ó Springer-Verlag Berlin Heidelberg 2011
276
Radiotherapy by itself is highly effective in erad-
icating macroscopic tumors and has a higher level of
efficacy in quantitative tumor cell kill compared to
chemotherapy alone. Macroscopic tumors especially
at an early stage without lymph node involvement
(cT1-3 cN0 cM0) can be controlled by radiotherapy
alone. While radiotherapy has the efficacy to destroy
all clonogenic cells of a macroscopic solid tumor,
chemotherapy can only reduce the total number of
tumor cells by 2–3 orders of magnitude. Though this
tumor cell kill is not sufficient for permanent local
tumor control by itself, it may be crucial in combined
modality treatment with radiation therapy improving
overall response and eventually survival by sterilizing
clonogenic tumor cells surviving radiotherapy. In
addition, chemotherapy may render clonogenic tumor
cells more susceptible to radiation therapy increasing
the net cell kill compared to radiotherapy alone by
modulating processes involved in tumor radioresis-
tance such as sub-lethal damage repair, repopulation
or intrinsic radiosensitivity. Furthermore chemother-
apy has the potential to control an early stage of
systemic cancer disease by sterilizing microscopic
metastases. This is an important aspect in the treat-
ment of advanced stage NSCLC by chemoradiation.
Therefore chemotherapy has become an integral part
in combined cancer treatment, especially in the
treatment of advanced stage NSCLC. An associated
higher acute toxicity caused by interaction of these
two treatments has to be considered, particularly for
concurrent chemoradiotherapy. Especially the risk of
late treatment toxicity should be kept at an acceptable
limit.
This chapter summarizes the pre-clinical data and
early-clinical evidence for the rational of combining
second generation drugs with radiotherapy in
advanced stage NSCLC.
2 Mechanism of Action of Second
Generation Chemotherapeutic
Agents and Their Interaction
with Radiotherapy
2.1 Platinum Compounds (Cisplatin
and Carboplatin)
Platinum-based compounds form a distinct class of
very potent anti-cancer agents characterized by its
M. Geier and N. Andratschke
unique metallic element. The oldest in its class,
Cisplatin, still represents the most widely used and
effective drug in chemoradiation. Its potent antitumor
effects are based on the inhibition of DNA synthesis
and the formation of DNA interstrand cross-links. It
has long been recognized as a potent radio-sensitizing
agent both in vitro and in vivo, though supra-additive
effects have not been consistently demonstrated in all
experimental studies. The mechanism of interaction
has not fully been elucidated. It has been assumed to
inhibit PLDR and SLDR (Douple and Richmond
1978) as well as act preferentially on hypoxic tumor
cells rendering them more susceptible to radiation
(Ziegler and Kopp 1987). Still, the radiation
enhancing properties may well mainly rely on its
independent cytotoxicity adding to the effect of the
combined treatment and the different toxicity profile
not overlapping with radiation-induced toxicity.
Regardless of the mechanism involved, it has been
shown that a close temporal interaction is necessary to
maximize the combined effects of radiotherapy and
Cisplatin. Optimal results with regard to radiation
enhancement have been observed when administered
with fractionated radiotherapy shortly before each
fraction (Dewit 1987). Carboplatin is a newer plati-
num derivative specifically lacking the renal toxicity
seen with Cisplatin. Exerting similar radiation
enhancing effects with a favorable toxicity profile
readily allowed for an effective introduction into
clinical chemoradiation protocols.
2.2 Etoposide
Topoisomerases are a class of enzymes necessary to
maintain the integrity of the genome during tran-
scription, replication and recombination by acting on
DNA topology (Binaschi et al. 1995). Etoposide as an
inhibitor of topoismerase II leads to stable and thus
irreparable DNA single- and double-strand breaks
(ratio approx. 10–20:1) by stabilizing the DNA
cleavage complex preventing religation of DNA.
Radiation-induced single-strand breaks are converted
to double-strand breaks in the presence of toposi-
merase inhibitors, especially in S phase of the cell
cycle (Chen et al. 1997). This way, Etoposide leads
to a significant increase in lethal double-strand
breaks and hence to an increased cytotoxicity of the
combined treatment.
Radiotherapy and Second Generation Drugs
2.3 Vincaalkaloide (Vinblastin,
Vindesine)
Vincaalkaloids—originally derived from Catharan-
thus roseus/vinca rose—are a class of drugs that
interfere with the formation and function of micro-
tubuli by interacting with tubulin, a microtubular
protein of the mitotic spindle apparatus necessary for
cell division. As microtubuli destabilizing agents bind
soluble and microtubuli-associated tubulin and thus
inhibit a correct configuration of the mitotic spindle,
they act particularly on proliferating cells.
At low concentrations cell cycle arrest in meta-
phase is induced. At higher concentrations microtu-
bule depolymerization and mitotic spindle destruction
are observed. The antitumor activity of Vinblastine
and Vindesine is thought to be primarily due to these
cell cycle phase-specific interactions (Jordan et al.
2004). Subsequently cell death occurs by several
mechanisms from different forms of mitotic slippage
or adaptation to mitotic catastrophe. Vindesine, a
semi-synthetic vinca alkaloid, derived of Vinblastine,
is three times more potent than Vincristine and nearly
10 times more potent than Vinblastine in causing
mitotic arrest in vitro.
The hypothetical benefit of combining radiother-
apy with the Vinblastine or Vindesine, i.e. supra-
additive cell kill due to the cell cycle arrest at the
radiosensitive M-phase, could not conclusively be
demonstrated in pre-clinical studies (Sui et al. 2005;
Van Belle et al. 1994).
2.4 Ifosfamide
The small molecule Ifosfamide belongs to the group
of alkylating agents. The exact mode of action by now
is not entirely clear, but it is most likely similar to the
other agents of that group. After biotransformation in
the liver by the cytochrome P450 oxygenases the
active metabolites of the pro-drug alkylate or bind
with many intracellular molecular structures, includ-
ing nucleic acids. The main cytotoxic action is caused
by the alkylation of DNA with formation of inter and
intra strand cross-links in the DNA that lead to cell
death. (Fleming 1997).
In vitro supra-additive effects could be shown
after exposure of different human cancer cell lines
to Ifosfamide combined with radiation assessed by
277
clonogenic survival. At the S-phase of the cell cycle it
has been suggested that especially the enhancement of
radiation effects could be mediated due to interference
of Ifosfamide with the repair pathways of radiation-
induced potentially lethal damage (Latz et al. 1998;
Latz and Weber 2002).
2.5 Mitomycin
Mitomycin, a bioreductive alkylating agent isolated
from Streptomyces caespitosus or Streptomyces lav-
endulae, has been initially used as an antibiotic before
its antitumor activity was recognized. Reductive
activation of the drug is required to bind DNA by
mono- or bifunctional alkylation which causes
cross-linking of the DNA strands with high efficiency
and leads to inhibition of DNA synthesis and function
(Verweij and Pinedo 1990).
Due to this mechanism Mitomycin C preferentially
kills hypoxic tumor cells. Assuming that normal tissues
are less hypoxic, the selective targeting of this cell
population has the potential to improve tumor cure
without compromising normal tissue complication
rates, though this differential effect seems only relevant
for a very low oxygen tension.
In vivo a significant enhancement of radiation
response of solid tumors could be shown in pre-
clinical studies administering Mitomycin C before
radiation. The enhancement seemed to be related both
to direct radiosensitization and independent cytotox-
icity against radio-resistant hypoxic cells (Grau and
Overgaard 1991).
3 Early Clinical Evaluation
Chemotherapy can be administered before, during or
after radiotherapy. The aims of the concepts are very
different. Sequential chemoradiotherapy adding
radiotherapy after chemotherapy treatment is used to
increase the rate of clonogenic cell kill in critical
areas with micro- or macroscopic tumor residuals that
are not treated sufficiently by the preceding chemo-
therapy. Concurrent chemoradiation may have several
advantages compared to the sequential protocols
besides independent cytotoxicity as it combines the
effects of spatial and temporal cooperation to increase
net tumor cell kill via additive or even supra-additive
278
effects and avoids the detrimental effect of treatment
prolongation and possible induction of repopulation
by chemotherapy.
The clinical phase I/II studies presented in the
following sections reflect quite nicely the aforemen-
tioned different rationales for combining second
generation drugs with radiotherapy either in a
sequential or a concurrent setting with or without
induction or consolidation chemotherapy. Particularly
the concurrent radiochemotherapy protocols employ-
ing low-dose platinum-based regimens were designed
to exploit synergistic effects by close temporal
cooperation as a results of daily or weekly adminis-
tration at presumed sub-toxic dose levels shortly
before each fraction while aiming at reducing acute
toxicity, especially acute esophageal reaction.
3.1 Sequential Radiochemotherapy
An Italian phase II trial evaluated sequential chemo-
radiation with three cycles of high-dose chemotherapy
consisting of Ifosfamide 3 g/m2 day 1, Carboplatin
200 mg/m2 days 1 and 2, Etoposide 120 mg/m2 days
1–3 as well as rhG-CSF support followed by normo-
fractionated radiotherapy to a total dose of 60 Gy.
Only 61% of the 61 enrolled patients completed the
intended chemoradiation regimen. The results regard-
ing survival were disappointing with a median
progression-free survival of 5.4 months and a median
1-year overall survival rate of 31%. Toxicity was
modest and mainly due to grade 3 or greater thrombo-
cytopenia in 24% of the administered chemotherapy
cycles (Scagliotti et al. 1996).
A phase II EORTC study compared response rates
and morbidity of sequentially combined high dose split
course radiotherapy with induction chemotherapy to
high dose split course radiotherapy alone. Induction
chemotherapy consisted of Cisplatin 100 mg/m2 on
days 1 and 22 and Vindesine 3 mg on days 1 and 8, and
22 and 29. Hypofractionated split-course radiotherapy
of 30 Gy in 3 Gy per fraction and 25 Gy per 2.5 Gy
fraction separated by a 21 days interval to a total dose
of 55 Gy was administered beginning with day 1 in the
radiotherapy arm and day 43 in the chemoradiation arm
with a third cycle of chemotherapy between the two
radiotherapy courses. Of 70 randomized patients with
stage III NSCLC 34 were evaluated in the chemoradi-
ation arm and 30 in the radiotherapy arm. The addition
M. Geier and N. Andratschke
of chemotherapy in this manner resulted only in an
increase of acute toxicity with no beneficial effects to
response rates/progression-free and overall survival
with an observed median survival of 12 months in both
arms and median time to progression of 30 weeks for
chemoradiation and 35 weeks for radiotherapy alone
(Planting et al. 1996).
In the GOTHA I trial hyperfractionated accelerated
radiotherapy was combined with simultaneous and
adjuvant chemotherapy alternating Cisplatin and
Vinblastin. Radiotherapy was given in 1.5 Gy single
dose in 42 fractions with b.i.d. treatment during weeks
2, 3, 6 and 7 to a total dose of 63 Gy. Chemotherapy
consisted of six cycles Cisplatin 70 mg/m2 (day 1)
and Vinblastin 5 mg/m2 (day 7) during week 1 and 5
overlapping with radiotherapy, and week 9, 13, 17,
and 21 afterwards. The long term results of the Suisse
study including 67 inoperable stage III patients were
published together with those of the consecutive
GOTHA II trial that evaluated the same hyperfrac-
tionated accelerated radiotherapy combined with a
different alternating chemotherapy including three
cycles of Cisplatin 60 mg/m2 and Mitomycin 8 mg/
m2 on day 1 and Vindesine 3 mg/m2 on days 1 ? 8
during weeks 1, 5, 9, 13, 17 and 21. The analysis with
a minimum follow-up of 3 years and an median
follow- up for survivors of 6 years showed a 1-, 3-,
5- and 8-year overall survival of 56, 27, 12 and 9%
with a median survival of 13.6 months. No significant
differences in survival for stage IIIA versus IIIB or
performance status or the two treatment arms could
be detected. Long time survival does not strongly
correlate with response rates. Acute toxicity consisted
mainly of grade 3 or greater hematological side
effects with lower rates of non-hematological toxicity
(e.g. mucositis and nausea) and very low rates of
grade 3–4 lung toxicity. Four treatment-related deaths
were reported (Mirimanoff et al. 1998).
The GOTHA II trial included 65 Patients treated
with split course hyperfractionated accelerated
radiotherapy to a total dose of 63 Gy in 1.5 Gy b.i.d.
in five fractions a week combined with an alternating
chemotherapy including three cycles of Cisplatin
60 mg/m2 and Mitomycin 8 mg/m2 on day 1 and
Vindesine 3 mg/m2 on days 1 ? 8 during weeks 1, 5,
9, 13, 17 and 21. Superior results regarding survival
with an acceptable increase of toxicity compared to
conventional radiotherapy alone were reported by the
suisse group (Mirimanoff et al. 1998).
Radiotherapy and Second Generation Drugs
The Japanese Phase II study JCOG 9306 assessed
the efficacy and toxicity of alternating chemoradiation
combining hyperfractionated accelerated radiotherapy
to a total dose of 66–70 Gy with 1.5 Gy b.i.d. with
Cisplatin 80 mg/m2 on day 1 and Vindesine 3 mg/m2
on days 1 and 8. Radiotherapy was given during
weeks 1, 2, 5, 6 and 9, whereas chemotherapy during
week 3 and 7 and optionally week 10. Of 41 enrolled
patients 32 completed the intended treatment. In 7
of the 41 Patients chemotherapy was discontinued
before completing at least two cycles, due to
treatment-related toxicity (3), patients refusal (1),
progressive disease (1) or complications unrelated to
treatment. Radiotherapy could not be completed
because of treatment-related toxicity, progressive
disease and complications in 3, 1 and 2 patients,
respectively. Median 3- and 5-year survival rates of
24 and 10% and a median survival of 18.4 months
were accompanied by at least grade 3 leucopenia and
esophagitis in 32 and 7 patients, respectively and late
esophageal toxicity of at least grade 3 in 2 patients.
In most of the patients therapy had to be paused
due to the resulting acute hematological side effects
(Sekine et al. 2002).
3.2 Concurrent Radiochemotherapy
3.2.1 Single Agent Regimens
3.2.1.1 Cisplatin
The RTOG trial 92-04 compared induction chemo-
therapy with Vinblastine and Cisplatin followed by a
concurrent chemoradiation with lower dose Cisplatin
every 2 weeks simultaneous with hyperfractionated
accelerated radiotherapy (HART) with concurrent
chemoradiation consisting of Cisplatin and Etoposide
and the same dosed HART (69.6 Gy 1.2 Gy per
fraction b.i.d.). Overall survival was the primary
endpoint of the study. For the 80 included patients
treated with the Cisplatin mono scheme the 1-year
overall survival was 65% with a median survival of
15.5 months and an 1-year progression-free survival
rate of 50%. Predominantly hematological grade 4
toxicity was reported in that arm similar to the earlier
RTOG trial. Non-hematological acute and late side
effects consisted mainly of esophageal toxicity with
grade III or higher acute toxicity in 6% and late
toxicity in 3% of the patients (Komaki et al. 1997).
279
In an earlier phase II Southwest Oncology Group
protocol standard fractionated thoracic irradiation to a
total dose of 61 Gy combined with concurrent daily
low-dose Cisplatin (5 mg/m2) followed by three
cycles of high-dose Cisplatin consolidation chemo-
therapy (100 mg/m2 on day 1 and 8) was studied for
feasibility and effectiveness in 64 eligible patients
with locally advanced unresectable NSCLC. 1- and
2-year actuarial survival rates of 56 and 24% and a
median survival for all patients of 14 months were
reported. Stage IIIa patients showed a better median
survival of 17 months and a 2 year survival rate of
38%, as compared with 10 months and 14% for stage
IIIb patients, respectively. 8% of the Patients could
not complete concurrent chemoradiation due to
toxicity. Acute grade 3 side effects were reported for
esophagitis (16%), leukopenia (14%), nausea (8%),
and vomiting (6%) (Hazuka et al. 1994).
In the EORTC 08912 phase I/II study Uitterhoeve
et al. investigated the feasibility of radiotherapy and
chemotherapy dose escalation given as concurrent
chemoradiation in 40 inoperable NSCLC patients.
Dose escalation was carried out at four different levels
increasing the total doses of a simultaneous integrated
boost radiotherapy subsequently from 55 Gy in 2.75
per fraction to 60.5 Gy giving two extra fractions at
levels I and II and to 66 Gy at levels III and IV giving
four extra fractions, respectively. Furthermore dose
escalation of concurrent daily Cisplatin (6 mg/m2)
was carried out beginning at level II and III com-
bining two extra fractions of radiotherapy and four
extra fractions at Level IV respectively with concur-
rent Cisplatin. The authors reported good overall
survival rates at 1 and 2 years with 53 and 40%,
respectively. This survival was associated with rather
low side effects regarding C grade 3 acute toxicity with
nausea in 8% and leucopenia and thrombocytopenia in
5% of the patients. Late toxicity for esophageal
symptoms C grade 3 was reported in 5% with only
grade 1 and 2 radiation pneumonitis in 3% of the
patients, respectively (Uitterhoeve et al. 2000).
An triple agent induction chemotherapy protocol
with Ifosfamide, Etoposide and Cisplatin preceding
thoracic radiotherapy combined with continuous
low-dose Cisplatin infusion (6 mg/m2/days) for
stage IIIb NSCLC patients was evaluated by Pujol
et al.. Induction chemotherapy consisted of three
courses of Ifosfamide 1.5 g/m2, Etoposide 100 mg/m2
and Cisplatin 25 mg/m2, given on days 1–4 of a
280
21 day cycle. Recombinant human methionyl granu-
locyte colony stimulating factor was used for hema-
topoietic support. A split-course normo-fractionated
thoracic radiotherapy (first course: 30 Gy/10; 4 week
rest period; second course: 25 Gy/10) and concurrent
continuous low-dose Cisplatin infusion of 6 mg/m2
daily was administered to patients with at least stable
disease after induction chemotherapy. This rather
aggressive protocol with intense induction chemother-
apy with high therapy-related toxicity and split-course
radiotherapy did yield a disappointing outcome regard-
ing locoregional progression and overall survival (Pujol
et al. 1999).
Another low-dose Cisplatin-based chemoradio-
therapy regime using a triple induction chemotherapy
protocol with Vindesine, Ifosfamide and Cisplatin and
subsequent Cisplatin concurrent to radiotherapy was
assessed by a Belgium phase II trial. From 1993 to
1995 23 stage III NSCLC patients were enrolled to
the study. Three cycles of Cisplatin 30 mg/m2 and
Ifosfamide 1,200 mg/m2 on days 1–3 plus Vindesine
3 mg/m2 on days 1 and 8 were administered every
4 weeks followed by an hypofractionated radiother-
apy to a dose of 30 Gy in 3 Gy per fraction and a
boost to an accumulative total dose of 52.2 Gy
in 2.2 Gy with every fraction preceded by daily
Cisplatin 6 mg/m2. In four patients induction could
not be completed due to one therapy-related death and
progressive disease in three patients and subsequent
radiotherapy was not administered. This Ifosfamide
containing chemoradiotherapy protocol showed dis-
appointing survival. Treatment was accompanied by
quite high toxicity which was predominantly of
hematologic origin, but also neurologic and pulmonal
grade 3 or greater toxicity was observed (Van den
Brande et al. 1998).
Several other smaller phase I/II studies have also
investigated the feasibility and effectiveness of daily
low-dose Cisplatin as a single agent concurrent to
radiochemotherapy. As the study design and the
results are similar to the above-mentioned studies,
they have been included in Table 1 for the sake of
completeness.
3.2.1.2 Carboplatin
Thomas et al. reported on a phase I study eval-
uating Carboplatin as radiosensitizer after Cisplatin-
based induction chemotherapy in NSCLC patients
with locally advanced disease. Induction of triple
M. Geier and N. Andratschke
chemotherapy consisting of Cisplatin, Mitomycin and
a vinca alkaloid was followed by a standard frac-
tionated thoracic radiotherapy to a total dose of
62–66 Gy with concurrent daily bolus or continuous
infusion of Carboplatin. A median survival of 12
months was reported for the 29 included patients. As
the dose escalation of Carboplatin showed limiting
thrombocytopenia for 15 mg/m2/days, 10 mg/m2
were recommended by the authors when used in this
setting (Thomas et al. 1997).
Dose escalation of Carboplatin concurrent to
accelerated hyperfractionated radiotherapy to a total
dose of 60 Gy in 1.5 per fraction b.i.d. followed by
four cycles of consolidating Carboplatin chemother-
apy (350 mg/m2) was assessed in an phase I study of
Kelly et al. including 30 patients with inoperable
NSCLC. Chemotherapy consisted of daily Carbo-
platin 25 mg/m2 or 30 mg/m2 concurrent to radio-
therapy. Two of six patients receiving 30 mg/m2
experienced grade 4 dose-limiting esophagitis, in
contrast to 3 of 24 patients in the 25 mg/m2 group.
During consolidation chemotherapy grade 4 throm-
bocytopenia was observed in one of 22 patients.
Median 1- and 2-year survival rates of 63 and 49%,
respectively, were reported by the author with an
median survival of 18.3 months (Kelly et al. 1998).
The feasibility and efficacy of concomitant
radiochemotherapy with standard fractionated radio-
therapy to a total dose of 66 Gy and concurrent daily
Carboplatin chemotherapy with 15 mg/m2 adminis-
tered after two cycles of induction chemotherapy
(on day 1 and 28) with Etoposide (100 mg/m2) on
days 1 to 3, and Carboplatin (350 mg/m2) on day
1 was evaluated in a phase II trial by Bardet et al.
Fourty patients with locally advanced unresectable
non-metastatic NSCLC with at least stable disease
after induction chemotherapy were treated with
above described concurrent chemoradiotherapy
starting on day 55 followed by two additional cycles
of Etopopside and Carboplatin for 4 weeks after
completion of chemoradiotherapy. Thirty eight per-
cent of the 37 patients who received full-induction
chemotherapy showed grade 3–4 hematological
toxicity with a response rate of only 11%. Twelve of
26 non-progressive patients received the additional
two cycles of Etoposide and Carboplatin. Median
survival was only 9 Months with 1 and 2 year
overall survival rates of 38 and 15%, respectively
(Bardet et al. 1997).
Table 1 Summary of phase I/II studies with second generation chemotherapy concurrent to radiotherapy
Author Number RTx CTx Overall 1 year 2 years 5 years Hematological Non- Remarks
of survival, (%) (%) (%) toxicity C3 hematological
patients median (%) toxicity C3
(months) (%)
Komaki et al. 80 Standard Cisplatin 15.5 65 62 (grade 4) Esophageal 3 Induction:
(1997) fractionated Cisplatin,
Vinblastine
Van den 19 Hypofractionated Cisplatin l.d. 10.6 47 16 Leukopenia 22 Neurotoxicity Induction:
Brande et al. daily 18; Cisplatin,
(1998) pneumonitis Ifosfamide,
11 Vindesine
Pujol et al. 44 Hypofractionated Cisplatin l.d. 12 49 19 5 Neutropenia 66 Late Induction:
(1999) split-course daily (3 years) (grade 4), pulmonary 23, Cisplatin,
Radiotherapy and Second Generation Drugs

leukopenia 34 esopahgeal 9 Ifosfamide,

(grade 4), Etoposide
thrombopenia
25 (grade 4)
van 40 Hypofractionated Cisplatin l.d. 10.5 Thrombopenia –
Harskamp split-course daily 2
et al. (1987)
Boven et al. 40 Hypofractionated Cisplatin l.d. 10.5 – –
(1988) split-course daily
Hazuka et al. 65 Standard Cisplatin l.d. 14 56 24 14 Esophageal Consolidation:
(1994) fractionated daily 16, nausea 8 Cispaltin;
(grade 3),
nausea 6
(grade 4)
Palazzi et al. 36 Hyperfractionated Cisplatin l.d. 8 37 – Esophageal Continuous
(1996) accelerated daily 14, late concomittant:
pulmonary 3 Cisplatin
(grade 5)
Sarihan et al. 15 Concomittant Cisplatin l.d. 16 – Nausea 60
(1998) boost daily
Ardizzoni 32 Standard Cisplatin l.d. 12.5 52 26 19 21 (RCTx), 31 Esophageal 6 Induction:
et al. (1999) fractionated daily (3 years) (Induction Cisplatin,
CTx) Vinblastine
(continued)
281
Table 1 (continued)
282

Author Number RTx CTx Overall 1 year 2 years 5 years Hematological Non- Remarks
of survival, (%) (%) (%) toxicity C3 hematological
patients median (%) toxicity C3
(months) (%)
Uitterhoeve 40 Hypofractionated Cisplatin l.d. 53 40 10 Nausea/ Phase I/II;
et al. (2000) daily vomiting 8,
late
esophageal 5
Thomas et al. 29 Standard Carboplatin 12 – Esophageal 10 Phase I
(1997) fractionated l.d. daily (at highest induction:
Carboplatin Cisplatin,
level of dose Mitomycin,
escalation) Vinca Alkaloid
Bardet et al. 40 Standard Carboplatin 9 38 15 38 (induction 21 Induction:
(1997) fractionated l.d. daily CTx), 13 Carbopaltin,
(RCTx) Etoposide;
Kelly et al. 30 Hyperfractionated Carboplatin 18.3 63 49 4 Esophageal 43 Consolidation:
(1998) accelerated l.d. daily (consolidation (grade 4) Carboplatin
CTx)
Kalemkerian 19 Standard Cisplatin l.d. 18 42 11 47 (RCTx), 38 Esophageal 42 Phase I;
et al. (1999) fractionated daily, (consolidation consolidation:
Etoposide CTx) Cisplatin,
l.d. daily Etoposide
Lee et al. 76 Hyperfractionated Cisplatin, 18.9 67 35 57 (grade 4) 6.6 (grade 4/5),
(1996, 1998) accelerated Etoposide esophageal 53,
pulmonary 25
Komaki et al. 82 Hyperfractionated Cisplatin, 14.4 58 33 (grade 4) Esophageal 38
(2002) accelerated Etoposide
Pottgen et al. 30 Hyperfractionated Cisplatin, 13 31 Leukopenia 63, Esophageal 33, Induction:
(2002) accelerated, Etoposide Thrombopenia Pneumonitis 3 Cisplatin,
standard 23 (grade 4) Etoposide
fractionated boost
Blanke et al. 21 Standard Cisplatin, 50.2 (weeks) 45 Leukopenia 55, Pulmonary 25, Early closure
(1997) fractionated Etoposide thrombopenia esophageal 40 due to
40 (grade 4) pulmonary
toxicity
(continued)
M. Geier and N. Andratschke
Table 1 (continued)
Author Number RTx CTx Overall 1 year 2 years 5 years Hematological Non- Remarks
of survival, (%) (%) (%) toxicity C3 hematological
patients median (%) toxicity C3
(months) (%)
Albain et al. 50 Standard Cisplatin, 15 17(3 year) 15 Neutropenia 32 Esophageal 12 Consolidation:
(2002) fractionated Etoposide (grade 4) (grade 3), Cisplatin,
esophageal 8 Etoposide
(grade 3)
Lau et al. 63 Standard Carboplatin, 13 21 Leukopenia 50, Esophageal 15 Poor risk
(1998) fractionated Etoposide tthrombopenia patients
23
Jeremic et al. 58 Hyperfractionated Carboplatin, 10 42 24 9.1 22 Esophageal 7, Elderly
(1999) accelerated Etoposide Pulmonary 4 patients
Radiotherapy and Second Generation Drugs

(oral)
Jeremic et al. 41 Hyperfractionated Carboplatin, 25 34(3 years) 29 30 Esophageal
(1999) accelerated Etoposide 15, Pulmonary
12
Tsuchyia 11 Hyperfractionated Cisplatin, 64 Leukopenia 91 Esophageal 27 Phase I
et al. (2001) accelerated Vindesine
10 Standard Cisplatin, 70 Leukopenia 90 Pneumonitis
fractionated Vindesine 20 (grade5)
Kubota et al. 70 Standard Cisplatin, 14.8 14.8 Leukopenia 93 Nausea/
(2000) fractionated Vindesine vomiting 27
split-course
Le Pechoux 34 Hyperfractionated Low-dose 53 12 6 (grade 4) Esophageal 9 Consolidation:
et al. (1996) accelerated Cisplatin, Cisplatin,
Vindesine Vindesine;
Byhardt et al. 42 Hyperfractionated Cisplatin, 12.2 54 28 45 (grade 4) Esophageal 24
(1995) accelerated Vinblastine
Furuse et al. 61 Standard Cisplatin, 16 36.7 Leukopenia 95, Nausea 16,
(1995) fractionated Mitomycin, Thrombopenia Esophageal 6
split-course Vindesine 45
Atagi et al. 22 Standard Cisplatin, 19 84.8 34.5 Leukopenia 82, Esophageal 5,
(2002) fractionated Mitomycin, thrombopenia pulmonary 5
Vindesine 27 (grade 4)
Lee et al. 161 Hyperfractionated Cisplatin, 15 51.2 25.1 14.8 – –
(2003) accelerated Mitomycin,
Vinblastine
283

l.d. low-dose
284
3.2.2 Double Agent Regimens
3.2.2.1 Cisplatin/Etoposid
There are several phase I and II studies evaluating
concurrent chemoradiation combining Cisplatinum
and the topoisomerase-II-inhibitor Etoposide with
either standard fractionated or hyperfractionated
accelerated radiotherapy that showed promising
results compared to radiotherapy alone or even other
platinum-based chemotherapy regimens.
In the phase II RTOG trial 91-06 two cycles of
Etoposide (50 mg day 1 alternating with 50 mg b.i.d.
days 1–21) and Cisplatin (40 mg/m2 on day 1 and 8
of a 28 day cycle) were administered concurrent
to hyperfractionated accelerated radiotherapy with
1.2 Gy b.i.d to a total dose of 69.6 Gy. Estimated 1-
and 2-year overall survival was 67 and 35%, respec-
tively and with a median survival of 18.9 months
quite promising. A subgroup of patients with less than
5% weight loss had even better survival rates with an
estimated 1- and 2-year survival of 70 and 42% and a
median survival of 21.1 month. Acute toxicity was
considerable with grade 4 hematologic side effects in
57% of patients. Non-hematological acute toxicities
higher than grade 3 were observed in 53 and 25%
regarding symptoms of the esophagus and lung,
respectively. These early phase II results could be
confirmed by a later published report on long-term
follow-up. After 5 years of minimum follow-up 5 of
18 eligible patients were still alive with no evidence
of disease. A 5 year survival rate of 22% was repor-
ted. One treatment-related death due to severe radia-
tion pneumonitis was reported (Lee et al. 1996, 1998).
Due to the high treatment-related toxicity observed
in the RTOG 91-06 trial, especially esophageal
toxicity, a subsequent randomized phase II RTOG
trial 92-04 tested the same treatment with reduced
doses of Etoposide (50 mg b.i.d on days 1–10) and
Cisplatin (50 mg/m2 on day 1 and 8) concurrent to
hyperfractionated accelerated radiotherapy. This
arm was compared to a treatment regime of induc-
tion chemotherapy with Vinblastine and Cisplatin
followed by a chemoradiation with lower doses of
Cisplatin every 2 weeks of daily radiotherapy to a
total dose of 63 Gy in 1.8 Gy per fraction. Treatment
arm with concurrent chemotherapy and hyperfrac-
tionated accelerated radiotherapy had a favorable
effect regarding time to in-field progression compared
to the standard fractionation arm (26 versus 45% at
M. Geier and N. Andratschke
2 years; 30 versus 49% at 4 years). Similar survival
rates with 5-year overall survival rates of 16% and a
median survival of 15.5 months compared to 13% and
16.4 months in the standard arm of the study were
observed. Non-hematological side effects were pre-
dominantly observed in the hyperfractionated arm,
especially with regard to acute and late esophageal
toxicity, though dose-reduced Etoposide led to a
decreased acute esophageal toxicity compared to the
RTOG 91-06 trial, C grade 3 toxicity 38 versus 53%,
respectively (Komaki et al. 2002).
The SWOG 9019 phase II evaluated chemora-
diotherapy with Cisplatin (50 mg/m2) on days 1, 8,
29, 33 and etopsoide (50 mg/m2) on days 1–5,
29–33 concurrent to standard fractionated radio-
therapy to a dose of 45 Gy in 1.8 Gy per fraction,
followed by a boost to a total dose of cumulative
61 Gy in 2 Gy per fraction and additional two
cycles of Cisplatin and Etoposide as consolidation
chemotherapy for 50 patients with pathologically
proven stage IIIB NSCLC. Boost treatment and
consolidation chemotherapy was administered
exclusive to patients with at least stable disease and
no change in pulmonary function. The study
revealed an overall median survival of 15 months
with 3 and 5 year survival rates of 17 and 15%,
respectively. The most frequent therapy-related
toxicity was hematological with grade 4 neutropenia
in 32% of the patients. Major non-hematological
toxicity was observed for esophagitis with grade
3 and 4 symptoms in 12 and 8% of the patients,
respectively (Albain et al. 2002).
In a more recent German phase I/II trial, including
30 stage III NSCLC patients two cycles of induction
chemotherapy consisting of Cisplatin (60 mg/m2/
day on days 1 and 7) and Etoposide (150 mg/m2/
day on days 3–5) followed by chemoradiation with
one cycle of Cisplatinum (50 mg/m2/day on days 1
and 7) and Etopside (100 mg/m2/day on days 3–5)
was evaluated with regard to overall survival and
local control. Radiation treatment was given as
hyperfractionated accelerated radiotherapy to a dose
of 45 Gy in 1.5 Gy b.i.d. followed by a normo-
fractionated boost of 20 Gy to a total cumulative dose
of 65 Gy. Acceptable toxicity with no treatment-rela-
ted deaths was reported with grade 3 and 4 esophagitis
in 20 and 13% of patients and grade 4 pneumonitis in
3% of the patients. With an actuarial 2-year survival
rate of 31% and a 21% local control rate, these results
Radiotherapy and Second Generation Drugs
compared favorably with the more toxic treatment
protocols reported so far (Pottgen et al. 2002).
Kalemkerian et al. intended to determine the
maximum tolerated dose of daily continuous intra-
venous infusion of low-dose Cisplatin and Etoposide
that could be administered concurrently to thoracic
radiotherapy in their phase I trial published in 1999.
Continuous intravenous chemotherapy at three dose
levels was given to 19 patients concurrently with
radiotherapy in single daily fraction doses of 45 Gy
followed by a 15–20 Gy boost and three cycles
of standard bolus infusion of Cisplatin 80 mg/m2 on
day 1 and an Etoposide 80 mg/m2 on days 1–3.
Maximum tolerated dose was determined as Cisplatin
5 mg/m2/day and Etoposide 18 mg/m2/day on 5 days
a week over 5 weeks. Main toxicity during concurrent
chemoradiotherapy was grade 3–4 esophagitis and
myelosuppression in 42 and 47% of the patients,
respectively. Treatment led to a median survival time
of 18 months with 2- and 5-year survival rates of 42
and 11%, respectively (Kalemkerian et al. 1999).
Blanke et al. conducted a phase II trial including
21 patients with locally advanced inoperable NSCLC
(stage IIIA or IIIB) to assess the response rate and
toxicity of standard fractionated radiotherapy to a
dose of 50.8 Gy in 1.8 Gy per fraction, followed by a
boost of 10 Gy in 2 Gy per fraction with concurrent
daily low-dose Cisplatin (5 mg/m2) before each
fraction of radiotherapy and Etoposide (20 mg/m2)
Monday to Friday on weeks 1, 2, 5, and 6. Additional
oral Etoposide (50 mg/m2) was given on the week-
end. An overall response rate of 65% led to a median
overall survival of 50.2 weeks and an 1-year survival
rate of 45%. Therapy was associated with an high risk
of severe radiation pneumonitis, observed in 25% of
the patients. This was responsible for the early closure
of the trial (Blanke et al. 1997).
3.2.2.2 Cisplatin/Vinblastine
This duplet-agent regimen was investigated in the
RTOG phase II study 90-15 with hyperfractionated
accelerated radiation treatment to a total dose of
69.9 Gy in 1.2 Gy b.i.d. combined with concur-
rent chemotherapy. Vinblastine 5 mg/m2 weekly was
given in five cycles and Cisplatin 75 mg/m2 on days
1, 29 and 50. Median survival time was 12.2 months
with a 1-year overall survival of 54%, estimated
2-year survival of 28% and a 1-year progression-free
survival of 38%. Acute toxicity was high (45%) with
285
predominantly hematological toxicity of at least grade
4 and three cases of septic death. Esophagitis was
the main non-hematological acute toxicity. Severe
late side effects occurred in about 10 percent of
patients with pulmonary, esophageal and hematolog-
ical symptoms (Byhardt et al. 1995).
3.2.2.3 Cisplatin/Vindesine
Tsuchiya et al. (2001) reported on the JCOG 9601
study, a randomized phase I radiation dose-escalation
trial evaluating concurrent radiochemotherapy with
either normo-fractionated or hyperfractionated accel-
erated radiotherapy. In the normo-fractionated group
an escalation from the standard dose level of 60 Gy in
30 fractions over 6 weeks to 70 Gy in 35 fractions
over 7 weeks was planned, whereas in the hyper-
fractionated accelerated arm an escalation from
54 Gy in 36 fractions over 3.6 weeks to two higher
dose levels of 60 Gy in 40 fractions and 66 in 44
fractions was planned. Simultaneous chemotherapy
consisted of two to three cycles of Cisplatin 80 mg/
m2 on day 1 and Vindesine 3 mg/m2 on days 1 and 8
every 4 weeks. 21 Patients with unresectable stage
IIIA-B NSCLC were enrolled to the study. Treatment
showed high limiting toxicity already at the first dose
levels in 4 of 10 patients in the normo-fractionated
arm and 7 of 11 patients in the hyperfractionated
accelerated arm. Toxicity consisted mainly of hema-
tological side effects of at least grade 3. Main
non-hematologic toxicity grade 3 or greater was only
observed in three patients in the hyperfractionated
arm. One-year overall survival rates accounted for
70% in the normo-fractionated and 73% in the
hyperfractionated accelerated arm, respectively. Due
to the observed high-toxicity radiation dose escalation
could not be performed in neither of the two groups
(Tsuchiya et al. 2001).
Long-term results of the earlier JCOG trial 8902
were published in 2000 and showed a median 5 year
survival rate of 14.8% and a median survival of
14.8 months for 74 evaluated, patients with unresec-
table stage IIIA-B NSCLC. Treatment consisted of
normo-fractionated split-course radiotherapy with two
courses of 20 Gy in 2 Gy per fraction with a 14 days
break followed by another course of 10–20 Gy
combined with simultaneous chemotherapy with
Cisplatin 100 mg/m2 on days 1, 29 and 57 and
Vindesine 3 mg/m2 on days 1 and 8 every 4 weeks.
Main toxicity C grade 3 was leucopenia observed in
286
93% of the patients. Two treatment-related deaths
occurred and were related to pneumonia and hem-
optysis (Kubota et al. 2000).
In a French phase II study 34 patients with locally
advanced NSCLC were treated with hyperfractionated
accelerated radiotherapy to a total dose of 60 Gy in
1.25 Gy per fraction b.i.d. with concurrent chemo-
therapy consisting of daily low-dose Cisplatin 6 mg/m2
and Vindesine 2.5 mg/m2 weekly, followed by two
cycles of consolidating chemotherapy with Cisplatin
120 mg/m2 on week 11 and 14 and vindesine
2.5 mg/m2 on weeks 11, 12 and 13. An encouraging
local failure rate of 53 and 56% at 3 and 5 years was
achieved with severe esophagitis seen in 9% of patients
and two toxicity-related deaths. Overall 1-, 3- and
5-year survival rates of 53, 33 and 12% were observed
(Le Pechoux et al. 1996).
3.2.2.4 Carboplatin/Etoposide
Treatment regimes using Carboplatin instead of
Cisplatin were evaluated for poor performance
patients who were medically not qualified for a
treatment with Cisplatin due to co-morbidity.
Activity and feasibility of chemoradiotherapy with
daily low-dose carboplatin (30 mg/m2) and Etoposide
(30 mg/m2) from Monday to Friday concurrent to
hyperfractionated accelerated radiotherapy to 69.6 Gy
in 1.2 Gy per fraction b.i.d. and increased chemother-
apy doses of 100 mg/m2, respectively on weekends
were assessed in a phase II trial by Jeremic et al.. For the
41 enrolled patients with stage III NSCLC encouraging
median survival of 25 months with 3- and 5-year sur-
vival rates of 34 and 29%, respectively were reported
by the authors, with mainly hematological (30% of
patients), esophageal (15%) and bronchopulmonary
(12%) acute side effects of at least grade 3 (Jeremic
et al. 1998).
Between 1988 and 1993 58 patients older than
70 years were enrolled in a phase II study to assess
feasibility, toxicity and efficacy of hyperfractionated
accelerated radiotherapy to a total dose of 51 Gy in
1.5 Gy per fraction b.i.d. concurrent to Carboplatin
400 mg/m2 on days 1 and 29 and oral E toposide
50 mg/m2 on days 1 to 21 and 29 to 42. Low-toxicity
rates were observed with grade 3 or greater hemato-
logical, esophageal and lung-related symptoms in 22,
7 and 4% of the patients without any late toxicity
grade 3 or greater. Overall survival and response rates
were comparable to other definitive radiotherapy
M. Geier and N. Andratschke
regimens in nonelderly patients with a 1-, 2- and
5-year overall survival of 45, 24 and 9.1%, respec-
tively and a median survival of 10 months. Local
control after 5 years was 13% with a median time to
local recurrence of 14 months (Jeremic et al. 1999).
Another phase II trial initiated by SWOG evaluated
the efficacy and toxicity of Carboplatin 200 mg/m2 on
days 1 and 3 and 29 and 31 combined with intravenous
Etoposide 50 mg/m2 on days 1 to 4 and 29 to 32
concurrent to normo-fractionated radiotherapy of
61 Gy in 1.8 to 2 Gy per fraction. Sixty-three patients
with stage III NSCLC and considerable cardiovascu-
lar, pulmonary and renal co-morbidity as well as
hearing loss, weight loss and peripheral neuropathy,
which precluded Cisplatin-based treatment were
included in the study. The treatment protocol was well
tolerated in this poor performance and high-risk patient
group, with grade 3 or greater side effects of leuco-
penia, thrombocytopenia and esophagitis in 50, 23 and
15% of the patients. No treatment-related deaths were
observed. This very encouraging low-toxicity regimen
yielded results comparable to Cisplatin-based chemo-
radiation treatment protocols in good risk patient with
a 2-year overall survival rate of 21% and a median
overall survival of 13 months (Lau et al. 1998).
3.2.3 Triple Agent Regimens
3.2.3.1 Cisplatin, Mitomycin, Vindesin
A Japanese group evaluated this triple agent chemo-
therapy scheme for concurrent chemoradiotherapy
consisting of Cisplatin 100 mg/m2 and Mitomycin
8 mg/m2 on days 1 ? 29 and Vindesine 3 mg/m2 on
days 1 ? 8 and 29 ? 36 combined with normo-
fractionated split course radiotherapy. Radiotherapy
consisted of two courses of 36 Gy in 2 Gy per fraction
each over 3 weeks starting on day 1 of chemotherapy
and a rest period of 10 days between the two cycles.
After this treatment a 2-year overall survival rate of
36.7% with a median survival of 16 months was
reported for the 61 eligible patients with unresectable
stage III NSCLC. Predominantly hematologic toxicity
of grade 3 or greater for leucopenia, thrombocytopenia
and anemia was observed in 95, 45 and 28% of patients,
respectively. Non-hematologic grade 3 or greater tox-
icity was quite low, though two treatment-related
deaths were reported due to interstitial pneumonitis and
pulmonary infection after esophagobronchial fistula
(Furuse et al. 1995).
Radiotherapy and Second Generation Drugs
From the same institution, a phase II study
enrolling 22 Patients with unresectable stage III
NSCLC was published in 2002. Treatment included
continuous radiotherapy with a total dose of 60 Gy in
2 Gy per fraction concurrent to an identical chemo-
therapy excepting slightly dose reduced Cisplatin
80 mg/m2 instead of 100 mg/m2 compared to the
earlier trial. The study could demonstrate a modestly
improved outcome regarding survival compared to
the split-course treatment with a median survival of
19 months and a similar 2 year survival rate of 34.5%.
Furthermore lower toxicity was observed for hemato-
logic ([= grade 3 leucopenia and thrombocytopenia in
81.8 and 26% of patients) as well as for non-hematologic
symptoms (Atagi et al. 2002).
3.2.3.2 Cisplatin, Mitomycin, Vinblastin
A South Korean group initiated a phase II study to
evaluate feasibility, toxicity and treatment outcome of
Mitomycin, Vinblastine and Cisplatin chemotherapy
concurrent to hyperfractionated accelerated radio-
therapy in 161 stage III NSCLC patients from 1993 to
1996. One hundred forty-six patients completed
treatment which consisted of Cisplatin 60 mg/m2 on
day 1 and 28, Vinblastine 6 mg/m2 and Mitomycin
6 mg/m2 on days 2 and 29 administered simulta-
neously with radiotherapy to a total dose of 64.8 Gy
to 70 Gy in 1.2 Gy per fraction b.i.d.. After a mini-
mum follow-up of 45 months 1-, 2- and 5-year overall
survival rates of 51.2, 25.1 and 14.8%, respectively
and a median survival of 15 months was reported.
Thrity-two patients with complete response had sig-
nificantly better survival (2/5 year survival 49.8/
39.2%) compared to patients with only partial
response (2/5 year 22.5/11.4%). Treatment was
accompanied by quite low toxicity with severe weight
loss in 13.7% of patients and maximum grade 2
pneumonitis in 42 Patients, although four treatment-
related deaths were reported (Lee et al. 2003).
4 Summary
Second generation chemotherapeutic drugs have
proven as a group of agents with high activity in
NSCLC, particularly platinum compounds like
Cisplatin and Carboplatin. With their mechanism of
action and thus presumed radiation enhancing prop-
erties these compounds have been incorporated in
287
many phase I and II trials to evaluate toxicity and
efficacy in combined radiochemotherapy protocols.
Not for all substances used unequivocal experimental
evidence for a true radio-sensitizing effect in the sense
of a supra-additive effect could be demonstrated,
though. Instead, the effects may well result from
independent additive cytotoxicity and a different non-
overlapping toxicity profile.
It is difficult to draw firm conclusions from these
phase I-II trials as they significantly differed with
regard to fractionation, single and total dose of radio-
therapy as well as the sequencing and dosage of che-
motherapy (sequential vs. simultaneous) and the
combination of agents used. In addition, patient inclu-
sion criteria and tumor characteristics like stage, grade
and histology were very heterogeneous. Still, a few
interesting conclusions can be made which led to the
introduction of those agents into further phase III trials.
Radiochemotherapy in combination with second
generation chemotherapy agents generally proved to
be feasible with acceptable, though significant toxic-
ity and appeared—depending on the chemotherapy
protocol—to be superior to radiotherapy alone,
especially when combined with concurrent chemo-
therapy. As the platinum compounds Cisplatin and
Carboplatin proved to be most potent in combination
with radiotherapy they formed the basis of all proto-
cols with concurrent radiotherapy either as single
agent or as part of multiple agent protocols. Concur-
rent radiochemotherapy protocols showed the most
consistent results with promising outcome data
though at the prize of considerable toxicity.
Triple agent concurrent regimens are feasible with
encouraging results. Nevertheless, with considerable
additional toxicity the true benefit over the potent
double agent regimen like Cisplatin/Etosposide
remains unclear.
High-dose of Ifosfamide containing induction
chemotherapy protocols as well as most of the
sequential chemoradiation protocols yielded disap-
pointing results both with regards to outcome and
toxicity and therefore failed to hold to the hypothet-
ical benefit of a sequential approach. Only studies
without induction chemotherapy using HART as their
radiotherapy regime intercalating chemotherapy in
between the split courses showed encouraging results.
Split-course regimens and hypofractionated pro-
tocols with insufficient biological effectiveness
showed disappointing results, possibly not only by
288
counteracting the effect of radiotherapy, but also by
obscuring a possible beneficial effect of the chemo-
therapy regime.
The results of low-dose platinum-based concurrent
radiochemotherapy regimens are very intriguing,
though whether the interaction is through synergistic
radio-sensitizing effects or rather reflects independent,
additive cytotoxicity due to cumulative toxic effects is
still a matter of debate. Non-hematologic toxicity,
particularly esophageal, became only relevant, when a
second chemotherapeutic agent was added to the
concurrent regimen.
Despite the heterogeneity of the studies, radio-
chemotherapy with second generation chemotherapy
proved to be feasible and—especially concurrent
double agent platinum-based protocols—appeared to
be superior to conventional radiotherapy alone and
has been considered a value treatment option in
inoperable advanced stage NSCLC worthwhile testing
in subsequent phase III trials.
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 Radiotherapy and Third Generation
Concurrent Chemotherapy Agents
Ross Bland, Puneeth Iyengar, and Hak Choy

Contents
1 Carboplatin and Paclitaxel..................................... 292
2 Vinorelbine and Gemcitabine ................................ 297
3 Docetaxel................................................................... 302
4 Irinotecan.................................................................. 303
5 Pemetrexed ............................................................... 304
6 Third Generation Agents and Dose Escalation ... 305
References.......................................................................... 305
Abstract
Evidence shows that treating locally advanced
non-small cell lung cancer (NSCLC) patients with
concurrent radiation and second generation chemo-
therapy agents provides a survival benefit when
compared to delivering the same therapy sequen-
tially. However, survival results remain dismal and
concurrent chemoradiation exhibits significant tox-
icity. As third generation chemotherapy agents have
become available, their radiation-sensitizing proper-
ties have been extensively studied in the laboratory.
Subsequently, clinical studies have been performed
to evaluate the potential benefit of incorporating
these newer agents in concurrent chemoradiation
regimens. This chapter aims to provide insight into
how these agents were transitioned from the labora-
tory bench to their current role in the standard of care
of patients with locally advanced disease.

Despite advances in the treatment of many cancers

over the last three decades, our ability to control
stage III lung cancer continues to be poor. A majority
of these lesions are not candidates for surgical
resection and are treated with a combination of che-
motherapy, biologic agents, and external beam radi-
ation. As part of concurrent therapy, systemic agents
primarily play a role in potentially sensitizing tumor
cells to the effects of ionizing radiation. They also
serve to attempt to control disseminated disease.
The original platinum-based drug, cisplatin, as
R. Bland  P. Iyengar  H. Choy (&) well as topoisomerase targeted systemic agents have
Department of Radiation Oncology, had a unique capacity to synergize with ionizing
UT Southwestern Medical Center at Dallas,
Dallas, USA radiation in promoting lung tumor cell death. How-
e-mail: Hak.Choy@utsouthwestern.edu ever, survival outcomes with these agents have not

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 291
DOI: 10.1007/174_2011_269, Ó Springer-Verlag Berlin Heidelberg 2011
292
been good enough and normal tissue toxicities have
been excessive. Therefore, there has been a great
effort over recent years to provide robust pre-clinical
evidence of the potential of new systemic agents to be
used concurrently with ionizing radiation in the
treatment of lung cancer. Slowly, but surely, this
preclinical work has translated into early and
advanced phase clinical trials that have offered hope
regarding a new generation of therapies.
This chapter will summarize some of these new
advances, from rationale and preclinical data to find-
ings in the latest clinical trials. We hope to offer some
insight into how these agents work with radiation in
promoting tumor kill under various circumstances. We
will also attempt to offer some hope regarding newer
classes of cytotoxic chemotherapeutics and their syn-
ergy with radiation. The format of the chapter hopefully
allows the reader the opportunity to appreciate the
evolution of third generation chemotherapies given
concurrently with radiation therapy from preclinical
data to altering practice patterns and standards of
care. Some of the concurrent systemic agents we
highlight and focus on include carboplatin, paclitaxel,
vinorelbine, gemcitabine, docetaxel, and pemetrexed.
A number of these agents have begun to represent part
of the standard of care for treatment of lung cancer in
the definitive setting, while others have been too toxic
and/or less than efficacious.
1 Carboplatin and Paclitaxel
A meta-analysis of all randomized trials from the
pretaxane era showed that adding cisplatin-based che-
motherapy to radiotherapy for locally advanced
NSCLC provided a 13% reduction in the risk of death.
However, the absolute survival advantage was a
modest 4% at 2 years and 2% at 5 years (NSCLC Coll
Group 1995). The results of this meta-analysis dem-
onstrated the benefit of chemotherapy but also made
clear the need for improved treatment regimens.
Meanwhile, there was a growing interest in paclitaxel,
a chemotherapy agent first approved for use in the
palliative therapy of patients with ovarian and breast
cancers resistant to conventional chemotherapy.
Paclitaxel’s mechanism of action involves regulation
of microtubule formation. Properly functioning
microtubules are required for formation of the mitotic
spindle during cell division. Microtubules are made up
R. Bland et al.
of polymers of tubulin in dynamic equilibrium with
tubulin heterodimers. In contrast to vinca alkaloids,
which promote disassembly of microtubules, paclitaxel
acts in the opposite direction to induce polymerization
(Rowinsky and Donehower 1995). In the presence of
paclitaxel, these abnormally stable microtubules are
dysfunctional and the dividing cell is halted in the G2/
M phase of the cell cycle (Schiff et al. 1979; Parness
and Horwitz 1981; Manfredi et al. 1982). Using ham-
ster cells in culture, Sinclair and Morton demonstrated
that cells in the M phase were most radiation sensitive
while those in early G1 and late S phases were the
most resistant. The ratio of colony-surviving fractions
for these two cell populations was almost fourfold
(Sinclair and Morton 1966). In a study using the human
leukemic cell line, HL-60, up to 70% of cells were
blocked in the G2/M phase after exposure to low-dose
paclitaxel (30 nmol/L) for 1 h. These paclitaxel-
exposed cells were also treated with radiation doses
ranging from 0 to 4 Gy at 24 h and the sensitizing
enhancement ratio of paclitaxel was reported to be 1.48
(Choy et al. 1993). Several studies showed that pac-
litaxel could provide radiation sensitization in the rel-
atively radiation resistant human astrocytoma cell line
and ovarian cell lines. In these studies, the concentra-
tion of paclitaxel and the fraction of cells in the G2 and
M phases of the cell cycle determined the degree of
enhancement. Paclitaxel exhibited an enhancement
ratio of 1.8 at 10 and 1.2 at 1 mmol/l (Tishler et al.
1992a, b; Stern et al. 1993). Researchers took advan-
tage of the synergy of action within the cell cycle when
utilizing paclitaxel and radiation in combined modality
therapy, especially in the setting of ordinarily radiation
resistant tumor systems.
Based on activity in advanced disease and preclin-
ical data indicating impressive radiation enhancement
of paclitaxel in various cell lines, a phase I trial of
paclitaxel with concurrent radiotherapy for inoperable
NSCLC was initiated (Choy et al. 1994). This study
demonstrated that thoracic radiotherapy could be safely
administered concurrently with weekly 3 h infusions of
paclitaxel at 60 mg/m2 for six weeks. Esophagitis was
the dose limiting toxicity. Notably, this was a lower but
more frequent dose when compared to the every-
3-week paclitaxel regimen used in phase II studies of
paclitaxel alone. Subsequently, a phase II study of
weekly paclitaxel and concurrent radiation for locally
advanced NSCLC (Choy and Safran 1995) was con-
ducted and showed encouraging response and survival
Radiotherapy and Third Generation Concurrent Chemotherapy Agents
rates when compared to the most active cisplatin-based
chemoradiation regimens (Dillman et al. 1990, 1996;
Lee et al. 1996; Schaake-Koning et al. 1992; NSCLC
Coll Group 1995).
Carboplatin, a cisplatin analog, was known to be
less nephrotoxic and emetogenic than cisplatin but
have similar antitumor activity (Rowinsky et al. 1993;
Klastersky et al. 1990, 1993; Kosmidis et al. 1997).
Data from preclinical studies indicated that carbo-
platin enhances ionizing radiation through such
mechanisms as radiosensitization of hypoxic cells,
inhibition of the repair of sublethal or potentially
lethal damage, binding to thiols, and increased
induction of chromosomal aberrations (Begg et al.
1987, 1989; Coughlin and Richmond 1989; Douple
1993). These findings suggested that, at least in vitro,
radiation enhancement by carboplatin is similar to
that exhibited by cisplatin. However, since compared
to cisplatin, carboplatin could provide a greater
intracellular platinum concentration during irradia-
tion, it was thought that carboplatin may result in
more effective synergy with radiation (Belani 1993;
Micetich et al. 1985). A phase II study examined
carboplatin 75 mg/m2 weekly in combination with
thoracic radiation. Overall the treatment was well
tolerated and showed a 1-year survival rate of 50% in
stage III NSCLC patients (Clark et al. 1998).
Laboratory data suggested a synergistic effect
when combining the two systemic antineoplastics
carboplatin and paclitaxel (Bunn and Kelly 1995).
In initial phase I and II trials, combination regimens
of carboplatin and paclitaxel used to treat advanced
(stages III and IV) NSCLC exhibited overall response
rates as high as 63% (Langer et al. 1995; Johnson
1999; Johnson et al. 1996; Vafai et al. 1995). Fur-
thermore, these studies demonstrated that combined
carboplatin and paclitaxel regimens for advanced
NSCLC had manageable toxicities. Based on the
success of these agents in advanced disease and their
known radiation enhancing properties, studies were
conducted to evaluate the activity and toxicity of
carboplatin and paclitaxel with concurrent radiation
therapy in patients with locally advanced NSCLC
(see Table 1). A multi-institutional phase II trial
administered weekly regimens of carboplatin (AUC
2 mg/mL 9 min) and paclitaxel (50 mg/m2) with
concurrent radiation therapy (66 Gy in 33 fractions)
followed by consolidation carboplatin (AUC 6 mg/mL
9 min) and paclitaxel (200 mg/m2) every three weeks.
293
This regimen resulted in an overall response rate of
76%, a one year survival rate of 56%, and acceptable
toxicity (Choy et al. 1998). In a phase II trial evaluating
weekly carboplatin (100 mg/m2) and paclitaxel
(45 mg/m2) with concurrent RT (60-65 Gy), Belani
et al. reported 1- and 3-year survival rates of 63 and
54%, respectively (Belani et al. 1997). The California
Cancer Consortium reasoned that more frequent
administration of paclitaxel should optimize its radia-
tion sensitizing effect. This led to a phase II trial to
evaluate the safety and efficacy of twice-weekly
paclitaxel (30 mg/m2), weekly carboplatin (AUC
1.5 mg/mL 9 min), and concurrent radiation therapy
(61 Gy) followed by consolidation with two 21-day
cycles of carboplatin (AUC 6 mg/mL 9 min) and
paclitaxel (200 mg/m2). This treatment regimen
resulted in a response rate of 71% and a median survival
time of 17 months and was deemed tolerable by the
investigators (Lau et al. 2001).
While studies showed that reduced dose carbo-
platin and paclitaxel with concurrent radiation was
effective and tolerable for locally advanced NSCLC,
the benefit of either induction or consolidation full-
dose chemotherapy in conjunction with concurrent
chemoradiotherapy was uncertain. A phase II ran-
domized three arm study was undertaken to address
this uncertainty (Belani et al. 2005). Arm 1, the
sequential arm, delivered two cycles of induction
carboplatin and paclitaxel followed by radiation.
Arm 2, the induction/concurrent arm, delivered two
cycles of induction carboplatin and paclitaxel fol-
lowed by weekly carboplatin and paclitaxel with
concurrent radiation. Finally, arm 3, the concurrent/
consolidation arm consisted of weekly carboplatin and
paclitaxel with concurrent radiation followed by two
cycles of consolidation carboplatin and paclitaxel. All
three treatment regimens were felt to be safe with
median survival times of 13, 12.7, and 16.3 months in
arms 1, 2, and 3, respectively. As expected, the two
arms involving concurrent chemoradiation exhibited
the greatest toxicity. Esophagitis was seen in 3% of
patients in arm 1, 19% of patients in arm 2, and 28% of
patients in arm 3. Lung toxicities were identified in 7%
of arm 1 patients, 4% of arm 2 patients, and 16% of
arm 3 patients. Although there was not a statistically
significant difference in survival between arms, the
results suggested an improved outcome with con
current chemoradiation followed by consolidation
chemotherapy.
Table 1 Summary of selected paclitaxel chemoradiation studies
294

Reference Study Number of Ind Conc Cons MST Comments

patients (months)
Choy et al. (1998) Phase II 40 – Carbo/Pac/66 Gy Carbo/Pac 20.5 Regimen appears safe and active.
Belani et al. (1997) Phase II 38 – Carbo/Pac/60-65 Gy – 63% Regimen appears safe and active.
(1 year)
Ratanatharathorn Phase II 30 – Carbo/Pac/60 Gy Carbo/Pac 14.5 Effective and tolerable regimen.
et al. (2001)
Lau et al. (2001) Phase II 34 – Carbo/Pac(2/ Carbo/Pac 17 Concurrent twice weekly Pac with
week)/61 Gy weekly Carbo is safe and active.
Solomon et al. Phase I/II 25 – P/Pac(2/week)/60 Gy Carbo/Pac 23.6 Concurrent twice weekly Pac with
(2003) weekly P is safe and active.
Kaplan et al. (2004) Phase II 19 – Carbo/Pac/66 Gy Carbo/Pac 13.9 Regimen is feasible and well tolerated.
Belani et al. (2005) LAMP, Phase II 257 Carbo/Pac 63 Gy – 13 Arm 3 was numerically most efficacious
Carbo/Pac Carbo/Pac/63 Gy – 12.7 but most toxic.

– Carbo/Pac/63 Gy Carbo/Pac 16.3

Akerley et al. CALGB 9534, Phase 40 Carbo/Pac Carbo/Pac/66 Gy – 27% Included patients with [5% weight
(2005) II (3 years) loss, but survival consistent with more
selective studies.
Divers et al. (2005) Phase I/IIa 35 P/Gem Gem/Pac q – 17 Regimen is safe and effective in good
3 weeks/60 Gy performance status patients.
Huber et al. (2006) CTRT99/97 214 Carbo/Pac 60 Gy – 14.7 Concurrent chemoradiation arm had
BROCAT, Phase III Carbo/Pac Pac/60 Gy – 18.7 improved survival.

Davies et al. (2006) S9712 54 – Carbo/E/61 Gy Pac 10.2 Compared to S429, in poor risk patients,
Pac consolidation does not increase
survival.
Vokes et al. (2007) CALGB 39801, 366 – Carbo/Pac/66 Gy – 12 Induction CT increased toxicity without
Phase II Carbo/Pac Carbo/Pac/66 Gy – 14 survival benefit. Low MSTs possibly
due to low dose 3rd generation CT.
(continued)
R. Bland et al.
 Radiotherapy and Third Generation Concurrent Chemotherapy Agents 295

MST median survival time, LAMP locally advanced multi-modality protocol, CALGB Cancer and Leukemia Group B, WJTOG West Japan Thoracic Oncology Group, Carbo
The first phase III trial to evaluate concurrent

Arm 3 was equally as efficacious but

carboplatin and paclitaxel with radiation therapy for

esophagitis but SS improvement in

With AM, no SS reduction in locally advanced NSCLC was conducted by the
Cancer and Leukemia Group B (CALGB) (Vokes

less toxic than other arms.

patient self-assessments. et al. 2007). CALGB 39801 was designed to test the
value of induction chemotherapy in the context of
concurrent chemoradiotherapy. Patients were ran-
domized to carboplatin and paclitaxel with concurrent
radiotherapy (concurrent arm), or to induction car-
Comments

boplatin and paclitaxel followed by carboplatin and

paclitaxel based concurrent chemoradiotherapy
(induction/concurrent arm). There was no statistically
significant difference in survival. Median survival was
(months)

12 months on the concurrent arm versus 14 months

carboplatin, Pac paclitaxel, MVP mitomycin/vindesine/cisplatin, AM amofostine, CT chemotherapy, SS statistically significant
MST

17.3

17.9

19.8
20.5

on the induction/concurrent arm. Additionally, the

22

induction/concurrent arm demonstrated increased

Carbo/Pac

neutropenia and overall maximal toxicity. This study

Irinotecan
Carbo/

failed to show a benefit for the role of induction

MVP
Cons

chemotherapy in the context of concurrent chemora-

–

diotherapy analogous to what was reported by Belani

Carbo/Irinotecan/60 Gy

et al. (2005). One possible explanation for the poor

Carbo/Pac/69.6 Gy,

Carbo/Pac/69.6 Gy,

performance of the concurrent arm, is that the patients

MVP/60 Gy (split)

Carbo/Pac/60 Gy

on this arm never received systemic full dose che-

1.2 Gy/bid AM

motherapy. The radiation-sensitizing dose was given

1.2 Gy bid

concurrently with radiation was not optimal for

Conc

treating micrometastatic disease.

Studies of concurrent chemoradiation demon-
strated improved survival at the cost of increased
Carbo/Pac

Carbo/Pac

toxicity, particularly esophagitis, when compared to

sequential chemoradiation (Komaki et al. 2003).
Ind

–
–

Movsas et al. performed a quality-adjusted survival

(QAS) analysis of several RTOG lung cancer studies
Number of

and found that the QAS of sequential chemoradiation

patients

was nearly equivalent to that of concurrent chemo-

243

456

radiation (Movsas et al. 1999). Reduction in esopha-

geal, upper GI and lung toxicities was associated with
the greatest improvement in QAS. In light of these
WJTOG0105, Phase
RTOG 9801, Phase

findings, RTOG 98-01 was designed to test amofos-

tine’s (AM) ability to reduce the severity of esopha-
gitis in concurrent chemoradiation regimens (Movsas
et al. 2003). AM is a cytoprotectant that is dephos-
Study

phorylated in tissue and subsequently acts as a scav-

III

III

enger of radiation induced oxygen free radicals

Table 1 (continued)

Movsas et al. (2003)

(Calabro-Jones et al. 1985; Wasserman and Chapman

Yamamoto et al.

2004). In RTOG 98-01, 243 patients with locally

advanced NSCLC were administered induction car-
Reference

boplatin and paclitaxel followed by hyperfractionated

(2010)

radiotherapy (69.6 at 1.2 Gy bid) with concurrent

carboplatin and paclitaxel. Patients were randomized
 296

Table 2 Summary of selected vinorelbine or gemcitabine chemoradiation studies

Reference Study Patients Induction Concurrent Consolidation MST Comments
(months)
Vokes et al. (2002) CALGB 9431, Phase II 175 P/Gem P/Gem/66 Gy – 18.3 Greater MSTs than in CALGB trials
P/Pac P/Pac/66 Gy – 14.8 using squential CTRT.

P/Vrb P/Vrb/66 Gy – 17.7

Zatloukal et al. Czech Republic 102 P/Vrb P/Vrb/60 Gy – 16.6 SS survival benefit to concurrent CTRT.
(2004) P/Vrb 60 Gy – 12.9
Lee et al. (2005) Phase II 40 Gem/Vrb P/E/63 Gy – 23.2 Regimen had promising survival results.
Fournel et al. GFPC-GLOT-IFCT 02-01, 133 P/Pac P/Vrb/66 Gy – 19.3 Similar toxicities but numercially
(2006) Phase II – P/Vrb/66 Gy P/Pac 16.9 greater MST in arm 1.

Kim et al. (2007) Phase III 134 P/Gem P/Pac/66 Gy – 12.6 Induction arm had SS worse PFS.
– P/Pac/66 Gy – 18.2
Rusu et al. (2007) Phase II 57 – Platinum/Vrb/RT Platinum/Vrb 15 Regimen is active and well tolerated.
Hirsh et al. (2007) Phase II 41 Carbo/ Gem/Pac/60 Gy – 25 Regimen is effective and well tolerated.
Gem
Krzakowski et al. Phase II 54 PO Vrb/ PO Vrb/P/66 Gy – 23.4 With oral Vrb, high rate of treatment
(2008) P completion. Phase III trial with oral Vrb
underway.
Choy et al. (2009) RTOG 0017, Phase I 27 – Carbo/Gem/63 Gy Carbo/Gem 13.3 Lowest dose Gem/Pac too toxic with
8 – Gem/Pac/63 Gy Carbo/Gem 12.9 RT. Established MTD of Carbo/Gem
with RT.
Blanco et al. (2008) ACROSS, Phase II 44 P/Gem Gem/68.4 Gy – 17.7 Regimen had substantial toxicity.
Leong et al. (2010) Phase II 42 Gem/Vrb Vrb/60-66 Gy – 17 This non-platinum regimen is feasible,
tolerable, and effective.
MST median survival time, CALGB Cancer and Leukemia Group B, CTRT chemoradiation, GFPC French Pneumonology Group, GLOT Groupe Lyon-Saint-Etienne d’Oncologie
Thoracique, IFCT Intergroupe Francophone de Cancérologie Thoracique, Carbo carboplatin, Pac paclitaxel, Vrb vinorelbine, P cisplatin, Gem gemcitabine, CTRT chemora-
diation, RT radiation therapy, CT chemotherapy, SS statistically significant, MTD maximum tolerated dose, PFS progression free survival
R. Bland et al.
Radiotherapy and Third Generation Concurrent Chemotherapy Agents
to receive AM 500 mg IV four times per week or no
AM during chemoradiation. The rate of grade 3 or
worse esophagitis was not significantly different
between arms (AM, 30 versus no AM, 34%). How-
ever, patient diaries reported significantly lower
swallowing dysfunction with AM and the quality of
life instrument (EORTC QLQ) demonstrated a sig-
nificant difference in pain that favored the AM arm.
Median survival rates were similar (AM, 17.3 versus
no AM, 17.9 months). Thus, while NCI-CTC toxicity
endpoints did not support the hypothesis that AM
given during concurrent chemoradiation reduces
esophagitis, the patient-derived self-assessments
suggested a possible benefit from AM. This discon-
nect between the patient’s evaluation of difficulty
swallowing and pain and the physician-related
assessments demonstrated the importance of patient
reported outcomes and motivated their use in sub-
sequent trials (Radiation Therapy Oncology Group
RTOG 0617).
Phase III evidence demonstrating the benefit of
concurrent chemoradiation over sequential chemora-
diation for locally advanced NSCLC was initially
provided by studies from the West Japan Lung Cancer
Group (WJLCG) and the Radiation Therapy Oncol-
ogy Group (RTOG) (Furuse et al. 1999; Curran et al.
2003). However, both of these studies employed
second generation chemotherapy agents. In contrast to
second generation agents that could be delivered at
full systemic dose concurrently with radiation, third
generation chemotherapy agents had to be adminis-
tered at less than systemic doses during radiation.
There was concern that third generation agents given
at reduced doses during periods of irradiation were
not optimally treating micrometastatic disease. The
disappointing results reported in the CALGB 39801
study may have added to the concern about using
third generation agents for chemoradiotherapy. To
assess the benefit of replacing full dose second gen-
eration agents with more frequent radiosensitizing
dose third generation agents for concurrent chemo-
radiotherapy, the West Japan Thoracic Oncology
Group (WJTOG) conducted a phase III study
(Yamamoto et al. 2010). The study compared three
arms: (control arm) cisplatin, vindesine, and mito-
mycin with concurrent radiation followed by cis-
platin, vindesine, and mitomycin consolidation;
carboplatin and irinotecan with concurrent radiation
followed by carboplatin and irinotecan consolidation;
297
carboplatin and paclitaxel with concurrent radiation
followed by carboplatin and paclitaxel consolidation.
The median survival times for the three study arms
were not significantly different (arm A: 20, arm B:
19.8, arm C: 22 months). Unfortunately, the study
was not able to demonstrate non-inferiority. While
difference in survival for the three arms was not sig-
nificant, hematologic and gastrointestinal toxicities
were more pronounced in the control arm. Other than
neurotoxicity, most of the toxicities were the mildest
in the carboplatin and paclitaxel arm. Based on these
data of efficacy and toxicity, the WJTOG selected the
carboplatin and paclitaxel study arm as the reference
treatment regimen for future phase III studies of
locally advanced NSCLC.
2 Vinorelbine and Gemcitabine
In addition to paclitaxel, other third generation che-
motherapy agents, such as vinorelbine and gemcita-
bine, have been incorporated in concurrent
chemoradiation regimens for locally advanced
NSCLC. Vinorelbine, a vinca alkaloid and potent
inhibitor of microtubule polymerization, gained
attention because of its broad spectrum of antitumor
activity seen in preclinical studies. Vinorelbine was
more active than other vinca alkaloids in almost all
models tested. Additionally, in a murine model
vinorelbine was shown to have synergy with cisplatin
(Cros et al. 1989). Vinorelbine was the first third
generation agent to receive FDA approval for
NSCLC. Crawford et al. reported improved survival
with vinorelbine compared to fluorouracil and leu-
covorin in patients with advanced NSCLC (Crawford
et al. 1996). Studies also demonstrated that vinorel-
bine plus cisplatin was superior to either agent alone
in the context of advanced disease (Le Chevalier
et al. 1994; Wozniak et al. 1998). Additionally, Le
Chevalier et al. showed the superiority of cisplatin
and vinorelbine over the previous French standard
of cisplatin and vindesine for advanced NSCLC
(Le Chevalier et al. 1994). Considering another third
generation chemotherapy agent that acts on microtu-
bules, paclitaxel, was recently shown to radiosensitize
cells, investigators studied vinorelbine’s interaction
with radiation. In the human lung carcinoma cell
line NCl-H460, vinorelbine was shown to potentiate
radiation in a cell cycle dependent manner with the
 298

Table 3 Summary of selected docetaxel chemoradiation studies

Reference Study Patients Induction Concurrent Consolidation MST Comments
(months)
Gandara et al. (2003) S9504, phase 83 – P/E/61 Gy Doce 26 Tolerable regimen with encouraging MST.
II
Vergnenègre et al. GFPC Phase 40 P/Vrb Doce/66 Gy – 13 Acceptable toxicity but modest survival rates.
(2005) II
Sakai et al. (2004) Phase II 32 – Bi-weekly Carbo/Doce Carbo/Doce 27 Concurrent bi-weekly CT regimen and RT was
60 Gy active with manageable toxicity.
Hanna et al. (2008) HOG, phase 203 – P/E/59.4 Gy – 23.2 Consolidation doce increased toxicity but not
III – P/E/59.4 Gy Doce 21.2 survival.

Kelly et al. (2008) S0023, phase 243 – P/E/61 Gy Doce 35 Gefinitib did not improve survival. Survival
III – P/E/61 Gy Doce/ 23 time compares favorably to other phase III
Gefinitib studies.

Jain et al. (2009) Phase II 61 – Carbo/Doce/63 Gy Carbo/Doce 12 Regimen has acceptable toxicity but
disappointing survival data.
Movsas et al. (2010) Phase II 83 – P/E/62 Gy Gem 16.1 Both arms were tolerable. In the Gem/Doce
– P/E/62 Gy Gem/Doce 29.5 arm, survival rate is higher than previous trials.

Segawa et al. (2010) Phase III 200 – M/V/P/60 Gy – 23.7 Trend toward improved survival in the
– P/Doce/60 Gy – 26.8 P/Doce arm.

Senan et al. (2011) Phase II 70 P/Doce P/Doce/66 Gy – 63.2% Both arms merit further testing in small volume
(1 year) (V20 \ 35%) disease.
– P/Doce/66 Gy P/Doce 65.5%
(1 year)
MST median survival time, P cisplatin, E etoposide, Carbo carboplatin, Doce docetaxel, SWOG Southwest Oncology Group, Hoosier Oncology Group
R. Bland et al.
Radiotherapy and Third Generation Concurrent Chemotherapy Agents
greatest potentiation ocurring when the cells were in
the G2 phase (Edelstein et al. 1996).
Gemcitabine, another third generation agent, is an
analog of the pyrimidine antimetabolite cytosine ara-
binoside (ara-C). However, gemcitabine accumulates
within tumor cells at much higher levels and for longer
periods of time than the active metabolite of ara-C
(Heinemann et al. 1988; Hertel et al. 1990). Like pac-
litaxel and vinorelbine, gemcitabine was shown to be
modestly superior to the second generation chemo-
therapy agents when used for advanced NSCLC
(Ginsberg et al. 2001; Bunn and Kelly 1998; Hoffman
et al. 2000; Johnson 1999; Bonomi et al. 2000;
Giaccone et al. 1998; Le Chevalier et al. 1994; Wozniak
et al. 1998; Sandler et al. 2000). Preclinical studies
revealed that gemcitabine exhibits cytotoxic synergy
with several agents including cisplatin (Nakamura et al.
1995; Tanzer et al. 1995). Additionally, laboratory
research showed gemcitabine to be a radiation sensi-
tizer of colon and pancreatic cancer cells (Shewach
et al. 1994; Lawrence et al. 1996).
For the same reasons as paclitaxel, vinorelbine and
gemcitabine each combined with a platinum com-
pound were attractive regimens to use for concurrent
chemoradiation for locally advanced NSCLC. These
third generation regimens had improved activity
over second generation regimens in advanced NSCLC
trials and preclinical research demonstrated they
were radiation sensitizers. In this context, CALGB
designed a three arm randomized phase II trial
(CALGB 9431) to evaluate paclitaxel, vinorelbine,
and gemcitabine in combination with cisplatin as
induction and concurrent chemoradiotherapy (Vokes
et al. 2002). This study and other select studies uti-
lizing vinorelbine and/or gemcitabine are summarized
in Table 2. Patients in each arm of the CALGB 9431
study received induction chemotherapy with cisplatin
and one of the newer agents followed by cisplatin and
the same newer agent concurrently with 66 Gy of
radiotherapy. Notably, this study was conducted
before there was evidence discouraging the use of
induction chemotherapy before concurrent chemora-
diation (Belani et al. 2005; Vokes et al. 2007). This
study revealed that all three regimens can be safely
delivered and have similar efficacy with median sur-
vival times for the gemcitabine, paclitaxel, and
vinorelbine containing arms of 18.3, 14.8, and
17.7 months, respectively. However, the three arms
exhibited different toxicity profiles. It was suspected
299
that gemcitabine might have the greatest radiation
associated toxicity. Indeed, esophagitis was most
pronounced in the gemcitabine arm with a 35% rate of
grade 3 and a 17% rate of grade 4 toxicity. However,
radiation pneumonitis was no more common in the
gemcitabine arm than the other two arms. The
investigators compared the overall median survival of
17 months seen in this trial to the median survival
times from two other studies that used second gen-
eration agents for concurrent chemoradiation (Furuse
et al. 1999; Curran et al. 2003). This comparison led
the investigators to conclude that the survival in this
study was greater than that seen in previous CALGB
trials most likely due to the benefit provided by
concurrent chemoradiation and less likely due to the
newer chemotherapy agents.
A group from the Czech Republic employed
vinorelbine in a study evaluating the benefit of con-
current chemoradiation (Zatloukal et al. 2004). This
study randomized patients to four cycles of cisplatin
and vinorelbine with radiotherapy commencing on the
second cycle (concurrent arm) or after completion of
chemotherapy (sequential arm). Consistent with pre-
vious phase III studies, the median survival was sig-
nificantly longer in the concurrent arm (16.6 months)
compared to the sequential arm (12.9 months). The
concurrent arm was more toxic but the added toxicity
did not affect the delivery of therapy and there were
no treatment related deaths. These results added to the
growing body of evidence that concurrent chemora-
diotherapy yields improved survival over sequential
chemoradiotherapy at the cost of increased, but
manageable toxicity.
A randomized trial by the French Pneumonology
Group (GFPC) provided evidence that vinorelbine
was a better drug than vindesine to combine with
cisplatin and mitomycin for the treatment of advanced
NSCLC (Perol et al. 1996). Subsequently, the Groupe
Lyon-Saint-Etienne d’Oncologie Thoracique (GLOT)
and GFPC jointly designed a phase III trial using
vinorelbine with cisplatin to compare sequential and
concurrent chemoradiotherapy for locally advanced
NSCLC (Fournel et al. 2005). The sequential arm
treated patients with cisplatin and vinorelbine induc-
tion chemotherapy followed by radiotherapy. The
concurrent arm treated patients with cisplatin and
etoposide and concurrent radiotherapy followed by
cisplatin and vinorelbine consolidation chemotherapy.
Although not statistically significant, the median
 300

Table 4 Summary of selected pemetrexed chemoradiation studies

Reference Study Patients Induction Concurrent Consolidation MST Comments
(months)
Gadgeel et al. Phase II 21 – P/Pem/66 Gy Doce NR RR 53%
(2008)
Gauden et al. Phase II 25 – Carbo/Doce/ Pem 22 RR 76%
(2009) 60 Gy
Germonpre et al. Phase II 30 P/Pem Pem/60 Gy – NR RR 69%
(2009) – Pem/60 Gy P/Pem NR
Govindan et al. CALGB 30407, 99 – Carbo/Pem/70 Gy Pem 22 Both regimens of full dose
(2008) Phase II – Carbo/Pem/Cetux/ Pem 22 Carbo/Pem/RT are feasible
70 Gy and tolerable.

Brade et al. (2010) Phase II 39 – P/Pem/61-66 Gy P/Pem 20 Full dose P/Pem/RT is active
and tolerable.
Choy et al. (2010) Phase II 76 – Carbo/Pem/64- Pem NR RR 38-41%
68 Gy
– P/Pem/64-68 Gy Pem NR
Xu et al. (2010) Phase II 21 – Carbo/Pem/60- Carbo/Pem NR RR 86%
66 Gy
Vokes et al. PROCLAIM, 600, nonsquamous – P/Pem/66 Gy Pem NA Currently evaluating benefit
(2009) Phase III (planned) – P/E/66 Gy P/E or P/Vrb or NA of full dose pem in concurrent
Carbo/Pac CTRT.

MST median survival time, P cisplatin, Pem pemetrexed, E etoposide, Carbo carboplatin, Vrb vinorelbine, CALGB Cancer and Leukemia Group B, CTRT chemoradiation
R. Bland et al.
Radiotherapy and Third Generation Concurrent Chemotherapy Agents 301

Table 5 Summary of selected studies with altered fractionation or escalated radiation doses
Reference Study Patients Induction Concurrent Consolidation MST Comments
(months)
Choy et al. Phase II 43 – Carbo/Pac Carbo/Pac 14.3 Regimen is well
(2000) 1.2 Gy BID/ tolerated with
69.6 Gy encouraging response
rate.
Reguart et al. Phase II 37 Plat/Gem Plat/Vrb/ Plat/Gem 15.4 Results are promising
(2004) 1.8 ? 0.88 Gy although toxicity is
boost/61.64 Gy considerable.
Casas et al. Phase II 32 Carbo/ Daily Pac/ Carbo/Pac 16.9 Acceptable efficacy and
(2011) Pac 1.8 ? 0.88 Gy less toxicity than the
boost/61.64 Gy trial in the row above.
Patel et al. Phase II 35 Carbo/ Topotecan/ – 17.9 Encouraging survival
(2007) Vrb 2 Gy bid, every with no severe
other week, esophagitis.
60 Gy
Schild et al. Phase I 15 – Carbo/Pac/70- – 37 MTD of RT was 74 Gy.
(2006) 78 Gy Phase II portion is
underway.
Stinchcombe Phase I/ 62 Carbo/ Carbo/Pac/60- – 25 Dose escalation
et al. (2008) II Pac 74 Gy compares favorably to
previous trials.
Socinski CALGB 69 Carbo/ Carbo/Pac/ – 24.3 Encouraging MST and
et al. (2008) 30105, Pac 74 Gy toxicity profile in arm 1.
Phase II Carbo/ Gem/74 Gy – 12.5 Arm 2 was too toxic.
Gem (closed
early)
Bradley et al. RTOG 53 – Carbo/Pac/ Optional 25.9 Among the best MSTs
(2010) 0117, 74 Gy in RTOG studies.
Phase II
MST median survival time, P cisplatin, Pem pemetrexed, E etoposide, Carbo carboplatin, Vrb vinorelbine, CALGB Cancer and
Leukemia Group B, CTRT chemoradiation

survival time for the concurrent arm was greater than
that seen in the sequential arm (16.3 versus
14.5 months). Despite 32% esophageal toxicity in the
concurrent arm compared to 3% in the sequential arm,
the results support the existing evidence for the use of
concurrent over sequential chemoradiotherapy.
Notably, since at the time of the design of this study
cisplatin and vinorelbine was not authorized in France
for concurrent use with radiation, this trial relied on a
second generation regimen, cisplatin and etoposide,
for the chemotherapy given concurrently with radia-
tion. However, the GLOT subsequently designed a
phase II study that did utilize cisplatin and vinorelbine
given concurrently with radiation (Fournel et al.
2006). The goal of this study was to evaluate the
sequencing of chemotherapy and concurrent chemo-
radiotherapy. Patients were randomized to receive
two cycles of cisplatin and paclitaxel followed by
cisplatin and vinorelbine with concurrent radiation
(induction/concurrent arm) or cisplatin and vinorel-
bine with concurrent radiation followed by two cycles
of cisplatin and paclitaxel (concurrent/consolidation
arm). This trial observed similar toxicities and
response rates in both arms but greater median sur-
vival time in the induction/concurrent arm (19.3
versus 16.9 months).
While induction and consolidation combinations of
carboplatin and gemcitabine had been studied, there
were no definitive studies establishing the use of
gemcitabine and carboplatin given concurrently
with radiotherapy for locally advanced NSCLC.
To determine the maximum tolerated dose of gem-
citabine for concurrent delivery with carboplatin and
radiotherapy, Choy et al. conducted RTOG 0017
302
(Choy et al. 2009). Considering the favorable
response rates of gemcitabine and paclitaxel as single
agents in NSCLC (Gatzemeier et al. 1996; Abratt
et al. 1994; Hatcher et al. 1998) as well as their
radiation enhancing properties, this phase I study
simultaneously evaluated the maximum tolerated
dose of gemcitabine and paclitaxel for concurrent
chemoradiation. This study was known as the
‘‘ping-pong trial’’ as dose cohorts were accrued to the
two treatment sequences in an alternating manner.
Patients in both sequences received carboplatin and
gemcitabine consolidation chemotherapy. The study
found the maximum tolerated dose of gemcitabine to
be 450 mg/m2/week when given concurrently with
carboplatin (AUC 2) and thoracic radiation (63 Gy).
The seven patients receiving this regimen experienced
two dose limiting toxicities (grade 4 neutropenia and
grade 3 esophagitis). The starting doses of gemcitabine
(300 mg/m2/week) and paclitaxel (30 mg/m2/week)
were too toxic to be administered concurrently with
63 Gy of thoracic radiotherapy. The median survival
times of 13.3 months for the concurrent carboplatin
and gemcitabine sequence and 12.9 months for the
gemcitabine and paclitaxel concurrent sequence were
lower than anticipated.
In the aforementioned CALGB 9431 trial that
evaluated paclitaxel, vinorelbine, and gemcitabine in
combination with cisplatin as induction and concur-
rent chemoradiotherapy, the gemcitabine arm had
similar activity as the other two arms and manageable
toxicity (Vokes et al. 2002). After several studies
suggested that 74 Gy could be safely and effectively
delivered (via three-dimensional (3D) planning) after
induction chemotherapy and with concurrent chemo-
therapy (Blackstock et al. 2001, 2006; Rosenman
et al. 2002; Socinski et al. 2000), the CALGB con-
ducted a multi-institutional phase II study (CALGB
30105) to evaluate two similar regimens: (arm A)
induction carboplatin and paclitaxel followed by
carboplatin and paclitaxel with concurrent radiother-
apy (74 Gy) and (arm B) induction carboplatin and
gemcitabine followed gemcitabine and radiation
therapy (74 Gy) (Socinski et al. 2008). Arm A had an
impressive median survival time of 24.3 months and
1-year survival rate of 66.7% which the investigators
attributed to using 3D planning to deliver a higher
dose of radiation compared to previous trials. 3D
planning allows for increased conformality of dose
around tumor with margin, potentially reducing dose
R. Bland et al.
to collateral normal tissue and allowing for dose
escalation. The arm using gemcitabine was closed
early secondary to treatment-related deaths. In two of
the three patients that died, a review of the radiation
plans showed greater than 40% of the total lung
volume was receiving at least 20 Gy. It has been
shown that V20 (volume of organ receiving greater
than 20 Gy) is a useful parameter for predicting
radiation pneumonitis (Graham et al. 1999). Given
this experience, the investigators concluded that any
future trial using aggressive radiotherapy should
include prospective definitions of healthy tissue con-
straints. Gemcitabine is known to be an effective
radiation sensitizer that may also excessively radio-
sensitize normal tissue (Blackstock et al. 2001, 2006).
The early closure of the gemcitabine containing arm
supports the notion that gemcitabine is associated
with greater toxicity than other third generation
agents when used concurrently with radiation. This
CALGB study is being followed up by a phase III trial
comparing standard dose (60 Gy) versus high-dose
(74 Gy) conformal radiotherapy with concurrent
and consolidation carboplatin and paclitaxel (RTOG
0617).
3 Docetaxel
Adding chemotherapy sequentially to radiation
therapy improved survival in locally advanced
NSCLC patients by reducing distant progression
(Sause et al. 1995). Compared to sequential, con-
current chemoradiation has improved survival by
reducing local recurrence with no effect on distant
control (Schaake-Koning et al. 1992). Since con-
current phase chemotherapy is limited by toxicity,
many trials have implemented induction or consol-
idation chemotherapy in hopes of reducing distant
progression.
Docetaxel, a taxane and third generation chemo-
therapy agent, is an attractive agent for consolidation
chemotherapy for several reasons. Preclinical models
suggested docetaxel has molecular mechanisms of
action, such as p27 induction and Bcl-2 phosphoryla-
tion, which are thought to be most effective after cells
have been exposed to DNA-damaging chemoradiation.
Additionally, these models showed that docetaxel
has activity against tumors with a p53 mutation
(Blagosklonny et al. 1996; Gumerlock et al. 1999).
Radiotherapy and Third Generation Concurrent Chemotherapy Agents
Out of the newer agents, docetaxel demonstrated the
greatest single agent activity in chemotherapy-naïve
patients with advanced NSCLC (Fossella 1999).
Additionally, docetaxel has been shown in phase II
studies to have second-line activity in patients who
failed prior cisplatin-based treatment regimens for
NSCLC (Fosella et al. 2000). Based on these preclinical
studies and encouraging clinical results, the SWOG
evaluated docetaxel for consolidation chemotherapy.
In SWOG 9504, a phase II study, patients were treated
with full dose cisplatin and etoposide with con-
current radiation followed by consolidation docetaxel
(Gandara et al. 2003). The important points of the
SWOG 9504 study and other select docetaxel studies
are highlighted in Table 3.
SWOG 9019, the predecessor trial to SWOG 9504,
evaluated cisplatin and etoposide with concurrent
radiation followed by consolidation cisplatin and
etoposide (Albain et al. 2002). The SWOG 9504 trial
used the same eligibility criteria, staging, documen-
tation procedures for T4 or N, and concurrent che-
moradiation regimen as was used in SWOG 9019.
SWOG 9504 replaced the consolidation cisplatin and
etoposide regimen used in SWOG 9019 with doce-
taxel with the idea that a comparison of the two trials
could provide some relative information on the effi-
cacy and safety of docetaxel as a consolidative regi-
men. The treatment in SWOG 9504 was found to be
generally tolerable and resulted in an impressive
median survival of 26 months compared to 15 months
seen in SWOG 9019.
The Hoosier Oncology Group (HOG) took the next
step in evaluating consolidation chemotherapy with
docetaxel by designing a prospective phase III study.
This study randomized patients to either (1) cisplatin
and etoposide with concurrent radiation or (2) cis-
platin and etoposide with concurrent radiation fol-
lowed by consolidation docetaxel. The median
survival time for the docetaxel arm was 21.5 months
and was not statistically significantly different from
the median survival time of 24.1 months seen in the
arm without docetaxel consolidation. Additionally,
the patients that received consolidation docetaxel
experienced greater toxicity including an increased
rate of hospitalization and premature death. The
investigators concluded that consolidation docetaxel
does not improve survival but does add toxicity and
therefore should no longer be used for patients with
unresectable stage III NSCLC (Hanna et al. 2008).
303
Using H460 human lung carcinoma cells, Amorino
et al. found that combination docetaxel and carbo-
platin enhances radiation’s effect on colony forming
units more than either drug separately (Amorino et al.
1999). Remarkably, the redistribution of cells into the
radiosensitive G2/M phase observed after paclitaxel
exposure was not seen after docetaxel exposure.
Considering these encouraging preclinical findings,
Choy et al. performed a phase I study of weekly
docetaxel and carboplatin with concurrent radiother-
apy in patients with locally advanced NSCLC (Choy
et al. 2001). The study showed the dose limiting
toxicity was esophagitis and the maximum tolerated
dose of docetaxel was 20 mg/m2 per week with
weekly carboplatin (AUC 2) and concurrent radiation.
Subsequently, a phase II study was performed to
assess the safety and efficacy of weekly docetaxel
(20 mg/m2) and carboplatin (AUC 2) administered
concurrently with radiotherapy (63 Gy) and followed
by docetaxel and carboplatin consolidation (Jain et al.
2009). While the toxicity was acceptable, the survival
rates of 45% at 1 year and 20% at 2 years were
disappointing.
4 Irinotecan
Camptothecin and its derivatives, such as irinotecan,
target the DNA relaxing enzyme topoisomerase I
(Hsiang et al. 1985; Hsiang and Liu 1988; Andoh
et al. 1987; Nitiss and Wang 1988). Camptothecin
stabilizes the topoisomerase I-DNA intermediate that
is formed when topoisomerase I cleaves DNA to
allow for uncoiling. The stabilized intermediate
interacts with the progressing replication fork and
results in a DNA double-strand break that is fatal to
the cell. Several studies have shown camptothecin
sensitizes cells to radiation in vitro and in vivo
(Kudoh et al. 1993; Rich and Kirichenko 1998).
Omura et al. found enhanced cell kill with combina-
tion radiation and irinotecan with the largest gains
occurring when irinotecan was administered just
before or just after irradiation (Omura et al. 1997).
Another study showed that comptothecin derivatives
radiosensitized MCF-7 breast cancer cells in a dose-
dependent manner with the greatest effect seen when
cells were exposed to the drug before or during
radiation (Chen et al. 1997). Additionally, in a study
using murine fibrosarcomas, radiation enhancing
304
effects were seen when topotecan, another campto-
thecin derivative, was administered 2 and 4 h before
radiation but not when administered 2 h after radia-
tion. The consistent findings in these preclinical
studies suggested irinotecan be administered before or
during radiotherapy take full advantage of its radio-
sensitizing properties.
After studies demonstrated concurrent chemoradi-
ation with irinotecan was safe and active in locally
advanced NSCLC (Takeda et al. 1999; Saka et al.
1997), several phase I trials evaluated the addition of
carboplatin in the concurrent phase Uejima 2002
(Uejima 2002; Yamada et al. 2002; Chakravarthy
et al. 2000). These preliminary studies reported nau-
sea, vomiting, and esophagitis as the dose limiting
toxicities of weekly irinotecan and carboplatin with
concurrent radiation. Additionally, these studies pro-
vided initial evidence of clinical activity for this
regimen, with response rates of 60-70%. Concurrent
chemoradiation with irinotecan has been studied in
the phase III setting in the aforementioned WJTOG
trial that compared second and third generation che-
motherapy in the treatment of locally advanced
NSCLC (Yamamoto et al. 2010). Arm B of this study
utilized carboplatin and irinotecan for concurrent
chemoradiation and consolidation chemotherapy.
This arm’s median survival time (19.8 months) was
not significantly different from the median survival
times of the other two arms. However, the other
experimental arm, which employed carboplatin and
paclitaxel for concurrent and consolidation chemo-
therapy, had a median survival time of 22 months and
the most favorable toxicity profile of the three arms.
The WJTOG concluded this arm should be a standard
regimen in the treatment of locally advanced NSCLC.
5 Pemetrexed
A meta-analysis of randomized trials showed that
concurrent chemoradiation improved overall survival
and locoregional progression when compared to
sequential chemoradiation (Auperin et al. 2007).
However, in this analysis the 3-year rate of distant
progression was similar for concurrent and sequential
chemoradiation at 39.5 and 39.1%, respectively. In
the trials studied in this meta-analysis, concurrent
phase chemotherapy was either a second generation
agent at full dose or a third generation agent at an
R. Bland et al.
attenuated dose. Pemetrexed, unlike other third gen-
eration chemotherapy agents, is capable of being
administered at full systemic dose concurrently with
thoracic radiotherapy. Consequently, investigators
have hypothesized that pemetrexed could be helpful
in reducing distant progression in patients treated with
concurrent chemoradiation.
Pemetrexed, a new generation antifolate, acts by
inhibiting several enzymes involved in nucleotide
synthesis, particularly thymidilate synthase (Joerger
et al. 2010; Solomon and Bunn 2005). This agent has
been shown to have activity in multiple tumor types
including NSCLC (Clarke et al. 1997; Rusthoven
et al. 1999; Smit et al. 2003). Pemetrexed appears to
be a good candidate for concurrent chemoradiation as
studies have suggested a synergy between premetr-
exed and radiotherapy in vitro (Bischof et al. 2002).
In a phase I study, Seiwert et al. demonstrated that
full dose pemetrexed (500 mg/m2) and carboplatin
(AUC 5 or 6) with concurrent thoracic radiation was
tolerable and active in patients with locally advanced
NSCLC or esophageal cancer (Seiwert et al. 2007).
Subsequently, several more phase I studies have
provided additional evidence to support the safety of
concurrent radiation with pemetrexed (Seiwert et al.
2007; Bischof et al. 2010), cisplatin and pemetrexed
(Brade 2010; Cardenal et al. 2009; Hensing et al.
2009, 2010), or carboplatin and pemetrexed (Seiwert
et al. 2007; Machtay et al. 2008; Heinzerling et al.
2010). All of these phase I trials have achieved full-
dose concurrent phase pemetrexed with no trial
requiring early termination due to toxicity. These
phase I studies exhibited acceptable rates of hema-
tologic toxicity, radiation pneumonitis, and esopha-
gitis leading to additional studies in the phase II
setting. Phase II studies testing pemetrexed-platin
combinations given concurrently with radiation for
locally advanced NSCLC resulted in promising
median survival times of 20–22 months (Brade 2010;
Govindan et al. 2008). Three randomized trials have
reported the consistent finding of a favorable treat-
ment by histology interaction for pemetrexed in
patients with advanced lung cancer of nonsquamous
histology (Peterson et al. 2007; Ciuleanu et al. 2008;
Scagliotti et al. 2008). Considering this histologic bias
and the promising results from phase II studies of
concurrent chemoradiation with pemetrexed-platin
regimens, investigators designed the PROCLAIM
study. This currently ongoing phase III study is
Radiotherapy and Third Generation Concurrent Chemotherapy Agents
evaluating pemetrexed and cisplatin with concurrent
radiotherapy followed by consolidation pemetrexed
for NSCLC of other than predominately squamous
cell histology (Vokes et al. 2009). A summary of
select pemetrexed trials is provided in Table 4.
6 Third Generation Agents and Dose
Escalation
Most of the recent studies of concurrent chemoradi-
ation for locally advanced NSCLC have explored
novel chemotherapy agents and additional chemo-
therapy outside the concurrent phase. With 2D radi-
ation planning techniques, dose escalation to improve
local tumor control has been impeded by inaccurate
tumor targeting and the associated injury to healthy
tissue. Consequently, 60 Gy has remained the stan-
dard dose since it was established in RTOG 73-01
(Perez et al. 1982, 1987). However, with the devel-
opment of 3D planning techniques, the tumor volume
can be more accurately targeted and dose-volume
calculations can be used to limit toxicity to healthy
tissue (Lee et al. 2006). Using 3D planning, the
RTOG, North Central Cancer Treatment Group
(NCCTG), and CALGB have explored delivering
escalated doses of thoracic radiation concurrently
with weekly carboplatin and paclitaxel. The phase I
component of RTOG 0117 determined that 74 Gy
was the maximum tolerated dose with concurrent
weekly carboplatin and paclitaxel (Bradley et al.
2010). In the phase II component, patients receiving
weekly carboplatin and paclitaxel with concurrent
radiation to 74 Gy had a median survival time of
25.9 months. Of note, out of 53 patients 12 had grade
3 or greater lung toxicity. A prospective phase I study
by the NCCTG reported results for 13 patients treated
to 70, 74, or 78 Gy (Schild et al. 2006). In this study,
the lower two doses were well tolerated while 78 Gy
was not. The median survival time for these 13
patients was 37 months. Patients in arm A of the
previously discussed CALGB 30105 study received
induction carboplatin and paclitaxel followed by
concurrent carboplatin and paclitaxel with 74 Gy
radiotherapy (Socinski et al. 2008). This treatment
regimen resulted in a median survival time of
24.3 months and manageable toxicities. Based on
these preliminary studies, the NCCTG, CALGB, and
ROTG have jointly initiated a phase III trial to
305
compare standard dose (60 Gy) versus high-dose
(74 Gy) conformal radiotherapy with concurrent and
consolidation carboplatin and paclitaxel in patients
with stage IIIA/IIIB NSCLC (RTOG 0617). Table 5
highlights the important aspects of select dose esca-
lation trials as well as trials that have examined novel
radiation dose fractioning.
In summary, our chapter has described some of the
rationale for combining systemic cytotoxic agents with
radiation in the treatment of lung malignancies in the
definitive setting. We have offered a view of the
mechanisms by which systemic agents have synergized
with radiation to promote improved tumor outcomes.
A number of systemic agents have also been described
that were ultimately too toxic or had inferior efficacy
when given concurrently with radiation. From the vast
number of studies presented, it is obvious that con-
current treatment is the optimal one with regards to the
greatest survival benefit in stage III lung cancer patients
who cannot undergo resection. However, it is also
obvious that much more can be done for this group of
patients. Current interest has been generated in esca-
lating radiation dose with concurrent systemics in the
setting of improved radiation delivery methods, limit-
ing toxicity to surrounding normal tissue. Another
paradigm taking shape is to combine targeted agents
with cytotoxic chemotherapy given concurrently with
radiation to inactivate multiple oncogenic pathways or
reduce the effectiveness of those biochemical pathways
effectuating resistance. Finally, there has been some
thought to combining systemic agents with stereotactic
radiation for early stage lung lesions in the hopes of
improving disease free survival. In general, there is a
great need for continuing to optimize concurrent ther-
apy from both the chemotherapy side as well as the
radiation side in promoting improved distant and local
control, respectively.
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 Conventional Radiation Therapy in Early
Stage Non-small-cell Lung Cancer
Branislav Jeremić, Sinisa Stanic, and Slobodan Milisavljevic
Contents
1 Introduction.............................................................. 315
2 Overall Results of Radiation Therapy .................. 316
3 Tumor Dose .............................................................. 319
4 Tumor Stage and Size............................................. 322
5 Treatment Volume................................................... 323
6 Prognostic Factors ................................................... 327
7 Toxicity...................................................................... 328
8 Quality of Life.......................................................... 331
9 Novel Approaches .................................................... 332
9.1 Stereotactic Radiation Therapy ................................. 332
9.2 Accelerated Hypofractionated Radiation
Therapy ...................................................................... 333
9.3 Accelerated Hyperfractionated Radiation Therapy
and Concurrent Radiation Therapy
with Chemotherapy ................................................... 334
10 Conclusions ............................................................... 334
References.......................................................................... 335
B. Jeremić (&)
Institute of Lung Disease, Sremska Kamenica, Serbia
e-mail: nebareje@gmail.com
S. Stanic,
Department of Radiation Oncology,
University of California Davis, Sacramento, USA
S. Milisavljevic
Department of Thoracic Surgery, University Hospital,
Kragujevac, Serbia
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_207, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
Surgery is standard treatment approach in patients
with early stage (I-II) nonsmall cell lung cancer.
However, there are patients who do not undergo
surgery due to existing comorbidities, advanced
age or refusal. They have traditionally been treated
with radiation therapy which provided median
survival times of [ 30 months and 5-year survival
rates of [ 30% in stage I disease.
1 Introduction
Surgery is considered a worldwide standard treatment
approach in patients with early stage (I/II) non-small-
cell lung cancer. It offers the best chance for cure and
results did not change substantially in the past three
decades. In the International staging system classifi-
cation (Mountain 1986), the 5-year survival rates for
pathological stage I/II were 68.5% for T1N0, 59% for
T2N0, 54.1% for T1N1 and 40.0% for T2N1. When
clinical staging is used, however, these results became
inferior: 61.9% for T1N0, 35.8% for T2N0, 33.6% for
T1N1, and 22.7% for T2N1 tumors. A similar analysis
was done for the purpose of the second and then third
staging classification (Mountain 1997; Goldstraw et al.
2007). According to the last staging classification
(Goldstraw et al. 2007). Stage I now has subdivision to
IA (T1a, b N0) and IB (T2a N0), while the stage II also
has two subdivisions, to IIA (T1a, b, T2a N1, T2b N0)
and IIB (T2b N1 and T3 N0).
The surgical/pathological staging is considered an
ultimate one, giving the best correlation with the out-
come. There are, however, also data from surgical series
315
316
on patients with early stage nonsmall cell lung cancer
when clinical staging is used (Mountain 1986; Naruke
et al. 1988). Although comparison of treatment outcome
based on pathological and clinical staging is not so fre-
quently observed in recent years, nevertheless, there is
still a subset of patients in whom clinical stage is used,
irrespective of treatment intention. Data from the sur-
veillance end results suggest that as many as 31% of all
patients with localized non-small-cell lung cancer do not
undergo lobectomy (Potosky et al. 2004). Majority of
these patients, although technically resectable, are not
undergoing surgery due to various reasons. The vast
majority of these patients are medically inoperable due
to pre-existing comorbidity, mostly cardiopulmonary,
presumably carrying high peri- and post-operative risk.
Another group of patients not undergoing surgery are
elderly, owing to presumed restricted cardiopulmonary
reserve, expected to occur even without overt cardio-
pulmonary disease. Finally, the smallest group of
patients not undergoing surgery and possibly the group
of patients having the major importance for radiation
oncologist are the patients who refuse surgery. This may
nowadays range from as low as nil to as high as[20% in
elderly treated with pneumonectomy (Whittle et al.
1991; Au et al. 1994; Mizushima et al. 1997). These
three groups of patients are those mostly offered radia-
tion therapy alone, being frequently considered ‘‘stan-
dard’’ treatment approach in this setting. Unfortunately,
the patients who undergo radiation therapy alone for
early stage nonsmall cell lung cancer mostly constitute
negative selection, materialized in their serious con-
comitant diseases, the use of clinical staging, and
insufficient staging as well. It is, therefore, quite clear
that the results of radiation therapy in this population
cannot be meaningfully compared to those of surgery,
even when one use the results from the surgical series
using clinical staging. Additionally, there is always a
bias in reporting radiation therapy versus surgical series
as well as institutional/investigator bias. Finally, differ-
ent process of decision-making (patients vs. physicians)
has to be accounted for, due to great variance observed
across the studies with the respect to the proportion of
patients refusing surgery.
There are no prospective randomized studies com-
paring radiation therapy alone with other treatment
modalities in patients with early stage non-small-cell
lung caner, including observation (no treatment). In spite
of the fact that one report (McGarry et al. 2002) showed
no advantage for radiation therapy over observation-
B. Jeremić et al.
only, serious flaws of that report, both methodological
and statistical, led to the raise of the concern (Jeremic
et al. 2003b) that observation-only should not be prac-
ticed in any case with early stage non-small-cell lung
cancer today. More recently, (Raz et al. 2007a, 2007b)
reviewed the California Cancer Center registry and
reported on a median survival of only 9 months in 1,432
patients with stage I non-small-cell lung cancer that
received no initial treatment. Indirect evidence support-
ing active treatment also came from the recent study
(Henschke et al. 2003) which showed that even smallest
tumors (i.e., stage I) when untreated had 8-year fatality
rate of 87, 94, and 88%, for tumors having sizes of 6–15,
16–25 and 26–30 mm, respectively. Although that study
focused on the role of surgery versus observation, it
would not be unreasonable to expect the same or similar
if the radiation therapy alone had been active treatment in
a study similar to this. This is especially so when one
considers excellent results obtained in the last decade
with the use of stereotactic radiation therapy in early
stage non-small-cell lung cancer. Although stereotactic
body radiation therapy is being increasingly used for
early stage medically inoperable non-small-cell lung
cancer, conventionally fractionated, three-dimensional
conformal radiation therapy is still used in radiation
oncology clinics since it does not require strong physics
support for a very rigorous quality assurance and pre-
cise immobilization, which cannot be tolerated by all
patients.
This chapter, therefore, summarizes achievements
of conventional radiation therapy in early stage non-
small-cell lung cancer. It aims to highlight its
advantages and underline its disadvantages, and also
enable better insight in a number of pre-treatment and
treatment characteristics in this setting, focusing on
curative radiation therapy.
2 Overall Results of Radiation
Therapy
Numerous studies unequivocally documented the out-
come of patients with operable non-small-cell lung
cancer in the last four decades, including mostly
patients with early (I/II) stage disease. The history of
radiation therapy in early stage non-small-cell lung
cancer started with the report of Morrison et al. (1963)
on 28 patients with ‘‘operable’’ lung cancer treated with
45 Gy who achieved the overall survival of 7% at
Conventional Radiation Therapy in Early Stage Non-small-cell Lung Cancer
5 years. While one may express disappointment with
these early and clearly inferior results (comparing to
nowadays standards and achievements), this should
come as no surprise due to the lack of modern diag-
nostic and planning tools (computerised tomography).
Similarly Coy and Kennelly (1980) provided results not
very different from those of Morrison et al. (1963).
They have achieved 5-year survival of 10% in 141
patients with T1-3 NX tumors treated with radiation
therapy doses of 50–57.5 Gy. It was Smart (1966) who
was the very first to indicate greater potential for radi-
ation therapy alone in this disease. Using total radiation
therapy doses of 40–55 Gy in 40 patients he obtained a
5-year survival of 22% and the median survival time of
approximately 24 months. Of the studies that followed
later on (Cooper et al. 1985; Haffty et al. 1988; Noordijk
et al. 1988; Zhang et al. 1989; Talton et al. 1990;
Sandler et al. 1990; Ono et al. 1991; Dosoretz et al.
1992; Kupelian et al. 1996; Cheung et al. 2000) some
enrolled patients without specifying results according
to the tumor stage, while others also enrolled a pro-
portion of patients in stage III NSCLC (Cooper et al.
1985; Zhang et al. 1989; Talton et al. 1990; Dosoretz
et al. 1992; Kupelian et al. 1996; Cheung et al. 2000).
As expected, there was a substantial variation in the
diagnostic tools used over the time and in the first
reports computerised tomography scanning for diag-
nostic and therapeutic (planning) purposes was not
used. Therefore, studies covering longer periods of
time were more likely to include a number of patients
with more (locoregionally) advanced disease
(Morrison et al. 1963; Smart 1966; Coy and Kennelly
1980; Cooper et al. 1985; Haffty et al. 1988; Noordijk
et al. 1988; Zhang et al. 1989; Talton et al. 1990;
Sandler et al. 1990; Ono et al. 1991; Dosoretz et al.
1992; Kupelian et al. 1996; Cheung et al. 2000). To
further extend this, even some of the reports published in
the eighties and the nineties of the last century suffered
from the very same matter (Cooper et al. 1985; Zhang
et al. 1989; Talton et al. 1990; Haffty et al. 1988;
Noordijk et al. 1988; Sandler et al. 1990; Ono et al.
1991). This may be one of the crucial issues in inter-
pretation of the overall results, since Sandler et al. (1990)
documented an improvement in survival of patients with
‘‘excellent’’ staging (chest CT scan, including the liver,
and bone scan) when compared to those having ‘‘good’’
staging (conventional tomography, liver–spleen scan,
and a bone scan), and particularly to those being staged
less vigorously. Confirmation for this came with recent
317
study of Fang et al. (2006) who evaluated the outcome of
200 patients with medically inoperable stage I non-
small-cell lung cancer and compared three-dimensional
with two-dimensional radiation therapy planning and
execution. The overall survival, disease-specific sur-
vival, and locoregional control rates were significantly
higher in patients treated with three-dimensional radia-
tion therapy. Two- and 5-year overall survival rates were
68, 36, 47 and 10%, respectively (p = 0.001). This was
confirmed by a multivariate analysis using overall sur-
vival and disease-specific survival. However, not all
investigators reported on the similar experience. In the
study of Lagerwaard et al. (2002), the 5-year overall
survival was only 12% which led authors to conclude
that three-dimensional radiation therapy did not improve
survival. Possible explanation for inferior results of
Lagerwaard et al. (2002) could include as much as one-
third of patients having a history of a previous malig-
nancy, smaller percentage of those refusing surgery,
larger proportion of those having T2 tumors as well as
the lack of confirmatory pathology in as much as 40% of
patients. One additional study (Bradley et al. 2003)
failed to show expected advantage of three-dimensional
conformal radiation therapy, likely as a consequence of
unfavorable patient characteristics. As much as 60% of
their patients had greater than 5% weight loss and almost
40% of patients received elective nodal irradiation that
may have caused toxicities that led to poor outcome.
Radiation therapy characteristics greatly varied
with the time, too. Doses as low as 18 Gy were
sometimes given, but went up to 80 Gy, while virtu-
ally all fractionation regimens were used: standard
(1.8–2.0 Gy per fraction), hypofractionated (up to
4 Gy per fraction), split-course (one or two weeks
split), or hyperfractionated (1.2 Gy b.i.d. fraction-
ation). Treatment machines used to deliver irradiation
also ranged from orthovoltage X-rays through cobalt-
60 to either low- or high-megavoltage X-rays of linear
accelerators, as well as did treatment prescription/
dose specification, patients positioning, number of
irradiated treatment fields per day, etc.
Whatever the differences and variances in the
aforementioned studies and the interpretation of their
respective results may have led to, when the data from
the literature were summarized (Jeremic et al. 2002)
they showed that radiation therapy alone was capable
of producing a median survival time of [30 months
([40 months in T1N0) since the mid-eighties of the
last century, with 5-year survival rates of [30% in
318
Fig. 1 CT of the chest in a 67-year old female with medically
inoperable, T1bN0M0, peripherally located, non-small-cell
lung cancer of the left lower lobe, status post 3D conformal
radiotherapy to a total dose of 64 Gy in 2 Gy fractions. a CT
prior to radiation therapy; b CT of the same patient nine months
stage I non-small-cell lung cancer (40% in T1N0) and
up to 25% in stage II non-small-cell lung cancer
(Fig. 1a, b). The evidence that came from the avail-
able studies published in the last decade reconfirms
these statements (Fang et al. 2006; Zhao et al. 2007;
Low et al. 2007; Hsie et al. 2007; Pemberton et al.
2009; Sandhu et al. 2009; Campeau et al. 2009;
Newlin et al. 2009; Watkins et al. 2010), while pre-
treatment and treatment characteristics (available
histology, staging, imaging, three-dimensional plan-
ning based on CT scanning) became always available
and, except time-dose-fractionation and the dose
prescription) almost uniform.
Not only the differences in radiation therapy
characteristics in the aforementioned studies exist, but
these results were also achieved in a cohort of sub-
stantially differing patient populations. An important
underlying issue, namely, the reason for not under-
going surgery, was recently recognized as one of the
major contributors to existing differences between
studies, including their outcomes. It was considerably
different across the studies, particularly when one
consider patient refusal which only recently started to
gain more attention. While the percentage of such
patients was usually around 10%, there are also sev-
eral studies in which it was[20% (Zhang et al. 1989;
Morita et al. 1997; Jeremic et al. 1997, 1999; Fang
et al. 2006), and in one study it was even 70%
B. Jeremić et al.
following completion of radiation therapy. Note a complete
response to conventionally fractionated radiotherapy. Three
years after radiation therapy, the patient is alive and without
evidence of locoregional disease recurrence or distant
metastases
(Jeremic et al. 2005). Interestingly, the highest med-
ian survival times (up to 36 months) and the highest
5-year survival rates (up to 35%) were observed in
these particular studies. It became widely accepted
opinion that these patients represent the population
which seems to be the one most likely to give true
insight in the effectiveness of radiation therapy in this
disease, simply because they are those resembling
surgical candidates at most. This is also observed in
studies using stereotactic radiation therapy in early
stage non-small-cell lung cancer. Reporting on overall
survival as an endpoint in this patient population
becomes more scientifically meaningful, due to less
cancer-unrelated events occurring. In other patient
populations (medically inoperable, elderly), the use of
cancer-specific survival or disease-specific survivals
must be mandatory to correct for events other than
cancer-related. Indeed, when 5-year cancer-specific or
disease-free survival rates were reported (Sandler
et al. 1990; Kaskowitz et al. 1993; Slotman and Karim
1994; Krol et al. 1996; Sibley et al. 1998; Cheung
et al. 2000; Zhao et al. 2007), they were usually twice
as high as those of overall survival, as presented in the
same studies, the difference being approximately
10–20% in favor of the former. Additionally, it is well
recognized fact that patients’ refusal inversely corre-
lates with the incidence of intercurrent deaths
(6–16%) (Zhang et al. 1989; Sandler et al. 1990;
Conventional Radiation Therapy in Early Stage Non-small-cell Lung Cancer
Jeremic et al. 1997, 1999). The incidence of the
intercurrent deaths, on the other side, directly
dependent on the increasing age and pre-existing
comorbidity (21–43%) (Noordijk et al. 1988;
Kaskowitz et al. 1993; Slotman and Karim 1994;
Morita et al. 1997; Sibley et al. 1998; Zhao et al.
2007). These important facts form a complicated
framework which has largely been underestimated in
the past. Contemporary studies must take these facts
into account and adapt the study designs and data
presentation so as to enable better insight into the
effectiveness of radiation therapy in this disease and
to enable easier comparison between the studies.
Irrespective of these shortcomings, results of radi-
ation therapy in recent years were occasionally com-
pared to those of surgery. While this matter will be a
subject of discussion in other chapters, here only a brief
emphasis will be made. In such one study, Hsie et al.
(2007) provided a single-institutional comparison of
outcomes of limited resection and radical radiation
therapy. Radiation therapy characteristics included a
CT-planned and delivered median radiation therapy
doses of 70 Gy (range, 60–75 Gy) and the median daily
fraction size of 2.5 Gy (range, 2.0–4.11 Gy). The
3-year actuarial survival for patients treated with lim-
ited resection was 62.7% and median survival was not
reached. The actuarial 3-year survival for patients
treated with radiation therapy was 55% and median
survival was 38 months (n.s.).
3 Tumor Dose
To start properly addressing the question of the
effectiveness of radiation therapy in early stage
non-small-cell lung cancer, one must start with the
radiation therapy dose itself. Data from the literature
identifies tumor doses used during the radiation
therapy course ranging from as low as 18 Gy to as
high as 90 Gy or as high as biologically equivalent
dose of 124.5 Gy. While this range of tumor doses
used should somehow enable getting information
regarding the anticipated dose–response (effect) issue,
it cannot artificially be detached from the issue of
tumor stage/size, since one of the long-lasting bio-
logical premises in radiation oncology is that larger
tumor sizes (presumably higher stage) require higher
tumor doses.
319
Dose–response relationship was evaluated by
many investigators. It has usually been observed that
higher doses carry favorable outcome. Some studies
used somewhat lower cut-off values (e.g., 40 or
50 Gy) which enabled comparison of palliative versus
curative treatments (Cooper et al. 1985; Sandler et al.
1990; Kupelian et al. 1996). It was Cooper et al.
(1985) who first noted improved survival with the
higher dose ([40 Gy compared to \40 Gy). Haffty
et al. (1988) noted an advantage of continuous course
(59 Gy) over split-course (54 Gy) regimen, not only
regarding overall survival, but local control as well.
The dose–effect upon survival was also evaluated in
the study of Zhang et al. (1989) who found that higher
doses (69–70 Gy) were more efficient than the lower
ones (55–61 Gy). However, Sandler et al. (1990)
could not confirm this, presumably due to a somewhat
narrow dose range in their study Hayakawa et al.
(1992) and Dosoretz et al. (1992) also confirmed
importance of higher doses on overall survival and
disease-specific survival, but warned on the use of
very high doses ([80 Gy) when conventional tools
were used for treatment planning/delivery (Hayakawa
et al. 1992) due to increased risk of treatment-related
toxicity and mortality Slotman and Karim (1994) did
not find an impact of the higher (48–56 Gy) versus
lower (32–40 Gy) doses of radiation therapy on either
overall survival or disease-specific survival in stage I
non-small-cell lung cancer. Kaskowitz et al. (1993)
and Sibley et al. (1998) both observed better overall
survival, though not statistically significant, for higher
doses ([65 and [64 Gy, respectively). Graham et al.
(1995) used tumor/dose/fractionation calculations as a
measure of the effectiveness of radiation therapy to
document better outcome with increasing tumor/dose/
fractionation values in multivariate analysis. Also,
Kupelian et al. (1996) and Morita et al. (1997)
showed impact of the dose on local response/control,
which was not always translated into a better survival
(Morita et al. 1997). Stage I/II non-small-cell lung
cancer should represent tumors with the smallest
burden of tumor cells, although imprecise staging
currently used (still based on tumor size rather than on
the volume) allows that even small-volume tumors
are placed in the higher staging category (e.g., stage
III) when invading certain intrathoracic and/or
mediastinal structures. While some of the existing
analyses favored even lower doses of radiation
therapy, it still remains preferable to use the doses
320
traditionally considered as ‘‘curative’’, being in the
order of [65–70 Gy with standard fractionation or its
equivalent when altered fractionation is used. This
suggestion should be even more valid nowadays with
widespread of three-dimensional treatment planning
and delivery, because it should enable better thera-
peutic benefit when compared to two-dimensionally
planned and executed radiation therapy used in the
past. Indeed, the data on the use of high-dose radia-
tion therapy (e.g., 80 Gy) show that it may indeed be
very beneficial. In the study of Watkins et al. (2010)
100 primary lung tumors in 98 patients of a clinical
stage I and II were treated with C70 Gy at 1.8–
2.5 Gy. The median prescribed dose was 80 Gy
(range, 70–90 Gy) with 84% of patients receiving
[79 Gy. The calculated biologically equivalent dose
(at 2 Gy per fraction with alpha/beta estimated at
10 Gy) was [95 Gy for 80 patients, and [99 Gy
for 50 patients. The estimated 2- and 3-year local
(in-field) controls were 53 and 50%, respectively,
while estimated 2- and 3-year overall survivals were
47 and 24%, respectively.
Also, Zhao et al. (2007) reported on the study
showing that high radiation dose may reduce the
negative effect of large gross tumor volume in
patients with medically inoperable stage I–II non-
small-cell lung cancer, In that study, multivariate
analysis showed that there was a significant interac-
tion between radiation dose and gross tumor volume
(p \ 0.001). In patients with biologically equivalent
dose of B79.2 Gy, the overall survival medians for
patients with gross tumor volume of [51.8 cm3 and
B51.8 cm3 were 18.2 and 23.9 months, respectively
(p = 0.015). If biologically equivalent dose was
[79.2 Gy, no significant difference was found
between two gross tumor volume groups. For
patients with gross tumor volume [51.8 cm3, the
overall survival; medians in those with biologically
equivalent dose of [79.2 Gy and \79.2 Gy were
30.4 and 18.2 months, respectively (p \ 0.001). If
gross tumor volume was B51.8 cm3, the difference
was no longer significant. Similarly, in the study of
Low et al. (2007) in 23 patients with stage I non-
small-cell lung cancer, the median survival for
patients who received a biologically equivalent dose
of C63.9 Gy was not reached as compared to
20 months in patients with biologically equivalent
dose of \63.9 Gy (p = 0.03).
B. Jeremić et al.
One should also take into consideration altered
fractionated regimens. Beside studies Jeremic et al.
(1997, 1999) who successfully used hyperfractionated
radiation therapy (69.6 Gy using 1.2 Gy b.i.d.) in
both stage I and II non-small-cell lung cancer,
accelerated regimens were also used, such as contin-
uous hyperfractionated accelerated radiation therapy
(Saunders et al. 1999a). Recent report of Pemberton
et al. (2009) not only reconfirmed its effectiveness,
but also brought to the light effectiveness of another
hypofractionated regimen, the one using 55 Gy in 20
daily fractions. Both regimens are almost exclusively
practiced in the UK. In that study, 137 patients treated
with CHART and 140 patients treated with 55 Gy
in 20 daily fractions were compared. The median
survivals were 16.6 and 21.4 months, while 2-year
survivals were 34 and 45% for the two regimens,
respectively. No formal comparison was provided in
this study, although provided statistical analysis
clearly indicated superiority of 55 in 20 daily frac-
tions over CHART.
Bradley et al. (2005) performed a phase I–II dose-
escalation study using three-dimensional conformal
radiation therapy in 177 patients with medically
inoperable stage I–III non-small-cell lung cancer
(RTOG 9311). Concurrent chemotherapy with radia-
tion was not allowed. The radiation dose was safely
escalated to 83.8 Gy for patients with lung V20\25%
and 77.4 Gy for patients with lung V20 between 25
and 36% utilizing fraction sizes of 2.15 Gy. The
highest dose level, 90.3 Gy was too toxic, resulting in
dose-related deaths in 2 patients. Less than 10% of
patients received elective nodal irradiation. Locore-
gional control, which was a secondary objective of
this dose escalation study, was achieved in 50–78% of
patients.
At the present time, different dose fractionation
schedules have been used in radiation oncology.
Doses have ranged between 60 and 70 Gy (Fig. 2). If
radiation therapy is delivered in once daily fractions,
five days per week, 1.8–2.0 Gy daily fractions are a
reasonable approach. In the United States, if stereo-
tactic body radiation therapy is not available in a
radiation oncology clinic, or a patient is unable to
tolerate stereotactic immobilization, conventionally
fractionated radiation therapy utilizing three-dimen-
sional conformal planning is considered, if possible to
a total dose of 70 Gy with 2 Gy per fraction and the
Conventional Radiation Therapy in Early Stage Non-small-cell Lung Cancer
Fig. 2 3D conformal radiotherapy treatment plan for a 69-year
old male with medically inoperable, T1bN0M0, peripherally
located, non-small-cell lung cancer of the right upper lobe,
status post CT guided fine needle aspiration. A dose of 70 Gy
was delivered in 2 Gy fractions with five conformal fields.
goal to keep total lung volume receiving 20 Gy (V20)
\35%. One of the disadvantages of conventional
fractionation is a long treatment course, 6–7 weeks.
In order to reduce the number of treatments required
to complete a definitive course of radiation therapy, a
new approach has emerged—accelerated hypofrac-
tionated radiation therapy, which typically employs
321
Heterogeneity correction was applied to take into account the
density differences. Note the dose distribution and volumes:
GTV = gross tumor volume, CTV = clinical target volume and
PTV = planning target volume
3.5–4.0 Gy per fraction, to a total dose of 48–60 Gy
(Soliman et al. 2011). This is not a type of stereotactic
body radiation therapy, but rather an alternative to
extremely hypofractionated stereotactic radiation.
This approach will be presented later in this chapter
when we discuss novel approaches in radiation ther-
apy for early stage non-small-cell lung cancer.
322
4 Tumor Stage and Size
When influence of tumor stage and/or size on treat-
ment outcome was evaluated, it was mostly observed
that smaller tumors and/or lower stage of the disease
carry an improvement in survival. Different cut-off
sizes were used in various studies, but sizes most
frequently used were \3 cm or \4 cm and these
tumors were frequently compared to larger ones.
Also, T1 stage was frequently compared to T2 stage
with regard to overall survival, disease-specific sur-
vival and local control. Multivariate analyses were
also used to in an effort to confirm independent
influence of T stage, frequently documenting that
T stage was the only prognosticator of the treatment
outcome (Kaskowitz et al. 1993; Graham et al. 1995;
Gauden et al. 1995; Jeremic et al. 1997; Fang et al.
2006). Additionally, better outcome for T1 versus T2
or for tumor size B3 cm versus [3 cm (Morita et al.
1997; Slotman et al. 1996; Sibley et al. 1998; Yu et al.
2008) was observed, although without statistical sig-
nificance. Contrary to these, there were also studies
that evaluated both T stage and particular tumor size,
with conflicting results. In the study of Kupelian et al.
(1996) T stage did not influence either overall sur-
vival or disease-specific survival or local control.
Interestingly, however, when tumor size was used as a
variable, it was found that tumors \5 cm had better
disease-specific survival and those \4 cm had better
local control, confirmed in both cases using multi-
variate analysis. Zhao et al. (2007) also showed
superior outcome for patients with stage I versus
those with stage II in multivariate analysis in that
study, as well as did Pemberton et al. (2009). In that
study, gross tumor volume was used as variable.
Several studies also demonstrated negative effect of
increasing gross tumor volumes on treatment out-
comes for radiation therapy in non-small-cell lung
cancer (Basaki et al. 2006; Bradley et al. 2002;
De Petris et al. 2005; Etiz et al. 2002 Yu et al. 2008).
Contrary to these, Willner et al. (2002) reported that
for tumors larger than 100 cm3, no dose effect was
seen. In their study, only two out of 45 tumors [100
cm3 were controlled for [2 years in patients with
various stages of the disease. While one may expect
impact of tumor stage/size on the outcome, it is rea-
sonable to expect that this would happen first at local/
regional level, and then on the overall survival,
B. Jeremić et al.
providing causal relationship between local control
and overall survival. Therefore, local/regional-recur-
rence free survival or disease-specific survival must
be included in the analysis as important initial end-
points. The distant metastasis-free survival must be
used, too, to provide better insight into the events
other than those occurring locoregionally. The pat-
terns of failure (detailed later in the chapter) were
shown to heavily depend on local/regional tumor
control in this disease. In one such analysis, Watkins
et al. (2010) showed that results were significantly
better for cT1N0 over cT2N0 tumors using estimated
2- and 3-year local control (66 vs. 42%), and disease-
free survivals (48 vs. 26%).
Important obstacles for clear and precise definition
of the role of tumor stage/size are staging systems
widely used in the last twenty years (Mountain 1986,
1997; Goldstraw et al. 2007). As already mentioned,
these surgical systems do not relate only to a tumor
size, but also to a particular tumor location, leading to
confusion when this (surgical) staging system is
applied to non-surgical setting, having different bio-
logical premises. Practical example of such a problem
is as follows: tumor of 1 cm would be, by virtue of its
size placed into T1 category, but if it involves main
bronchus at C2 cm distal to the carina, it would be
designated as T2. This may be even more so in the
case of a tumor of the same size invading chest wall,
being automatically placed into the T3 category. This
issue may be an important one owing to the log-cell
kill nature of anticancer action of radiation therapy.
There are requests for continuous revision of current
international staging system, which should make both
T and N staging more specific/detailed, computer-
enabled measurements of T and N volumes enabled
and, therefore, efforts/results are easier to interpret/
compare. Indeed, several aforementioned studies have
successfully shown that gross tumor volume can be
used as important predictor of treatment outcome.
Positron emission tomography (PET) has become a
standard modality for staging non-small-cell lung
cancer (Lin and Alavi 2009). With regard to intra-
thoracic nodal staging, PET has a definite role in
communities in which mediastinoscopy is not avail-
able, whereas the impact can be quite limited in
institutions in which invasive mediastinal staging is
available. Although the role of PET scanning in
staging will be discussed in a separate chapter, two
questions seem as important ones. The first question is
Conventional Radiation Therapy in Early Stage Non-small-cell Lung Cancer
whether positive PET scans in the mediastinum
require mediastinoscopy. Since the false-positive rate
of PET in the mediastinum is 15–20% (Detterbeck
et al. 2004), most physicians agree that positive
results on PET scan should be confirmed by a biopsy
and mediastinoscopy should be recommended. The
second question is whether negative PET scans in the
mediastinum obviate the need for mediastinoscopy.
It is still controversial whether or not to confirm a
negative PET scan result in the mediastinum by
mediastinoscopy. If false-negative rate of PET in the
mediastinum is only 5–8% (Detterbeck et al. 2004),
mediastinoscopy can potentially be avoided. Some
physicians would argue that this false-negative rate is
low enough to be acceptable while others would
debate that one should not rely on a negative PET
study, particularly in patients with central tumors,
adenocarcinoma histology, and N1 nodal involvement
by CT imaging. Cerfolio et al. (2006) recommended
consideration of mediastinoscopy in PET negative
patients with adenocarcinoma, upper lobe tumors, or
tumors with maximum SUV C10. Presently, in the
United States, many believe that negative PET scan in
the mediastinum obviate the need for mediastinos-
copy only in patients with T1 peripheral tumors,
while for all other cases mediastinoscopy should be
strongly considered. Radiation oncologists, however,
often face another challenge: the majority of medi-
cally inoperable patients with early stage non-small-
cell lung cancer decline mediastinoscopy, as an
invasive diagnostic procedure. In this situation, radi-
ation oncologists have no other choice than to use
clinical staging by PET/CT for treatment volume
definition.
5 Treatment Volume
Another issue of particular importance in the field of
radiation therapy of lung cancer is the ‘‘optimal’’
treatment volume. Unfortunately, as with preceding
issues, disadvantages of the existing, largely retro-
spective and literature apply here as well. Neverthe-
less, it seems that this issue is focusing on the issue of
using or omitting elective nodal irradiation, which
would be a synonym for elective radiation therapy of
hilum with or without a part or whole of the medi-
astinum in cases of stage I or a part or whole of the
mediastinum in stage II non-small-cell lung cancer.
323
To better address this issue, one must consider it
together with the irradiation dose used for elective
treatment. Some studies used doses of 40 Gy in 20
daily fractions (Zhang et al. 1989; Talton et al. 1990;
Hayakawa et al. 1992; Slotman et al. 1996; Morita
et al. 1997; Hayakawa et al. 1999) which can not be
considered as adequate to treat microscopic disease.
While some were using 45 Gy in 20–22 fractions
(Morrison et al. 1963; Haffty et al. 1988; Kupelian
et al. 1996) which can be considered as standard of
practice, it is of unproven efficacy in lung cancer.
Additionally, if we extrapolate the data from squa-
mous-cell carcinoma of the head and neck, than one
would need 50 Gy given with 2.0 Gy standard frac-
tionation to treat microscopic disease successfully.
Close to this level were doses used by Kaskowitz
et al. (1993) by Morita et al. (1997) in part of their
patients, and by Jeremic et al. (1997, 1999), with
hyperfractionated radiation therapy dose of 50.40 Gy
using 1.2 Gy b.i.d. fractionation applied by the latter.
Finally, because of the fear that there may be an
increased risk of subclinical nodal spread in some
lymph node regions, others have also adapted other-
wise strict institutional policy and included some
nodes at risk into the limited field radiation therapy,
giving it, therefore, a form of ‘‘electively-limited’’
radiation therapy, usually based on primary tumor
location (central tumor location or tumor adjacent to
the mediastinum (Senan et al. 2002; Lagerwaard et al.
2002).
However, the choice and the number of the treat-
ment fields and the dose prescription was not always
clearly specified, causing somewhat less precise
interpretation of the data. This is so particularly
regarding the second part of the radiation therapy
course, which, by using various combinations of
radiation therapy fields to treat visible tumor only
(mostly obliques and/or laterals), provides an unin-
tentional treatment contribution to the nodal areas at
risk. This contribution for a particular radiation ther-
apy plan was not documented at all in the past studies
and was, therefore, unknown. However, Martel et al.
(1999) showed that three-dimensional conformal
radiation therapy used to deliver starting doses of
69.3–84 Gy to gross tumor volume resulted in 100%
of the ipsilateral hilum, 59% of the low paratracheal
region, 57% of the aortopulmonary region, 97% of the
subcarinal region and 57% of the contralateral hilum
receiving C50 Gy. Another report from the same
324
institution (Hayman et al. 2001) showed no isolated
elective nodal failures when three-dimensional con-
formal radiation therapy was used in patients with
non-small-cell lung cancer, although there were
3(6%) failures in the lymph nodes outside the plan-
ning target volume. Rosenzweig et al. (2001) also
used similar three-dimensional conformal radiation
therapy (range, 50.4–81 Gy; median, 68.4 Gy) with-
out elective nodal radiation therapy to observe 2-year
rate of elective nodal control in 88% patients with
tumors locally controlled. With unintentional nodal
radiation therapy, a dose of [40 Gy was delivered to
ipsilateral superior mediastinum in 34% patients, to
the inferior mediastinum in 63% patients and to the
subcarinal region in 41% patients. It is, therefore,
obvious that not just conventional radiation therapy
but also three-dimensional conformal radiation ther-
apy (using ‘‘limited’’ radiation therapy fields, e.g.,
those covering only macroscopically/radiographically
visible tumor) frequently result in higher dose to the
nodal regions that one may initially assume. If one
intends to document the necessity of elective nodal
radiation therapy in this setting, a policy of clear
documentation of the dose to the regions presumably
harboring microscopic spread must be mandatory.
Unfortunately, even most recent publications on
the use of three-dimensionally conformal radiation
therapy in inoperable non-small-cell lung cancer,
including more or less cases of early stage non-small-
cell lung cancer, do not document incidental nodal
irradiation, yet claiming that no elective irradiation
was performed (Belderbos et al. 2003; Bradley et al.
2003; Lagerwaard et al. 2002).
In some studies institutional policy regarding
elective nodal irradiation did not change over the time
(Jeremic et al. 1997, 1999), while some (Sandler et al.
1990; Graham et al. 1995) did not provide results
according to radiation therapy volume. While Doso-
retz et al. (1992) found no impact of elective nodal
irradiation on the treatment outcome, Kupelian et al.
(1996) and Sibley et al. (1998) found better overall
survival, disease-specific survival and local control in
patients undergoing elective nodal irradiation, though
insignificant, probably due to a small number of
events. Morita et al. (1997), however, clearly docu-
mented superior complete response rates and overall
survival in patients undergoing elective nodal irradi-
ation and lower distant metastasis rate in patients
undergoing elective nodal irradiation.
B. Jeremić et al.
So far, there is only one prospective randomized
trial which evaluated the issue of elective nodal
irradiation in this setting (Yuan et al. 2007). In this
trial 200 patients were randomized between involved-
field radiation therapy to 68–74 Gy and elective nodal
irradiation to 60–64 Gy. Patients in the involved-field
arm achieved better overall response rate (90 vs. 79%,
p = 0.032) and better 5-year local control rate (51 vs.
36%, p = 0.032) than those in the elective nodal
irradiation arm. Unfortunately, it remained unclear if
the poorer outcome from elective nodal irradiation
was due to the lower radiation therapy dose or the use
of elective nodal irradiation.
When focusing on the issue of elective nodal
irradiation one must also consider the incidence of
occult lymph node (hilar and/or mediastinal) metas-
tasis. If the initial clinical staging based on comput-
erised tomography scanning is ultimately verified
during operation, the incidence of nodal metastases in
stage I non-small-cell lung cancer may be as high as
26% (Glazer et al. 1984; Heavey et al. 1986; Black
et al. 1988; Conces et al. 1989), supporting, thus, a
consistent finding over the decades that surgical/
pathological upstaging is seen in approximately 25%
of cases of T1N0 and approximately 35% of cases of
T2N0 cases (Martini and Beattie 1977; Naruke et al.
1988; Ginsberg et al. 1995). Data from surgical
studies also showed similar incidence of unsuspected
lymph node metastasis when T1 stage was divided by
tumor size, 18% in T1a (\2 cm) and 23% in T1b
(2–3 cm) tumors (Koike et al. 1998). They have,
therefore, effectively supported previous findings of
surgical studies in early stage non-small-cell lung
cancer which clearly showed increasing incidence of
lymphatic invasion/metastasis which occurs with
increasing size of the tumor (\1.0 cm, 1.1–2.0 cm and
[2.0 cm had approximately 0, 17 and 38% of such
incidence, respectively) (Ishida et al. 1991). When
immunohistochemical staining was used in patients
with peripheral adenocarcinoma of B2.0 cm, occult
nodal (hilar and/or mediastinal) (micro) metastases
were detected in 20% of patients (Wu et al. 2001).
Additionally, on multivariate analysis, nodal micro-
metastasis was an independent prognosticator of sur-
vival, which was in agreement with previous studies
(Chen et al. 1993; Passlick et al. 1996; Dobashi et al.
1997; Maruyama et al. 1997). Also, occult nodal
metastases were significantly more frequent in poorly
differentiated tumors, confirming previous findings
Conventional Radiation Therapy in Early Stage Non-small-cell Lung Cancer
(Takizawa et al. 1998). Although direct comparison
between surgery and radiation therapy regarding this
issue is not likely to be performed, nevertheless,
widely adopted philosophy of the surgical approach
suggested as preferred/mandatory treatment for T1N0
patients (i.e., lobectomy) would include systematic
removal of all hilar and mediastinal lymph node
content (Ishida et al. 1991; Ginsberg et al. 1995). Its
radiotherapeutic equivalence would be radiation
therapy field instituted to treat some, if not all, lymph
node regions (hilar and/or mediastinal).
On the other side, recent review of the data on the
patterns of recurrence after radical radiation therapy
in early stage non-small-cell lung cancer available in
the literature (Jeremic et al. 2002) showed that pre-
dominant type of failure remains local, being reported
as either isolated or initial in approximately 11–55%
cases (ultimate up to 75%). An isolated/initial regio-
nal failure was reported to occur in only 0–7% cases
(ultimate up to 15% cases), while the distant metas-
tasis mostly lies between these two (isolated/initial in
3–33% cases and ultimate in up to 36% cases). These
findings could support the use of more localized
fields, because it was stressed that the major concern
should be the gross tumor burden and not a micro-
scopic one (Williams et al. 2000). However, in the
recent study of Yu et al. (2008) in elderly patients
([70 years of age), involved field radiation therapy
led to 36.7% elective nodal failures. Importantly, the
median time to elective nodal failure was 55 months
(range, 49–61 months). These figures may, at least
partially, explain why radiation therapy-alone studies
along with short (e.g., 3 years) follow-up are likely to
underestimate true incidence of isolated nodal failures
when one uses involved-field radiation therapy in this
disease. Recent use of positron emission tomography
scanning in lung cancer has shown that it may be
successful not just in detecting subclinical distant
spread (MacManus et al. 2001) but also in detecting a
subclinical regional spread. Farrell et al. (Farrell et al.
2000) investigated 84 patients without hilar or medi-
astinal lymph node enlargement on computed tomog-
raphy. Histopathological N0 disease was confirmed in
73 patients, 63 of whom had no hilar or mediastinal
activity on fluorodeoxyglucosae-positron emission
tomography scan (86%) while hilar or mediastinal
lymph node activity and distant metastases were found
in 3, 6, and 1 patient, respectively. Thus positron
emission tomography rather overestimated more
325
advanced disease in 12% of the patients as compared
to chest tomography with false negative findings in 11
patients (13%). In a series by Marom et al. (1999)
(52) nodal staging by computerised tomography,
positron emission tomography and histopathological
analysis disclosed N0 status in 42, 29, and 32 patients,
respectively. However, with regard to hilar lymph
node involvement, both computerised tomography
and positron emission tomography were positive in 6
patients, three of whom were confirmed by patho-
logical analysis. Hence, the rates of false-negative
staging by computerised tomography and false posi-
tive staging by positron emission tomography were
due to differences in mediastinal lymph node assess-
ment which is of particular importance when assess-
ing the role of positron emission tomography in stage
I/II lung cancer. These findings are supported by a
study by Saunders et al. (1999b) (53) who assessed
the rate of N2 and N3 mediastinal lymph node
involvement by positron emission tomography and
computerised tomography in a series of 97 patients
under consideration for surgery. True negative find-
ings were observed in 65 and 62 patients for positron
emission tomography and computerised tomography,
respectively. However, the rate of false negative
findings differed substantially with 5 patients by
positron emission tomography and 12 patients by
computerised tomography. Thus, positron emission
tomography offers particular advantages of comput-
erised tomography imaging with regard to exclusion
of mediastinal lymph node involvement while
assessment of hilar nodal disease may be equally
difficult by computerised tomography and positron
emission tomography. It is expected that positron
emission tomography may help better to delineate the
tumor itself, exclude possible areas of regional/distant
spread, and enable dose-escalation which seems to be
possible in the cases with limited lung volume
included in the radiation therapy fields. Finally,
additional advantage of the positron emission
tomography is that it can be used for the purpose of
treatment planning, owing to increased capability of
image fusion (with computerised tomography).
Radiation targeting with fused FDG-PET and CT
images altered the radiation therapy volume in over
58% of patients in comparison with CT targeting
(Bradley et al. 2004). One of the significant advan-
tages of PET is its ability to discriminate tumor tissue
from atelectasis. Decreases in the target volumes in
326
patients with atelectasis lead to decreases in normal-
tissue toxicity.
Nevertheless, more information on various bio-
logical properties and actual differences between
various subgroups of patients and tumors (e.g., his-
tology, tumor grade) are needed. They must be
gathered before one can embark on investigation of
various radiotherapeutic issues in this disease. In one
such attempt Sawyer et al. 1999) used the data
obtained from 346 patients undergoing complete
resection of early clinical stage non-small-cell lung
cancer to identify predictors of subclinical nodal
involvement. Findings of preoperative bronchoscopy,
tumor size, tumor grade and histology were all com-
bined to create risk groups for N1/N2/local/regional
recurrence; they have found that the risk of subclini-
cal nodal involvement was at least 15.6% in the best
(low risk) subgroup, while all other patients had
atleast 35% of such a risk. Increasing risk correlated
with increasing size and grade of tumor, accompanied
with positive findings of bronchoscopy. In a similar
approach, Suzuki et al. (2001) attempted to determine
predictors of lymph node and intrapulmonary metas-
tasis in 389 patients with clinical stage IA non-small-
cell lung cancer undergoing major lung resection and
complete mediastinal lymph node dissection. Of
them, eighty-eight (23%) patients had pathological
lymph node involvement or intrapulmonary metasta-
ses. Significant predictors of local or regional spread
included grade of differentiation and pleural
involvement. When both risk factors were present,
more than 40% of clinical stage IA non-small-cell
lung cancer patients had pathologic involvement of
lymph nodes or intrapulmonary metastases. The same
group (Suzuki et al. 1999) previously investigated
clinical predictors of N2 disease in 379 patients with
clinical N0–N1. There were 68 (17.9%) patients with
pathologic N2 stage. Multivariate analysis showed
that tumor size, high serum carcinoembryonic antigen
level and adenocarcinoma histology were significant
predictors of N2 disease. Finally, Fuwa et al. (2008)
investigated the indication for radiotherapy in 396
patients with operable peripheral early (T1N0) non-
small-cell lung cancer by using the data such as age,
gender, Brinkmann’s index, histology, grade of dif-
ferentiation, tumor diameter and the level of carci-
noembryonic antigen as factors involved in lymph
node metastasis. They showed that this risk was low
in those with well differentiated carcinoma and those
B. Jeremić et al.
with moderately differentiated lesions measuring
B1.5 cm in diameter.
One of the challenges in radiation oncology is how
to accurately define microscopic tumor extension and
clinical target volume for radiation therapy in patients
with non-small-cell lung cancer. Grills et al. (2007)
did a clinicopathologic analysis of microscopic
extension in T1N0 lung adenocarcinoma in 35
patients who underwent surgical resection. The mean
microscopic extension beyond the gross tumor was
7.2 mm and the margin required to cover microscopic
extension in 90% of patients was 9.0 mm. Giraud
et al. (2000) did a similar analysis in 70 non-small-
cell lung cancer surgical resections specimens and
found that the microscopic extension was different
between adenocarcinoma and squamous-cell carci-
noma. To cover 95% of microscopic extension, a
margin of 8 and 6 mm must be added for adenocar-
cinoma and squamous-cell carcinoma, respectively.
Patients with early stage non-small cell lung cancer
frequently received only fine-needle aspiration biopsy
for pathologic diagnosis. Although fine-needle aspi-
ration can usually distinguish between small-cell lung
cancer and non-small-cell lung cancer, it is difficult to
distinguish between different histologic subtypes of
non-small-cell lung cancer (Edelman and Gandara
2009). As a result, pathology reports sometimes
describe only ‘‘malignant cells consistent with non-
small-cell lung cancer’’ and radiation oncologists
come into dilemma how to define microscopic
extension and what margin to apply.
Currently, in radiation oncology a treatment plan-
ning CT with contiguous 3 mm slice thickness is
usually required to define gross tumor volume (GTV),
clinical target volume (CTV) and planning target
volume (PTV). If elective nodal irradiation is not
used, the primary tumor and clinically positive lymph
nodes seen on CT ([1 cm in short axis diameter) or
pre-treatment PET scan (maximum SUV [2.5) typi-
cally constitute the GTV. The GTV in the lung should
be delineated with the ‘‘lung window’’ setting, while
mediastinal GTV should be outlined with the
‘‘mediastinal window’’ setting. Additional 0.5–1.0 cm
margin is added to the GTV to account for micro-
scopic tumor extension and create the CTV. Typi-
cally, 1.5 cm in the superior-inferior dimensions and
at least 1.0 cm in the in the axial plane is added to the
CTV to create the PTV. While CTV margin accounts
for microscopic tumor extension, the PTV margin
Conventional Radiation Therapy in Early Stage Non-small-cell Lung Cancer
accounts for tumor motion and set-up error. If
4DCT scan is available, tumor motion can be seen
during a respiratory cycle and maximum intensity
projection (MIP) dataset (Underberg et al. 2005) is
used to generate internal target volume (ITV),
which includes tumor and its respiratory motion. An
additional margin is added to the ITV to create the
PTV, although this margin can be significantly
reduced if daily image guidance is used. The PTV
is treated with three-dimensional conformal fields
shaped to deliver the prescription dose while
restricting the dose to the normal tissues. When a
linear accelerator is used, 6–12 MV energy photons
should be used for treatment planning, and doses
should be calculated with heterogeneity corrections
that take into account the density differences within
the irradiated volume.
Owing to somewhat conflicting results, identified
when discussing this issue (Jeremic 2004, 2007;
Belderbos et al. 2008, 2009) no reliable recom-
mendations can be made concerning elective nodal
irradiation, although prevailing opinion in the year
2011 is to omit elective nodal irradiation. However,
there seems to be a subgroup of patients with
increased risk of developing nodal metastasis, iden-
tification of which must be one of the priorities of
research in this field. Contrary to that, it is reason-
able to assume that at least for small peripheral, low-
grade tumors it would be the best to administer
involved-field radiation therapy (omitting elective
nodal irradiation), due to lowest incidence of occult
nodal metastasis. Ultimately, however, more infor-
mation regarding biology of these tumors is needed
because identification of potential factors contribut-
ing to higher incidence of subclinical regional lymph
node metastasis would help to optimize radiation
therapy fields and enable successful dose-escalation
at the primary tumor level.
6 Prognostic Factors
In addition to radiation therapy-related factors, there
were also attempts to investigate the influence of
various pre-treatment, both patient- and tumor-
related, prognostic factors using either overall
survival or cause-specific survival/disease-specific
survival as endpoints. Gender seems not to play a
major role in the outcome of patients (Coy and
327
Kennelly 1980; Sandler et al. 1990; Hayakawa
et al. 1992; Rosenthal et al. 1992; Slotman and
Karim 1994; Gauden et al. 1995; Morita et al.
1997; Jeremic et al. 1997, 1999; Lagerwaard et al.
2002; Zhao et al. 2007; Pemberton et al. 2009).
Fang et al. (2006), however, showed that male
gender carries independent influence on overall
survival and adversely influencing it.
Majority of the available reports also observed no
influence of the age on treatment outcome (Morrison
et al. 1963; Noordijk et al. 1988; Sandler et al. 1990;
Kaskowitz et al. 1993; Krol et al. 1996; Jeremic et al.
1997, 1999; Hayakawa et al. 1992; Slotman and
Karim 1994; Slotman et al. 1996; Gauden et al. 1995;
Rosenthal et al. 1992; Zhao et al. 2007; Pemberton
et al. 2009). This was also shown in the study of
Campeau et al. (2009) on the use of radiation therapy
alone and radiation therapy and concurrent chemo-
therapy. However, Morita et al. (1997) found detri-
mental effect of age of [80 years on overall survival,
though not providing data on other endpoints such as
cause-specific survival. Similarly, Sibley et al. (1998),
however, used both uni- and multivariate analysis to
show that younger age positively correlated with
overall survival and cause-specific survival. Both
studies, however, provide no explanation at all or
perhaps a hypothesis for such finding. The same
remains true for the report of Lagerwaard et al. (2002)
who found detrimental effect of increasing age
(patients were grouped as having age \70, 70–75, and
[75 years) on overall survival, but not on cause-
specific survival or local and distant tumor control.
Similar was observed by Firat et al. (2002) in a uni-
variate analysis, though not confirmed by the multi-
variate analysis. Fang et al. (2006) showed that age
C70 years was an independent prognosticator of
inferior survival. Recent analyses focusing on elderly
with early stage non-small-cell lung cancer (Furuta
et al. 1996; Hayakawa et al. 2001; Gauden and
Tripcony 2001) showed similar outcome for this
patient population when treated with radiation therapy
alone, which may go as high as 36% when 5-year
cause-specific survival was used as an endpoint
(Furuta et al. 1996).
Influence of the performance status on treatment
outcome is still controversial. Both Dosoretz et al.
(1992), Slotman and Karim (1994), Kaskowitz et al.
(1993) (23), Gauden et al. (1995) and Pemberton
et al. (2009) found no influence of performance status
328
on either overall survival or disease-specific survival,
while Rosenthal et al. (1992), Hayakawa et al. (1992),
Kupelian et al. (1996) (14), Jeremic et al. (1997,
1999) as well as Hsie et al. (2007) did note its effect
on either overall survival and/or disease-specific sur-
vival/relapse-free survival as well. In the study of
Lagerwaard et al. (2002) the World Health Organi-
zation performance status score was an independent
prognosticator of OS, and the same was observed in
the study of Firat et al. (2002) using the Karnofsky
performance status score in a univariate analysis.
Likewise, conflicting results are seen with weight loss
(Fang et al. 2006; Pemberton et al. 2009; Campeau
et al. 2009).
Investigating influence of histology on treatment
outcome, only Sibley et al. (1998) found an
improvement in cause-specific survival for squamous
histology, while Gauden et al. (1995) observed so for
the mixed (adenocarcinoma/squamous-cell carci-
noma) histology using both overall survival and
relapse-free survival as endpoints. Lagerwaard et al.
(2002) observed an independent and favorable influ-
ence of unknown histology (versus squamous-cell
histology and non-squamous-cell histology) on over-
all survival. All other studies observed no such effect
(Sandler et al. 1990; Dosoretz et al. 1992; Hayakawa
et al. 1992; Rosenthal et al. 1992; Dosoretz et al.
1993; Slotman and Karim 1994; Slotman et al. 1996;
Jeremic et al. 1997; Firat et al. 2002; Pemberton
et al. 2009), including radiochemotherapy studies
(Campeau et al. 2009). Only Hayakawa et al. (1992)
observed better outcome for tumors located in the
upper lobes or the superior segment of the lower
lobes, while all other studies excluded its possible
effect when comparing central versus peripheral
location (Ono et al. 1991; Slotman and Karim 1994;
Slotman et al. 1996; Jeremic et al. 1997; Cheung et al.
2000; Lagerwaard et al. 2002).
In addition to various clinical prognostic factors, a
number of biological and molecular characteristics of
lung cancer may influence treatment outcome. While
they have been investigated in surgical patients
(Slebos et al. 1990; Tateishi et al. 1991; Fontanini
et al. 1992; Pastorino et al. 1997), these information’s
are basically lacking in medically inoperable early
stage non-small-cell lung cancer patients treated
with radiation therapy either alone or given with
chemotherapy.
B. Jeremić et al.
7 Toxicity
Although treatment-related deaths have already been
documented in as early as the very first report
(Morrison et al. 1963) after 45 Gy given in 20 daily
fractions over 4 weeks, this issue has not been sys-
tematically addressed over the years. Frequently
authors did not provide information on toxicity at all
(Coy and Kennelly 1980; Cooper et al. 1985; Zhang
et al. 1989; Rosenthal et al. 1992; Krol et al. 1996),
while others only mentioned either absence or rarity
of, mostly ‘‘serious’’, toxicity (Noordijk et al. 1988;
Sandler et al. 1990; Dosoretz et al. 1992; Gauden
et al. 1995; Slotman et al. 1996; Morita et al. 1997;
Hayakawa et al. 1999). When data were provided
without specifying the toxicity criteria, there was
usually no report on high-grade (C3) toxicity. Mild to
moderate (corresponding to grades 1 and 2) esopha-
gitis was usually seen in up to two-thirds of patients,
while mild to moderate pneumonitis was usually seen
in approximately 20% of patients. This was observed
regardless of tumor/dose fractionation pattern or
whether elective nodal radiation therapy was used or
not. However, Hayakawa et al. (1992) described four
out of 13 (31%) patients dying of pulmonary insuffi-
ciency due to bronchial stenotic changes after
receiving [80 Gy in 2 Gy daily fractions at the
proximal bronchi.
There were only several studies that reported on
toxicity using grading systems. Graham et al. (1995)
reported on mild to moderate acute toxicity in 103
patients with early stage non-small-cell lung cancer
treated with 18–60 Gy (median primary dose, 60 Gy
in 30 fractions), of whom 80% received elective
nodal radiation therapy. One patient developed
European Organization for the research and treat-
ment of Cancer/Radiation Therapy Oncology Group
(Cox et al. 1995) grade 3 pneumonitis and there
were also only three cases of late grade 2 lung tox-
icity. Jeremic et al. (1997) treated 49 patients with
stage I non-small-cell lung cancer with hyperfrac-
tionated radiation therapy doses of 69.6 Gy via
1.2 Gy b.i.d. fractionation to show only 2 (6%) grade
3 acute toxicities (bronchopulmonary and esophageal)
and 3 (9%) grade 3 late toxicities (bronchopulmonary,
esophageal and osseous), although the ipsilateral
hilum was electively treated to a 50.40 Gy dose with
Conventional Radiation Therapy in Early Stage Non-small-cell Lung Cancer
the same fractionation. Jeremic et al. (1999) again
used Radiation Therapy Oncology group (Cox et al.
1995) toxicity criteria to report on the same hyper-
fractionated radiation therapy regimen (69.6 Gy using
1.2 Gy b.i.d. fractionation) in 67 stage II non-small-
cell lung cancer patients. Although elective medias-
tinal irradiation was used in all cases, there were only
2 bronchopulmonary and two esophageal acute grade
3 toxicities (total n = 4.6%) and only one broncho-
pulmonary and two esophageal late grade 3 toxici-
ties (total n = 3.4%). Sibley et al. (1998) observed
2 (1.5%) grade C3 complications, one being fatal
pneumonitis 2 months after the completion of
66 Gy in 2 Gy fractions, the other being severe
oxygen-dependent pneumonitis unresponsive to ste-
roids after 64 Gy in 2 Gy fractions. Both patients
had their mediastinum region encompassed. How-
ever, no information on grading system used in that
study was provided. Finally, Lagerwaard et al.
(2002) observed grade 1–2 esophagitis according to
the Radiation Therapy Oncology Group in 16%
patients with no symptoms consistent with late
esophageal toxicity. Grade 2 or higher on South-
west Oncology Group scale was observed in 6%
patients. In the latter group of reports (Jeremic
et al. 1997, 1999; Graham et al. 1995; Sibley et al.
1998), high-grade (C3) acute esophagitis and
pneumonitis were documented in up to 3% of cases,
and the same applies to the high-grade late toxicity,
with no apparent differences between various radi-
ation therapy regimens, although Lagerwaard et al.
(2002) used multivariate analysis to document det-
rimental effect of radiation dose of 70 Gy or more
on the incidence of acute esophagitis.
In none of these series it was not specifically
reported that these toxic events have happened in
elderly patients. When, however, study population
was completely confined to elderly with early stage
non-small-cell lung cancer, no significant radiation
therapy-related complications were found and inci-
dence of both acute and late high-grade (3 and 4)
toxicity was similar among all age groups (Gauden
et al. 1995; Gauden and Tripcony 2001). Even when
radiation therapy-related deaths occurred and were
reported on (Hayakawa et al. 2001), again, there was
no difference between elderly (5%) treated with
highest dose levels (80 Gy) and their non-elderly
counterparts (4%) treated the same way.
329
Major problem with the data from the literature is a
great variety of both pre-treatment and radiation ther-
apy-related factors, such as the total dose, fractionation
or treatment fields, not just between the institutions, but
intrainstitutionally, too. These have greatly obscured
the overall picture and prohibited us from having firm
conclusions. While it is a well-established premise that
higher total dose, higher dose per fraction, and larger
volume of the lung irradiated should lead to more
toxicity (Moss et al. 1960; Holsti and Vuorinen 1967;
Rubin and Casarett 1968; Mah et al. 1987; McDonald
et al. 1995), both acute and late, it is unknown to what
extent other, radiation therapy-unrelated factors such as
pre-existing comorbidity, infections, or simply natural
processes such as sclerosis present in elderly, may add
to the occurrence of toxicity (Rubin and Casarett 1968;
Braun et al. 1975; Prasad 1978; Garipagaoglu et al.
1999). Some, however, have shown that concomitant
chronic obstructive pulmonary disease did not increase
the risk of radiation pneumonitis (Prasad 1978).
Acute high-grade toxicity may also be interesting
as a contributing (causal) factor leading to more
treatment interruptions which, on the other side, may
adversely influence treatment outcome (Cox et al.
1993; Chen et al. 2000; Jeremic et al. 2003b). In the
first-ever analysis devoted to this issue exclusively in
early stage non-small-cell lung cancer (Jeremic et al.
2003b), of a total of 116 patients treated with total
tumor doses of 69.6, 1.2 Gy b.i.d. fractionation, 44
patients refused surgery while 72 patients were
medically inoperable due to existing co-morbid states.
Medically inoperable patients had worse KPS
(p = 0.0059) and more pronounced weight loss
(p = 0.0005). Among them, 12 patients experienced
high-grade toxicity and 11 out of these 12 patients
were with either acute (n = 6) or ‘‘consequential’’
late (n = 5) high-grade toxicity that requested inter-
ruption in the hyperfractionated radiation therapy
course (range, 12–25 days; median, 17 days). Patients
who refused surgery achieved superior survival
when compared to medically inoperable patients
(p = 0.0041), as well as superior local recurrence-
free survival (p = 0.011), but not different distant
metastasis-free survival (p = 0.14). Cause-specific
survival also favored patients who refused surgery
(p = 0.004). Multivariate analysis showed indepen-
dent influence as the reason for not undergoing
surgery on overall survival (p = 0.035), but not on
330
local recurrence-free survival (p = 0.084) or cause-
specific survival (p = 0.068). Patients who refused
surgery did not experience high-grade toxicity (0/44),
whereas 11 of 72 patients with medical inoperability
and co-morbid states experienced high-grade toxicity
and had treatment interruptions to manage toxicity
(p = 0.0064). Patients without treatment interruptions
had significantly better overall survival (p = 0.00000),
local recurrence-free survival (p = 0.00000), and
cause-specific survival (p = 0.00000) than those with
treatment interruptions. When corrected for treatment
interruptions, the reason for not undergoing surgery
independently influenced overall survival (p = 0.040),
but not local recurrence-free survival (p = 0.092) or
cause-specific survival (p = 0.068). In contrast to this,
treatment interruption was independent prognosticator
of all three endpoints used (p = 0.00031, p = 0.0075
and p = 0.00033, respectively). When 11 patients with
treatment interruptions were excluded, the reason for
not undergoing surgery still affected overall survival
(p = 0.037) and cause-specific survival (p = 0.039)
but not local recurrence-free survival (p = 0.11).
Multivariate analyses using overall survival, cause-
specific survival and local recurrence-free survival
showed that the reason for not undergoing surgery
affected overall survival (p = 0.0436), but neither
cause-specific survival (p = 0.083) nor local recur-
rence-free survival (p = 0.080). Late high-grade tox-
icity also becomes interesting from the standpoint of
prolonged survival of these patients. Prolonged follow-
up is, therefore, necessary. It may also be advantageous
in terms of detecting second cancers, both lung and
non-lung, that occur in long-term survivors after the
first radiation therapy (Jeremic et al. 2003a). If diag-
nosed at an early stage, these patients may experience
similar outcome as with the first radiation therapy.
Reporting of toxicity poses an additional problem,
because only rarely scoring systems have been used.
Additionally, such reporting was almost always done
on an actual (crude) basis, and not on the actuarial
one. While the former method may be acceptable,
although not preferable, for acute toxicity, it should
be strongly discouraged as totally inappropriate for
late toxicity.
With the wide introduction of computerised three-
dimensional treatment planning in recent years, it is
now widely possible to tailor the dose to tumor and
spare surrounding healthy tissues. In particular, the
use of dose–volume histograms enabled a preliminary
B. Jeremić et al.
step in quantitative assessment of competitive treat-
ment plans and a screening tool to select ‘‘the best’’
available plan (Drzymala et al. 1991), usually coupled
with other quantitative indices such as normal-tissue
complication probability and tumor control probabil-
ity (Kutcher and Burman 1987; Lyman and Wolbarst
1987; Burman et al. 1991). They may enable an
increase in the dose delivered to tumor, necessary for
better tumor control (Armstrong et al. 1993;
Robertson et al. 1997). they can also give useful data
for characterization of the dose–volume relationship
and the development of pneumonitis (Martel et al.
1994; Oetzel et al. 1995; Kwa et al. 1998; Graham
et al. 1999) and reduced dose to not just lung (Graham
et al. 1994), but other critical normal tissues as well
(Maguire et al. 1999; Bahri et al. 1999). Multivariate
analysis by Graham et al. (1999) revealed that the
total lung volume receiving 20 Gy (V20) to be the
single independent predictor of pneumonitis. In this
study with three-dimensional treatment planning,
actuarial incidence of [Grade 2 pneumonitis by
24 months was 7% for V20 between 22 and 31%, and
13% for V20 between 32 and 40% (Fig. 3). Nowa-
days, when intensity modulated radiation therapy is
used; the question remains whether total lung V20 is
enough to predict the incidence of radiation pneu-
monitis. Yom et al. (2007) was among the first to
provide clinical data regarding the rate of high-grade
radiation pneumonitis in patients treated with inten-
sity modulated radiation therapy. The 12-month
incidence of radiation pneumonitis in patients with
lung volume receiving 5 Gy (V5) \70% was 2%,
while for those with V5 [70%, the rate was 21%
(Yom et al. 2007). When 60–70 Gy is delivered in
1.8–2.0 Gy fractions utilizing three-dimensional
conformal radiation therapy planning, it is prudent to
keep total lung V20 \35%. With intensity modulated
radiation therapy planning low dose spillage is higher
and it is reasonable to keep total lung V5 \70% as
suggested by Yom et al. (2007). There is, however, a
considerable variation in total lung volume definition.
While some radiation oncologists define the total lung
volume as the total lung volume minus the gross
tumor volume, others define this volume as the total
lung volume minus the clinical target volume, which
includes gross tumor volume with an expansion for
microscopic extension. Since the majority of papers
reporting the incidence of radiation pneumonitis
are retrospective with different total lung volume
Conventional Radiation Therapy in Early Stage Non-small-cell Lung Cancer
Fig. 3 Dose volume histogram for the treatment plan shown in
Fig. 1. Note that 95% of the planning target volume (PTV)
receives the prescription dose (70 Gy). Total lung volume
definitions, it can be sometimes difficult to compare
data from two different institutions.
8 Quality of Life
The quality of life in patients treated with radiation
therapy becomes increasingly important issue in lung
cancer, but no clear data exist in early non-small-cell
lung cancer treated by radiation therapy alone. To
address this issue, Movsas et al. (1999) used a quality-
adjusted survival time model which takes into account
331
receiving 20 Gy (V20) was 14.6%. (The clinical target volume
was subtracted from the total lung volume for total lung V20
calculation.)
survival as well as toxicity by weighting the time
spent with a specific toxicity as well as local or distant
tumor progression. Each of the number of toxicities
was weighted with increasing severity as the toxicity
increased in grade. Nine hundred seventy-nine
patients with stage II–IIIB (vast majority of stage III;
no stage I) inoperable non-small-cell lung cancer
were enrolled on six prospective phase II and III
studies that ranged from standard radiation therapy
(60 Gy), hyperfractionated radiation therapy
(69.6 Gy), induction chemotherapy followed by
standard radiation therapy, induction chemotherapy
332
and concurrent radiochemotherapy and concurrent
chemotherapy and hyperfractionated radiation ther-
apy. Patients \60 years old had improved survival
with more aggressive therapy (with chemotherapy
added to radiation therapy), while those[70 years old
achieved the best quality-adjusted survival time with
standard radiation therapy alone. The same authors
used the Quality-adjusted time without symptoms
(Q-Twist) in the same group of patients enrolled
during Radiation Therapy Oncology Group studies in
locally advanced non-small-cell lung cancer, a
minority of whom were stage II (Movsas et al. 2000).
A quality-adjusted survival analysis subtracted from
survival time spent with toxicity and/or relapse.
While an overall benefit in Q-Twist was seen with the
addition of chemotherapy to radiation therapy, the
advantage of more aggressive therapy was limited to
patients \70 years old. In patients [70 years, no
radiation therapy/chemotherapy regimen had a supe-
rior Q-Twist than radiation therapy alone. None of
these analyses provided separate analysis for patients
with early stage non-small-cell lung cancer.
A study by Langendijk et al. (2000) on the pre-
treatment quality of life in inoperable non-small-cell
lung cancer (stage I, 21%; stage II, 1%) disclosed that
World Health Organization performance status,
weight loss, and age were all significantly associated
with quality of life. Among the different respiratory
symptoms assessed by the European Organization for
the research and treatment of cancer quality of life
questionnaire-C30 score, dyspnoea was the only item
that significantly correlated with global quality of life.
Furthermore, changes of dyspnoea subsequent to
treatment were significantly associated with global
quality of life as well. Unfortunately, neither analysis
of treatment-related toxicity and quality of life was
included in this study nor there was a separate anal-
ysis relating to early stage non-small-cell lung cancer.
9 Novel Approaches
9.1 Stereotactic Radiation Therapy
Stereotactic radiation therapy is an extremely hypo-
fractionated form of radiation therapy for early stage
non-small-cell lung cancer. Historically, high preci-
sion radiation therapy in a form of stereotactic radi-
osurgery was successfully introduced in cases of brain
B. Jeremić et al.
metastasis, including those originating from primary
lung cancer in mid-eighties of the last century (Sturm
et al. 1987; Flickinger et al. 1994; Alexander et al.
1995). It had also been shown that stereotactic frac-
tionated radiation therapy is an effective treatment
approach for both malignant and nonmalignant neo-
plasms because it combines the accurate focal dose
delivery of stereotactic radiosurgery with the biolog-
ical advantages of fractionated radiation therapy
(Dunbar et al. 1994; Kooy et al. 1994; Varlotto et al.
1996). It was also indicated that stereotactic frac-
tionated radiation therapy can be advantageous over
stereotactic radiosurgery in tumors [3 cm or those
located in the vicinity of critical organs (Dunbar et al.
1994; Varlotto et al. 1996). This experience led to
application of stereotactic techniques in numerous
extracranial tumor sites, including that of lung
(Blomgren et al. 1995; Uematsu et al. 1998; Uematsu
et al. 2001; Fukumoto et al. 2002; Nagata et al. 2002;
Hara et al. 2002; Hof et al. 2003; Onimaru et al. 2003;
Whyte et al. 2003; Lee et al. 2003; Timmerman et al.
2003). While initial studies included patients with
lung metastasis and those with early stage non-small-
cell lung cancer, more recent reports concentrated
exclusively on the latter. Separate chapter focusses on
the use of stereotactic radiation therapy in early non
small cell lung cancer. Breiefly, though, suffice to say
that initial results were indeed impressive. Local
tumor control was obtained in at least 85% of
patients, while 2–3 year survivals went up to 60–70%,
all accompanied with very low toxicity. Recently
published prospective phase II data in medically
inoperable patients with early stage non-small-cell
lung cancer demonstrated 3-year primary local tumor
control [90% and 3-year overall survival of 56–60%
(Baumann et al. 2009; Timmerman et al. 2010).
While detailed overview of the technological and
biological principles would follow in a latter chapter,
suffice to say that these results await longer followup
and possible comparison with sublobar resection in
patients who cannot tolerate lobectomy. Prospective
randomized trials comparing stereotactic radiation
therapy with conventionally fractionated radiation
therapy are also warranted since the majority of
published data with conventional fractionation come
from the era of 2D planning. With no doubt, com-
parison of this data with modern data from the 3D era
and stereotactic body radiation therapy is an unfair
comparison.
Conventional Radiation Therapy in Early Stage Non-small-cell Lung Cancer
9.2 Accelerated Hypofractionated
Radiation Therapy
Accelerated hypofractionated radiation therapy is a
moderately hypofractionated form of radiation ther-
apy for early stage non-small-cell lung cancer. While
stereotactic body radiation therapy typically employs
C8 Gy, accelerated hypofractionated radiation ther-
apy employs lower doses of radiation therapy, usually
3.5–4.0 Gy fraction to a total cumulative dose of
48–60 Gy. Although high doses with conventionally
fractionated 1.8–2.0 Gy radiation therapy were fea-
sible when the volume of irradiated lung was limited,
overall treatment time was extended to more than
7 weeks. For many medically inoperable patients with
early stage non-small-cell lung cancer even a 7-week
course of radiation therapy can be difficult since the
majority of patients have serious comorbidites. Thus,
accelerated hypofractionated radiation therapy allows
a shorter treatment course without typical require-
ments for stereotactic body radiation therapy such as
accurate patient immobilization, precise accounting
for tumor motion and, image guidance.
In Slotman et al. (1996) reported their experience
in 31 patients with T1-2N0 non-small-cell lung can-
cer. A dose of 48 Gy in 4 Gy fractions was delivered
with five fractions per week over a period of two and
a half weeks. Gross tumor volume was treated with a
margin of at least 1.5 cm for the first 40 Gy and a
margin of at least 0.5 cm for the boost phase with no
elective nodal irradiation. The majority of patients
were medically inoperable (87%) and none of the
patients underwent a surgical staging procedure. The
mean tumor diameter was 3.2 cm and most tumors
were peripherally located. A recurrence was seen in
19% of patients, 3-year overall survival was 42% and
median overall survival was 33 months. Faria et al.
(2006) in Canada published their results in 32 patients
with early stage non-small-cell lung cancer. Most
patients had T1-2N0 disease and although T1-2N1
patients were eligible, 94% of patients had N0 disease
by CT staging. With 3D planning, a dose of 52.5 Gy
in 3.5 Gy fractions was delivered with five fractions
per week over a period of 3 weeks. Gross tumor
volume with a 1.0–1.5 cm margin was treated without
elective nodal irradiation. The 2-year local relapse-
free survival was 76%, 2-year overall survival 56%
and median overall survival 29 months Another
Canadian study by Soliman et al. (2011) included 118
333
patients, mostly medically inoperable with periph-
erally located T1-3N0 non-small-cell lung cancer.
A dose of 48–60 fractions was delivered in 4 Gy
fractions with most patients receiving 48–52 Gy.
Gross tumor volume was treated with 1.0–1.5 cm
margin without elective nodal irradiation. The 2- and
5-year local control rates were 76.2 and 70.1%,
respectively. The 2- and 5-year overall survival rates
51 and 23.3%, respectively, while median overall
survival was 26.5 months. Based on this experience,
the National Cancer Institute of Canada opened a
Phase II trial of 3D conformal radiation therapy to
deliver 60 Gy in 4 Gy fractions for medically inop-
erable patients with T1-3N0 non-small-cell lung
cancer (NCIC BR.25) The study was conducted
between 2006 and 2008 and the results from
this prospective, multi-institutional trial are pending
(Soliman et al. 2011).
Bogart et al. (2010) in the United States reported a
phase I dose-escalation study of accelerated hypo-
fractionated radiation therapy in 39 medically inop-
erable patients with T1-2N0 non-small-cell lung
cancer (CALBG 39904). A dose of 70 Gy was
delivered while the daily fraction size was escalated
from 2.41 Gy in 29 fractions to 4.11 Gy in 17 frac-
tions. Without elective nodal irradiation, gross tumor
volume with at least 1.5 cm margin was treated with
3D conformal radiation therapy and heterogeneity
correction. The major response rate was 77% (31%
complete response, 46% partial response) and 23% of
patients had stable disease. After a median follow-up
time of 53 months, median overall survival was
38.5 months. Treatment was well tolerated without
grade 4 or higher toxicity.
Obviously, the intent of accelerated hypofraction-
ated approach is not to develop a new type of ste-
reotactic radiation therapy, but rather to find an
alternative to extreme hypofractionation with the
stereotactic approach. Accelerated hypofractionated
radiation therapy does not require a stereotactic type
of immobilization, precise accounting for tumor
motion and prolonged time on treatment couch nec-
essary to deliver each fraction of radiation therapy.
For patients who cannot tolerate stereotactic radiation
therapy immobilization or treatment process, accel-
erated hypofractionated radiation therapy can be an
alternative approach. This moderately hypofraction-
ated regimen has a potential to become an alternative
to stereotactic radiation therapy, particularly in small
334
community radiation oncology practices if further
prospective clinical trials confirm its efficacy.
9.3 Accelerated Hyperfractionated
Radiation Therapy and Concurrent
Radiation Therapy
with Chemotherapy
Evidence also slowly emerged for the use of concur-
rent radiation therapy and chemotherapy, although it
has been done only rarely. In an Australian study (Ball
et al. 2001), 24 patients randomized to concurrent
carboplatin versus conventionally fractionated radical
RT (60 Gy) alone achieved an MST of 41.6 months
versus 19.5 months and an estimated 2-year survival
rate of 77 versus 27% (p = 0.042), although stage was
not an independent prognosticator in that study
involving mostly Stage III non-small-cell lung cancer
patients. A recent subset analysis (Bentzen et al. 2000)
of 169 patients with stage I–IIA non-small-cell lung
cancer initially enrolled in the continuous hyperfrac-
tionated accelerated radiotherapy (CHART) study
(Saunders et al. 1999a) showed a benefit of 13% at
2 years (37 vs. 24%) and 6% at 4 years (18 vs. 12%)
for CHART (54 Gy) over conventionally fractionated
radical radiation therapy (60 Gy). In a recent pro-
spective phase II trial, Jeremic et al. (2005) used
concurrent hyperfractionated radiotherapy and low-
dose daily chemotherapy consisting of carboplatin and
paclitaxel in a phase II study. Fifty-six patients started
their treatment on day 1 with 30 mg/m2 of paclitaxel.
Hyperfractionated radiotherapy using 1.3 Gy b.i.d. to
a total dose of 67.6 Gy and concurrent low-dose daily
carboplatin 25 mg/m2 and paclitaxel 10 mg/m2, both
given daily (but excluding weekend days) during the
radiation therapy course, starting from the second day.
The median survival time was 35 months, and 3- and
5-year survival rates were 50 and 36%, respectively.
The median time to local progression has not been
achieved, but 3- and 5-year local progression-free
survival rates were 56 and 54%, respectively. The
median time to distant metastasis has not been
achieved, but 3- and 5-year distant metastasis-free
survival rates were 61 and 61%, respectively. The
median and 5-year cause-specific survivals were
39 months and 43%, respectively. Acute high-grade
(C3) toxicity was hematological (22%), esophageal
(7%), or bronchopulmonary (7%). No grade 5 toxicity
B. Jeremić et al.
was observed. Late high-grade toxicity was rarely
observed (total 10%). The patient population in this
study was very favorable. The majority of patients
were in a good Karnofsky performance Status score,
none had weight loss of [5 and 70% of patients
enrolled into this study actually refused surgery.
Campeau et al. (2009) recently reported on 73 patients,
who were treated either with concurrent radiation
therapy and chemotherapy (n = 39) or radiation
therapy alone using total dose of either 60 Gy
(n = 23) or 50–55 Gy (n = 11). Intention-to-treat
analysis showed that the 2-year survival for concurrent
regimen was 57% and that for radiation therapy alone
regimens combined was 33%, clearly favoring con-
current regimen. Also, the 2-year local progression-
free survival was 66 and 55% for the combined and
radiation therapy group alone, respectively.
10 Conclusions
A proportion of early stage non-small-cell lung cancer
undergoes radiation therapy alone due to several
reasons. Although this patient population must be
considered unfavorable, radiation therapy alone
remains standard treatment option in these patients
which are frequently named as technically operable
but medically inoperable. Although survival figures
are still lower than those obtainable with surgical
candidates, even when clinically staged, with con-
ventional high-dose radiation therapy the median
survival times of up to 35 months and 5-year survival
of up to 35% have been obtained. These figures are
even better when cause-specific survival is used.
Various radiation therapy characteristics are exam-
ined showing that there seems to be a favorable effect
of high doses on outcome, as well as it seems to be
favorable effects of smaller size/lower stage. While
there is no general agreement on the use of elective
nodal irradiation, some tumors (e.g., small, peripheral
lesions) seem as the most suitable for limited radia-
tion therapy. Unfortunately, discrepancies between
surgical and radiotherapeutic series regarding the
staging procedures, treatment procedures in this dis-
ease as well as the documentation of the pattern of
failure make any conclusion unreliable. They, how-
ever, call for more cooperation between technology
and biology in order to more selectively apply one or
another approach. Suggesting that limited field
Conventional Radiation Therapy in Early Stage Non-small-cell Lung Cancer
radiation therapy must be used for the sake of dose
escalation (leading to better tumor control and/or less
toxicity) would inevitably lead to misuse of these
technologies and false interpretation of the results.
Pattern of failure after radiation therapy alone clearly
identified local component as predominant, while
observed rare isolated nodal relapses are in contrast
with surgical findings in the same disease. Of a
number of pre-treatment patients and tumor charac-
teristics occasionally examined gender and age
probably do not influence survival. Performance sta-
tus and weight loss may exert its influence on sur-
vival, but possible effects of tumor location and
histology remain controversial. Reported toxicity of
radiation therapy is confined to mild to moderate
bronchopulmonary and esophageal toxicity. Although
it is reported as rare event, except in cases with very
high doses when given after conventional planning,
it’s reporting needs to be substantially improved and
systematically addressed. Quality of life is an issue
completely underrepresented and needs to be focused
upon, especially with expected increase in the long-
term survivors with the use of sophisticated tools for
treatment planning and delivery which will enable
further dose escalation in this disease.
Some, if not all, of the issues discussed above
could have been settled in case of existing prospective
randomized studies. Unfortunately, they are lacking,
although patients with early stage non-small-cell lung
cancer were sometimes included in prospective
studies evaluating the effect of various altered frac-
tionated regimens, alone or with concurrent chemo-
therapy, mostly, however, without specifying its
outcome. Pure hyperfractionated radiation therapy
alone or with either induction or concurrent chemo-
therapy (Cox et al. 1990; Sause et al. 1995; Lee et al.
1996; Komaki et al. 1997), accelerated radiation
therapy via concomitant boost (Byhardt et al. 1993)
were used, but without specifying the outcome in this
patient population. When accelerated hyperfraction-
ated radiation therapy using concomitant boost was
used with doses as high as 73.6–80 Gy, the median
survival time for patients with stage I/II was
34 months and the median local progression-free
survival was 23 months (Maguire et al. 2001). In an
Australian study (Ball et al. 1999), patients random-
ized to concurrent carboplatin versus conventionally
fractionated radical radiation therapy (60 Gy) alone
achieved the median survival time of 41.6 months
335
versus 19.5 months and an estimated 2-year survival
of 77 versus 27%, p = 0.042), although stage was not
an independent prognosticator in that study involving
majority of stage III non-small-cell lung cancer
patients. In a recent subset analysis (Bentzen et al.
2001) of 169 patients with stage I–IIA non-small-cell
lung cancer initially enrolled in the continuous
hyperfractionated accelerated radiotherapy study
(Saunders et al. 1999a) there was a benefit of 13% at
2 years (37 vs. 24%) and 6% at 4 years (18 vs. 12%),
for continuous hyperfractionated accelerated radiation
therapy (54 Gy) over conventionally fractionated
radical radiation therapy (60 Gy), respectively. It
showed again that community of radiation oncologists
dealing with lung cancer must use prospective ran-
domized trials to ask simple and meaningful questions
and to obtain answers which may instantly be used in
the clinic, a task having a major importance in this
disease.
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 Stereotactic Ablative Radiotherapy
for Early Stage Lung Cancer
John H. Heinzerling and Robert D. Timmerman
Contents
1 Introduction.............................................................. 343
2 Techniques and Technological Advances
in SABR for Lung Tumors.....................................
2.1 Patient Positioning and Immobilization....................
2.2 Daily Imaging for Patient Repositioning Prior
to Treatment...............................................................
2.3 Tumor Motion Assessment .......................................
2.4 Tumor Motion Control ..............................................
2.5 Target Volume Delineation and Treatment
Planning .....................................................................
3 Radiobiological Aspects of SABR.......................... 350
3.1 Tumor Biology .......................................................... 350
3.2 Normal Tissue Radiobiology and Tolerance............ 351
4 Clincal Results in Primary Lung Cancer............. 353
4.1 Medically Inoperable Patients with Early
Stage Lung Cancer .................................................... 353
4.2 Medically Operable Patients ..................................... 356
5 Toxicity...................................................................... 357
6 Conclusions ............................................................... 358
References.......................................................................... 358
R. D. Timmerman (&)
Effie Marie Cain Distinguished Chair
in Cancer Therapy Research,
Department of Radiation Oncology,
University of Texas Southwestern Medical Center,
5801 Forest Park Road, Dallas, TX 75390-9183, USA
e-mail: robert.timmerman@utsouthwestern.edu
J. H. Heinzerling
Department of Radiation Oncology,
University of Texas Southwestern Medical Center,
Dallas, TX, USA
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_258, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
Stereotactic ablative radiotherapy (SABR), also
known as stereotactic body radiation therapy
(SBRT) utilizes advanced techniques of immobi-
344 lization, image guidance, and unique field arrange-
345 ments to deliver precise, oligofractionated
radiotherapy to a variety of tumor types. SABR
346
346 has been established as a technologically innova-
347 tive therapy for early stage non-small cell lung
cancer (NSCLC) and has emerged as the standard
347
treatment option for medically inoperable patients
through utilization of prospective, multi-institu-
tional trials. Recent trials continue to evaluate the
role of SABR in the medically operable and
borderline operable population, and will compare
surgical resection and SABR as treatment modal-
ities in these patients. This chapter reviews the
techniques utilized in SABR, the evidence for use
of SABR in early stage lung cancer, its extension
of use to medically operable patients, and the
toxicities associated with this emerging technique.
1 Introduction
Stereotactic radiosurgery first emerged as a technique
in the 1950s created by Lars Leskell to treat intra-
cranial neoplasms using single large dose per fraction
treatments (Leskell 1951). These treatments were a
fundamental change from the perception of conven-
tionally fractionated radiotherapy (CFRT) classically
used to exploit the radiobiological differences between
normal and neoplastic tissues. Leskell established the
principles of immobilization and precise targeting
343
344
utilizing a frame with fiducial markers to define an
intracranial coordinate system that allowed treatment
guidance, patient immobilization, and facilitated
accurate dose delivery with maximization of normal
tissue sparing. Based on the success of intracranial
radiosurgery, pioneers such as Henric Blomgren,
Ingmar Lax, and Minoru Uematsu developed tech-
nologies that would allow similar treatment accuracy
for targets within the body (Blomgren et al. 1995; Lax
et al. 1994; Uematsu et al. 1998). While tumors within
the skull have no additional movement once the skull
has been immobilized, body tumors are subject to
forces within the body such as respiratory breathing,
cardiac contraction, and gastrointestinal peristalsis.
Thus, researchers from Sweden extended patient
immobilization and fiducial targeting to the body
through construction of a body frame, and attempted
to reduce internal motion of targets related to respi-
ration in order to allow high doses of radiation to be
administered extracranially. New dosimetric methods
were created to use multiple, non-coplanar beams with
compact aperture dimensions to mimic the conver-
gence of beams seen in Gamma KnifeÒ treatments.
These methods to treat body tumors have collectively
been termed stereotactic ablative radiotherapy
(SABR) (Loo et al. 2011), also known as stereotactic
body radiation therapy (SBRT) (Timmerman et al.
2003a, b). SABR is defined by the American College
of Radiology (ACR) and American Society of Ther-
apeutic Radiology and Oncology (ASTRO) as the use
of very large dose per fraction, and specific guidelines
have been established for treatment implementation
and quality assurance (Potters et al. 2004).
SABR is radiobiologically unique from CFRT.
SABR treatments cause dramatic effects within tar-
geted tissues both disruption of cell division and
function, leading to the associated term ‘‘ablative’’
radiotherapy. An order of magnitude of higher frac-
tional doses of 10–20 Gy compared to conventional
fraction doses of 1.8–2 Gy lead to biologic ablation of
cells leaving them dysfunctional not only to divide,
but also to perform other cellular functions. Normal
tissue toxicity is also affected by these ablative
effects, and thus it is essential to avoid unnecessary
treatment of normal tissue surrounding the target.
Improvements in imaging, targeting, on board image
guidance, dosimetric methods, and radiation delivery
devices have allowed increased sparing of surround-
ing normal tissues and made these high dose per
J. H. Heinzerling and R. D. Timmerman
fraction treatments possible despite their profound
potency. These methods have been extended to treat
various primary and metastatic tumors including lung,
liver, pancreas, kidney, adrenal gland, and prostate
(Rusthoven et al. 2009a, b; Timmerman et al. 2010a,
b; Madsen et al. 2007; Koong et al. 2004; Chawla
et al. 2009; Timmerman et al. 2007a, b).
An estimated 222,000 new cases of lung cancer
were diagnosed in 2010, with about 30% of patients
presenting with early stage disease. The majority of
these patients undergo surgical resection with 5 year
survival rates of approximately 60–70% (Naruke et al.
1988; Nesbitt et al. 1995). While surgical resection is
the standard therapy in these patients, many patients
cannot tolerate surgery because of comorbidities
related to lung and cardiac function. In the past, these
patients were treated with conventional radiation typi-
cally given to a dose of approximately 45–66 Gy in
fractions of 1.8–2 Gy over 6 weeks, resulting in a
5 year survival of approximately 10–30% (Kaskowitz
et al. 1993; Wisnivesky et al. 2005). Exploration of high
dose per fraction treatments for primary lung cancer
has now shown high rates of local control and survival
more comparable to surgical series. The tech-niques
utilized in SABR treatments, the unique biologic
effects, the associated toxicity, and its careful explo-
ration through prospective clinical trials in patients
with early stage lung cancer will be discussed below.
2 Techniques and Technological
Advances in SABR for Lung Tumors
Safe and effective SABR treatments require ensuring
accuracy and precision achieved by reliable and
reproducible patient immobilization; daily image
guidance for precise repositioning prior to treatment;
assessment and accounting for tumor and organ
motion consistently between planning and treatment;
and the use of multiple, non-coplanar treatment fields
to ensure adequate target coverage with rapid fall off
of dose to surrounding normal tissues. These princi-
ples allow the reduction of normal tissue exposure to
high and intermediate doses, minimizing the proba-
bility of normal tissue complications while ensuring
accurate high dose delivery to the target. Because of
the proximity several critical structures including
normal lung tissue, bronchi, chest wall, esophagus,
heart, brachial plexus, and spinal cord, realization of
Stereotactic Ablative Radiotherapy for Early Stage Lung Cancer
Fig. 1 Example of fiducial system in a stereotactic body frame
with coordinates corresponding to target location
these SABR principles is of greatest importance to
ensure safe treatment with minimal toxicity while
achieving adequate tumor control. For CFRT,
emphasis on correlation of the static treatment plan to
actual treatment is less critical than for SABR because
of the large margins placed around the target, the
homogeneous dose distributions, and the more
‘‘forgiving’’ fractionation typically seen with limited
field CFRT. This, however, is not the case for SABR
treatments, and all effort should be made to ensure the
accuracy of equipment used in simulation, planning,
and treatment delivery. Recently, the American
Association of Physicists in Medicine (AAPM) pub-
lished their best practice guidelines for SABR treat-
ments including equipment and QA procedures
(Benedict et al. 2010). Many of the technological
advances within radiation therapy have been devel-
oped to allow increased safety of oligofractionated
treatment and will be discussed here.
2.1 Patient Positioning
and Immobilization
Because SABR treatments are often longer than
conventional radiotherapy treatment sessions, con-
sistent, reproducible, and comfortable patient immo-
bilization is essential for ensuring treatment accuracy.
Several available systems designed for stereotactic
patient positioning and immobilization are currently
commercially available and include body frames,
vacuum cushions, and thermal plastic restraints. Some
of these devices feature a fiducial system mimicking
345
Fig. 2 Example of frame system, the elekta stereotactic body
frame showing external coordinate system, vacuum pillow, and
integrated respiratory motion control with abdominal
compression
that of brain radiosurgery headframes that are rigidly
attached and registered to the target. Fiducials
are simply reliable ‘‘markers’’ whose position can be
consistently and confidently correlated to both the
target (tumor) and treatment device (frame) (Fig. 1).
‘‘Frame’’ systems provide both immobilization and
a fiducial system that can approximate initial target
localization independently from other image guidance
systems (e.g., room lasers and cone-beam CT), which
is then enhanced and adjusted by utilizing image
guidance as described below (Lax et al. 1994; Yenice
et al. 2003; Herfarth et al. 2001; Wang et al. 2006). In
addition, these systems often integrate motion control
techniques such as abdominal compression (Fig. 2).
‘‘Frameless’’ systems rely on the combination of
markers and imaging methods to effectively relocate a
reference position within the patient. For example,
implanted fiducial seeds within the tumor can be
accurately relocated on a daily basis using imaging
techniques (Murphy 1997; Chang et al. 2004; Wulf
et al. 2000; Fuss et al. 2004). Newer technologies
used in SABR treatments include electromagnetic
transponders that can be tracked throughout treatment
to ensure accurate positioning during the entire
treatment course (Balter et al. 2005).
As with any system, assessment must be made by
each institution on its ability to achieve accuracy in its
primary objective: consistent patient immobilization
and target localization. Staff training and quality
assurance programs are essential for proper implica-
tion of any device, no matter its claimed accuracy.
Since no one system has been shown to be superior,
achieving patient comfort that avoids positions in
346
Fig. 3 Example of CBCT to validate target position prior to SBRT lung treatment. After realignment of CBCT to the planning
CT, couch shifts are shown in the bottom right and are applied prior to treatment
which the patient fights gravity or requires cumber-
some positions for the patient to support is of utmost
importance when incorporating SABR into any radi-
ation oncology program.
2.2 Daily Imaging for Patient
Repositioning Prior to Treatment
Image guidance provides target localization and vali-
dation of patient position prior to treatment. Typically
this is performed with computed tomography (CT)
(CT on rails), or cone-beam CT (CBCT) incorporated
into the treatment unit (Jaffray et al. 2002) (Fig. 3).
Because lung tumors are very distinct on CT scan, pre-
treatment reference volumes can be registered to the
image and adjustments can be reliably made on the
day of treatment. Appropriate adjustments are made
typically with couch shifts to align pretreatment target
position to the newly acquired CT data. CBCT scans
are often slow in acquisition time and thus are more
like slow CT to estimate respiratory associated motion
J. H. Heinzerling and R. D. Timmerman
prior to treatment (Wang et al. 2007), but improve-
ments are being made including respiratory-correlated
CBCT or 4D CBCT to attempt to characterize motion
on a daily basis immediately prior to treatment (Sonke
et al. 2005).
Advanced image guidance, typically including
mounted in-room kV imagers, has allowed monitor-
ing of target or fiducial position during treatment as
well (Verellen et al. 2003; Chang et al. 2003; Shirato
et al. 2000). This has minimized uncertainty associ-
ated with external reference points and has allowed
accurate internal tumor localization in near real-time.
2.3 Tumor Motion Assessment
Because of their proximity to moving organs such as
the diaphragm and heart, lung tumors have significant
motion up to 5 cm (Chen et al. 2001; Mageras et al.
2004). This motion can vary quite significantly
depending on tumor location as well as patient to
patient (Heinzerling et al. 2008; Liu et al. 2007;
Stereotactic Ablative Radiotherapy for Early Stage Lung Cancer
Fig. 4 Example of target definition on fast, spiral CT (a) compared to maximum intensity projection (MIP) from 4DCT
(b) showing underestimation of target excursion on fast CT
Stevens et al. 2001). Classic 3D imaging with fast
spiral CT studies can misrepresent target position by
obtaining images of the tumor in a specific phase of
the respiratory cycle, leading to extreme errors in
target position definition (Chen et al. 2004) (Fig. 4).
Thus, a personalized assessment for each patient is
required to characterize tumor motion. This was
typically achieved in the past with fluoroscopy and
more recently with 4-D computed tomography
(4DCT) (Fig. 5), during which several CT images are
obtained over multiple respiratory cycles and corre-
lated with a surrogate for breathing motion. Images
are then reconstructed into several respiratory phases
(typically 10) to show anatomy through an entire
respiratory cycle.
Other techniques to quantify target motion include
slow CT (Lagerwaard et al. 2001), breath-hold tech-
niques (Mageras and Yorke 2004), and respiratory-
correlated PET-CT or MRI (Kooch et al. 2004). If
tumor motion exceeds 5–10 mm, tumor motion con-
trol as described below is recommended so as to avoid
excess toxicity.
2.4 Tumor Motion Control
Several methods exist to control tumor motion and
include techniques to reduce tumor motion (damp-
ening), correlate treatment with tumor position (gat-
ing), or track the tumor position (chasing). Ways to
347
dampen tumor motion include abdominal compres-
sion, which places a pressure device on the abdomen
to dampen the motion of the diaphragm (Lax et al.
1994; Wulf et al. 2000; Heinzerling et al. 2008;
Negoro et al. 2001). Other techniques such as deep
inspiration breath-hold or active breathing control
(ABC) arrest or freeze the tumor in a reproducible
position within the respiratory cycle (Yin et al. 2001;
O’Dell et al. 2002; Murphy et al. 2002). Respiratory
gating utilizes respiratory cycle monitoring combined
with a surrogate to trigger delivery of radiation during
a specific segment of the respiratory cycle (expiration
or inspiration) (Vedam et al. 2001; Kimura et al.
2004; Wang et al. 2001; Kini et al. 2003) (Fig. 6).
Finally, tumor tracking systems actually move the
radiation beam path to follow the motion of the tumor
(Kuriyama et al. 2003; Sharp et al. 2004; Schweikard
et al. 2004; Shirato et al. 1999). Regardless of the
method used, careful assurance of accuracy, repro-
ducibility, as well as prudent implementation of
motion data into treatment planning is essential for
precise treatment delivery.
2.5 Target Volume Delineation
and Treatment Planning
Target volumes are defined using mechanisms that
quantify both tumor volume as well as tumor motion
such as 4-dimensional CT described above. The gross
348
Fig. 5 4DCT in the coronal plane showing a T1 tumor in
inhalation, exhalation, and maximum intensity projection (MIP)
with lines demarcating a the tumor cranio-caudal motion
envelop (also known as the internal target volume, ITV), and
Fig. 6 Example of a respiratory gating tracing in which the breath-
ing signal (top) is correlated with beam on/off status (bottom)
tumor volume (GTV) is typically defined on CT in
lung windowing. In certain cases, when the tumor is
hard to differentiate from surrounding normal struc-
tures, MRI or PET/CT can be useful to accurately
determine tumor volume. A good example of this is in
lung tumors adjacent to the chest wall or associated
with lung atelectasis or consolidation (Fig. 7). In
these situations, PET/CT can be helpful for delineat-
ing targets more precisely.
Typically in SABR, like in brain radiosurgery, the
GTV is equal to the clinical target volume (CTV),
keeping the volume of normal tissues exposed to high
J. H. Heinzerling and R. D. Timmerman
b the poor correlation of tumor and diaphragm motion between
inhalation and exhalation (i.e., the diaphragm moves consider-
ably more than the tumor)
doses to a minimum. An internal target volume or
ITV can also be delineated based on the volume
needed to encompass tumor motion. An additional
margin is then added to the defined volume to account
for daily setup error and machine tolerances, which
constitutes the planning treatment volume (PTV).
SABR requires conformal dose distributions that
allow rapid dose fall-off outside of the tumor volume.
This is accomplished by utilizing beams that are
highly shaped to the target allowing sharp collimation
of beam fluence outside of the target and using mul-
tiple beams (typically 10–15) or large angle arc
rotations (Cardinale et al. 1999; Liu et al. 2006;
Papiez et al. 2003). Use of non-opposing beams is
encouraged to ovoid overlap of dose at points of
entrance and exit. In most circumstances, non-copla-
nar beams are also preferred to provide more isotropic
dose fall-off in all directions. Typical beam arrange-
ments for lung SBRT is seen in Fig. 8.
The resulting dose distribution seen in Fig. 9 shows
relatively isotropic dose fall-off in all directions.
Reducing high dose spillage outside of the
intended treatment volume is critical for preventing
normal tissue toxicity of organs at risk. Ablation is
likely to occur not only in the target itself, but also
in the shell of normal tissue immediately outside of
Stereotactic Ablative Radiotherapy for Early Stage Lung Cancer 349

Fig. 7 PET/CT showing primary lung tumor with high SUV (a, b) with distal consolidation showing low SUV uptake (c, d). Use of
PET/CT for tumor delineation in this case allows decreased target volume and better sparing of normal tissue dose

Fig. 8 Typical non-coplanar beam arrangement for SABR treatment of right (a) and left (b) sided lung tumors
350
Fig. 9 Dose distribution of left sided primary lung tumor
showing isotropic dose fall-off with non-coplanar beam
arrangement
the PTV. Thus, the high dose spillage outside of the
target is directly related to the toxicity that can occur
with SABR. Tubular structures within the lung can
be obliterated and cause subsequent downstream
effects such as atelectasis or consolidation. Because
of this, SABR protocols commonly define criteria
related to the conformality of target dose and the
compactness of intermediate dose. Examples of this
include evaluations of parameters such as ‘‘R50’’
defined as the ratio of the 50% prescription isodose
volume to the PTV, and ‘‘D2 cm’’defined as the
maximum dose 2 cm from the PTV in any direction.
These parameters, which change with PTV dimen-
sions, allow evaluation of intermediate dose spillage
that can cause more global organ damage. Confor-
mality index or the ratio of the prescription isodose
volume to the PTV volume should be kept below 1.2
and typical PTV coverage should be 95–100% with
99% of the PTV covered by 90% of prescription
dose. In addition, normal tissue dose constraints are
being developed and modified based on existing data
from patients treated with SABR to help predict
toxicity based on dose-volume relationships. These
constraints specifically relate to total dose, fraction-
ation, and volume of specific normal tissues.
Because dose-volume relationships in the setting of
hypofractionation are not well understood, these
constraints are frequently modified based on patient
outcome data in ongoing multicenter trials evaluat-
ing SABR. Figure 10 shows an example DVH from
the same case shown in Fig. 9.
Notice that despite the high prescription dose
(60 Gy in 3 fractions), the volume of lung getting
J. H. Heinzerling and R. D. Timmerman
20 Gy (V20) is quite low (\5%) compared to what is
normally seen in CFRT (20–35%). Yet, because this
dose is given in 3 fractions, using classic parameters
such as V20 can be misleading and lead to excessive
toxicity.
3 Radiobiological Aspects of SABR
3.1 Tumor Biology
Conventional understanding of tumor radiobiology
has been mostly obtained through experimentation of
lower doses per fraction when compared to SABR,
which involves very high doses in few fractions.
Because of these origins, traditional radiobiology has
been challenged when applied to ablative, oligo-
fractionated treatments. Typically, the cell survival
curve for ionizing radiation has been used to
describe the surviving fraction versus dose, and
classically has been illustrated by the linear-qua-
dratic (LQ) formula (Hall et al. 1972; Rossi and
Kellerer 1972) (Fig. 11).
With CFRT, daily doses ranging from 1.5 to
3.0 Gy are used which occur on the ‘‘shoulder’’ of the
survival curve, allowing cells to be able to repair
some of the radiation damage. Higher fractional doses
([3 Gy) occur on the linear portion of the curve
predicting a greater proportion of cell kill. Several
authors have challenged the LQ model for daily doses
beyond the shoulder (6–8 Gy), claiming that it grossly
overestimates cell kill in this range (Park et al. 2008;
Marks 1995; Guerrero and Li 2004). Several modifi-
cations have been proposed to correctly model SABR
dose response curves, including utilization of the
older multitarget model to ascertain a ‘‘single fraction
equivalent dose’’ for oligofractionated treatments
ranging from 7–10 Gy, thus eliminating any influence
of the classic LQ model (Park et al. 2008; Marks
1995). Another proposal modifies the existing LQ
model by incorporating aspects of the lethal-poten-
tially lethal model, which accounts for ongoing radi-
ation repair processes that occur during radiation
exposure (Guerrero and Li 2004). Regardless of the
proposal, the predicted tumor cell kill becomes
significantly different when compared to the LQ
model, preventing overestimation of cell kill for large
fraction sizes used in SABR.
Stereotactic Ablative Radiotherapy for Early Stage Lung Cancer
Fig. 10 Dose volume
histogram from SABR
primary lung treatment to
60 Gy in 3 fractions showing
low V20 (\5%)
These newly proposed models have created
important implications when dose-fractionation
schemes are compared for SABR. In addition, factors
such as treatment delivery time and dose rate become
significant considerations for predicting cell kill dur-
ing SABR. For example, evaluation of clonogenic
survival in vitro when exposed to high doses of
radiation from 12 to 18 Gy shows that in glioma cell
lines, cell kill can be significantly affected by treat-
ment duration changing from 1.5 to 2 h (Benedict
et al. 1997). A review of this topic has concluded that
for treatments lasting longer than 30 min, significant
loss of cytotoxicity may be seen in high dose per
fraction treatments (Fowler et al. 2004). More
research is needed both in vitro and in vivo to better
model high dose-fractional treatments (Timmerman
and Story 2006), including different radiobiologic
351
effects of SABR such as vascular and stromal effects
that are not seen with CFRT (Kirkpatrick and
Dewhirst 2008; Fuks and Kolesnick 2005), normal
tissue effects after SABR, preservation of immune
response (Lee et al. 2009; Curiel 2007), and the
combination of effective mechanisms with targeted
drugs.
3.2 Normal Tissue Radiobiology
and Tolerance
With high dose per fraction treatments given with
SABR, different types of normal tissue can possess
unique radiation tolerance characteristics. Serial
structures such as airways, nerves, vessels, and
bowel are linear or branching structures where
352
Fig. 11 A plot of the logarithm of cell survival with increasing
single fraction dose is initially curvilinear (known as the
shoulder) followed by a linear relationship. Giving the same
total dose of radiation by multiple smaller fractions (e.g., 2 Gy)
repeats the shoulder with each fraction resulting in considerably
more cell survival than for a single large dose. The linear-
quadratic formalism appropriately models the curvilinear
shoulder portion of the survival curve but overestimates cell
loss in the linear portion
damage at any point along their path can cause
downstream dysfunction. This is in contrast to par-
allel structures such as lung alveoli, kidney neph-
rons, and gland acini, where damage to one portion
does not necessarily affect adjacent tissue. Within
the thorax, both serial and parallel normal tissues
exist in close proximity including serially
functioning small and large airways, esophagus, and
brachial plexus adjacent to parallel functioning
alveoli/capillary complexes. In addition, the heart,
pericardium, pleura, bones, and chest wall, which are
difficult to assign as parallel versus serial have
unique mechanisms of injury and tolerance to high
dose per fraction treatment.
In contrast to CFRT, which often causes minor,
repairable irritation of serially functioning airways,
SABR dose schedules can cause significant damage to
large and small airways within the lung leading to
mucosal injury and downstream collapse. Similar
damage can be inflicted on blood vessels traveling
along the routes of these airways. Loss of lung
parenchymal function (either ventilation or perfusion)
most often leads to effects on oxygenation parameters
J. H. Heinzerling and R. D. Timmerman
including arterial oxygen pressure on room air (PO2)
and diffusing capacity for carbon monoxide (DLCO)
after high dose per fraction treatment (Timmerman
et al. 2003a, b). Decreases in lung capacity mea-
surements such as FEV1 and FVC are less commonly
seen. Because downstream effects are related to
upstream damage, targets in close proximity to large
airways such as those near the hilum and central chest
are especially prone to high levels of downstream
damage and should be treated with great care (see
section on central tumors for more discussion). Direct
damage to parallel functioning tissues such as the
alveoli occurs at relatively low threshold dose; how-
ever, the overall volume of parallel tissue in a healthy
organ is typically very large. Much of this parallel
functioning tissue constitutes a reserve (i.e., func-
tional capacity beyond what is actually needed for
activities of daily life). So long as the reserve (extra
volume of tissue) is preserved, patients will avoid
symptomatic dysfunction. Unlike serially functioning
tissues, delivering damaging dose above the threshold
creates little additional dysfunction within parallel
tissue; rather, the key to avoiding toxicity is to min-
imize exposing volumes of tissue at or above the
threshold dose. As SABR is inherently a volume-
sparing technique, parallel tissue dysfunction can be
dramatically minimized compared to conventional,
large volume irradiation techniques. For instance,
rates of pneumonitis seen in SABR for lung tumors
are far less than CFRT (Timmerman et al. 2003a, b).
Therefore, as discussed above, the dose fall-off region
or ‘‘gradient region’’ should be mechanistically
reduced to ensure that damage to parallel structures is
kept to a minimum.
Other serial tissues can also show dramatic
differences in toxicity between what is classically
seen in CFRT versus SABR. Esophagitis, while
commonly seen with CFRT, is typically self limiting
and resolves 2–4 weeks after treatment completion.
After SABR, however, high dose to the serial
esophageal tissue can cause esophageal strictures.
Pleural and pericardial effusions can also develop
with SABR dose schedules due to irritation of the
pericardium or pleura, especially in tumors adjacent
to the heart or chest wall. Typically, these fluid col-
lections will reabsorb without any necessary inter-
vention, but they are important to characterize
because of their absence in CFRT. Other, more rare
late effects with SABR that have been described in
Stereotactic Ablative Radiotherapy for Early Stage Lung Cancer
serial tissues include aneurysms, fistulas, and neur-
opathies, and should caution to investigators to
monitor doses to all serial functioning tissues
including large blood vessels and large nerves such as
brachial plexus, phrenic, and intercostal nerves. More
follow up is still needed from previously completed
clinical trials to describe other late effects of SABR
that have not yet manifested themselves.
4 Clincal Results in Primary Lung
Cancer
SABR provides a local, ablative dose particularly
effective at eradicating gross visible tumor, making it
an ideal treatment for limited visible disease without
regional or distant spread. In contrast, SABR is not
particularly appropriate for treating microscopic dis-
ease either adjuvantly or prophylactically because of
its likelihood of causing collateral damage to normal
tissues with high dose per fraction treatment. A dis-
ease that is localized after ideal staging workup and
has a low probability of regional or distant metastatic
spread represents the ideal setting for which the
principles of SABR could be applied and provide
benefit when compared to CFRT. Thus, small-cell
lung cancer and advanced (node positive) non-small-
cell lung cancer (NSCLC) are conditions where
SABR is unlikely to be used effectively except pos-
sibly as a boost to gross disease. Early stage NSCLC
and limited lung metastases in patients with con-
trolled systemic disease are diseases where the prin-
ciples of SABR could be exploited to achieve higher
rates of tumor control.
4.1 Medically Inoperable Patients
with Early Stage Lung Cancer
Surgical resection remains standard therapy for
patients with stage I non-small-cell lung cancer
(NSCLC), with 5 year survival rates of approximately
60–70% (Naruke et al. 1988; Nesbitt et al. 1995).
Patients determined to be medically inoperable have
been treated in the past with standard fractionated
radiotherapy, typically given to a dose of approxi-
mately 45–66 Gy in fractions of 1.8–2 Gy over
6 weeks, with 5 year survival of approximately 10–
30% (Kaskowitz et al. 1993; Wisnivesky et al. 2005).
353
Based on data suggesting a dose–response relation-
ship in these patients, use of oligofractioned SABR
was first explored in the inoperable patient
population.
Early retrospective experience using SABR for
primary lung tumors showed effective responses for
primary lung tumors with a wide variety of dose-
fractionation schemes (Blomgren et al. 1995; Nyman
et al. 2006; Uematsu et al. 2001; Uematsu et al.
1998). Yet, many of the criteria for patients to be
treated differed, and most of the experiences had
small patient numbers treated with quite variable
dose–fractionation schemes. In addition, patients
were typically treated at one center, and often the
follow up was short, making reporting of late toxici-
ties seen with these treatments inadequate. Conse-
quently, to truly study SABR within an interpretable
forum, investigation with clear, predefined selection
criteria, consistent doses, strict quality assurance, and
adequate follow up is needed through the use of
prospective trials.
Indiana University carried out a phase I dose-
escalation study in patients with stage I medically
inoperable NSCLC to both evaluate toxicity for
SABR in primary lung cancer and to determine the
maximum tolerated dose (MTD) (Timmerman et al.
2003a, b; McGarry et al. 2005). Forty-seven patients
with T1-2 N0 NSCLC were treated with consistent
SABR techniques in 3 fractions. Independent escala-
tion trials were performed for 3 different tumor
cohorts: T1, T2 \ 5 and T2 5–7 cm. All intrathoracic
tumor locations were treated including central tumors.
Doses were escalated from 24 Gy over 3 fractions
(8 Gy per fraction) up to 72 Gy in 3 fractions (24 Gy
per fraction). The MTD was not reached for T1 or T2
tumors \ 5 cm despite reaching doses of 60–66 Gy
in 3 fractions. For T2 tumors larger than 5 cm, the
MTD was determined to be 66 Gy in 3 fractions after
dose limiting toxicity that included pneumonia and
pericardial effusion was seen at the 72 Gy dose level.
Impressive tumor response was seen at all dose levels
(Fig. 12), but on longer follow up, ten local failures
were seen out of 47 patients at a median follow up of
15.2 months. Nine of the ten failures were in patients
who received B16 Gy per fraction. As patients con-
tinued to be followed, radiologic changes surrounding
the tumor were seen including fibrotic changes in the
lung (Matsuo et al. 2007), but were not typically
associated with any symptoms. Often, these changes
354
Fig. 12 Example of response seen after SABR in early stage primary lung cancer. Dramatic tumor response can be seen as early
as 2–3 months with total radiologic disappearance often by 1 year
can be mistaken for tumor recurrence (Matsuo et al.
2007; Takeda et al. 2008). but follow up PET scan
and biopsies showed no evidence of tumor recurrence
in the majority of patients treated in the higher dose
cohorts.
Because of the encouraging tumor response and
tolerable toxicity seen in the phase I experience, the
Indiana group further evaluated SABR in this patient
population with a 70 patient phase II trial (Timmer-
man et al. 2006; Fakiris et al. 2009). Small tumors
were treated with 60 Gy in 3 fractions while larger
tumors received 66 Gy in 3 fractions, with 35 patients
enrolled to each cohort. The study was powered for a
target local control rate of 80%, which would repre-
sent a dramatic improvement over results seen with
CFRT. Patients continued to be followed for toxicity
related to treatment. The initial results of the trial
were published early because of new detection of
treatment related toxicity not seen in the phase I trial.
Actuarial 2 year local control was 95% with a median
follow up of 17.5 months, and overall survival was
56% at 2 years. The majority of deaths were found to
be related to comorbid illnesses seen in this frail
patient population, rather than death associated with
lung cancer. Again, toxicity was tolerable, with less
than 20% of patients experiencing high grade toxicity,
but there were 6 treatment related deaths. Severe
toxicity (Grades 3–5) was significantly more likely to
occur in patients with ‘‘central’’ tumors, defined as
tumors near the proximal bronchial tree (see Sect. 5).
The trial was recently updated after a median
follow up of 50 months showing 3-year local con-
trol and survival of 88 and 42%, respectively
J. H. Heinzerling and R. D. Timmerman
(Fakiris et al. 2009). Several series from the U.S.,
Europe, and Asia have duplicated local control rates
seen in these clinical trials from Indiana, with varying
dose and fractionation schemes. Local control rates
range from 80 to 95% and are summarized in Table 1.
Based on the encouraging results seen in the
Indiana experience, the Radiation Therapy Oncology
Group initiated a multi-institutional phase II study in
2002. RTOG 0236 completed accrual of 59 patients in
October of 2006. Eligible patients were purely med-
ically inoperable (not confounded by those refusing
surgery) and included peripheral T1 or T2/3 tumors
B5 cm. Patients with tumors within 2 cm of the
‘‘proximal bronchial tree’’ (Fig. 13) were excluded
based on the toxicity seen in the phase II study from
Indiana University.
Patients were treated to 60 Gy in 3 fractions based
on planning without tissue heterogeneity correction
(assuming the body is solid water). Forty-four patients
had T1 tumors, 11 had T2 tumors, and no patients
enrolled had T3 tumors. Extensive central accredita-
tion, conduct, and dosimetry constraints were devel-
oped prior to the opening of the trial by the RTOG
Lung, Physics, and Image-Guided Therapy commit-
tees to ensure meaningful quality assurance of SABR
techniques and that patients received consistent
treatment according to protocol guidelines at all of the
participating centers. The results of this trial were
recently published in the 2010 theme issue on cancer
for the Journal of the American Medical Association
(Timmerman et al. 2010a, b). Severe toxicity was
limited in this trial, with only 12.7% of patients with
grade 3 treatment related toxicity, and only 3.6% with
Stereotactic Ablative Radiotherapy for Early Stage Lung Cancer 355

Table 1 Summary of primary tumor control results for SABR treatment of stage I lung tumors
Author Treatment Local control Single Fraction Equivalent Dose (Dq = 2 Gy)
(%) (Timmerman et al. 2007a, b)
Europe/North America
Timmerman, 2003 (Timmerman et al. 8–16 Gy 9 3 60 (2 years) 20–44 Gy
2003a, b) McCarty et al. 2005) 18–24 Gy 9 3 90 (2 years) 50–68 Gy
Zimmerman, 2005 (Zimmermann et al. 12.5 Gy 9 3 87 (3 years) 43.5 Gy
2005)
Nyman, 2006 (Nyman et al. 2006) 15 Gy 9 3 80 (crude) 41 Gy
Timmerman, 2006 (Timmerman et al. 20–22 Gy 9 3 95 56–62 Gy
2006) (2 ? years)
Baumann, 2006 (Baumann et al. 2006) 15 Gy 9 3 80 (3 years) 41 Gy
Fritz, 2008 (Fritz et al. 2008) 30 Gy 9 1 81 (3 years) 30 Gy
Hof, 2007 (Hof et al. 2007) 19–24 Gy 9 1 50 (2 years) 19–24 Gy
26–30 Gy 9 1 72 (2 years) 26–30 Gy
Pennathur, 2007 (Pennathur et al. 2007) 20 Gy 9 1 84 (crude) 20 Gy
Asia
Nagata, 2005 (Nagata et al. 2005) 12 Gy 9 4 94 (3 years) 42 Gy
Xia, 2006 (Xia et al. 2006) 5 Gy 9 10 95 (3 years) 32 Gy
Hara, 2006 (Hara et al. 2006) 30–34 Gy 9 1 80 (3 years) 30–34 Gy
Koto, 2007 (Koto et al. 2007) 15 Gy 9 3 or T1 78, T2 40 41–46 Gy
7.5 Gy 9 6 (3-years)

grade 4 toxicity. Only one failure was seen at the
primary tumor site, leading to a 3-year primary tumor
control rate of 98%. The local control rate was
determined to be 91% with three additional patients
having failure within the involved lobe outside of the
treated area. Regional failure within hilar or medias-
tinal lymph nodes was low despite non-surgical
staging, with a 3-year loco-regional control of 87%.
Eleven patients, however, failed in distant sites, the
majority within 1 year of treatment. Despite these
failures, disease-free and overall survival were also
encouraging in this trial with 3-year rates of 48 and
56%, respectively. Because these survival results are
only modestly poorer than the results with definitive
surgical resection despite the frail population in which
the study was conducted (Naruke et al. 1988; Nesbitt
et al. 1995; Ginsberg and Rubinstein 1995), explora-
tion of utilizing SABR techniques within the medi-
cally operable population was deemed feasible and is
discussed below.
Other multicenter prospective trials utilizing
SABR in the medically inoperable population have
been performed internationally. The Dutch Group
have published prospective results of SABR where
treatment was based on patient characteristics related
to tumor size and location (Lagerwaard et al. 2008).
After treating 200 ? patients (80% were medically
inoperable), local control was over 90% while severe
late toxicity was under 5% with their ‘‘risk adapted’’
approach. A Nordic study group similarly reported
65% 2-year overall survival in a group of 57 medi-
cally inoperable patients. Local control at 2-years was
93% using their 3 fraction SABR regimen (Baumann
et al. 2009). The Japanese Clinical Oncology Group
has been accruing to a prospective trial treating
medically inoperable patients with T1 tumors using 4
fractions of 12 Gy. This trial continues to accrue, but
the results of utilizing this fractionation scheme in
medically operable patients was recently presented
and are discussed below.
The ideal dose for SABR treatment of early stage
lung tumors continues to be explored in the clinical
trial setting. Dose-fractionation schemes differ from
reported trials as shown in Table 1, and the follow-up
time for these existing series is still limited. The
optimal dose-fractionation schedule likely varies with
356
Fig. 13 Diagram showing the anatomical delineation of ‘‘central or perihilar’’ tumors
tumor stage and location, and no randomized studies
have been completed thus far comparing different
fractionation schemes. From the experience from
Indiana, severe toxicity was high in tumors within the
central lung (Fig. 12), leading to exclusion of these
patients on the subsequent RTOG 0236 trial. The
RTOG has now opened a seamless phase I/II trial to
address the question of escalating doses in 5 fractions
for centrally located tumors (RTOG 0813). Patients
will start at a dose of 50 Gy in 5 fractions with
escalation up to 12 Gy per fraction to determine the
MTD for central tumors in the inoperable patient
population. The RTOG has also begun to explore
other dose-fractionation schemes in peripherally
located tumors, comparing 34 Gy in 1 fraction to
48 Gy in 4 fractions. The least toxic of these two
regimens will be compared to the 20 Gy 9 3 regimen
J. H. Heinzerling and R. D. Timmerman
used in RTOG 0236 in a randomized phase III trial to
follow.
4.2 Medically Operable Patients
Because of the high tumor control and acceptable
toxicity seen with SABR for early stage NSCLC in the
inoperable population, the use of SABR in patients
able to undergo surgical resection is being explored in
the U.S., Europe, and Asia. A large retrospective
experience from Japan included a significant number
of operable patients and showed a 3-year survival of
88% (Onishi et al. 2004). On the basis of this data, the
Japan Clinical Oncology Group initiated a clinical trial
evaluating SABR in peripheral T1 NSCLC for oper-
able patients (JCOG 0403). All patients were treated
Stereotactic Ablative Radiotherapy for Early Stage Lung Cancer
with a dose of 48 Gy in 4 fractions. The initial results
of this trial were recently presented at the American
Society of Therapeutic Radiology and Oncology
annual meeting in San Diego in November 2010. 3-
year overall survival was 76%, an encouraging result
for the first prospective multicenter trial in this pop-
ulation. However, there were 25 patients with pro-
gressive disease, and the 3-year local progression free
survival was only 68.5%, which is significantly lower
than previous experience in the inoperable population
suggesting that there may be a need for higher doses in
these patients.
In the U.S, the RTOG has completed a trial (RTOG
0618) evaluating SABR treatment of early stage
NSCLC in the operable population to evaluate SABR
as an alternative to surgery in these patients. Eligible
patients included peripheral T1 or T2/3 tumors
B5 cm. Patients were all considered to be reasonable
candidates for surgical resection by a qualified tho-
racic surgeon and baseline pulmonary function tests.
Because these patients have a high probability of
cure, strict follow up for response was performed in
order to promptly identify local failures so that sal-
vage therapy with surgical resection could be per-
formed. Based on the surgical literature from the U.S.,
SABR in this population will be required to achieve a
local control rate of 90% or better to compete with
surgical resection. This trial has now completed and
focus within North American cooperative trial groups
has turned to direct randomized comparison between
surgical resection and SABR for early stage lung
cancer. The RTOG and American College of Sur-
geons Oncology Group (ACOSOG) have opened a
randomized phase III trial comparing sublobar
resection to SABR in high risk operable patients with
stage I NSCLC. With a primary endpoint of 3-year
overall survival, the trial explores whether SABR can
be an acceptable alternative to surgical resection in
this patient population with an overall survival rate
not more than 10% less than patients receiving sub-
lobar resection.
5 Toxicity
Because of the high doses per fraction that SABR
utilizes, there is potential for higher rates of normal
tissue toxicity than conventionally fractionated radi-
ation if the techniques discussed above are not
357
implemented. As discussed in Sect. 4, normal tissue
toxicity seen with SABR can often involve severe
destruction of medium and small airway passages
with consequential late effects including airway
strictures leading to downstream dysfunction. While
normal tissue dose constraints are implemented into
prospective trials, these constraints are often based on
a small number of cases where the toxicity were
observed, mathematical models, or even educated
guessing because of the short follow-up experience
within the literature. Observations of toxicity continue
to be reported and analyzed in a prospective fashion
and linked with dosimetric endpoints in order to
modify SABR dose constraints for normal tissues.
Some of the main toxicities observed in the pro-
spective experience of SABR for lung tumors will be
discussed here.
The phase I study from Indiana established the
maximum tolerated dose for 3 fraction SABR in the
medically inoperable population (Timmerman et al.
2003a, b). All patients underwent pre and post-treat-
ment evaluation of pulmonary function and were
closely monitored for a minimum observation period
for toxicity prior to dose escalation. Common low
grade toxicity included fatigue in all patients. Car-
diopulmonary toxicity was reasonable and included
10 patients who had a 10% decline in one measured
value of pulmonary function (FEV1, FVC, DLCO,
and PO2). The majority of these patients had eventual
return to baseline. The two parameters that most
commonly declined after treatment were DLCO and
PO2. Two patients had a dose limiting toxicity,
including one patient with grade 3 pneumonitis
(despite this being predicted as the most likely tox-
icity), and one with grade 3 hypoxemia. Given the
very frail patient population in this trial, the toxicity
observed was quite acceptable.
As discussed above, the phase II study from the
Indiana group exposed higher levels of severe pul-
monary toxicity in tumors adjacent to the central and
perihilar structures within the lung. Low grade tox-
icities in this trial included fatigue, musculoskeletal
pain, and radiation pneumonitis. Fourteen patients
had more severe toxicity, including decline in pul-
monary function tests, pleural effusions, and pneu-
monias, leading to 6 deaths that may have been a
result of the treatment. The majority of deaths were
due to pneumonia, and on multivariate analysis,
central tumor location was a strong predictor of
358
having a severe toxicity. Four of the six deaths were
in patients with central tumors, and these patients had
an 11-fold increased risk of having a severe toxicity
compared to patients with peripheral tumors. As sta-
ted above, investigation into different SABR regimens
to treat tumors located within the zone of the proxi-
mal bronchial tree is ongoing.
Based on the phase II results from Indiana, RTOG
0236 limited 3 fraction SABR to peripheral tumors
only, and subsequently showed improved rates of
toxicity for treatment of medically inoperable
patients. Grade 3–4 toxicity was seen in 15 patients
(28%) treated on RTOG 0236, and no treatment
related deaths were seen. Most of the toxicity seen
was pulmonary or musculoskeletal. Dose-volume
information collected from this and other early
experience with SABR will be used to both validate
and modify parameters used for normal tissue toxicity
in these patients (Dunlap et al. 2010).
6 Conclusions
SABR has utilized innovation within the engineering
and physics of radiation therapy to increase treatment
accuracy and to allow delivery of oligofractionated,
ablative doses of radiation. This technological
advancement has allowed the exploration of high dose
per fraction treatments leading to observation of
unique radiobiological outcomes that have challenged
the principles of conventional fractionation. The
technologic and biologic benefits of SABR have been
observed most dramatically in patients with early
stage lung cancer. Use of SABR in these patients has
now been established as the standard treatment option
for medically inoperable patients through careful
study in the prospective, multi-institutional clinical
trials described above. Toxicity of this treatment has
been well characterized in the clinical trials, allowing
for appropriate selection of candidates for SABR.
Because of the encouraging control rates seen in
medically inoperable patients, study of SABR has
now been extended to medically operable patients and
is being compared to surgical resection in ongoing
randomized clinical trials.
As systemic therapy becomes more effective for
solid tumors, it was thought that local treatments such
as radiotherapy and surgical resection would be less
utilized in cancer therapy. Interestingly, however, the
J. H. Heinzerling and R. D. Timmerman
opposite is occurring within oncologic therapy. As
systemic therapy proves more effective, local failure
is becoming an increasingly more common method of
failure, making local control progressively more
critical to patient outcome. Thus, the techniques and
ablative doses utilized with SABR will become more
important not only in early stage disease, but also in
metastatic disease as a measure for consolidation or
ablation of resistant cancer deposits after systemic
therapy. In addition, customization of therapy to
patient specific tumor characteristics will become
increasingly important in the future as biological,
clinical, and technical research within oncology cre-
ates paradigms to facilitate adaptive therapy (Song
et al. 2005; Martinez et al. 2001; Bortfeld and
Paganetti 2006). Within adaptive therapy, pretreat-
ment diagnostic information including imaging,
staging, and tissue characteristics (proteomic,
genomics, and predictive assays) will be integrated to
design patient specific therapy (Potti et al. 2006).
Patients can be monitored during treatment with
similar methods and treatments can be adjusted
including the need for adjuvant therapies and to avoid
toxicity from treatment. This paradigm avoids the
‘‘one size fits all’’ mantra in current oncologic ther-
apy, and utilizes a tailored approach to constantly
reevaluate and respond to queues in order to redirect
therapy toward better patient outcome. As we con-
tinue towards this goal of adapting therapy, it will
continue to be crucial to utilize well designed pro-
spective trials so that therapeutic tools such as SABR
can be refined to their optimal potential.
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 Postoperative Radiotherapy for Non-Small
Cell Carcinoma
Ellen Kim and Mitchell Machtay

Contents Abstract
The role of post-operative radiotherapy (PORT)
1 Introduction.............................................................. 363 in treatment of non-small cell lung cancer
2 Patterns of Failure................................................... 364 (NSCLC) is unclear. Currently, the available
evidence suggests that PORT is indicated for
3 Results of PORT in Stage I NSCLC ..................... 364
stage II and III (node-positive) NSCLC, but not
4 Results of PORT in Stage II and III for stage I NSCLC. However, it is still disputed
(Node-Positive) NSCLC .......................................... 365
in which cases patterns of failure necessitate
5 Indications for PORT.............................................. 366 further treatment following surgery, and if it is
6 Toxicity and Mortality Risks of PORT ................ 367 warranted, the question becomes whether to do
radiotherapy instead of or with (before, during, or
7 Techniques for PORT ............................................. 368
after) chemotherapy. Study of PORT is further
8 PORT and Adjuvant Chemotherapy .................... 368 complicated by the improvement of radiotherapy
9 Conclusions and Future Directions ....................... 369 techniques in recent decades, and the shortage of
References.......................................................................... 369 well-defined prospective randomized trials since
their implementation. Advances in technology
have allowed more precise administration of
higher doses of radiation with lower exposure of
healthy tissues, resulting in greater local control
and lower treatment-related toxicities. Weighing
the benefits and risks to determine the overall
usefulness of PORT is difficult and will require
future studies.

1 Introduction

M. Machtay (&) Lung cancer treatment and prognosis depends on

Department of Radiation Oncology, several factors, including tumor histology, patient
Case Western Reserve University, performance status and extent of disease. The latter is
Cleveland, OH, USA
e-mail: mitchell.machtay@uhhospitals.org usually indicated by TNM stage. Clinical staging is
relatively unreliable, with disease often restaged to a
E. Kim
Case Western Reserve University School of Medicine, more advanced stage according to results of patho-
Cleveland, OH, USA logic staging following surgery.

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 363
DOI: 10.1007/174_2011_315, Ó Springer-Verlag Berlin Heidelberg 2011
364
Although it has not been rigorously proven through
randomized trials, surgery is currently considered the
standard primary treatment for medically operable
patients with non-small cell lung cancer (NSCLC)
who do not have evidence of mediastinal or distant
tumor involvement. Surgery optimizes the chance for
local control and provides maximal pathologic stag-
ing information to guide future therapy.
Adjuvant chemotherapy is now recommended for
selected patients with NSCLC resected stage II–III. This
is based on several well-designed, ‘‘positive’’ random-
ized trials. Postoperative radiation therapy (PORT) for
NSCLC, in contrast, remains controversial. PORT
improves local control, particularly for node-positive
(stage II/III disease), but its effect on survival is unclear.
Historical prospective randomized trials to study PORT
outcomes mostly came from the 1960 and 1970s, prior to
major advances in radiation techniques. These older
studies not only failed to show a survival benefit to
PORT, but concluded a detrimental effect in stage I and II
disease. However, recent studies suggest that PORT can
improve not only local control but also actual survival for
pathologic N2 patients. Patients with pathologically
resected N2/IIIA disease should be strongly considered
for PORT in addition to adjuvant chemotherapy.
2 Patterns of Failure
In order to assess the potential usefulness of adjuvant
therapies, it is essential to understand the patterns of
failure after surgery. However, as shown in a multi-
institutional retrospective study of 306 patients with
resected stage I NSCLC, the definitions of patterns of
failure can have a dramatic impact on the reported data
on patterns of failure (Varlotto et al. 2010). This may
contribute to the wide range, 20–50%, of reported
rates of local–regional recurrence, particularly in the
1980 and 1990s (Kelsey et al. 2006). Varlotto and
Colleagues, in this series, reported a 29% local failure
rate for stage I NSCLC when using a definition whereby
any ipsilateral lung failure was considered a local
failure. However, when using a tighter definition of
local failure (ipsilateral hilum/mediastinum or bron-
chial stump—areas typically covered by a conformal
radiotherapy portal) the local failure rate was only 16%.
Sawyer et al. (1997) conducted a retrospective
review of 224 patients who underwent complete
resection of N2 NSCLC at the Mayo Clinic between
E. Kim and M. Machtay
1987 and 1993, the largest study evaluating PORT in
N2 NSCLC at the time. The patients were divided
into a group who received surgery alone and a group
who received surgery and thoracic PORT; the groups
were otherwise similar in gender, age, histology,
number of lymph nodes involved, etc. The actuarial
4-year local recurrence rate and actuarial 4-year sur-
vival rate were 60/17% for surgery alone and 22/43%
for surgery plus PORT. These results were highly
statistically significantly in favor of PORT, and the
authors concluded that adjuvant thoracic radiotherapy
may improve local control and survival.
Adjuvant chemotherapy, once controversial like
PORT, has now been established as beneficial based
on randomized clinical trials (Arriagada et al. 2004;
Strauss et al. 2008; Winton et al. 2005; NSCLC meta-
analysis collaborative group 2010). The benefit of
chemotherapy appears to be related to a slight (4–15%)
decrease in the rate of distant metastases. However,
adjuvant chemotherapy alone does not seem sufficient
to provide adequate loco regional control. A retro-
spective study of 98 patients by Taylor et al. (2003)
found stage IIB and IIIA NSCLC patients who
received surgery and adjuvant chemotherapy had
5-year actuarial local control rate of only 54%. A recent
study by Le Pechoux (2011) likewise found a rate of
local–regional failure in excess of 20% following
complete resection and adjuvant chemotherapy of
pathological stage II–III N2 NSCLC, confirming the
need to continue investigating the potential advantages
of additional PORT.
3 Results of PORT in Stage I NSCLC
Most of the prospective studies of outcomes of PORT
for early stage NSCLC were performed prior to 1985.
This was before the routine use of computed tomog-
raphy (CT) and positron emission tomography (PET)
scans. It was also prior to the widespread use of
modern linear accelerators and 3-dimensional (3D)
radiotherapy (RT) treatment planning. As discussed
previously, appropriate treatment and prognosis
depend on accurate staging; even now, clinical stag-
ing can be difficult and unreliable. High quality
images from CT to PET scans also help in planning
areas for radiation treatment. There have also been
improvements in radiation source intensity and
application techniques that have reduced morbidity
Postoperative Radiotherapy for Non-Small Cell Carcinoma
and mortality by treating smaller and often irregular
volumes with smaller margins (Le Pechoux 2011).
In 1980, Van Houtte et al. completed a randomized
trial with 175 patients with pathological stage I
NSCLC and no node involvement who received
complete resections. PORT was found to have a
detrimental effect on overall survival, with 5-year
overall survival rates of 24% with PORT, compared
to 43% in the control group. Van Houtte et al. rea-
sonably concluded that thoracic radiation therapy
should not be performed on N0 NSCLC following
surgical resection (Van Houtte et al. 1980). This was
confirmed in the PORT meta-analysis (PORT meta-
analysis trialists Group 1998).
Trodella et al’s controlled randomized study pub-
lished in 2002 was one of the few studies to suggest a
benefit of PORT in stage I NSCLC. In contrast to the
above listed trials, treatments were planned with CT, and
radiotherapy was administered with linear accelerator
and 3D beam angles. The patients with pathological
stage I NSCLC all had complete resection, treated
between 1989 and 1997. The study concluded that
PORT resulted in lower local recurrence rate, without
acute toxicity or negative impact on overall or disease-
free survival, and with a positive trend (not statistically
significant) in survival. The authors endorsed further
investigation of PORT, particularly with advances in
radiotherapy technique (Trodella et al. 2002).
The PORT Meta-analysis Trialists Group’s upda-
ted meta-analysis included results of 10 randomized
trials, including that of Trodella et al, with a total of
2232 cases of NSCLC. The meta-analysis concluded
that PORT has a detrimental effect on survival of
Stage I (and II) NSCLC patients (Burdett et al. 2005).
For now, the general body of evidence seems to
suggest that PORT may be more detrimental than
beneficial in stage I NSCLC (Table 1). Indeed, some
clinicians may argue that the risk for recurrence of
stage I disease is not high enough to warrant PORT
(Le Pechoux 2011). Re-evaluation may be necessary
as RT techniques improve over time.
4 Results of PORT in Stage II and III
(Node-Positive) NSCLC
Notwithstanding the results of the PORT meta-anal-
ysis Trialists Group results, the situation for node-
positive (stage II/III) NSCLC is less clear than for
365
stage I NSCLC. Most randomized trials in node
positive NSCLC suggest that PORT improves loco-
regional control though effect on survival has been
unclear (Weisenburger 1994; Stephens et al. 1996;
Dautzenberg et al. 1999; Feng et al. 2000; Mayer
et al. 1997). The Dautzenberg paper (which used
suboptimal radiotherapy techniques and doses) was
strongly ‘‘negative’’ against PORT, but most other
studies are underpowered to make any conclusions
about PORT in node-positive NSCLC.
Given the shortcomings of the randomized trials
(Table 1), it is appropriate to review lower level of
evidence papers (retrospective reports). There are
many retrospective studies showing that PORT
improves survival for node-positive NSCLC. For
example, Dai et al. (2011) performed a retrospective
study of 221 cases in a Beijing hospital and found that
PORT can significantly improve the survival as well as
local and distant recurrences of patients with resected
pathological stage IIIA-N2 NSCLC. Five-year overall
survival of the 96 patients (43.4%) who received PORT
was 36.6%, compared to 30.6% of patients who did not
receive PORT. PORT and non-PORT groups had sta-
tistically significantly different overall survival and
disease-free survival. PORT was found to be a signifi-
cant positive prognostic factor and an independent
prognostic factor for overall survival in univariate and
multivariate analyses. Furthermore, locoregional
recurrence-free survival (LRFS) and distant metasta-
sis-free survival (DMFS) rates were significantly
higher in the PORT than in the non-PORT groups, with
5-year LRFS/DMFS rates of 63.9/43.8% and 46.7/
23.6%, respectively. Of the 221 cases in this study, 161
(72.9%) also received adjuvant chemotherapy while 60
(27.1%) did not; PORT improved survival significantly
in both these groups considered separately. These
results appear to confirm the data from other recent
retrospective reports (Zou et al. 2010; Moretti et al.
2009; Scotti et al. 2010).
Douillard et al. published a secondary analysis of
the large ‘‘ANITA’’ (adjuvant chemo) trial (Douillard
et al. 2008). They performed a secondary analysis of
the large adjuvant navelbine international trialist
association (‘‘ANITA’’) randomized trial. Without
considering pathologic N stages separately, PORT
groups had shorter 5-year overall survival (33% in
observation and 44.6% in adjuvant chemotherapy
group) than the non-PORT groups (43% in observa-
tion and 51% in adjuvant chemotherapy group).
366 E. Kim and M. Machtay

Table 1 Results of selected randomized trials of postoperative radiotherapy (PORT) for NSCLC
Study # patients Stage XRT dose Survival with Survival without LRF with LRF without
(Gy) XRT (%) XRT (%) XRT (%) XRT (%)
Van Houtte et al. (1980) 202 I–III 60 24a 43a 2 11
Weisenburger (1994) 230 II, III 50 40 40 3a 21a
Feng et al. (2000) 317 II, III 60 43 41 13a 33a
Lafitte et al. (1996) 163 I 45–60 35 52 15 17
a
Stephens et al. (1996) 308 II, III 40 25 25 18 29a
Mayer et al. (1997) 155 I–III 50–56 30 20 6 24
a a
Dautzenberg et al. (1999) 720 I–III 60 30 43 28 34
b b
Debevec et al. (1996) 74 III 30 32 20
Trodella et al. (2002) 104 I 50 67a 58a 2a 22a
a
Statistically significant difference (P \ 0.05)
b
Data not available

However, quite different results were found when
pathologic N1 and N2 stages were considered sepa-
rately. There was an insufficient quantity of cases to
make any conclusions about pathologic N0 cases.
Considering only pathologic N1 cases, PORT was
found to have better survival than observation alone,
but PORT and adjuvant chemotherapy was found to
have poorer survival than adjuvant chemotherapy
alone. Considering only pathologic N2 cases, for both
observation and adjuvant chemotherapy groups,
patients who received PORT had better survival than
those in the same group who did not receive PORT.
The Douillard and other retrospective papers can
be understandably criticized as falling short of the
high level of evidence demanded by modern evalua-
tors of medical therapeutics. A small randomized trial
in the United States in which patients were assigned
to adjuvant chemotherapy with or without PORT
closed early due to suboptimal accrual. Prospective
randomized multi-center clinical trials are currently
ongoing in France and China (Le Pechoux 2011;
Dai et al. 2011). A proposal for attempting another
similar randomized trial in the U.S. was considered
infeasible.
5 Indications for PORT
There is currently no consensus for which patients
should receive PORT (Machtay 2008). The use of
PORT decreased during the 2000s, probably in reaction
to the negative results of the 1998 meta-analysis (1998);
however, the rationale for PORT remains the same as
for radiotherapy for other malignancies. First, patients
at high risk for locoregional recurrence can be identi-
fied; second, properly and appropriately used radio-
therapy can improve locoregional control; third, the
benefits of locoregional control outweigh the toxicities
of radiation so that overall, it is clinically beneficial to
the patient to undergo radiotherapy (Machtay 2008).
Radiotherapy in the context of PORT for NSCLC
fulfills the first two of these reasons. However, the third
hypothesis requires further investigation. Current
randomized trials that may provide more guidance are
still ongoing (Dai et al. 2011; Le Pechoux 2011).
The following are patient selection criteria based on
information presently available. Patients with N2 dis-
ease should receive adjuvant chemotherapy, based on
level 1 evidence of improved survival. PORT should be
strongly considered for these patients as well (Machtay
2008; Decker 2008). Physicians may want to consider
the extent of mediastinal adenopathy in the decision
process. A retrospective study by Matsugama et al.
(2008) suggested that PORT was more effective for
multiple station metastases than single station metas-
tasis. Thus, though prospective randomized trials are
warranted, these results suggest that PORT can reduce
local recurrence and improve overall survival, at least
for patients with multiple station N2.
Patients should have good performance status,
good cardiopulmonary reserve and pre-PORT organ
function testing (Machtay 2008). Patients should also
Postoperative Radiotherapy for Non-Small Cell Carcinoma
be willing and able to comply with careful intra- and
post-treatment medical care and visits (Machtay
2008). Ideally, PORT should be applied using the best
technology available, such as 3D conformal (CRT),
intensity modulated (IMRT), and/or proton-beam
radiotherapy, limiting radiation dose to adjacent vital
organs and using a target dose B54 Gy (Machtay et al.
2001; Machtay 2008).
6 Toxicity and Mortality Risks
of PORT
For at least 30 years, PORT has been suggested to
improve local control for patients with resected
NSCLC (Van Houtte et al. 1980; Weisenburger 1994;
Stephens et al. 1996; Mayer et al. 1997; Keller et al.
2000; Trodella et al. 2002), but a major concern is
that toxicity outweighs this survival benefit. Most of
the time, the toxicities of PORT are transient and
modest in intensity (radiation dermatitis, esophagitis).
However, more serious adverse events can occur, and
cause of death can be difficult to determine, especially
when patients have pre-existing medical conditions
and other comorbidities of smoking (Kelsey et al.
2008). Dautzenberg et al. (1999) showed significantly
increased risk of death from non-cancer causes in
patients randomized to receive PORT.
In the well-known Lung Cancer Study Group
(LCSG) study of 230 patients randomized to PORT or
observation, Weisenburger (1994) also published the
details of toxicities. In the PORT group, they noted
that 24% of patients had serious esophagitis, 20% had
gastrointestinal symptoms, 11% had dermatologic,
and 10% had neurologic toxic reactions. PORT and
control groups had statistically non-different pul-
monary toxic reactions. Two patients in the PORT
group, compared to one patient in the control group,
experienced adverse events that were so severe as to
be life threatening. It must be noted that these patients
were randomized between 1978 and 1985, so it is
possible that they overestimate the current toxicities
associated with modern treatment planned PORT
(Saynak et al. 2010).
The greatest concern about PORT is that it may
cause death due to pulmonary and/or cardiac deteri-
oration even in the absence of a recognized treat-
ment-related toxicity event (Machtay et al. 2001;
Dautzenberg et al. 1995, 1999). Based on published
367
information from randomized trials, Kelsey, Marks,
and Wilson noted that most non-cancer deaths occur
close to the first 2 years after completion of therapy,
and are related to cardiopulmonary disease. Kelsey,
Marks, and Wilson conjectured that acute toxicities
generally assumed to be transient, such as esophagitis,
may actually predispose the patients to lethal respi-
ratory and cardiac complications (Kelsey et al. 2008).
Several studies have provided evidence that PORT
toxicity has decreased with improvements in planning
and treatment technology. Lally et al. (2007) conducted
a large retrospective study of 6,148 patients diagnosed
with ipsilateral lymph node positive NSCLC between
1983 and 1993 who received surgery (pneumonectomy
or lobectomy) using Surveillance, Epidemiology, and
End Results (SEER) data. They investigated the impact
of PORT on cardiac mortality, the main cause of death
from intercurrent disease due to irradiation of heart
tissue. PORT was found to increase the risk of cardiac
mortality with statistical significance for patients
diagnosed between 1983 and 1988, but not for patients
diagnosed between 1988 and 1993.
Machtay et al. (2001) reviewed 202 patients
diagnosed with pathologic stage II or III NSCLC
between 1982 and 1998 and found an actuarial rate of
death from intercurrent disease (DID) to be 13.5%,
statistically insignificantly greater than the estimated
10% for a matched population. Further investigation
revealed that DID was associated with higher total
radiation dose; the risk of DID was 2% for patients
with dose \54 Gy, compared to 16% for patients who
received higher doses. This reinforced the hypothesis
that a higher incidence of DID was significantly
associated with higher daily doses of radiation
(Le Pechoux 2011). It should be noted that the
Dautzenberg trial used a high total dose (60 Gy) and
fraction size (2.5 Gy) of radiation.
In a similar study, Wakelee et al. (2005) analyzed the
risk of DID in stage II and IIIA NSCLC patients
following surgical resection and either PORT or che-
moradiotherapy. In their randomized trial of 488
patients, 242 patients received PORT (50.4 Gy in 28
daily fractions) and 246 patients received PORT with
cisplatin and etoposide administered concurrently. They
concluded that the actuarial overall 4-year DID rate was
not significantly different between the two groups.
Masson-Cote et al. (2011) conducted a retrospec-
tive chart review of 153 lung cancer patients who
received PORT between 1995 and 2007, examining
368
the differences in locoregional control and survival
between patients who were treated with 2-dimen-
sional (2D) compared with 3D PORT. Kaplan–Meier
analysis showed that the 3D technique had far
superior results than 2D technique, with a 5-year
locoregional control rate of 81% compared to 56%.
Toxicity was similar and modest in both groups.
A recent retrospective study by Dai et al. (2011) of
patients with pathologic stage IIIA-N2 NSCLC cate-
gorized the causes of death. A total of 221 patients
were diagnosed between 2003 and 2005; 96 (43.4%)
patients received PORT, and 140 had died by the time
of the last follow-up in 2009. One hundred twenty-
three (87.9%) of the 140 deaths were cancer related,
including 53 who had received PORT and 70 who had
not. Seventeen (12.1%) of the 140 deaths were
categorized as non-cancer-related and were evenly
distributed in the PORT and non- PORT groups.
Technologic advances have improved staging,
planning, and control of radiation administration,
sparing more normal tissue, so that modern PORT for
NSCLC does not significantly increase the risk of
intercurrent deaths (Machtay et al. 2001). This redu-
ces the risks of PORT in NSCLC treatment, reducing
one of the primary reasons against PORT. Further
investigation will be required to find the optimal
conditions and treatments for PORT.
7 Techniques for PORT
As noted above, PORT has a strong potential to
increase local control (and thereby survival), and also
to cause serious toxicities, even cardiopulmonary
death. It is thus critical that meticulous radiation
therapy treatment planning be employed.
One of the criticisms of the older series of PORT is
that they used Cobalt-60 radiotherapy beams rather
than linear accelerator-based RT. Among other limi-
tations, Co-60 beams have a wide ‘‘penumbra,’’
meaning that radiotherapy scatter dose outside the
radiotherapy portal is substantially greater than linear
accelerator-based RT. Phlips et al. (1993) showed that
patients treated with PORT using linear accelerator
had a significantly better outcome than patients trea-
ted with Co-60.
Volume irradiated likely depends not only on the
prescribed radiotherapy dose, but also on the volume
of tissue irradiated. Miles et al. (2007) created models
E. Kim and M. Machtay
to mathematically relate survival with tumor stage
and field size based on the available clinical data.
Exploring the balance of benefits of cancer-specific
survival afforded by PORT and risks of radiation-
induced mortality, they found that radiation-induced
mortality seems proportional to the cube of the field
size. The changes in survival predicted by this
formula corresponded to survivals reported in the
available literature.
A full review of the technical details for radiation
treatment planning for PORT is beyond the scope of
this chapter, but the important factors in planning
PORT Radiotherapy are: (1) Adequate coverage of
the area(s) at high risk of local recurrence (bronchial
stump, hilum, partial mediastinum and (2) protection
of critical normal lung and heart tissue from excessive
irradiation. 3D conformal RT with detailed attention
to dose-volume histograms (DVH) is critical to the
safe planning and delivery of PORT. The target vol-
ume should generally not be irradiated [54 Gy and
the lung V20 (volume % of lung receiving C20 Gy)
must be minimized, preferably B25%.
8 PORT and Adjuvant Chemotherapy
As noted above, adjuvant chemotherapy has become
the standard of care for stages II–IIIA NSCLC. This is
largely based on the results of three randomized trials
of cisplatin-based adjuvant chemotherapy regimens as
given by Arriagada et al. (2004), Douillard et al.
(2008), and Winton et al. (2005) that showed that
cisplatin-based adjuvant chemotherapy improved
survival among patients with completely resected
NSCLC. The impact of adjuvant chemotherapy on
locoregional control is less well-documented in the
current literature (Saynak et al. 2010).
The balance of risks and benefits of PORT fol-
lowing surgical resection remains more unclear, and
thus the sequencing of adjuvant chemo and PORT is
unclear. A randomized trial of 488 clinical stage II or
IIIA NSCLC patients by Keller et al. (2000) con-
cluded that concurrent cisplatin-based chemotherapy
along with PORT did not improve either locoregional
control or survival when compared to PORT alone
after surgery. The Radiation Therapy Oncology
Group (Bradley et al. 2005) reported that their study
of 88 patients with surgical resection for pathologic
stage II or IIIA NSCLC patients who received
Postoperative Radiotherapy for Non-Small Cell Carcinoma
postoperative concurrent paclitaxel/carboplatin and
PORT found the combination to be safe and that it
seemed to have an improved overall and progression-
free survival compared to previously reported trials.
This suggests that further study is warranted.
However, at this time, concurrent chemo-RT in the
adjuvant setting is thus not routinely recommended.
Most centers prefer a sequence in which adjuvant
chemo is given first, followed by PORT.
9 Conclusions and Future Directions
Local–regional failure after surgery remains an
important problem in the management of NSCLC.
The most significant factor predictive for local–
regional failure is node positivity, particularly N2
(mediastinal) adenopathy. It is generally agreed that
PORT reduces the risk of local–regional failure sub-
stantially; however the effect of PORT on overall
survival is unclear. It is possible that the beneficial
effects of PORT are outweighed in some patient
groups by morbidity and mortality from PORT.
Although there are some international randomized
trials re-investigating the use of PORT, it is unlikely
that definitive conclusions will be reached very soon.
Thus, current recommendations are that most patients
with Stage I and II disease not receive PORT (unless
there is evidence of residual cancer). Patients with
Stage III (N2) disease should be offered PORT, rec-
ognizing that adjuvant chemotherapy should be the
higher priority for these patients because of the lat-
ter’s greater effect on overall survival. There is still
much to learn about patterns of failure and clinical
and biologic factors that predict for local–regional
failure after surgery. Future studies to assess this are
needed in order to refine the precise indications for
PORT and how to integrate PORT with adjuvant
chemotherapy.
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 PDT-Lung
Ron R. Allison
Contents
1 Introduction............................................................ 371
2 Historical Perspective............................................ 372
3 Fundamentals of PDT ........................................... 372
3.1 Photosensitizer ......................................................... 372
4 Illumination ............................................................ 373
5 Photodynamic Reaction ........................................ 373
6 Dosimetry................................................................ 374
7 Fluorescence and Photo Diagnosis ...................... 374
8 Rationale for Pulmonary PDT............................. 374
9 PDT Procedure ...................................................... 375
10 PDT-Morbidity....................................................... 376
11 Clinical Outcomes.................................................. 376
11.1 Obstructing Endobrochial Lesions.......................... 376
11.2 Early Lung Cancer .................................................. 377
11.3 Multiple Primary Lung Cancer ............................... 377
11.4 Down Staging .......................................................... 377
11.5 Peripheral Lesions ................................................... 378
11.6 Pleural Tumors ........................................................ 378
11.7 PDT in Combination with Radiation...................... 378
12 Conclusion .............................................................. 378
References.......................................................................... 378
R. R. Allison (&)
Twenty-first Century Oncology, 801 WH Smith Blvd,
Greenville, NC 27834, USA
e-mail: rallison@rtsx.com
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_220, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
The role of Photodynamic Therapy (PDT) in the
current multi-disciplinary approach to thoracic
oncology is analyzed and reviewed. The simplicity
of drug, light and reaction resulting in excellent
clinical response has brought PDT to a worldwide
audience. This chapter reviews the scientific and
clinical rationale for thoracic PDT including
photosensitizers, light sources, photodynamic reac-
tion, dosimetry and fluorescence. The actual treat-
ment procedure, clinical outcomes from the peer
reviewed literature, limitations and morbidities
associated with this light-based therapy are also
detailed.
1 Introduction
Photodynamic Therapy (PDT) has a long clinical
track record of success in the treatment of pul-
monary malignancy (Allison et al. 2004a, b).
The simplicity of this intervention in combination
with high-response rates has brought PDT to a
worldwide audience (Dougherty and Marcus 1992).
Further PDT can serve as a model therapy for
tumor ablation in which functional preservation is
often achieved without undue acute or chronic
toxicity. This chapter will review the fundamental
scientific basis of PDT, treatment procedures and
precautions, clinical outcomes and indications and,
ultimately, the place of PDT in the modern multi-
disciplinary decision-making process and therapy
of lung cancer.
371
372
2 Historical Perspective
PDT was discovered serendipitously by Oscar Raab, a
medical student (Raab 1900). Raab was examining
the fluorescent characteristics of dyes on infusoria.
Raab noted and examined the unexpected deaths of
these microorganisms when the dye was illuminated
intensely. In combination with his colleagues and
professor, notably Von Tappenier, Jesionek and
Joldlbauer, the oxygen-dependent nature of this
Photodynamic Reaction (PDR) was elucidated and
this new form of light-based treatment rapidly
developed (Von Tappeiner and Jesionek 1903). By
1907 a textbook of PDT was available and PDT
offered excellent ablation of various forms of cuta-
neous malignancy (Von Tappeiner and Jesionek
1907). Still, PDT did not firmly establish itself and
was lost to medicine. The use of dyes and later por-
phyrins, for fluorescent detection, as potential radia-
tion sensitizers and, ultimately, for PDT was again
seen intermittently in the scientific literature during
the 1950s and early 1960s (Allison et al. 2004a, b;
Daniell and Hill 1991). However, it was not until the
tireless efforts of Dougherty in the 1970s that PDT
achieved a worldwide audience (Dougherty 1996). In
contrast to prior attempts, Dougherty spearheaded the
development of a clinically versatile and commer-
cially successful photosensitizing drug, light sources
and clinical trials showing efficacy in a wide variety
of malignancies particularly pulmonary lesions. Dur-
ing the early 1980s PDT achieved worldwide regu-
latory approval as an intervention for select thoracic
tumors. Since those early approvals, the PDT treat-
ment process has been refined and enhanced allowing
for continued success today.
3 Fundamentals of PDT
Arbitrarily we will divide PDT into three compo-
nents: Photosensitizing agent (PS), light source
and photodynamic reaction (PDR) (Allison et al.
2004a, b). In reality creating a successful PDR
requires appropriate localization and accumulation of
PS in the target tissue followed by illumination of this
PS with a specific intensity and wavelength of light.
All of this must coalesce in time and space to generate
the oxygen-dependent PDR. Upon creation of the
R. R. Allison
PDR a rapid vascular shutdown is often noted as
necrosis and/or apoptosis of the target tissue. The
clinical result is lesion ablation with excellent cos-
metic and functional treatment outcome. To better
understand the PDT process we will examine each
component, as described below.
3.1 Photosensitizer
The PS transfers light energy to create what is termed
a type II photochemical reaction which results in
rapid generation of highly destructive singlet oxygen
radicals (Allison and Sibaba 2010). As photosynthe-
sis, another form of light energy transfer, is critical to
life on earth, it should not be surprising that numerous
natural and synthetic substances are able to transfer
light energy. But to be considered a PS the light
energy transfer must result in a type II reaction. While
thousands of potential PS agents exist only a handful
has been brought through clinical trials and even
fewer are commercially available for therapy.
A clinically successful PS will have some or all of
the following characteristics: (Allison and Sibaba
2010) ability to concentrate in target tissue, clearance
from non-target normal tissue, reliable reactivity only
upon illumination, relatively rapid clearance from the
subject, pain-free therapy, ease of drug delivery
(topical, oral, IV), controllable PDR, synthetic ease
and purity, reproducible formulation and non-toxicity
until activated. It must also have regulatory approval
and commercial availability. Many outstanding PS
have been discovered but due to lack of commercial
production they are not available to help patients.
Not surprisingly the porphyrins, which form the
back bone of chlorophyll and hemoglobin, two highly
successful structures for transfer of oxygen, have
served as the basis for clinically successful PS
development. In particular, two PS agents have found
success in pulmonary PDT.
PhotofrinÒ—This proprietary mixture of porphyrin
monomers, dimers and oligomers was the product of
Dr. Dougherty’s pioneering work in PDT and has
remained the most commonly utilized PS agent for
more than 30 years. PhotofrinÒ is commercially
available from Axcan Pharma but is also manufac-
tured by numerous ‘‘unofficial’’ manufacturers whose
drug appears similar to PhotofrinÒ in both name and
content. This PS allows for treatment time of
PDT-Lung 373

10–20 min per lesion which is satisfactory during

bronchoscopy. Therapy is painless and with photo-
frinÒ highly reliable. It is usually dosed at 2 mg/kg
and around 48 h post intravenous infusion a differ-
ential concentration exists between pulmonary tumors
and surrounding normal tissue. This may allow for
permanent lesion ablation without permanent normal
tissue damage. The major drawback is that enough
PhotofrinÒ is retained in normal tissue, including the
skin, for 6 weeks so that unintentional sunlight
exposure during this time frame will create a poten-
tially significant burn in the exposed skin.
MACEÒ—a chlorine-based PS. Mono-l-aspartyl
Chlorine e6 has recently achieved regulatory status in
Japan for pulmonary PDT. This synthetically pure PS
has a more rapid clearance from normal tissue and
skin allowing for a 2–3 week period of photosensi-
tivity. A differential between normal tissue and tumor
is noted at 4 h post intravenous infusion allowing for
same day infusion and PDT as compared to the two-
day waiting period for photofrin. The drug is intra-
venously infused at 40 mg/m2.
4 Illumination
Each PS has both a specific activation wavelength and
also intensity of light required for activation. As sun-
light contains multiple wavelengths and is also an
intense source of illumination energy it can activate
any PS. Since all current PS accumulate to a certain
degree in the skin avoiding sunlight exposure is a
critical aspect in minimizing morbidity. Clinically
useful wavelengths for PS activation are in the red light
range (600 nm and above). Red light penetrates tissue
to about 1 cm which is more than satisfactory for
treatment of in situ and non-bulky invasive pulmonary
lesions. PhotofrinÒ activates at 630 nm and MACEÒ at
664 nm. Wavelengths above 800 nm are absorbed
preferentially by water so the illumination window by
light for successful PDT is rather limited. More bulky
lesions can be treated through repeated PDT sessions
or via interstitial placement of the light source within
the tumor. Currently portable diode lasers are able to
generate enough power to activate the PS (Mang et al.
1987). A laser tuned to the specific activation wave-
length of PhotofrinÒ or MACEÒ is commercially
available. These lasers are coupled to fiber optics that
are brought to the region requiring illumination.
Fig. 1 The Photodynamic Reaction. The active photosensi-
tizer (PS) may follow several pathways including one that
generates toxic singlet oxygen (PDR)
A flashlight-like forward projecting micro lens fiber
optic is commercially available as is a diffusion fiber
which illuminates in all directions. Recently Light
Emitting Diodes (LED) tuned to the PS wavelength
have become available and are much less expensive
both in purchase outlay and use than lasers. On the
forefront of illumination are highly portable battery
operated light sources allowing for prolonged or
repeated (metronomic) illumination protocols.
5 Photodynamic Reaction
The successful culmination of PS activation by the
appropriate intensity and wavelength of illumination
is the PDR (Allison and Sibaba 2010). This is illus-
trated in Fig. 1. As mentioned this is the generation of
toxic singlet oxygen as a product of the type II (PDR)
reaction. In this process the inert PS is converted to
the active triplet energy state via proton transfer from
light. The PS will transfer the energy which cleaves
an oxygen molecule ultimately generating the singlet
oxygen. The active PS can also generate a toxic type I
reaction via generation of hydroxyl radicals cleaved
from water. A direct cytotoxic, non-oxygen mediated
type III reaction may also occur. An additional
pathway is that the active PS may lose energy via
release of light, termed fluorescence. This visible
release of light can be of great clinical utility as will
be described later.
374
Clinically with the intense illumination currently
employed the PDR presents with vascular shutdown
and a hypoxic appearing lesion. The type II reaction
generally results in cellular necrosis via destruction of
cell and vascular membranes which is where the PS
accumulates. As PS does not accumulate in DNA,
PDT is considered a non-mutagenic therapy. The
release of cellular debris initiates a cytokine cascade
which may potentiate an immune-type response. In
contrast, an apoptotic death appears favored from a
prolonged or metronomic illumination. Manipulating
the PDR is an area of active research.
6 Dosimetry
Light dosimetry is far more complicated than, for
example, dosimetry in radiation therapy (Sibata et al.
2000). The interaction of light with matter remains to
be better defined. However, clinicians use PS drug
dose, drug infusion to light initiation interval (DLI)
and light intensity as a crude but reproducible means
to achieve dosimetric success. Each PS will have a
unique and optimal drug dose, DLI and intensity of
light for activation. Until light dosimetry is better
defined and measured, PDT will not be able to
achieve its full potential.
Clinically, patients metabolize PS on an individu-
alized basis. So when using a standard drug dose,
light dose and DLI, some patients will have more
intense PDT than others due to what appears to be a
genetic characteristic of metabolism and, perhaps,
immune response. For example, some of these indi-
viduals retain more PS drug both in tumor and normal
tissue creating a very brisk PDR.
Currently the concept of photo bleaching is used to
assist in PDT dosimetry. As PS accumulates to a
greater degree in malignancy than normal tissue the
current guidelines are to employ a clinically deter-
mined amount of PS that floods the tumor but
attempts to stay below the threshold of a clinically
significant PDR in surrounding normal tissue. Thus
the PS in normal tissue will be used up (photo-
bleached) but not generate significant or permanent
toxicity. If too much PS is infused the malignant
region will still retain extra PS, but the surrounding
normal tissue will also have enough PS to generate a
PDR which could be morbid. Ideally the optimal drug
dose and illumination dose would be individualized
R. R. Allison
based on the patient’s metabolic and treatment char-
acteristics. This is an area of active research.
7 Fluorescence and Photo Diagnosis
As mentioned one pathway for PS activation leads to
the release of visible or detectable light, termed
fluorescence (Allison and Sibaba 2010). The fluores-
cence phenomena can be exploited to assist in
determining the extent of disease which may be
unclear to the naked eye in visible light. Under fluo-
rescence lesions become very obvious compared to
nearby non-fluorescing normal tissues. This fluores-
cence phenomenon is sometimes called photo diag-
nosis. Change in the fluorescence before and after
PDT may also be a means of dosimetry. Full loss of
fluorescence can indicate tumor death. Thus treatment
could be individualized based on loss of fluorescence
rather than by using the current methods of dosimetry
(Allison and Sibata 2008).
Pulmonary lesions may also auto-fluoresce based
upon inherent chromophores in tumors (Dooms et al.
2010). Commercially available auto-fluorescent
bronchoscopy units have already shown tremendous
value in lesion detection as well as during surveil-
lance bronchoscopy of high-risk populations. The use
of auto-fluorescence, PS fluorescence and fluorescent
changes post PDT is an area of active research.
8 Rationale for Pulmonary PDT
PDT is one of many interventions available for pul-
monary lesions (Moghissi and Dixon 2003). PDT can
be employed simultaneously or sequentially with
external beam radiation, brachytherapy, stenting,
YAG laser, cryotherapy, chemotherapy or surgery.
The versatility of PDT is one of this therapy’s
stronger points. For select in situ or early invasive
lesions PDT alone can be curative. Bulky obstructing
endobronchial lesions can be palliated. PDT can be
used to downstage cancers for resection or as an
adjunct for tight or positives margins post-operatively
or intra-operatively.
In general PDT is used as part of a multi-disci-
plinary approach for pulmonary disease control either
in a curative or palliative settings. Unlike other
interventions PDT can be repeated to allow for
PDT-Lung 375

Fig. 2 Obstructing lesion

(left) of airway treated by
photofrin PDT, 2 mg/kg,
200 J Red light. Two weeks
post PDT (right) shows com-
plete response. (Photo’s cour-
tesy of Gordon Downie)

prolonged disease control. Interestingly PDT appears

to work regardless of histology as long as PS can be
activated by appropriate light source. One important
point is that following illumination PDT can take
hours or days to generate a clinical response so that it
is not indicated in the emergent setting. Further, blood
will preferentially absorb red light so hemostasis is
required for successful PDT. Also of importance is
that for photofrinÒ one must generally wait 48 h after
infusion to achieve a selective PDR. This shows the
need for other intervention in the emergent pulmonary
setting.

9 PDT Procedure

The actual PDT procedure for pulmonary disease has

evolved to the point that it can reproducibly ablate
lesions without undue acute or chronic mobility
(Moghissi and Dixon 2008). Following informed
consent the PS is introduced intravenously and
allowed time to concentrate in the lesion. Endobron-
chial tumors are generally approached endobronchi-
ally. This can be via rigid or fiber optic bronchoscope.
Thoracic surgeons often use general anesthesia and
apply the rigid bronchoscope to visualize central
lesions. Pulmonologists use conscious sedation and
apply fiber optic scopes to visualize lesions. Fluo-
rescent technology such as the life scope or other
similar devices can be employed to enhance lesion
visualization. Upon lesion visualization, the fiber
optic for treatment connected to a light source
designed to activate that particular PS is brought to
the lesion. This is generally accomplished by passing
Fig. 3 Fiber optic in place and illuminating tumor bed
the fiber optic through the bronchoscopes biopsy
channel. Various diffusing fibers of lengths from 1 to
5 cm can be employed for illumination. For longer
lesions the illuminating fiber can be stepped to ensure
total lesion illumination. For bulky tumors ([1 cm
Deep) the light source may be inserted into the mass
either mechanically or often after YAG laser or
equivalent tunneling procedures. A typical PDT out-
come is shown in Figs. 2 and 3. The PDT procedure
can be offered in stented regions as well. Self-
expanding stents are not injured by the non-thermal
light treatment of PDT. Opaque stents will diminish
light transmittance so additional treatment time can
be required in this instance. Again, PDT can be
376
delivered in previously irradiated regions either from
external beam or brachytherapy. In contrast to other
endobronchial procedures PDT can be directly
observed which ensures accurate targeting. At the
completion of the PDT session tumors appear dusky
and hypoxic. At 48 h (or sooner) post PDT, a second
bronchoscopy session is always undertaken to remove
necrotic debris and if viable tumor is seen an addi-
tional PDT session is possible when photofrinÒ is the
PS. Necrotic tumor can be brought out in bulk via
cryotherapy which may also assist in improving
tumor control. It is critically important to always
include follow up bronchoscopy post PDT to ensure
adequate pulmonary toilet. Failure to do so can result
in fatal airway obstruction, fortunately a quite rare
consequence.
More peripheral lesions can be treated via trans-
bonchial application of the light source using endo-
bronchial navigational guidance. These navigational
tools have opened new pathways for PDT to more
peripheral lesions. CT-guided placement of light
sources is also possible for peripheral lesions as is a
video-assisted thoracoscopic approach (Moghissi
et al. 2003). An open surgical procedure with lesion
resection or debulking followed by planned PDT is
also an option for nodules and diffuse tumors such as
mesothelioma. For diffuse lesions multiple light
sources are required to minimize treatment times.
10 PDT-Morbidity
Morbidity can occur immediately following PS infu-
sion as the individual becomes photosensitive within
minutes of infusion. Individuals who will not follow
sunlight precautions should not undergo PDT. Photo-
sensitivity to sunlight exposed anatomy can occur even
with only a few minutes of sunlight exposure. Clini-
cally this is treated as one would a moderate to severe
sunburn, generally using steroids and pain control.
PDT treatment is non-thermal and does not have a
significant rate of added acute morbidity compared to
bronchoscopy alone or when employed with other
endobronchial or surgical approaches. With the rou-
tine addition of follow-up bronchoscopy emergent
airway obstruction is virtually non-existent. Even
when combined with HDR Brachytherapy, morbidity
appears limited, and generally mild, except in a very
rare case of fistula (Sanfilippo et al. 2001).
R. R. Allison
Current light sources produce intense illumination.
During treatment both patients and practitioners need
to wear eye protecting goggles. Eye injury or blind-
ness can result from improper safety procedures.
11 Clinical Outcomes
Among the first clinical success for PDT was the
treatment of pulmonary lesions (Kato et al. 1996).
Early studies included mostly central endobronchial
advanced cases that had failed radiation therapy and
other intervention such as YAG Laser or electrocau-
tery. Pulmonary palliation was generally achieved
showing not only PDT’s ability as salvage therapy but
also its relative safety in combination with other
treatments. In a more recent review it appears that
intentionally offering multi-modal salvage allows for
prolonged survival and palliation for locally advanced
endobronchial disease (Santos et al. 2004).
Currently PDT has focused on the treatment of
early lesions. In combination with fluorescence
detection, high rates of lesion ablation with preser-
vation of pulmonary function are routinely achieved
(Weigel et al. 1999). Select publications from the
PDT literature follow.
11.1 Obstructing Endobrochial Lesions
These highly symptomatic tumors lead to respiratory
compromise, hemoptysis and infection and can be
fatal. Local palliation improves quality of life and can
prolong survival. In an early pivotal study Moghissi
et al. (1993) reported a randomized trial comparing
laser ablation to PDT for symptomatic central endo-
bronchial tumors. Response rates leading to pulmon-
ary palliation were equivalent and approached 80%,
however, PDT offered a statistically significant and
meaningful prolongation of palliation measured in
months. Similarly a randomized trial comparing pal-
liative radiation therapy (30 Gray/10fx) to radiation
therapy (30 Gray/10fx) and PDT reported superior
pulmonary palliation with the addition of PDT again
measured in months (Lam et al. 1987).
In a report by Minnich et al. (2010) on PDT to 133
patients, mainly with obstructing lesions of the main
stem bronchus, one or two PDT sessions allowed for a
clinically significant reduction in dyspnea as well as
PDT-Lung
prolonged pulmonary palliation. Only four patients
reported a photosensitivity reaction. Of note is that
patients in this series had failed prior endobronchial
therapies.
Similarly in a report of 100 cases of PDT to
patients with advanced unresectible lung cancer
(Moghissi et al. 1999), PDT achieved excellent pul-
monary palliation. Two-year survival was 20%
revealing the ability of PDT to offer very prolonged
palliation in select cases. A number of other studies
show excellent salvage rates of 80% or more with
PDT alone (Moghissi and Dixon 2003).
11.2 Early Lung Cancer
This is a heterogeneous group of lesions varying from
in situ to minimally invasive disease. Invasive lesions
can spread to regional lymph nodes, and as these
nodes cannot be treated by PDT, patient selection is
critical. Ultrasound, to assist in-depth invasion, can be
of critical utility (Miyazu et al. 2002). In contrast to
resection PDT will maintain the pulmonary paren-
chyma, an attractive reason to employ this modality.
Further, patients medically inoperable or who refuse
surgery can still undergo therapy to prevent disease
progression. In a study from the Mayo clinic one or
two PDT sessions eliminated early invasive or in situ
disease in 92% of patients (Cortese et al. 1998).
Similar excellent outcomes has been noted by other
investigators. Moghissi et al. (2007), with several year
follow-up, reported that one or rarely two PDT ses-
sions allowed a 100% pathologic complete response
for lesions centrally located. No patient had pul-
monary compromise and only one had sunlight sen-
sitivity. Furuse et al. (1993) achieved an 81% CR rate
with a single PDT session and a second session was
able to salvage most failures. Of note in this series of
51 patients, sunburn from photosensitivity reaction
was noted in 25%, showing the need for sunlight
exposure precautions. Furukawa et al. (2005), in a
series of 114 patients, achieved a 93% CR for lesions
up to 1 cm but only a 60% CR for larger lesions. The
larger lesions could often be salvaged by multiple
PDT session or other interventions. This proves that
in bulky lesions, single session PDT treatment is
limited to illumination depth of about 1 cm. More
recently, the use of MACE, rather than photofrin, as a
PS has been reported. MACE is on label and
377
commercially available in Japan. Kato, in a series of
reports (Furukawa et al. 2005; Kato et al. 2003; Usuda
et al. 2007), showed a 92% complete response with
this drug. Interestingly this group employs fluores-
cence and auto-fluorescence to improve targeting and
to monitor treatment outcome. With its short period of
cutaneous photosensitivity MACE has become the
preferred PS for pulmonary disease in Japan.
11.3 Multiple Primary Lung Cancer
In general these individuals are heavy smokers with
limited lung function. Treatment options are limited
but PDT has found a niche here. In a study from Japan,
patients with multiple primary lung cancers underwent
either PDT alone or PDT to some lesions and surgery to
other lesions. PDT alone or in conjunction with surgery
allowed for 100% CR with all patients alive and
breathing well (Usuda et al. 2010). An aggressive sur-
gical approach of pneumonectomy or lobectomy and
PDT was presented by Jung et al (Jung et al. 2010).
Post-operative mortality was 9%. The authors felt that
PDT alone or in combination with limited resection
could achieve excellent outcome, perhaps avoiding the
mortality associated with the larger surgery. In a study
from Russia, multiple lesions smaller than 1 cm could
be routinely ablated by PDT and was the treatment of
choice for early synchronous or metachronous multiple
primary lung cancers (Sokolov et al. 2010).
11.4 Down Staging
As surgical resection remains the best chance for cure
for advanced lung cancer PDT has been examined in a
neo-adjuvant role for tumor debulking to allow for
excision. In a study of 41 patents, Ross et al. (2006)
reported that half the patients were down staged enough
by PDT for curative resection. A small cohort had
complete pathologic response to pre-operative PDT
treatment. Pre-operative PDT also allowed for com-
plete resection in a report by Mortman and Frankel
(2006) as well as DeArmond et al. (2008). PDT allowed
for resection in 22 of 26 cases reported by Okunaka
Tetsuya et al. (1999). In this study a statistically
significant increase in survival was also noted for T3
lesions (Main Bronchus) when comparing pre-
operative PDT to no PDT for this cohort of patients.
378
11.5 Peripheral Lesions
With technologic advances peripheral lesions have
become amenable to PDT. These tumors can be
approached in various ways including video-assisted
thorascopy (Moghissi et al. 2003), CT-guided place-
ment of illumination fibers and via bronchoscopy
augmented with guidance. Using CT guidance, cath-
eters were placed in peripheral tumors and then fiber
optics introduced for illumination. As reported by
Okunaka et al. (2004) high tumor response rates were
noted but as might be expected, a 20% pneumothorax
rate was also seen. Moghissi et al. (2003) described a
direct visualization procedure via VATS that also
achieved high response without pneumothorax.
11.6 Pleural Tumors
Mesothelioma and advanced non-small-cell cancers
can progress plurally leading to demise. Current
options are limited and PDT has been explored for
their indication. In preliminary studies the combina-
tion of maximal resection followed by PDT to the
involved anatomy was undertaken. (Friedberg et al.
2004; Du et al. 2010). Multiple light sources are
required for this extensive volume of illumination. In
select cases radiation has also been added to the
treatment mix. While preliminary, high-response rates
are possible but due to technical difficulties morbidity
occurs. Further study is warranted.
11.7 PDT in Combination with Radiation
As mentioned, early PDT trials included patients who
had failed other interventions, particularly radiation
therapy. High-response rates without undue morbidly
were seen. One of the few randomized trials in pul-
monary PDT explored the intentional combination of
external beam therapy with PhotofrinÒ PDT (Lam
et al. 1987). Patients with histologically proven, un-
resectable, obstructive, non-small-cell bronchogenic
carcinoma were randomized to radiation therapy
alone or radiation therapy followed by PDT. While
the size of the study was small, 80% of radiation
therapy alone patients had symptomatically pro-
gressed by 12 week post therapy, compared to only
20% in the PDT + radiation group. Further only
R. R. Allison
patients in the radiation + PDT cohort achieved
complete remission which offered prolonged survival.
PDT has also been intentionally combined with
HDR Brachytherapy. In a study by Freitag et al.
(2004), 32 patients with bulky endobronchial non-
small-cell lung cancer underwent photofrin PDT
followed by five fractions of HDR (4 Gray delivered
to 1 cm depth). HDR was delivered weekly starting
on week six post PDT. At 2-year follow-up 26
patients were NED (81%). All these individuals were
salvaged by additional PDT, HDR or external beam
radiation. No severe complications or hospitalization
were seen. In particular no fistula or hemoptysis was
reported. Similar outcomes were reported by
Weinberg et al. (2010). In this series of nine cases,
HDR was generally the initial therapy with three once
weekly HDR sessions delivering 5 Gray to 5 mm
followed 1 month later by photofrin PDT. A complete
response rate of 80% was noted with all patients who
achieved CR remaining NED for up to 5 years. Two
cases of mild sunlight photosensitivity were seen.
12 Conclusion
Photodynamic therapy has a long and successful track
record in the treatment of pulmonary malignancies. PDT
can ablate a wide variety of histologies as long as the
drug can be infused and light sources can be brought to
the lesion. Of critical importance is that time is required
for lesion response so that PDT should not be employed
up front in situations where pulmonary compromise
exists. The great strength of PDT is that it can be
employed simultaneously or serially with other estab-
lished oncologic interventions to assist in disease control
in thoracic cancer. PDT fits in well with the concept of a
multi-disciplinary approach to thoracic oncology.
Viewing PDT as complimentary rather than competitive
ensures the patient the best chance of clinical benefit.
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 The Role of Radiofrequency Ablation
in the Treatment of Stage 1 Non-Small
Cell Lung Cancer
John M. Varlotto, Julia A. Shelkey, and Rickhesvar P. Mahraj

Contents
1 Introduction.............................................................. 382
2 Patient Selection and Evaluation........................... 382
3 Technique.................................................................. 383
4 Results ....................................................................... 385
4.1 Clinical Results.......................................................... 385
4.2 Ablate and Resect Studies......................................... 390
5 Follow-Up.................................................................. 391
6 Summary................................................................... 393
References.......................................................................... 394
Abstract
Currently, the standard of care for stage I non-small
cell lung cancer (NSCLC) is surgical resection.
Although this treatment modality has been demon-
strated to have 5 year survival rates approaching
80%, there need to be effective alternative treat-
ments for patients who are medically inoperable.
Radiofrequency ablation (RFA) has emerged as a
minimally-invasive therapy to fill this void. This
modality has been found to be most effective for
treatment of small (\3 cm), peripheral lesions that
are located distal to vasculature, large airways, and
the mediastinum. The most common complications
after RFA include pneumothorax, pneumonia, and
pleural effusion. To date, accurate assessment of the
efficacy of RFA has been difficult to determine due
to short follow-up times of current studies and the
lack of standard definitions of local recurrence as
well as toxicity. Current literature has suggested
local progression rates ranging from 20 to 42%, but
assessment by prospective trials with long-term
follow-up and standardized definitions of toxicity
and local control are needed to determine the true
benefit of this procedure.

J. M. Varlotto (&)
J. A. Shelkey

Radiation Oncology—CH63,
Penn State Hershey Cancer Institute,
500 University Drive, Abbreviations
PO Box 850, Hershey,
PA 17033, USA
AICD Automatic implantable cardioverter
e-mail: jvarlotto@hmc.psu.edu defibrillator
R. P. Mahraj
AZ Ablation zone
Department of Radiology, C Centigrade
Penn State Hershey Medical Center, CA Complete ablation
500 University Drive, Hershey, CN Complete necrosis
PA 17033, USA

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 381
DOI: 10.1007/174_2011_230, Ó Springer-Verlag Berlin Heidelberg 2011
382 J. M. Varlotto et al.

CR Complete response concerning percutaneous RFA of lung neoplasms in

CSS Cancer specific survival the recent literature. This technique directly destroys
CTCAE Common terminology criteria for tumor cells by delivering a high-frequency, alternat-
adverse events ing current with frictional heating and ionic agitation.
DFS Disease-free survival Consequently, cell membrane alteration, protein
DR Distal recurrence denaturation, and necrosis around the electrode are
EBUS Endobronchial ultrasound directly produced. However, this process can indi-
EP Extrapulmonary recurrence rectly stimulate the immune system because it relea-
F/U Follow-up ses large amounts of tumor antigen and tissue debris
GGA Ground-glass attenuation into the systemic circulation (Fietta et al. 2009;
H&E Hematoxylin and eosin staining Widenmeyer et al. 2010). The treatment of lung
H&M nodes Hilar and mediastinal nodes neoplasms may be ideal for RFA because the sur-
IA Incomplete ablation rounding pulmonary tissue may cause an insulating
IP Intrapulmonary recurrence effect whereby the heat is concentrated within the
LC Local control tumor. The low thermal conductivity of the neigh-
LR Local recurrence boring lung tissue has been demonstrated to greatly
MAM Monoclonal anti-mitochondrial increase radiofrequency-induced temperatures within
antibodies a defined ablation target (Liu et al. 2006).
Mn Months The purpose of this chapter is to describe the
NS Not stated technique, results, complications, and follow-up
NSCLC Non-small cell lung cancer evaluation of Stage I Non-small cell lung cancer
PFS Progression-free survival (NSCLC) patients treated with RFA.
PNB Percutaneous biopsy
Pneumo Pneumothorax
R Recurrence 2 Patient Selection and Evaluation
RECIST Response evaluation criteria in solid
tumors The treatment approach for effective management of
RF Radiofrequency early stage NSCLC is evolving to mirror complex dis-
RFA Radiofrequency ablation ease presentations and patient situations, as well as to
RT External beam radiotherapy accommodate the many different therapeutic options.
RT-br Brachytherapy For early stage lung cancer, surgery offers survival rates
RTOG Radiation therapy oncology group as high as 79.5% at 5 years (Koike et al. 1998). Many
S Survival patients, however, are inoperable due to either co-mor-
SBRT Stereotactic body radiation therapy bidities or the development of new or recurrent lung
SVB Supravital blue staining cancer following past therapeutic intervention. Under
these circumstances, radiofrequency ablation is a mini-
mally-invasive technique that represents an additional
tool to treat patients in these situations.
The decision to offer this method of treatment is best
1 Introduction considered in a multi-disciplinary group setting. Tho-
racic surgeons, radiation oncologists, thoracic inter-
Interstitial hyperthermia via the radiofrequency abla- ventional radiologists, and medical oncologists should
tion of a primary lung cancer was first described be involved in determining the most appropriate treat-
during an open thoracotomy in 1983 (Lilly et al. ment strategy. This plan should include evaluation of
1983). The first report of modern, percutaneous surgical technique (lobectomy versus limited resec-
radiofrequency ablation in patients with lung malig- tion), conventional radiotherapy versus SBRT, and
nancies was published in 2000 (Dupuy et al. 2000). RFA or combined modality treatment. RFA can be
Due to the technique’s minimal invasiveness, there considered as a sole treatment option or with other
has been considerable interest and multiple case series local modalities (external beam radiotherapy, SBRT,
The Role of Radiofrequency Ablation in the Treatment of Stage 1 Non-Small Cell Lung Cancer
brachytherapy) to achieve local tumor obliteration with
the goal of cure or palliation.
Absolute contraindications exist, including severe
COPD with FEV1 \0.5 L, severe pulmonary artery
hypertension, co-existent pneumonia, past pneumo-
nectomy, and uncorrectable coagulopathy. Further-
more, the treatment of lesions located centrally next
to large vessels must be individualized due to the
higher risks of ineffective ablation and complications.
Patients with automatic implantable cardioverter
defibrillators (AICDs) and pacemaker devices repre-
sent a special risk and require expert electrophysio-
logical management. Stereotactic body radiation
therapy (SBRT), microwave, and cryoablation repre-
sent alternative ablation techniques for such patients.
As with selection of patient for other curative
treatments, a thorough diagnosis and staging should
be preformed. At our institution, FDG-PET as well as
percutaneous biopsy (PNB) of extrathoracic lesions as
necessary are part of the standard pre-treatment
staging. Nodal staging is preferred. A bronchoscopy
with nodal sampling via endobronchial ultrasound
(EBUS) is considered. If nodal sampling via EBUS is
negative and a patient can tolerate general anesthesia
a mediastinoscopy is performed. As per past guide-
lines, if the staging work-up with FDG CT/PET is
negative, patients with clinical T1 tumors in the outer
2/3 of the hemithorax can forego invasive nodal
sampling (Detterbeck et al. 2007).
3 Technique
The procedure can be performed under conscious
sedation or general anesthesia. General anesthesia is
usually reserved for extreme pain, lack of patient
co-operation, and necessity for airway control during
suspended respiration. If bleeding is a significant risk,
double-lumen endotracheal tubes are recommended.
Most patients who are able to tolerate a CT-guided
needle biopsy of the lung are generally candidates for
RFA (McTaggart and Dupuy 2007).
RFA utilizes a radiofrequency generator to supply
power through an electrode. The electrode is in the
shape of needle, which is placed under CT-fluoro-
scopic guidance into the lesion. The patient essen-
tially becomes part of an electrical circuit in which a
radiofrequency generator produces an alternating
electrical field. Heat is located within the needle,
383
which causes ions within the tumor to oscillate lead-
ing to frictional heat. The area of coagulation necrosis
achieved is related to the strength of the radiofre-
quency energy, the current-carrying time, the diame-
ter and shape of the electrode, and the composition of
the surrounding tissues. The lung may be particularly
suited for this technique due to the insulating effect
provided by the surrounding, air-filled, pulmonary
parenchyma, which improves the effectiveness of
RFA by concentrating the heat energy in the tumor
(White and D’Amico 2008). Cellular death is induced
by thermal coagulation necrosis at an optimal heating
temperature of 60–1058C (Matsuoka and Okuma
2007). Above this temperature, carbonization and gas
formation occur, which in turn lead to an increase in
tissue impedance and restriction in frictional heating
of the tumor tissue (White and D’Amico 2008).
There are three systems approved by the FDA to
ablate soft tissue tumors that can also be used to
therapeutically destroy lung tumors. They all have an
automatic feedback of either temperature (RITA
Medical Systems Freemont, CA) or a specific change
in impedance (Valleylab: Boulder, CO; and Boston
Scientific LeVeen CoAccessTM Electrode System,
Natick, MA). The authors’ experience is with the
Valleylab, cool-tip system and RITA Medical
Systems. The cool-tip system is preferred for small
lesions under 2 cm, while the RITA system is used for
large lesions of 2–3 cm. The Valleylab, cool-tip sys-
tem causes less collateral damage to normal tissues
and prevents tissue charring (excessive tissue
destructive near the electrode resulting in less effec-
tive treatment of distal tumor tissue) due to its use of a
single small gauge needle and because of a continu-
ous infusion of iced-water around the probe as the
tumor is heated resulting in improved radiofrequency
(RF) energy distribution and increased ablation
diameter (Casal et al. 2010) (Fig. 1a, b). The different
needle types are selected based on tumor size and
location, as well as preference and availability.
Needle size generally ranges from 14 to 17 gauge.
Larger tumors ([3 cm) are also associated with worse
local control via RFA (Lanuti et al. 2009; Lee et al.
2003). However, larger electrodes can produce
necrosis measuring up to 4–5 cm in diameter. This
allows for the treatment of a 3 cm lesion with a 1 cm
margin of normal lung. Preferentially, when available,
a multiple tine system is used to heat larger lesions
and reduce procedure times because of its ability to
384
Fig. 1 a Pathologic specimen demonstrating complete abla-
tion due to effective heating throughout the tumor. b Pathologic
specimen that demonstrates charring with viable tumor within
the treatment zone. Charring prevents homogeneus thermal
energy transfer throughout tumor, resulting in ineffective
treatment in tumor sites distal to the RFA probe
open like the spokes of an umbrella. For peripheral
lesions, pleuritis and rib pain can be avoided by
deliberately inducing a small pneumothorax during
the procedure (Fig. 2a, b).
A particular problem is encountered with large
blood vessels ([3 mm) near a tumor. The vasculature
constantly cools the heated tissue because the flowing
blood causes conduction loss from the area being
treated. This difficulty is commonly known as the
heat-sink effect (Rose et al. 2006). As a result, tumors
J. M. Varlotto et al.
in continuity with large blood vessels may be sub-
optimally treated with RFA.
CT volumetric scanning with multi-planar recon-
struction are effective methods to evaluate and guide
needle placement within the tumor. RFA is ideally
performed under CT-fluoroscopic guidance, which
allows real-time needle guidance for speed and
accuracy. Probe placement depends on the size of the
lesion and the thermal ablation volume characteristics
of the needle. A single needle may be re-inserted into
the lesion multiple times to achieve overlapping
volumes that can completely ablate the tumor. Mul-
tiple placements are particularly helpful for irregular
lesions. The average time for a single 2–3 cm volume
ablation is 12 min.
Assessment of adequate thermal ablation of the
tumor requires demonstrating a minimal core tumor
temperature of 608C and evaluating the thermal injury
occurring to the normal lung surrounding the tumor.
The latter has been shown using porcine lung models
in which the ground-glass attenuation (GGA) CT scan
changes taking place in the lung correspond to hem-
orrhage that occurs beyond the volume of tissue
necrosis produced by thermal ablation (Yamamoto
et al. 2005). Knowledge of pre-ablation lesion size is
important so that thermal injury can be demonstrated
beyond the margin of the lesion. This assessment can
be made complex due to procedure-related enlarge-
ment of the solid portion of the tumor and the syn-
chronous development of the peripheral zone of
GGA. As a guideline, 0.5–1 cm of circumferential
GGA surrounding the lesion indicates a satisfactory
treatment endpoint. Additional ablation with reposi-
tioning of the electrode needle should be considered
to treat areas where GGA is absent (Fig. 3a, b). One
group of investigators, however, cautioned that the
extent of the GGA may not be indicative of the exact
extent of coagulation necrosis (Hiraki et al. 2007).
Post-procedure recovery follows conscious seda-
tion or post-anesthesia recovery standards. The lung
puncture site should be kept dependent for 2–3 h.
Antitussive medications may be beneficial and ade-
quate pain control as well as monitoring of vital signs is
necessary. Chest X-rays should be taken at 1 and 4 h
following the procedure to exclude pneumothorax or
occult pulmonary hemorrhage. Patients may be dis-
charged 6–8 h the same day or observed overnight as
indicated. A mild fever is common for the initial 2 days
following the procedure (Yamamoto et al. 2005).
The Role of Radiofrequency Ablation in the Treatment of Stage 1 Non-Small Cell Lung Cancer 385

Fig. 2 a Peripheral-based
tumor presenting for RFA.
b A controlled pneumothorax
(injection of 250 cc of air in
this example) was used to
separate the tumor from the
chest wall in order to prevent
complications including
pleuritis, neuritis, and bone
pain

Fig. 3 a Thermal ablation of a

2.4 cm NSCLC with absence
of GGA noted anteriorly
indicating incomplete tumor
necrosis. b Effective ablation
achieved radiographically after
repositioning of the electrode
anteriorly

an ultrasound-guided technique. Hiraki et al. (2007)

4 Results
4.1 Clinical Results
The results of RFA in the treatment of Stage I lung
cancer are summarized in Table 1. Some series also
included metastatic tumors and/or more advanced lung
cancers, but the information in the tables contains only
details concerning stage I patients unless otherwise
indicated. All patient series are retrospective single
institution investigations, except the report by Lencioni
et al. (2008), which was a multi-institutional, prospec-
tive study. A percutaneous, CT-guided RFA technique
was used in most studies. Ambrogi et al. (2007), how-
ever, treated some tumors involving the chest wall with
were the only investigators who used CT-fluoroscopy,
which allows for real-time imaging at the expense of a
much higher procedure-related radiation exposure (Rose
2008). In general, the patients selected for RFA were
mostly medically-inoperable secondary to multiple
medical co-morbidites with only a small minority
refusing surgery. Patient follow-up in all series was
generally limited secondary to patient longevity.
Tumors that were selected for treatment were generally
small and peripheral in location. Central tumors were
avoided because of the heat-sink effect, complications
due to proximity of nearby vital structures, and the
necessity of longer needle trajectory through the aerated
lung (Pennathur et al. 2010; Steinke et al. 2005; Gilliams
and Lees 2007; Lee et al. 2003). In most series, the aim of
Table 1 Summary of current clinical studies using RFA for treatment of Stage I lung cancer
386

Author #/size LR Definition F/U Local Control Complications Survival

Patient (mn)
Pop.
Lencioni* 13/ all \ 3.5 cm, Modified RECIST using CT Scan 1 month after 15* 92% CSS Major Complications- 2 yr S-75% and
2008 median 1.7* treatment as reference drainage needed* CSS-92%
1. Large or
symptomatic
pneumo-19.7%;
2. Pleural effusion-
NSCLC and CR = complete ablation of tumor lasting one year 2.9%
Lung
Metastases Minor complications-
self-limited
1. hemorrage-2.18%
2. pneumo-20.4%
3. effusion-8.02%
Hiraki T 20/ Mean tumor CR-No contrast enhancement in entire ablation zone, 21.8 72, 63, & 63% at 1, 2, Pneumothorax-57% S-90, 84, 74 at
2007 size = 2.4 or when the ablation zone exhibited a peripheral rim and 3 years 1, 2, and
(1.3-6 cm) of contrast-enhancement that was concentric, 3 years
symmetric and uniform with smooth margins.
IA-14 Pleural effusion-17%
Stage I Progression-circumferential enlargement. Irregular, Median time for local
NSCLC scattered, nodular, or eccentric foci in the AZ progression = 9 months One chest tube CSS-100, 93, 83
only IB-6 placement-rest at 1, 2, and
conservative 3 years
treatment
Pennathur 19/2.6 Modified RECIST-Based upon CT size and mass 29 42% local progression Pneumo-63%-pigtail S-95%-1 yr,
2007 (1.6-3.8 cm) quality; higher SUV or larger area on PET Scan catheter 68%-2 yr

Stage I Median time to local Prolonged air

NSCLC progression = 27 months leak [ 5 days-5%
only
Beland* 79/2.5 LC-lack of contrast enhancement in AZ 17 57%-no recurrence* NS Median DFS
2010 (1.5-5.5 cm) 38% LR 23 months*

NSCLC 19(24%)-RT Progression-focal enhancement [ 15 HU compared 18% IP

with unenhanced series
Different 9(11%) –RT-Br 18% Nodal
Stages
(continued)
J. M. Varlotto et al.
Table 1 (continued)
Author #/size LR Definition F/U Local Control Complications Survival
Patient (mn)
Pop.
94% Stage I Benign peritumoral enhancement-Symmetric rim of 6% Mixed
peripheral enhancement of \ 5 mm up to 6 mn after
ablation

7% Stage IIIB Growth on serial CT scans-used for patients intolerant 21% DR

of contrast
R related to size and
stage;
RT and RT-br
borderline
significance for R
Lanuti 2009 31pts/2.0 Lack of focal or diffuse enlargement of ablated lesion 17.3 31.5% LR Pneumo-13% S-2 & 4 yr-78%,
(0.8-4.4 cm) on CT and no evidence of eccentric enhancement on 47%
PET with minimum of 3 mn of FU;
Stage I
NSCLC only 3 with stable Progression of FDG H&M nodes after 3 mn-local
disease failure 50% LR with Pneumonia-16% 3 yr PFS and
received RT size [ 3 cm(3/6) DFS-58%, 39%
Effusion-21%

BP fistula-8%

Chest tube-8%

Transient recurrent
nerve palsy-1%
Rossi 2006 15 LUNG Increasing size or enhancement at tumor site-using 30 Day 11.4 mn 20% LR No major 9/15 alive
Ca/2.2 ct scan, repeat procedure-if 30 day positive, then mark as complications* without disease
The Role of Radiofrequency Ablation in the Treatment of Stage 1 Non-Small Cell Lung Cancer

(1.0-3.5 cm)* failure progression

NSCLC and 13.3% IP 5pneumo-no
Lung progression drainage*
Metastases
20% EP Progression 4pneumonias*
(continued)
387
Table 1 (continued)
388

Author #/size LR Definition F/U (mn) Local Control Complications Survival

Patient
Pop.
Lee 2003 10/4.1 cm Any residual portion of lesion with 12.5 mn* 60% CR 10% major compl including mean
enhancement [ 10HU after 2 pneumo-thoracostomy; survival = 13.3 mn
contrast = viable tumor; 1ARDS*

NSCLC and Previously enhancing, but currently 40% PR

Lung unenhancing areas = necrosis;
Metastases
complete necrosis = nonenhancing Complete necrosis in all 6
area with a diameter [ initial viable tumors \ 3 cm, and in 23%(6/26)
tumor tumors [ 3 cm
Ambrogi 50(36 FU with contrast-enhanced ct scan, but 31* radiological CR-59%* 5/50-10% pneumothorax-2/ Median
2007 StageI)/ no definition of LR given 5 required pleural S = 25 mn*
NS, but drainage*
NSCLC all \ 5 cm

Different
Stages
Abbreviations
NSCLC = Non-small cell lung cancer
RECIST = Response evaluation criteria in solid tumors
CR = Complete response
CSS = Cancer specific survival
S = Survival
LR = Local recurrence
IP = Intrapulmonary recurrence
DR = Distal recurrence
DFS = Disease-free survival
Pneumo = Pneumothorax
PFS = Progression-free survival
EP = Extrapulmonary recurrence
* = Rates reported for total population of the study, not particularly for patients with Stage I NSCLC
LC = Local control
R = Recurrence
H&M nodes = Hilar and mediastinal nodes
NS = Not stated
AZ = Ablation zone
F/U = Follow-up
Mn = Months
J. M. Varlotto et al.
The Role of Radiofrequency Ablation in the Treatment of Stage 1 Non-Small Cell Lung Cancer 389

Table 2 Summary of ablate and resect studies using RFA for treatment of lung neoplasms
Author Pt # with Tumor size Time Method of Definition Response Conclusion
population stage I interval assessment of response
NSCLC
Schneider* 14 1.7–3.5 immediate Histology-HE CN 5 CN CN in 35.7%
Schneider staining
et al. 2011

NSCLC and NADH Scattered 7 Scattered High rate of

Lung (Supravital vital tissue vital tissue tumor cells
Metastases staining)- remaining
performed in IA, [ 20% after RFA
22/32 vital tissue casts doubt
procedures 2 IA, [ 20% on RFA as
vital tissue curative
Monoclonal concept
anti-
mitochondrial IA did not
Antibodies- depend
performed in whether
18/32 primary or
procedures secondary, 2/
10 primary
lung and 2/7
mets with
adenoca had
IA
Ambrogi* 9 Max size of 5/9 Histology- Absence of CN in 6/9 Mean size
Ambrogi 3.5 cm immediate H&E staining tumor cells 2.3 cm with
et al. 2006 resection; with H&E CN

NSCLC- 6-Stage I Mean size 4/9

Stage I and II 3-StageII 2.8 cm resection Mean size of
after lesion with
15 days IA = 3.1 cm
All 1 cm
away from ALL IA-no
major blood more than
vessels and 10% of
airways treated area
with viable
tumor

Margin
\5 mm in all
three cases of
IA, average
margin 8 mm
in CA
Nguyen* 8 Mean tumor Immediate Histology- Absence of CA in 3-all Routine
Nguyen et al. size = 2.2 cm resection H&E cells by \2 cm; H&E
2005 NADH IA noted in 5 staining
staining tumors, 3 of could not
which were differentiate
\2 cm viable from
NSCLC- 7-StageI NADH nonviable
Stage I and II 1-Stage II cells
CN Complete necrosis, IA Incomplete ablation, CA Complete ablation
390
treatment was to treat the tumor with a 5–10 mm margin
beyond visible tumor in all directions (Beland et al.
2010; Pennathur et al. 2010). Most investigative series in
Table 1 obtained CT scans immediately after treatment
to assess the extent of the GGA.
It is difficult to ascertain the benefit of RFA due to the
different radiologic definitions of local recurrence (LR)
and because of the short follow-up of this population of
mostly poor-prognostic, medically-inoperable patients.
Additionally, two patient series treated selected patients
with adjuvant radiotherapy (Beland et al. 2010; Lanuti
et al. 2009). As shown in Table 1, median follow-up
ranged from 15 to 31 months. This limited follow-up
prevents adequate assessment of the effectiveness of
RFA as a method to obtain durable tumor control.
Although one series noted that the median time to local
progression was only 9 months (Hiraki et al. 2007),
another series noted a much longer median time to local
progression at 27 months (Pennathur et al. 2007).
Beland et al. (2010) noted that recurrences were spo-
radically identified throughout the 2 years of follow-up
and recommended continuous close follow-up during
this time. Size was noted to be related to LR, with sizes
greater than 3 cm associated with LR in the series by
Lee et al. (2003) and Lanuti et al. (2009). Another
investigation noted that both size and stage were related
to recurrence and, in addition, that there was non-sig-
nificant trend in favor of reduced recurrences in patients
receiving external beam radiotherapy (RT) or brachy-
therapy (RT-br) (Beland et al. 2010). Nevertheless,
local progression ranges from 20 to 42% at the local
tumor site. Evaluation of treatment toxicity is rendered
difficult due to the short patient follow-up, lack of
assessment via an established toxicity scale, and the
retrospective nature of most series noted in Table 1. The
most common complications include pneumothorax
(13–63%) and pleural effusion (10–21%). Pneumonias
were reported in two of the series and occurred 16 and
26.6% of the time, respectively. Other rare, but serious
complications listed included hemorrhage, ARDS, and
bronchopleural (bp) fistula.
4.2 Ablate and Resect Studies
Results of the ablate and resect studies are listed in
Table 2. Schneider et al. (2011) reported the results of
32 patients, 14 of whom had Stage I non-small cell
lung cancer (NSCLC) and the remaining patients had
J. M. Varlotto et al.
metastatic lung tumors. The patients comprising the
series by Ambrogi et al. (2006) and Nguyen et al.
(2005) were mostly patients with Stage I NSCLC.
Complete ablation rates ranged from 35.7 to 66.7%.
The series (Ambrogi et al. 2006) with the highest rate
of complete ablation used only hematoxylin and eosin
staining (H&E), a technique that others thought was
unreliable (Nguyen et al. 2005; Schneider et al. 2011).
The series of Schneider et al. (2011) used monoclonal
anti-mitochondrial antibodies (MAM) and supravital
blue staining (SVB) in addition to routine H&E
staining. Patients with complete necrosis were
required to have no evidence of tumor by either SVB
or MAM, but it is not clear if the Stage I patients were
assessed by MAM, SVB, or both. Although the
number of patients in each series is small, it appears
that complete tumor necrosis was associated with size
in two studies (Ambrogi et al. 2006; Nguyen et al.
2005) and ablation margins in one study (Ambrogi
et al. 2006). Interestingly, Schneider et al. (2011)
noted that all four tumors with incomplete ablation
were adenocarcinomas (two metastatic colon cancer
and two primary lung cancers). Complete necrosis
and scattered vital tissue were noted in the other 15
tumors of various histologies. Past pathologic reports
have demonstrated that margins needed to encompass
95% of the primary NSCLC tumor extension were
greater for adenocarcinoma (8 mm) than squamous
cell carcinoma (6 mm) (Giraud et al. 2000). These
results suggest that adenocarcinomas, whether pri-
mary or metastatic, may require greater ablation
margins.
Although the ablate and resect studies examined
immediate tumor cell kill, RFA may be associated
with delayed tumor cell killing by stimulating the
immune system. Therefore, assessment of tumor
response by the pathologic assessment after immedi-
ate ablation may underestimate the responsiveness of
tumors to this technique. In one recent patient series
containing 14 primary and 6 metastatic lung tumors,
RFA led to an increase in neutrophils, monocytes, and
pro-inflammatory cytokines when serum was obtained
3 days after the procedure. Starting 30 days after
RFA and persisting for up to 90 days after treatment,
further serum tests demonstrated a persistent reduc-
tion in the immunosuppressive CD 25 ? Foxp3
T-regulatory cells with an increase in CD4 ?
T-cell proliferation and the number of interferon
gamma-secreting cells (Fietta et al. 2009). Similarly,
The Role of Radiofrequency Ablation in the Treatment of Stage 1 Non-Small Cell Lung Cancer
Fig. 4 a FDG-avid Stage I NSCLC presenting for RFA. b At 6 months there is complete loss of FDG avidity despite residual
mass on CT corresponding to complete tumor necrosis
RFA was associated with the elevation of tumor
antigen-specific antibodies in another patient series
(Widenmeyer et al. 2010).
5 Follow-Up
The appearances of treated lung cancer after RFA are
well documented (Bojarski et al. 2005; Yasui et al.
2004; Jin et al. 2004). The authors’ experience is to
follow tumor size and contrast-enhancement patterns
on CT Scans every 3 months for the first year and
twice a year thereafter. Loss of FDG-avidity at
6 months on CT/PET can be used to confirm the
absence of tumor when a residual mass is noted on CT
scan (Fig. 4a–b).
Immediate CT following RFA demonstrates GGA
surrounding the tumor in 84% of cases and represents
pulmonary bleeding and/or increased blood flow.
Within 1 week, the GGA changes to dense opacity
(Yasui et al. 2004). As noted previously, successful
treatment is usually associated with a larger ablation
zone than the original tumor size (Yamamoto et al.
2005) (Fig. 5). The ablation zone usually remains
larger during the first 3 months following the RFA
procedure. During this time period, transient and
reversible locoregional nodal enlargement can some-
times be appreciated (Sharma et al. 2010). After
3 months, continued increase in growth of the abla-
tion zone should be viewed as suspicious for incom-
plete tumor destruction and recurrent tumor (Bojarski
et al. 2005). Successful treatment is associated with
391
progressive contraction of the lesion and resolution of
any pleural changes distal to the immediate ablation
zone, as well as loss of contrast enhancement of the
lesion. A thin (\5 mm) pattern of peripheral/rim
enhancement, corresponding to reactive hyperemia, is
also associated with successful treatment (Anderson
et al. 2009). Cavities develop within the ablation zone
in up to 20–58% of patients and are more commonly
seen in lesions that significantly enlarge by more than
200% from their original size (Fig. 6). Most patients
with cavities have no specific symptoms, and the
cavities usually spontaneously contract with time
(Okuma et al. 2007; Steinke et al. 2003). Other
reactive CT findings that are considered to be benign
include bubble lucencies and pleural thickening
within or near the ablation zone (Pennathur et al.
2007). When pleural effusions occur, they are usually
self-limiting, but can show FDG avidity (Higaki et al.
2008).
The use of FDG-PET may prove to be a predictive
test for treatment failure or success. Higaki et al.
(2008) suggest that immediate FDG PET with resid-
ual activity before inflammation develops is likely to
predict residual disease. Later assessment can dem-
onstrate three basic patterns as follows:
(1) A diffuse increase followed by continued
decreasing activity.
(2) Little change with sub-pleural lesions and rim
activity followed by a collapse of the lesion with
decreasing focal activity over time.
(3) Immediate residual activity or eccentric residual
activity invariably showing progression over time.
392 J. M. Varlotto et al.

Fig. 5 Sequential CT scan following RFA of NSCLC. Site of tumor initially enlarges, followed by progressive contraction in
volume and changing shape over time. Note initial pleural thickening subsequently resolves
The Role of Radiofrequency Ablation in the Treatment of Stage 1 Non-Small Cell Lung Cancer 393

Fig. 6 Small 7 mm squamous cell lung cancer. Note larger GGA with cavitary complication which progressively contracts

effusion, occurring in 13–63% and 10–21%, respec-

6 Summary
Since the first published report of modern percuta-
neous RFA for the treatment of lung neoplasms in
2000, a number of largely retrospective studies have
demonstrated local control rates of 58–80%, with
median follow-ups of 15–31 months. The primary
complications of RFA are pneumothorax and pleural
tively. RFA is most effective with peripheral lesions
due to less concern for the heat-sink effect and due to
the lower likelihood of complications. Prospective
trials with careful long-term follow-up assessing diff-
erent radiologic definitions of local control and using
a known toxicity scale (i.e. common terminology
criteria for adverse events (CTCAE v4.0)) are greatly
needed.
394
Due to the ability of SBRT to control greater 90% of
primary tumors (Timmerman et al. 2010) and because
this technique does not require hospitalization, most
medically inoperable Stage I NSCLC patients are
treated with SBRT at Penn State Hershey Cancer
Institute. Central-based tumors within 2 cm of the
proximal bronchial tree (Timmerman et al. 2006) are
preferentially treated on RTOG 0813. RFA is consid-
ered for small (\1 cm) peripheral tumors in patients
with limited prognosis due to the limitations of SBRT
including field dimensions of at least 3.5 cm (due to the
loss of electronic equilibrium with small beam aper-
tures) and possible greater incidence of rib pain. RFA
is also considered for the rare patients experiencing
primary tumor failure after SBRT.
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 Lung Dose Escalation
Bradford S. Hoppe and Kenneth E. Rosenzweig

Contents
1 Introduction.............................................................. 400
2 Reducing Target Volumes ...................................... 400
3 Reducing Normal-Tissue Irradiation .................... 401
4 Early Studies ............................................................ 401
5 Radiation Dose Intensification Alone .................... 401
6 Dose Escalation with Concurrent
Chemotherapy .......................................................... 404
7 Current Status of Dose Escalation ........................ 407
8 Conclusions ............................................................... 407
References.......................................................................... 407
Abstract
RTOG 73-01 established standard doses of radia-
tion for the treatment of patients with stage III
non-small-cell lung cancer at 60 Gy in 2 Gy per
fraction. However, overall survival was still poor,
and local failures were a continuing problem. Over
the next 30 years, a number of single institution
and multi institution studies have been performed,
attempting to improve overall survival by reducing
local failures through radiation dose escalation
either alone or in combination with chemotherapy
with promising results. Additionally, new technol-
ogy has been developed that can improve tumor
imaging, deliver more conformal RT with less
dose to normal structures, and decreased the set-up
uncertainties, which has increased the therapeutic
ratio and now allows for even safer dose escala-
tion. The present chapter reviews these studies and
discusses the current status of radiation dose
escalation for patients with stage III NSCLC.

Abbreviations

RTOG Radiation Therapy Oncology Group

NSCLC Non-small-cell lung cancer
RT Radiation therapy
B. S. Hoppe (&) Gy Gray
University of Florida Proton Therapy Institute,
SEER Surveillance, epidemiology and end
2015 North Jefferson St, Jacksonville,
FL 32206, USA result
e-mail: bhoppe@floridaproton.org CT Computed tomography
K. E. Rosenzweig FDG-PET Fluorodeoxyglucose positron emission
Mount Sinai School of Medicine, tomography
One Gustav L. Levy Place, Box 1236, GTV Gross tumor volume
New York, NY 10029, USA

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 399
DOI: 10.1007/174_2011_298, Ó Springer-Verlag Berlin Heidelberg 2011
400 B. S. Hoppe and K. E. Rosenzweig

ENI Elective nodal irradiation radiation delivery systems, and a better understanding
CTV Clinical tumor volume of the relationship between radiation dose-volume
PTV Planning target volume histograms of critical organs and treatment-related
kV Kilovoltage morbidity. As a result, safe dose escalation over
3D Three-dimensional 60 Gy is now more feasible (even with larger tumors)
4D Four-dimensional and a major focus of current clinical research studies.
PT Proton therapy
IMRT Intensity-modulated radiation therapy
BID Twice daily 2 Reducing Target Volumes
MTD Maximum tolerated dose
MSKCC Memorial Sloan–Kettering Cancer Target volumes have reduced over the last 20 years
Center due to reductions in: (1) gross tumor volume (GTV),
UM University of Michigan because of improved imaging, (2) clinical target
NKI Netherlands Cancer Institute volume (CTV), because of the elimination of elective
UNC University of North Carolina nodal irradiation, and (3) planning target volume
3D-CRT Three-dimensional conformal (PTV), because of reduced set-up uncertainty from
radiotherapy new imaging and immobilization techniques.
NTCP Normal-tissue complication probability Although computed tomography (CT) scanners
DVH Dose-volume histogram have been in use since 1973, it took close to 20 years
Veff V effective for them to become integrated into RT treatment
rMLD Relative mean lung dose planning. CT scans provide three-dimensional (3D)
CALGB Cancer and Leukemia Group B information regarding tumor volume as well as
NCCTG North Central Cancer Treatment Group demonstrate enlarged and pathologic lymph nodes.
An analysis based on surveillance, epidemiology and
end result (SEER) data showed that between 1994 and
2005, the use of CT-based simulation for the treat-
ment of thoracic malignancies increased from
1 Introduction 2.4 to 77.6%. Patients who had CT-based simula-
tion also had an improved survival as compared to
Poor outcomes in patients with unresectable non- patients who received conventional simulation
small-cell lung cancer (NSCLC) have been attrib- (Chen et al. 2011).
uted, in part, to low rates of local control with Over the last decade, fluorodeoxyglucose positron
traditional doses of definitive radiotherapy (RT). emission tomography (FDG-PET) imaging has also
Overall survival rates in NSCLC are expected to been used in conjunction with CT to aid in identifying
improve with better local control rates, which is malignant lymph nodes that were not enlarged
possible with higher radiation-dose levels. Unfortu- (negative on CT scan) and aid in separating the actual
nately, the therapeutic ratio for treating lung cancer tumor from atelectasis due to obstruction from the
with radiation has traditionally been small, due to tumor. Thus, GTVs have become easier to identify
the sensitivity of the lung and resulting pneumonitis and areas of uncertainties that were previously
and esophagitis with higher radiation doses. Thus, included in the GTV can now be more safely
dose escalation in patients with NSCLC has histor- eliminated.
ically been a double-edged sword with improved Historically, elective nodal regions have been
local control rates with higher doses, but corre- irradiated to doses of 45–50 Gy as part of the target
spondingly higher treatment-related morbidity and volume in patients with NSCLC. However, following
mortality. various series identifying distant and local relapses as
Over the last 20 years the therapeutic ratio of RT the primary sites of relapse, researchers began to
for NSCLC has widened due to reduced normal lung selectively eliminate the traditional elective nodal
tissue treated with high doses of radiation through a sites (Bradley et al. 2005; Rosenzweig et al. 2007;
reduction in the target volume, more sophisticated Hayman et al. 2001). Elimination of these elective
Lung Dose Escalation
nodal sites considerably reduces irradiation to normal
tissue, which can significantly impact treatment
morbidity and mortality. In a phase III study from
China (Yuan et al. 2007), patients were randomized to
concurrent chemoradiation and either elective nodal
irradiation (ENI) with 60–64 Gy of RT or no ENI and
higher doses of RT (68–74 Gy). The group that
received ENI demonstrated higher rates of pneumo-
nitis (29 vs. 17%; p = 0.044), while better 2 year
overall survival rates were found in the group treated
with higher doses and no ENI (39.4 vs. 25.6%;
p = 0.048). As a result, most thoracic radiation
oncologists are eliminating ENI from their treatment
plan.
CTV and PTV margins in lung cancer treatment
have been reduced due to several innovations. Mar-
gins for daily set-up errors have been minimized
through patient-specific immobilization devices,
which, compared to no immobilization, are able to
more accurately reproduce patient positioning at the
time of simulation. Additionally, daily cone-beam CT
scans or orthogonal kV imaging allows for the repo-
sitioning of patients according to internal anatomy or
the actual tumor, thereby significantly reducing the
margins allotted for set-up errors compared with skin
marks alone (Yeung et al. 2009). Lastly, with the use
of respiratory gating systems and 4D-CT scans, tumor
motion can be objectively measured and accounted
for, which can lead to smaller margins.
3 Reducing Normal-Tissue
Irradiation
Three-dimensional treatment planning became pos-
sible when CT scans were integrated into radiation
treatment planning, allowing for more complex plans
that better spared normal tissue and improved target
coverage. Further improvements in target coverage
and reductions in irradiated normal tissue have been
achieved with the implementation of more conformal
radiation delivery systems, including intensity-
modulated radiotherapy (IMRT), image guidance, and
proton therapy (PT) (Sura et al. 2008; Bral et al. 2010;
Sejpal et al. 2011). These techniques are discussed in
more detail in other chapters.
Studies evaluating dose escalation in NSCLC dis-
cussed in this chapter must be considered in the
context of the limitations in technology and patient
401
set-up when the trial is under investigation. Most of
the current technologies used by treating physicians to
reduce both the dose to normal structures and the
margins of uncertainty in tumor delineation and set-
up have only been included in the most recent studies
that are now under investigation.
4 Early Studies
Radiation Therapy Oncology Group (RTOG) trial
73-01 (Perez et al. 1980) was one of the first dose
escalation studies. It not only established 60 Gy at
2 Gy per once-daily fraction as the standard of care
for unresectable NSCLC, it also pointed out glaring
problems in the management of NSCLC that required
further investigation. The study randomized 376
patients with T1-3 N0-2 NSCLC to either 40 Gy split
course (20 Gy at 4 Gy per fractions followed by a
break followed by another 20 Gy at 4 Gy per frac-
tion), 40 Gy at 2 Gy per once-daily fraction, 50 Gy at
2 Gy per once-daily fraction, or 60 Gy at 2 Gy per
once-daily fraction. Radiation techniques were two-
dimensional (2D) and treatment fields included full
elective nodal irradiation. Intrathoracic relapses for
40 Gy split, 40, 50, and 60 Gy were 44, 52, 42, and
33%, respectively. Overall survival rates also
improved with increasing radiation-dose levels at 24
and 30 months. However, severe or life threatening
toxicity developed more frequently in the 60 Gy arm
with 14% compared with 5% of patients getting 50 Gy,
7% of patients getting 40 Gy, and 13% in the 40 Gy
split course. The study determined that 60 Gy should
be the standard radiation treatment dose with which
to compare future studies. Although higher doses were
found to be associated with better outcomes, patients
in both groups had high rates of extra-thoracic and
unirradiated lung relapses. Thus, treatment intensifi-
cation was needed to improve outcomes.
5 Radiation Dose Intensification
Alone
RTOG 83-11 (Cox et al. 1990) was a phase I/II
hyperfractionation dose escalation study that ran-
domized 884 patients with inoperable NSCLC to
either 60, 64.8, 69.6, 74.4, or 79.2 Gy at 1.2 Gy per
twice-daily (BID) fraction. The study took advantage
402
of the theoretical benefit of hyperfractionated radia-
tion to improve the therapeutic ratio, allowing for
safer dose escalation. Radiation was delivered to the
entire mediastinum, ipsilateral hilum, and contralat-
eral hilum to 50.4 Gy followed by a boost to the
primary lung cancer. Although rates of significant
toxicities were similar amongst the different radiation
dose arms, overall survival rates for the entire cohort
were not significantly affected by radiation dose
either. In a subgroup of good performance status
patients, however, a survival advantage was seen at
12 and 24 months with radiation doses of 69.6 Gy
or higher (p = 0.07), but there were no further
improvement in doses above 69.6 Gy. Comparing
these results to RTOG 83-21, for which patients were
randomized to standard radiation of 60 Gy at 2 Gy
per daily fraction with or without thymosin, a survival
advantage appeared likely with the hyperfractionated
dose intensification of 69.6 Gy (median survival of
8 months with 60 Gy at 2 Gy per daily fraction
compared with 13 months with hyperfractionation).
Based on the results of RTOG 83-11 and those
from the Cancer and Leukemia Group B (CALGB)
trial 84-33, which demonstrated a survival advantage
to induction chemotherapy prior to standard 60 Gy at
2 Gy per once-daily fraction (Dillman et al. 1996), the
RTOG developed protocol 88-08. RTOG 88-08 ran-
domized 498 patients with stage II–IIIB NSCLC with
good performance status and \5% weight loss to
60 Gy at 2 Gy per once-daily fraction, 69.6 Gy at
1.2 Gy per BID fraction, or induction chemotherapy
of cisplatin and vinblastine followed by 60 Gy at
2 Gy per once-daily fraction (Sause et al. 1995). RT
was delivered with ENI to 50.4 Gy, followed by a
boost to the primary disease and lymph nodes
[2.5 cm in diameter as seen on pretreatment CT
scan. The results showed a median survival of
11.4 months with 60 Gy of radiation alone and a
marginal benefit with hyperfractionated radiation to
69.6 Gy with a median survival of 12 months.
Importantly, induction chemotherapy followed by
60 Gy had a median survival of 13.2 months, thus
establishing a new standard of care for good perfor-
mance patients with stage III NSCLC. Interestingly,
when the pattern of relapses in this study was evalu-
ated, the RTOG failed to identify any improvements
in local control with induction chemotherapy, despite
the improvement in overall survival (Komaki et al.
1997). This finding elucidated the complexity of
B. S. Hoppe and K. E. Rosenzweig
identifying local relapses in patients with lung cancer
treated with RT.
Following this study, RTOG 93-11 evaluated dose
escalation using once-daily doses of 2.15 Gy per
fraction (without inhomogeneity corrections) to find
the maximum tolerated dose (MTD) (Bradley et al.
2005). The study allowed patients who had received
induction chemotherapy (*20%) and included 50%
of patients with stage I disease and 50% with stage
II–IIIB disease. This trial was based on previous data
that correlated radiation pneumonitis with the volume
of lung receiving 20 Gy (Graham et al. 1999) and
placed 179 patients into one of three dose escalation
groups based on the lung V20. Patients with a lung
V20 \ 25% received escalating doses to 70.9, 77.4,
83.8, and 90.3 Gy, while patients with a V20 between
25 and 36% received escalating doses to 70.9, 77.4,
and 83.8 Gy. Furthermore, ENI was eliminated and
all patients underwent CT-based treatment planning
with the GTV delineating the tumor and enlarged
lymph nodes [1 cm and a 1 cm GTV to PTV margin
expansion. The results from the study demonstrated
that doses for patients with a V20 \ 25% could be
safely escalated to 83.8 Gy with 15% rates of sig-
nificant pulmonary toxicity at doses greater than
77.4 Gy. In addition, those patients with a V20
between 25 and 36% could be escalated to 77.4 Gy
with 15% rates of pulmonary toxicity after doses
greater than 70.4 Gy. Although dose did not affect
local–regional control or overall survival, the authors
point out that those outcomes were not the main
objective of the study with only a few patients on
each of the many arms. Local–regional control still
remained a problem despite these higher doses of
radiation: the overall rate of relapse was 38 and 18%
of patients experienced only a local failure. The
limited number of isolated regional failures (\10%)
confirmed that nodal relapses were rare and that ENI
could be excluded without negatively impacting dis-
ease control or overall survival. Due to the results
from this study and data emerging from other trials
evaluating concurrent chemotherapy and RT, the next
stage of RTOG studies would involve radiation dose
escalation with concurrent chemotherapy.
Memorial Sloan–Kettering Cancer Center
(MSKCC; New York, NY), University of Michigan
(UM; Ann Arbor), and The Netherlands Cancer
Institute (NKI; Amsterdam) performed their own
single institution dose escalation studies (Table 1).
Lung Dose Escalation 403

Table 1 Phase I dose escalation studies

Study/ RT ENI Chemotherapy Lung constraint # Of Lowest Highest MTD
Author technique patients dose (Gy) dose (Gy) (Gy)
UM 3D-CRT No Induction (*20%) Veff (0.32–0.4) 21 63 69 65.1
Veff (0.25–0.31) 18 63 75.6 75.6
Veff (0.19–0.24) 22 65.1 84 84
Veff (0.13–0.18) 20 69.3 102.9 102.9
Veff (0–0.12) 11 84 102.9 102.9
MSKCC 3D-CRT No Induction (16%) NTCP \ 25% 104 70.2 90 84
RTOG 3D-CRT No Induction (*15%) V20 \ 25% 127 70.9 90.3 83.8
9311
V20 (25–37%) 48 70.9 77.4 77.4
NKI 3D-CRT No Induction (18%) Veff (0.32–0.4) 3 60.75 60.75 60.75
Veff (0.25–0.31) 16 74.25 81 74.25
Veff (0.19–0.24) 23 74.25 87.75 81
Veff (0.13–0.18) 22 74.25 87.75 81
Veff (0–0.12) 24 81 94.5 94.5
China 3D-CRT Yes Induction and Adjuvant V20 \ 25% 15 72 78 78
V20 (25–37%) 20 72 78 78
V20 [ 37% 15 69 75 75
Carolinas 3D-CRT Yes Induction V35 \ FEV1*35 44 73.6 86.4 80
RTOG 3D-CRT No Concurrent V20 \ 30% 17 74 75.25 74
0117
UNC1 3D-CRT Yes Induction and V20 \ 35% 29 60 74 74
Concurrent
UNC2 3D-CRT Yes Induction and V20 \ 35% 29 78 90 90
Concurrent
NCCG 3D-CRT No Concurrent V20 \ 40% 15 70 78 74

From 1991 to 2003, MSKCC enrolled 104 patients,
including 28% with stage I/II NSCLC and 68% with
stage III NSCLC, on a three-dimensional conformal
radiotherapy (3D-CRT) study (Rosenzweig et al.
2005). Patients were included even if they received
induction chemotherapy (16%) and radiation was
delivered at 1.8 Gy once-daily fractions up to 81 Gy
and then at 2 Gy once-daily fractions for higher doses
with a dose escalation scheme of 70.2, 75.6, 81, 84,
and 90 Gy (for smaller tumors only). The objective of
the study was to determine the MTD of 3D-CRT for
patients with NSCLC. ENI was included for the first
20 patients treated to 70.2 Gy; however, three of these
patients developed severe toxicity (two grade 3 and
one grade 5 pneumonitis), resulting in protocol
modifications. Subsequently, the target volume elim-
inated ENI and included the GTV to PTV margin
between 10 and 15 mm. Furthermore, the protocol
incorporated lung DVH data to ensure that the nor-
mal-tissue complication probabilities (NTCP) were
limited to \25%. The dose was escalated and the
MTD exceeded 90 Gy. Thus, 84 Gy was determined
to be the MTD with only 1 of 21 patients developing a
severe toxicity. Although this was a phase I study,
dose was analyzed in relation to local control and
overall survival. The investigators found that with
doses of [80 Gy, overall survival was improved in
patients with stage I/II disease (p = 0.05) and in
patients with stage III disease (p = 0.02). Further-
more, local control was improved with doses [80 Gy
(88%) compared with doses \80 Gy (14%).
UM’s phase I dose escalation study utilized lung
DVH data to stratify patients into one of five separate
dose escalation groups (Hayman et al. 2001; Narayan
404
et al. 2004). Dose escalation would begin at 84 Gy and
end at 102.9 Gy with Veff \ 12% (bin 1), begin at
69.3 Gy and end at 102.9 Gy with a Veff of 0.13–0.18
(bin 2), begin at 65.1 Gy and end at 92.5 Gy with a Veff
of 0.19–0.24 (bin 3), begin at 63 Gy and end at 92.4 Gy
with a Veff of 0.25–0.31(bin 4), or begin at 63 Gy and
end at 84 Gy with an NTCP[ 31% (bin 5). The target
volume included the gross tumor and any lymph nodes
[1 cm on CT, which was then expanded to 0.5 cm
include the CTV. The PTV was created by expanding
the CTV between 0.5 and 1 cm. The study enrolled 104
patients, including 25 who received induction chemo-
therapy (allowed after 1997). The study results deter-
mined an MTD of 65.1 Gy in patients in bin 5, while
they were 102.9, 102.9, 84, and 75.6 Gy for bins 1, 2, 3,
and 4, respectively. Interestingly, in those patients who
completed their prescribed radiation, the median sur-
vival for stage I/II patients was 20 months and for stage
III patients it was 16 months. Although most relapses
occurred distantly (52%), 34% of the relapses did occur
within the PTV alone. Eliminating the ENI did not
appear to affect outcomes given there were no isolated
failures in the regional nodes, although three patients
relapsed in nodal regions simultaneously with local or
distant failures.
From 1998 to 2003, 88 patients were enrolled in a 3D-
CRT study by the NKI in a phase I/II dose escalation trial
(Belderbos et al. 2006). Similar to the UM study, patients
were separated into one of five risk groups based on their
relative mean lung dose (rMLD). Induction chemo-
therapy was allowed (18%) and the GTV was expanded
1–2 cm to create the PTV. No ENI was delivered.
3D-CRT was restricted to 6 weeks with a fixed frac-
tion size of 2.25 Gy per fraction. If more than 30
fractions were needed, BID radiation was given. Group 1
(rMLD = 0–0.12) included only stage I (n = 19) or II
(n = 5) patients started at 81 Gy and was safely esca-
lated to 94.5 Gy. Group 2 (rMLD = 0.12–0.18) and
Group 3 (rMLD = 0.18–0.24) started at 74.25 Gy and
went up to 87.75 Gy, but the MTD was reached at
81 Gy. Group 4 (rMLD = 0.24–0.31) started at
74.25 Gy and was escalated to 81 Gy, but the MTD was
reached at 74.25. Group 5 (rMLD = 0.31–0.4) only
enrolled three patients and was safely treated to
60.75 Gy. Although dose could safely be escalated using
3D-CRT, no advantage to a higher dose was found in any
group aside from Group 1. In this study, eliminating ENI
resulted in few nodal failures and the local–regional
failure rate was 28%.
B. S. Hoppe and K. E. Rosenzweig
CALGB 39904 was a prospective trial that asses-
sed accelerated, once-daily radiation therapy for early
stage NSCLC (Bogart et al. 2010). The total dose of
radiation remained at 70 Gy, but the dose per fraction
increased and the number of fractions decreased with
each dose escalation level. The final cohort treated
patients with 4.11 Gy per day for 17 fractions. The
major response rate was 77% and the median survival
was a favorable 38.5 months.
The Carolina Conformal Therapy Consortium per-
formed a phase I study from 1997 to 2002 of 44 patients
with stage III NSCLC who were given induction che-
motherapy with carboplatin/paclitaxel or carboplatin/
vinorelbine followed by accelerated hyperfractionated
3D-CRT. Radiation targets included the
GTV ? 0.5 cm for the CTV and another 0.5 cm for the
PTV. ENI was delivered at 1.25 Gy BID to a total dose
of 45 Gy, while the PTV got 1.6 Gy BID to escalated
doses of 73.6, 80, and 86.4 Gy. The results demon-
strated an MTD of 80 Gy, regardless of the chemo-
therapy used. Despite ENI in this study, there were still
two regional failures in the 45 Gy region and five local
failures in the high-dose region.
Another study evaluating induction chemotherapy
followed by radiation dose escalation came from
Fudan University (Shanghai, China). In this study, 50
patients with stage II/III NSCLC were enrolled and
divided into one of three groups based on their V20
(\25, 25–37, and [37%). Mitomycin, vindesine, and
cisplatin were given as induction chemotherapy and
then as adjuvant chemotherapy following RT. Dose
escalation started at 69 Gy in each arm and continued
to 78 Gy at 3 Gy per fraction increments. The radi-
ation volume included ENI to 42 Gy followed by a
boost to the GTV with a 1–1.5 cm margin. The MTD
was 78 Gy for the two groups with a lung V20 \ 37%
and it was 75 Gy in the group with a V20 [ 37%.
Unfortunately, despite this dose escalation with
induction chemotherapy, the 2 year local–regional
progression-free survival was 41%, leaving room for
improvement.
6 Dose Escalation with Concurrent
Chemotherapy
A number of studies have evaluated concurrent che-
moradiation for locally advanced NSCLC. The RTOG
began its chemoradiation studies with RTOG 88-04,
Lung Dose Escalation
which was a phase II study evaluating induction
cisplatin and vinblastine followed by concurrent
cisplatin with once-daily RT to 60 Gy. This was
followed up by RTOG 90-15 with concurrent cisplatin
and vinblastine with dose escalation using hyper-
fractionated RT to 69.6 Gy. Due to the excessive rate
of hematologic toxicity in that study, it was subse-
quently followed up by RTOG 91-06, a study evalu-
ating a less aggressive chemotherapy, concurrent
cisplatin with daily etoposide with BID RT to
69.6 Gy. Due to the promising results from 88-04 and
91-06, a phase II randomized trial, RTOG 92-04, was
performed comparing these two regimens (Komaki
et al. 2002). This study demonstrated reduced in-field
relapse rates with the RT dose escalation to 69.6 Gy
BID, but also a significantly increased risk of early
and late esophagitis with this treatment arm.
RTOG 94-10 randomized 595 patients with stage
II–III NSCLC to the newly established gold standard:
induction chemotherapy followed by 60 Gy at 2 Gy per
fraction (arm 1; similar to CALGB 84-33 and RTOG
88-08), to concurrent chemotherapy and 60 Gy at 2 Gy
per fraction (arm 2), and to concurrent chemotherapy
with RT dose escalation to 69.6 Gy at 1.2 Gy per BID
fraction (arm 3). Chemotherapy consisted of cisplatin
100 mg/m2 and vinblastine 5 mg/m2 on days 1 and 29
in the daily RT arms, while the third arm of BID RT
received cisplatin 50 mg/m2 on days 1, 8, 29, and 36,
and oral etoposide to 50 mg given BID for 10 weeks.
RT was delivered using 2D techniques to large treat-
ment volumes including the elective nodal regions. The
primary objective of the trial was to evaluate whether
concurrent chemotherapy and RT had a better overall
survival than induction chemotherapy followed by RT.
Additionally, it was evaluating whether RT dose
escalation to 69.6 Gy given BID concurrently with
chemotherapy would be better than concurrent che-
moradiation to 60 Gy. Although the results have never
been formally published as a manuscript, data reported
in an abstract, demonstrated median survivals of 14.6,
17, and 15.2 months for arms 1, 2, and 3, respectively
(Curran 2000). Although the study confirmed that
concurrent chemoradiation was better than induction
chemotherapy followed by RT, it did not demonstrate
improvement with RT dose intensification to 69.6 Gy
BID over 60 Gy daily in overall survival. However,
it did demonstrate improved local–regional control
with the more intensified RT: 34% compared with
43% in the concurrent chemotherapy arm to 60 Gy.
405
The local–regional control is thought to have not
translated into improved overall survival rates because
of the increased 68% grade 3+ nonhematologic toxicity
experienced in the RT dose intensification arm com-
pared with 48% in arm 2. The investigators thus con-
cluded that with crude 2D-RT techniques and large
treatment volumes, RT dose intensification above
60 Gy was not possible. Other investigators have
confirmed the improvement in overall survival dem-
onstrated with concurrent chemoradiation.
Although RTOG 94-13 failed to demonstrate an
improvement in survival with concurrent chemother-
apy and dose escalation to 69.6 Gy BID compared with
63 Gy given once a day, data emerging from RTOG
93-11 demonstrated the ability to safely dose escalate
through the use of 3D-CRT and the elimination of ENI.
Thus, RTOG 0117 was developed to evaluate dose
escalation with concurrent chemotherapy utilizing
modern RT techniques. (Table 2) In the phase I portion
of the study, 17 patients with stage I–IIIB NSCLC
were enrolled with treatment consisting of weekly
paclitaxel 50 mg/m2 and carboplatin area under the
concentration (AUC) of two given concurrently with
escalating doses of RT. Initially, patients were to
receive 75.25 Gy at 2.15 Gy per fraction, 80.5 Gy at
2.3 Gy per fraction, 79.5 at 2.65 Gy per fraction, and
75 Gy at 3 Gy per fraction; however, because of
excessive toxicity at the first dose level, the dose
changed to 74 Gy at 2 Gy per fraction. All patients
received 3D-CRT and the target volume was similar to
RTOG 93-13. Patients were also required to have a lung
V20 \ 30%, mean esophagus dose \34 Gy, and an
esophageal V55 of \30%. Due to excessive toxicity in
the 75.25 Gy arm, the study was de-escalated to 74 Gy,
at which acceptable toxicity occurred with only one
grade 4 event in seven patients (Bradley et al. 2010).
The phase II portion of RTOG 0117 borrowed the
74 Gy arm at 2 Gy per fraction from the phase I portion
(n = 9) and enrolled another 46 patients. The results
demonstrated a median survival of 21.6 months for
patients with stage III NSCLC, which compared quite
favorably to the concurrent chemoradiation arm to
63 Gy from RTOG 9410 (17 months). Furthermore,
only 12 patients experienced grade 3 or higher lung
toxicity and 21 patients experienced grade 2 or higher
esophagitis (Bradley et al. 2010).
While RTOG 0117 included dose escalation with
concurrent chemotherapy, the North Central Cancer
Treatment Group (NCCTG) and the University of
406 B. S. Hoppe and K. E. Rosenzweig

Table 2 RTOG non-small cell lung cancer studies

Study/ Patients RT dose RT ENI Chemotherapy Median Acute (%) Late (%)
Author technique OS Grade 3/4/5 toxicity
non-hematologic
RTOG 7301 97 40 Gy split 2D Yes None 9.3 13
103 40 Gy 10 7
91 50 Gy 11 6
85 60 Gy 12 14
RTOG 83-11 83 60 Gy BID 2D Yes None 9.2 7.0 8.6
127 64.8 Gy BID 6.3 13.0 5.7
220 69.6 Gy BID 10 10.0 8.5
211 74.4 Gy BID 8.7 12.0 7.0
207 79.2 Gy BID 10.5 11.0 10.7
RTOG 88-08 60 Gy 2D Yes None 11.4 NA NA
60 Gy Yes Induction 13.8 NA NA
69.6 Gy BID Yes None 12.3 NA NA
RTOG 9204 81 63 Gy 2D Yes Induction and 16.4 35.0 25.0
concurrent
81 69.6 Gy BID 2D Yes Concurrent 15.5 54.0 40.0
RTOG 9410 201 60 Gy 2D Yes Induction 14.6 NA NA
201 60 Gy Concurrent 17 48.0 NA
193 69.6 Gy BID Concurrent 15.2 68.0 NA
RTOG 0117 55 74 Gy 3D No Concurrent 21.6 61.0 22.0

North Carolina (UNC; Chapel Hill) conducted their
own protocols investigating dose escalation with
concurrent chemotherapy. The NCCTG 0028 was a
phase I study where 15 patients with unresectable
NSCLC underwent dose escalation from 70 to 78 Gy
in 4 Gy increments. RT was delivered using 3D-CRT,
limiting the lung V20 \ 40%, and no ENI was
delivered. The results found the MTD to be 74 Gy in
combination with weekly carboplatin (AUC 2) and
pacilitaxel (50 mg/m2), which were consistent with
the findings of RTOG 0117.
Between 1996 and 1999, 62 patients were enrolled
on a phase I/II study conducted by UNC that
included stage III NSCLC (Rosenman et al. 2002).
Patients received induction chemotherapy (carboplatin/
paclitaxel) followed by concurrent weekly carboplatin/
paclitaxel with escalating 3D-CRT doses from 60 to
74 Gy. ENI was performed to doses between 46 and
50 Gy. A generous margin of at least 1.5 cm was gen-
erated to create the PTV. The first 29 patients comprised
the phase I arm of the study. On this arm, dose escalation
began at 60 Gy and was followed by doses of 66, 70, and
74 Gy. Once 74 Gy had been reached and was deter-
mined to be safe (there was only one case of grade 3
esophagitis), the phase II component began, with the
enrollment of an additional 33 patients to receive 74 Gy.
The median survival was 24 months with only 8 patients
(13%) developing local–regional relapse as the only
site of failure, although 35% of patients had a local
failure as a component of their relapse. RTOG grade 3/
4 esophgagitis developed in only five patients (8%) and
no grade 3/4 pneumonitis developed.
Considering the promising results of their dose
escalation study, UNC developed a follow-up study
that escalated the radiation dose from 78 Gy to 82, 86,
and 90 Gy (Fried et al. 2004). Twenty-nine patients
were enrolled in this study and all patients received
induction chemotherapy consisting of carboplatin
(AUC = 5), irinotecan (100 mg/m2), and paclitaxel
(175 mg/m2) followed by concurrent chemotherapy
Lung Dose Escalation
(carboplatin AUC 2 and paclitaxel 45 mg/m2 weekly).
Although 3D-CRT was used for radiation treatment
planning, the study also included ENI to doses between
40 and 50 Gy. The study safely escalated the dose from
78 to 90 Gy without reaching the MTD. Acute grade 3
esophagitis developed in 16% of patients. Late toxici-
ties consisted of one patient with grade 3 pneumonitis
that resolved and two patients with fatal hemoptysis.
7 Current Status of Dose Escalation
Due to the successes with RTOG 0117, NCCTG0024,
and the UNC dose escalation studies, RTOG currently
has a randomized controlled trial, RTOG 0617, to
confirm the benefits of radiation dose escalation with
concurrent chemotherapy. The study, which is cur-
rently ongoing, is a 2 9 2 study on which patients
with stage III NSCLC are randomized to between 60
and 74 Gy of radiation with concurrent weekly pac-
litaxel and carboplatin with or without cetuximab.
The study’s main objective is to evaluate for
improved overall survival and is aimed at enrolling
500 patients. Radiation is being given on the study
either by 3D-CRT or IMRT and ENI is not being
delivered. Patients on this study will be undergoing
PET-CT scan as part of their staging. An important
aspect of this study is its use of some of the most up-
to-date radiation delivery systems (i.e., IMRT) and
imaging scans (i.e., PET-CT scan) available. Thus,
the study results will be highly relevant to the future
direction of cooperative groups.
8 Conclusions
Safer dose escalation with RT beyond standard doses of
radiation established by RTOG 73-01 has been possible
with advances in imaging and radiation technology.
Higher doses of radiation, even with the omission of
ENI, appear to improve local–regional control; how-
ever, overall survival and distant metastases remain a
huge problem. Although dose escalation with concur-
rent chemotherapy has been possible, outcomes from
phase I and II studies have not been confirmed in a
phase III study. The current RTOG 0617 study is
addressing these critical issues in a randomized con-
trolled trial while also investigating one of the newest
targeted agents in lung cancer: cetuximab. Results from
407
this study should guide researchers towards the next
step in phase I and II studies for NSCLC.
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 Radiochemotherapy in Locally Advanced
Non-small-Cell Lung Cancer
Branislav Jeremić, Francesc Casas, and Asuncion Hervas-Moron

Contents Abstract
Locally advanced nonsmall cell lung cancer is one
1 Introduction.............................................................. 409 of the major battlegrounds in clinical research in
2 Radiation Therapy Alone ....................................... 410 lung cancer due to opportunities for all the treatment
options to be employed either alone or in various
3 Neoadjuvant (Induction) Chemotherapy
Followed by Radiation Therapy ............................ 412 combinations in both curative and palliative setting.
In curative setting, though, recent evidence recon-
4 Concurrent Radiochemotherapy............................ 415
firms advantage of concurrent radiochemotherapy
5 Neoadjuvant (Induction) Chemotherapy over other existing treatment options. It is expected
Followed by Radiation Therapy Versus that with novel radiotherapy technologies and new
Concurrent Radiochemotherapy............................ 417
generations of drugs overall results in this disease
6 Optimization of Concurrent are further improved.
Radiochemotherapy ................................................. 420
7 New Approaches in Radiation Therapy
and Chemotherapy of Locally Advanced
Nonsmall-Cell Lung Cancer................................... 423
1 Introduction
8 Conclusions ............................................................... 425
References.......................................................................... 425 Approximately one-third of all patients with nonsmall
cell lung cancer present with a locally advanced,
mostly stage III disease. Patients falling into this
group represent a heterogeneous group of patients.
According to the two staging systems widely adopted
in the community of thoracic oncologists (Mountain
1986, 1997), this is almost synonymous to stage III,
although numerous, mostly non-surgical reports,
included also a proportion of patients with stage II
disease into this group of patients. The most recent
attempt of the International Association for the Study
of Lung Cancer included also non-US and non-sur-
B. Jeremić (&)
Institute of Lung Diseases, Sremska Kamenica, Serbia gical patients in order to increase the overall number
e-mail: nebareje@gmail.com of patients suitable to analysis, increase statistical
F. Casas power to detect small difference, improve sensitivity
University Clinic, Barcelona, Spain analysis and, hence, provide necessary evolution
A. Hervas-Moron of the staging principles in lung cancer. The series of
Hospital Ramon y Cajal, Madrid, Spain articles extensively documented various aspects of

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 409
DOI: 10.1007/174_2011_232, Ó Springer-Verlag Berlin Heidelberg 2011
410
this important issue (Goldstraw and Crowley 2006;
Groome et al. 2007; Rami-Porta et al. 2007; Rusch
et al. 2007; Postmus et al. 2007; Goldstraw et al.
2007). It should be noted that both previous and
current staging systems were nevertheless surgical, i.e.
those in which major principle remained the ability to
surgically extirpate of the tumour and lymph nodes.
The only issues which do matter in these systems is the
size of the tumour (e.g. 3 or 5 cm in largest diameter),
its location (e.g. 2 cm or more from carina), and inva-
sion of neighbouring structures (e.g. chest wall or
heart). These systems even nowadays, unfortunately,
do not take into account tumour volumes at all! That
said, a major principle of anticancer action of both
radiation therapy and chemotherapy, and that is log-cell
kill, is not considered at all. This is an extremely
important issue, especially in a number of tumours
which could have similar tumour volume, but which
could have been designed a different stage in case of
different location or invasion of neighbouring struc-
tures. This is especially important in stage III nonsmall
cell lung cancer which has also underwent a change in
the most recent staging revision. It still, however, has
11 (!) different T and N combinations, ranging from
T4N0 to T1N3. The contribution of T and N compo-
nent, to a particular stage obviously greatly vary.
Although stage subgroupings should reflect similar
prognosis, one crucial issue remained unanswered: is
there a ‘‘effect trade-off’’ when adverse effect of an
increasing T stage is, perhaps, levelled-off with
decreasing N stage, or perhaps which one of these two
descriptors may be more important than the other one
and if so, then exactly when? Finally, since volumes of
these descriptors could also vary (depending on their
size, and/or location), the nature of non-surgical cell
kill (i.e. log cell kill) favours the volume use in this
discussion. It is expected that future staging system
revisions may start taking into account tumour volume,
as should be much easier to do nowadays due to pow-
erful computers used for CT, MRI and PET scanning.
Locally advanced nonsmall cell lung cancer has
been the major battleground for investigating various
treatment options. Surgery (e.g. in very selected
T4N0), radiation therapy (altered fractionation regi-
mens with curative intention in stage III or palliative
hypofractionated regimens in mostly stage IIIB
patients) and chemotherapy (in stage IIIB in numer-
ous clinical studies investigating effect of various
chemotherapeutic agents) can all be used alone in this
B. Jeremić et al.
disease. This, however, is not so frequent practice
nowadays in the majority of patients who can tolerate
more intensive (combined) treatment approach owing
to the mounting evidence that they could successfully
be treated with such a combined modality approach.
In practice this means, a bimodality (radiochemo-
therapy) or a trimodality approach, the latter one
being detailed in another chapter.
2 Radiation Therapy Alone
Locally advanced nonsmall cell lung cancer has fre-
quently been treated with radiation therapy alone. Due
to its characteristics, radiation therapy was relatively
well tolerated. It offered good palliation and since there
have been very few alternatives, only a few studies
validating its efficacy exist. More than 40 years ago, the
Veterans’ Affairs group reported on a study where
radiation therapy had been compared to best supportive
care for locally advanced nonsmall cell lung cancer.
Radiation therapy led to an improvement in the median
survival time, but no 2-year survivors were seen in
either arm (Roswit et al. 1968). Legitimate criticism of
this study include rather primitive staging procedures
(many patients in both arms would likely have Stage IV
disease if modern imaging was used), and outdated
radiation therapy techniques (from today’s standpoint).
More recently, however, similar results were obtained
in another randomized study. The 2-year survival was
18% with radiation therapy dose of 50 Gy versus 0%
for observation with palliative radiation therapy
administered when severe local symptoms developed
(Reinfuss et al. 1999). In another randomized cooper-
ative group study from the US patients were random-
ized to radiation therapy versus single agent vindesine
(Johnson et al. 1990), while the third arm contained
both modalities. The study showed no survival advan-
tage for radiation therapy. However, in this study there
was a substantial crossover in this trial, with many
patients in the vindesine arm ultimately receiving
thoracic radiation therapy. Although this study sug-
gested no survival advantage to ‘‘early’’ radiation
therapy, this should not imply no advantage at all for
radiation therapy.
Regardless of the shortcomings from the studies,
radiation therapy has been considered as the mainstay
of therapy for locally advanced non-small cell lung
cancer in the past. In the benchmark trial, continuous
Radiochemotherapy in Locally Advanced Nonsmall-Cell Lung Cancer
course of radiation therapy with doses of 50–60 Gy
has been shown to be superior to either 40 Gy split-
course or continuous course schedule (Perez et al.
1986). The 60 Gy-continuous course schedule has
then been adopted as the standard radiation therapy all
over the world. However, the results obtained with
radiation therapy alone given that way were unsatis-
factory, since the median survival time was approxi-
mately 9–10 months and the overall 5-year survival
rate was only 3–6% in prospective randomized trials
(Holsti and Matson 1980; Petrovich et al. 1981; Perez
et al. 1987). Since various retrospective and pro-
spective randomized studies have revealed that both
local and systemic failure play an important role in
the poor survival of these patients (Petrovich et al.
1977; Cox et al. 1979; Perez et al. 1986), various
means of improving local and systemic control of this
disease were sought.
In the domain of radiation therapy alone, altered
fractionation regimens have been used to improve
local control (Cox et al. 1993; Saunders and Dische
1990; Byhardt et al. 1993). The Radiation Therapy
Oncology Group (Cox et al. 1990) has investigated
hyperfractionated radiation therapy with 1.2 Gy b.i.d.
fractions and reported improved survival in a sub-
group of patients with favourable prognostic factors
treated with hyperfractionated radiation therapy with
doses C69.6 Gy compared to that obtained with the
standard treatment (60 Gy/30 fractions/6 weeks).
Continuous hyperfractionated accelerated radiation
therapy (CHART) was tested against standard frac-
tionation radiation therapy in inoperable non-small-
cell lung cancer and it was shown be beneficial
(Saunders et al. 1999). This treatment design was,
unfortunately, extremely complicated for daily clini-
cal practice which has prevented it from widespread
use, even in the UK. Several attempts to modify it
included the omission of week-end days or neoadju-
vant chemotherapy, both of which effectively destroy
its underlying principle and that was accelerated
fractionated radiation therapy to combat accelerated
tumour clonogen proliferation. It was then not sur-
prising that the CHART Weekend-less CHARTWEL
trial which compared 66 Gy in 33 daily fractions with
60 Gy in 40 fractions in 18 treatment days (t.i.d.)
has not found a survival advantage for accelerated
regimen (Baumann et al. 2005). Recent years
also brought attempts to combined acceleration and
hyperfractionation in less demanding regimen, such
411
as hyperfractionated accelerated radiation therapy
(Mehta et al. 1998) which also proven to be effective
in this setting.
Studies using altered fractionated regimens
reconfirmed the duality of patterns of failure in
patients treated with radiation therapy alone. These
facts again stressed the need for inclusion of chemo-
therapy into the overall treatment plan: to improve
both local/regional control and combat possible dis-
tant (microscopic) spread, the latter not addressed by
the radiation therapy. Unfortunately, the results of
early studies designed with that aim were neither
encouraging nor different from that obtained with
radiation therapy alone. Timing of chemotherapy
administration was usually adjuvant (i.e. post-radia-
tion therapy) and it consisted of non-platinum based
drugs (Reynolds and O’Dell 1978; White et al. 1982).
Radiation therapy-induced fibrotic changes in lungs
that prevented successful blood/drug perfusion and,
therefore, drug supply to the tumour-bearing area,
was the main reason for such observation. Relative
inefficiency of then-available drugs, mostly consid-
ered as first-generation chemotherapy drugs, origi-
nating in the pre-cisplatin era (Reynolds and O’Dell
1978; White et al. 1982) was also implicated in this
inefficiency.
Contrary to this, radiation therapy and platinum-
based chemotherapy have been increasingly practiced
around the world in the last three decades. A number
of possible combinations have arisen, largely
exploiting different aspects of such combination,
frequently focusing on the issue of timing/scheduling.
Induction (neo-adjuvant) chemotherapy followed by
radical radiation therapy (Dillman et al. 1990; Sause
et al. 1995), ‘‘sandwich’’ chemotherapy and radiation
therapy (Le Chevalier et al. 1992) as well as con-
current radiochemotherapy (Schaake-Koning et al.
1992; Jeremic et al. 1995, 1996, 1998) have all gained
widespread use, sometimes with very similar results
obtained with these approaches, with quite different
radiobiological background. To further obscure the
overall picture, both radiation therapy and chemo-
therapy have evolved over the years. A number of
different time/dose/fractionation radiation therapy
regimens have been used (Cox et al. 1990; Byhardt
et al. 1993; Saunders and Dische 1990). They paral-
leled the introduction of the third generation of drugs,
namely paclitaxel (Johnson et al. 1996; Herscher et al.
1998), docetaxel (Millward et al. 1996; Mauer et al.
412
1998), vinorelbine (LeChevalier et al. 1994; Masters
et al. 1998), gemcitabine (Manegold et al. 1997;
Vokes et al. 1998), irinotecan (Fukuoka et al. 1992;
Oshita et al. 1997) and topotecan (Lynch et al. 1994;
Perez-Soler et al. 1996). In most recent years, a
number of new chamotherapy agents as well as tar-
geted agents have been introduced into the clinical
research in this disease, with the latter two being a
subject of separate chapters of the book.
3 Neoadjuvant (Induction)
Chemotherapy Followed
by Radiation Therapy
Major aims of this type of combined radiation therapy
and chemotherapy are (1) to decrease tumor burden,
which may permit delivery of radiation therapy to a
reduced tumor volume and (2) to combat micromet-
astatic disease, believed to be present at the time of
starting treatment. Increased drug delivery with less
overall toxicity (especially those expected to occur
within the radiation therapy treatment field, i.e.
pneunomitis and esophagitis) is also one of the pos-
sible advantages if compared to concurrent adminis-
tration. Potential disadvantages of induction treatment
include (1) prolonged overall treatment time, (2)
excessive toxicity due to chemotherapy preventing or
delaying the delivery of full radiation therapy dose,
(3) chemotherapy-induced tumor cell resistance
resulting in reduced radiation therapy efficacy, as well
as (4) accelerated tumor clonogen repopulation,
expected also to occur during the chemotherapy phase
of the combined treatment (Byhardt et al. 1998;
Byhardt 1999). Several phase III trials have demon-
strated a survival benefit for induction chemotherapy,
confirmed with recent updates providing a long-term
data.
The Cancer and Leukemia Group B 8433 was the
landmark trial comparing sequential radiochemo-
therapy versus radiation therapy alone for the treat-
ment of locally advanced nonsmall cell lung cancer
(Dillman et al. 1990). Between 1984 and 1987, 155
patients with clinical or surgical T3 or N2 and M0
nonsmall cell lung cancer were treated with induction
chemotherapy followed by radiation therapy or radi-
ation therapy alone. All patients had a good perfor-
mance status and minimal weight loss. Induction
chemotherapy consisted of cisplatin (100 mg/m2,
B. Jeremić et al.
days 1 and 29) and vinblastine (5 mg/m2, days 1, 8,
15, 22 and 29). Radiation therapy to a total dose of
60 Gy in 30 fractions was given in both arms and
began on day 50 in the combined-modality arm. The
addition of chemotherapy did not impair the ability to
deliver radiation therapy; 88% of patients in the
combined-modality arm and 87% of patients on the
radiation therapy alone arm completed radiation
therapy per protocol. Although there were no treat-
ment-related deaths on either arm, the addition of
chemotherapy increased the number of hospital
admissions for vomiting (5% vs. 0%) and infection
(7% vs. 3%). In the initial report (Dillman et al.
1990), induction chemotherapy improved median
survival (13.8 vs. 9.7 months, p = 0.0066) and 3-year
survival of patients treated with radiochemotherapy
(23% vs. 11%). Seven year follow-up of that study
confirmed superiority of induction chemotherapy
(median survival, 13.7 vs. 9.6 months, p = 0.012)
over radiation therapy alone (Dillman et al. 1996).
The Cancer and Leukemia Group B experience was
subsequently been confirmed by other modern cis-
platin-based trials (Table 1).
The Radiation Therapy Oncology Group/Eastern
Cooperative Oncology Group trial was a trial which
randomized 458 patients with favourable prognosis
(good performance status, minimal weight loss)
locally advanced nonsmall cell lung cancer to receive
either once daily radiation therapy to 60 Gy in 2 Gy
fractions or the same radiation therapy with two
cycles of induction cisplatin and vinblastine (Sause
et al. 1995), or the radiation therapy given twice daily
(1.2 Gy b.i.d.) to a total dose of 69.6 Gy. The median
survival was statistically superior (p = 0.03) for the
combined modality arm (13.8 months) versus either
the standard radiation therapy arm (11.4 months), or
the twice daily radiation therapy arm (12.3 months).
Prolonged follow up of this study reconfirmed supe-
riority of combined-modality therapy. However, long-
term survival rates remained less than 10% (Sause
et al. 2000).
French experience was provided in a phase III trial
with radiation therapy alone versus combined radia-
tion therapy-chemotherapy (Le Chevalier et al. 1991).
In this trial, 353 patients with unresectable locally
advanced squamous cell or large cell lung carcinoma
were randomized to either radiation therapy alone
(65 Gy in 2.5 Gy fractions) or three monthly cycles of
cisplatin-based chemotherapy followed by the same
Radiochemotherapy in Locally Advanced Nonsmall-Cell Lung Cancer 413

Table 1 Stage III nonsmall-cell lung cancer at University Hospital, Kragujevac, Serbia
Study Year Phase N Hfx RT (bid) CHT MST (mos) Survival
3 yr (%) 4 yr (%) 5 yr (%)
1 1995 III 61 64.8 – 8 7 7 5
56 64.8 CE 13 16 16 16
52 64.8 CE 18 23 21 21
2 1996 III 66 69.6 – 4 11 9
65 69.6 CE/d 22 23 23
3 1998 II 41 69.6 CE/d/w 25 34 29 29
4 2001 III 98 69.6 CE/d 20 29 29 20
97 69.6 CE/d/w 25 34 23 23
5 2005 II 64 67.6 CT/d 28 37 28 26
Hfx RT (bid) hyperfractionated radiation therapy, CHT chemotherapy, MST median survival time, C carboplatin, E etoposide,
T paclitaxel, d daily, w weekend

radiation therapy regimen and followed again by
the same chemotherapy. A significant decrease in
distant metastases for the combined-modality arm was
observed and the median (12.0 vs. 10.0 months) and
2-year survival rates (21% vs. 14%, p = 0.02) were
improved as well (Le Chevalier et al. 1992). Long-
term follow up provided, unfortunately, more sobering
facts: only 8% of patients had continued local control
at 5 years (Arriagada et al. 1997), while 5-year sur-
vival rates remained poor at 6 and 3% (for the two
arms), likely a consequence of the high rate of local
failure on both arms. An intriguing question remained
unanswered: was improvement in the distant metas-
tasis control a consequence of starting the treatment
with induction chemotherapy or it was a mere reflec-
tion of higher total doses being given (post-radiation
therapy chemotherapy was also given)?
The Medical Research Council also performed a
trial which randomized 447 eligible patients with good
performance status and localized, inoperable nonsmall
cell lung cancer to receive either radiation therapy
alone or cisplatin-based induction chemotherapy fol-
lowed by the same radiation therapy (Cullen et al.
1997). On both arms, the median radiation therapy dose
in both arm was rather low, 50 Gy. The median survival
time was improved with the addition of chemotherapy
(13.0 vs. 9.9 months, p = 0.056), although this dif-
ference was of borderline (in)significance.
What these trials have demonstrated is that the
addition of platinum-based induction chemotherapy
to radiation therapy results in improved survival over
that obtained with the same radiation therapy when
the latter is given alone. While this certainly holds
true for short-term survival, long-term survival figures
remained to be dismal, indicating that only modest
improvements in long-term survival have been
achieved. Contrary to these, several smaller random-
ized trials have failed to confirm a survival benefit for
the addition of induction chemotherapy, although low
statistical power of these studies may have prevented
them to detect small differences in survival (Mattson
et al. 1988; Morton et al. 1991; Crino et al. 1993;
Planting et al. 1996). Three large meta-analyses have
demonstrated a small but consistent survival benefit
for the addition of induction chemotherapy to radia-
tion therapy for locally advanced nonsmall cell lung
cancer (Non-small Cell Lung Cancer Collaborative
Group 1995; Marino et al. 1995; Pritchard and
Anthony 1996).
Since it became obvious that induction chemo-
therapy followed by conventionally fractionated,
radical radiation therapy unequivocally brings an
increase in the locoregional failures, investigators
made efforts to overcome this big clinical problem by
offering more intensive latter (radiation therapy) part
of the combined treatment. By doing so, Clamon et al.
(1999) compared then standard induction chemo-
therapy consisting of cisplatin/vinblastine followed
by standard radiation therapy (60 Gy in 30 daily
fractions). Radiation therapy was given either with or
without concurrently given weekly 100 mg/m2 of
carboplatin as radiosensitizer (enhancer). No differ-
ence in overall survival (the median survival time:
13.4 vs. 13.5 months; 4-year survival: 13% vs. 10%;
414
p = 0.74) was found between the radiosensitized and
non-radiosensitized groups of patients. These results
showed that induction cisplatin/vinblastine followed
by conventionally fractionated radical radiation ther-
apy and concurrent chemotherapy that does not nec-
essarily obtain good and consisting results, being
inferior in the study of Clamon et al. (1999) to what
was expected from previous two studies (Dillman
et al. 1990; Sause et al. 1995). They have shown that
even when sensitized by carboplatin, standard fraction
radiation therapy can not compensate for accelerated
proliferation of surviving tumor clonogens which
occur during the induction (chemotherapy) phase of
treatment. Furthermore, the results of the study of
Clamon et al. (1999) were not different from those
obtained by hyperfractionated radiation therapy alone
in the Radiation Therapy Oncology Group/Eastern
Cooperative Oncology Group study 8808 (Sause et al.
1995) or the same hyperfractionated radiation therapy
(69.6 Gy using 1.2 Gy twice-daily) in the study of
Jeremic et al. (1996).
More recently, in an attempt to intensify the second
part (i.e. radiation therapy) of the combined treatment
even more, Vokes et al. (2002) reported on randomized
phase II study of Cancer and Leukemia Group B (9431)
which used two cycles of induction chemotherapy
(cisplatin/gemcitabine or cisplatin/paclitaxel or cis-
platin/vinorelbine) followed by the two cycles of the
same chemotherapy concurrently with conventionally
fractionated radical radiation therapy (66 Gy) in 175
patients with unresectable stage III nonsmall cell lung
cancer. Response rates were 74, 67, and 73% for the
three arms, respectively. While the median survival
time for all patients was 17 months, 3-year survival
rates for the three groups were 28, 19, and 23%,
respectively. Although authors concluded that the use
of concurrent radiochemotherapy could have led to the
improvement in outcome when compared to previous
Cancer and Leukemia Group B experience with
induction treatments (Dillman et al. 1990, 1996;
Clamon et al. 1999), it did not improve treatment out-
come when one considers other combined modality
options such as concurrent radiation therapy and che-
motherapy. Several studies of the similar design only
reconfirmed these observations. They have clearly
shown that ANY intensification of the latter/major part
of the combined treatment approach via concurrent
radiochemotherapy is not effective, once you have
started with induction chemotherapy. Several studies of
B. Jeremić et al.
Cancer and Leukemia Group B (Clamon et al. 1999;
Vokes et al. 2002; Akerley et al. 2005; Socinski et al.
2008) showed that there is no compensation for insuf-
ficient start (i.e. with chemotherapy). Other attempts,
such as the use of three daily fractions of radiation
therapy (Belani et al. 2005), also proved to be ineffec-
tive. In that trial which compared standard fractionation
radiation therapy versus hyperfractionated accelerated
radiation therapy, all patients in both arms received
induction chemotherapy with carboplatin/paclitaxel.
Concurrent chemotherapy was not used during the
radiation therapy course. Unfortunately, the study
did not meet its accrual goals and was closed early;
nonetheless 111 patients were analyzed and the
results suggest a slight though statistically insignificant
advantage to hyperfractionated accelerated radiation
therapy (median survival and 2- and 3-year actuarial
survival: 22.2 months, 48 and 20% vs. 13.7 months, 33
and 15%, respectively) (Belani et al. 2005). All in all,
whatever you do after you start with chemotherapy,
failure is inevitable and comes fast. With this approach,
you can only achieve more toxicity (Vokes et al. 2002;
Socinski et al. 2008) and even if you use the modern
radiation therapy tools such as three-dimensional
radiation therapy and attempt treatment intensification
by escalating the total dose, again, one cannot achieve
better outcome. Indeed, impressive 12% mortality in
the most recent CALGB attempt (Socinski et al. 2008)
to combine induction chemotherapy with subsequent
radiation therapy and concurrent chemotherapy led
investigators to early stopping the trial.
Underlying radiobiological principles of this
observation can easily be materialized in a recently
identified fact of never-achieved improvement in
local control in locally advanced nonsmall cell lung
cancer treated with induction chemotherapy followed
by either conventionally fractionated radical radiation
therapy or even stronger, radiochemotherapy. El
Sharouni et al. (2003) has compared CT scans pre-
and post-induction chemotherapy, with emphasis on
the time from the last induction chemotherapy cycle
to the time of radiation therapy treatment planning CT
was actually done. That way they have been able to
measure an increase in gross tumour volumes (GTVs)
and subsequently define volume doubling times.
During the waiting period (for the planning CT scan
and start of radiation therapy), a total of 41% of all
tumours became incurable, with the ratio of GTVs
being in the range of 1.1–81.8! Tumour doubling
Radiochemotherapy in Locally Advanced Nonsmall-Cell Lung Cancer
times ranged 8.3–171 days, with the median of
29 days. When translated into more clinical language,
these findings clearly say that even if one may have
thought (due to insufficient CT-based imaging) that
response occurs (and that it matters), there is actually
an opposite development, with surviving tumour
clonogens repopulating fast, leading tumours to
regrow to the state of incurability. Recent confirma-
tion of these observations came from Bozcuk et al.
(2010) who attempted to correlate the benefit from
neoadjuvant chemotherapy before radiotherapy in
non-small cell lung cancer using a meta-analytical
approach with meta-regression analysis. They have
used thirteen randomized clinical trials to date,
encompassing 2776 patients. Time to radiotherapy
was inversely associated with the benefit from neo-
adjuvant chemotherapy at 2 (p = 0.050) and 3 years
(p = 0.093). This meta-analysis highlighted the
importance of shorter time to radiotherapy to maxi-
mize nonsmall cell lung cancer patients’ survival.
4 Concurrent Radiochemotherapy
This combined modality approach denotes the admin-
istration of both modalities at the same time, meaning
that chemotherapy is given during the course of radical,
curative radiation therapy. A number of variations
exist, including chemotherapy being administered on a
3-weekly basis, bi-weekly, weekly, or daily, although
concurrent radiation therapy–chemotherapy employ-
ing third generation drugs (e.g. paclitaxel) also wit-
nessed administration of the drug twice or trice weekly.
Whatever was the design of concurrent radiation ther-
apy–chemotherapy, its main aim is to address the issue
of locoregional and distant disease at the same time,
from the outset of the treatment as intensively as pos-
sible. This, unfortunately, may lead to increased tox-
icity (mostly acute) which may require dose reductions
or treatment interruptions, both adversely influencing
treatment outcome. On the other side, with this
approach three of radiobiological premises, namely
spatial cooperation, independent cell kill and syner-
gistic action, as postulated by Steel and Peckham
(1979), can be exploited.
Concurrent radiation therapy–chemotherapy was
compared to radiation therapy alone, the former
aiming mostly on an improvement at local tumour
control. A number of prospective randomized phase
415
III studies investigated this issue (Soresi et al. 1988;
Schaake-Koning et al. 1992; Trovo et al. 1992;
Blanke et al. 1995; Jeremic et al. 1995, 1996; Bonner
et al. 1998; Groen et al. 2004; Ball et al. 1999).
Relatively low total radiation therapy dose (Soresi
et al. 1988; Trovo et al. 1992) and chemotherapy
being given in an insufficient total dose (Soresi et al.
1988) may have been among reasons for such
observation. All three positive studies used protracted
chemotherapy dosing. While an European Organiza-
tion for Research and Treatment of Cancer study
(Schaake-Koning et al. 1992) tested both daily and
weekly cisplatin with split-course radiation therapy,
showing superior outcome for daily cisplatin/radia-
tion therapy, Jeremic et al. first used biweekly and
weekly (Jeremic et al. 1995) and then daily (Jeremic
et al. 1996) carboplatin/etoposide with hyperfrac-
tionated radiation therapy doses of 64.8 (Jeremic et al.
1995) and then 69.6 Gy (Jeremic et al. 1996). The
best results were obtained with low-dose daily che-
motherapy given during the hyperfractionated radia-
tion therapy course, with 4–5 year survival rates
being at the order of 20% (Jeremic et al. 1995, 1996).
Survival advantage in these three studies was a con-
sequence of an advantage at local tumour level,
confirming radiobiological expectations that low-dose
daily chemotherapy may have acted synergistically
with radiation therapy, and enhanced its effects on
local tumour level. Also as expected, no influence on
distant metastasis control was noted. Ulutin et al.
(2000) designed a three-armed study to compare the
effects of sequential and concurrent radiation ther-
apy–chemotherapy in locally advanced non-small cell
lung cancer. Each treatment arm consisted of 15
patients with histologically confirmed stage III non-
small cell lung cancer. In group 1, the main treatment
approach was split-course radiation therapy alone. In
group 2, 6 mg/m2 of cisplatin was applied daily and
concurrently with split-course radiation therapy. In
group 3, two cycles of etoposide, ifosfamide, and
cisplatin chemotherapy, which ended 3 weeks before
split-course radiation therapy, was applied. Overall
response rates were 40, 66, and 53% in groups
1–3, respectively. Median survival was 10, 11, and
10 months for groups 1–3, respectively. Recently,
another study from Turkey (Cakir and Egehan 2004)
provided additional evidence that concurrent radiation
therapy (64 Gy in 32 daily fractions) and cisplatin
(20 mg/sqm, days 1–5, weeks 2 and 6) offers survival
416
advantage over the same radiation therapy alone
(3-year survival, 10% vs. 2%). Combined treatment
approach also offered better locoregional control
(p = 0.0001) and disease-free survival (p = 0.0006).
Most recently, West Japan Thoracic Oncology Group
(Yamamoto et al. 2010) presented the data from a
phase III trial of concurrent thoracic radiation therapy
(WJTOG0105) which was conducted to compare
third-generation chemotherapy with second-genera-
tion chemotherapy in patients with unresectable
stage III nonsmall-cell lung cancer. Eligible patients
received the following treatments: A (control), four
cycles of mitomycin (8 mg/sqm on day 1)/vindesine
(3 mg/sqm on days 1, 8)/cisplatin (80 mg/msqm on
day 1) plus thoracic radiation therapy 60 Gy
(treatment break for 1 week); B, weekly irinotecan
(20 mg/sqm)/carboplatin (area under the plasma
concentration–time curve, 2) for 6 weeks plus tho-
racic radiation therapy 60 Gy, followed by two
courses of irinotecan (50 mg/sqm on days 1, 8)/car-
boplatin (area under the plasma concentration–time
curve 5 on day 1); C, weekly paclitaxel (40 mg/sqm)/
carboplatin (area under the plasma concentration–
time curve, 2) for 6 weeks plus thoracic radiation
therapy 60 Gy, followed by two courses of paclitaxel
(200 mg/sqm on day 1)/carboplatin (area under the
plasma concentration–time curve 5 on day 1). The
median survival time and 5-year survival rates were
20.5, 19.8, and 22.0 months and 17.5, 17.8, and
19.8% in arms A–C, respectively. While no signifi-
cant differences in overall survival were apparent
among the treatment arms, noninferiority of the
experimental arms was not achieved. The incidences
of grade 3–4 neutropenia, febrile neutropenia, and
gastrointestinal disorder were significantly higher in
arm A than in arm B or C (p \ 0.001). Chemotherapy
interruptions were more common in arm B than in
arm A or C. Arm C was equally efficacious and
exhibited a more favourable toxicity profile among
three arms. This study confirmed effectiveness of
third-generation chemotherapy and concurrent radia-
tion therapy in this setting. In a similar study, also
coming from Japan, Segawa et al. (2010) reported on
a phase III trial comparing docetaxel and cisplatin
combination chemotherapy with mitomycin, vinde-
sine, and cisplatin combination chemotherapy with
concurrent thoracic radiotherapy in locally advanced
non-small-cell lung cancer. Patients age 75 years or
younger with locally advanced nonsmall cell lung
B. Jeremić et al.
cancer, stratified by performance status, stage, and
institution, were randomly assigned to two arms
consisting of docetaxel 40 mg/sqm and cisplatin
40 mg/sqm on days 1, 8, 29, and 36) or mitomycin,
vindesine, and cisplatin chemotherapy with concur-
rent thoracic radiation therapy. Two hundred patients
were allocated into either the docetaxel and cisplatin
or mitomycin, vindesine, and cisplatin arm. The
survival time at 2 years, a primary end point, was
favourable to the docetaxel and cisplatin arm
(p = 0.059 by a stratified log-rank test as a planned
analysis and p = 0.044 by an early-period, weighted
log-rank as an unplanned analysis). There was a trend
toward improved response rate, 2-year survival rate,
median progression-free time, and median survival in
the docetaxel and cisplatin arm (78.8, 60.3%, 13.4,
and 26.8 months, respectively) compared with the
mitomycin, vindesine, and cisplatin arm (70.3, 48.1%,
10.5, and 23.7 months, respectively), which was not
statistically significant (p [ 0.05). Grade 3 febrile
neutropenia occurred more often in the mitomycin,
vindesine, and cisplatin arm than in the docetaxel and
cisplatin arm (39% vs. 22%, respectively; p = 0.012),
and grade 3–4 radiation esophagitis was likely to be
more common in the docetaxel and cisplatin arm than
in the mitomycin, vindesine, and cisplatin arm (14%
vs. 6%, p = 0.056). Authors concluded that the
docetaxel and cisplatin chemotherapy combined with
concurrent thoracic radiation therapy is an alternative
to mitomycin, vindesine, and cisplatin chemotherapy
for patients with locally advanced nonsmall cell lung
cancer.
Additional and important observation coming from
clinical trials data accumulated over the years is that
those studies/arms which used high-dose chemother-
apy (mimicking classic chemotherapy administration
and necessarily given with more split between the
consecutive chemotherapy cycles) concurrently with
radiation therapy neither observed any impact on
distant metastasis control, nor did so on local level.
Beside the overall treatment success, another advan-
tage of low-dose concurrent chemotherapy over high-
dose chemotherapy and concurrent radiation therapy
is that the former type of concurrent radiochemo-
therapy leads to less high-grade acute toxicity and,
consequently, better treatment compliance, less
treatment interruptions, which influence on treatment
outcome (Cox et al. 1993). Recently, Harada et al.
(2009) retrospectively compare the survival and
Radiochemotherapy in Locally Advanced Nonsmall-Cell Lung Cancer
toxicities associated with radiochemotherapy using
full-dose and weekly regimens in patients with stage
III non-small cell lung cancer. Fifty-nine patients
were enrolled; 36% of the patients were treated with
full-dose regimens and 64% with weekly regimens. In
both univariate and multivariate analyses, treatment
with weekly regimens was associated with a better
overall survival than that with full-dose regimens
(2-year survival rates: 75% for weekly regimens vs.
41% for full-dose regimens). The toxicities and
compliance in the two groups were comparable.
Weekly regimens exhibited more favourable overall
survival as compared to full-dose regimens in this
retrospective study. These results support previous
observations that low-dose daily chemotherapy
(Schaake-Koning et al. 1992; Jeremic et al. 1995,
1996, 2005) provide good treatment results including
the toxicity which is lower than that observed when
high-dose radiation therapy and concurrent high-dose
chemotherapy are administered in this setting. As
such an example, results of studies coming from the
University Hospital, Kragujevac, Seriba are chrono-
logically outlined in Table 1.
5 Neoadjuvant (Induction)
Chemotherapy Followed
by Radiation Therapy Versus
Concurrent Radiochemotherapy
The studies using induction chemotherapy followed
by radical radiation therapy showed a survival
advantage for the combined approach owing to the
improvement in the distant metastasis control. It is a
finding opposite to that of the studies using concurrent
radiation therapy–chemotherapy, which unequivo-
cally showed improvement in survival owing to
the improvement in locoregional tumour control.
Considered from the standpoint of exploitable
mechanisms of combined radiation therapy and che-
motherapy (Steel and Peckham 1979), the induction
regimens enabled the therapeutic benefit due to spatial
cooperation only. Neither independent cell kill nor
enhancement of tumour response could be noted
because there was no significant difference in loco-
regional tumour control, as one may expect if the two
mechanisms of action would have happened. On the
other side, in concurrent studies, spatial cooperation
did not work, while both independent cell kill and
417
enhancement of tumour response may have occurred.
In the low-dose (daily) chemotherapy arms of the
concurrent studies, however, it seems unlikely that
independent cell kill occurred (and if so, then to a
much lesser degree due to lower daily and total doses
of chemotherapy), leaving, thus, enhancement of
tumour response as the only and likely alternative.
In order to compare induction chemotherapy fol-
lowed by radical radiation therapy to concurrent
radiation therapy and chemotherapy, several clinical
trials were performed. The very first full publication
came from The Cancer and Leukemia Group B
(Clamon et al. 1999) who reported on a randomized
phase II trial where induction chemotherapy (cis-
platin–vinblastin) was followed with either radical
radiation therapy alone and then followed with four
additional chemotherapy cycles (regimen 1) or with
concurrent radical radiation therapy and six weekly
doses of carboplatin (regimen 2). The additional four
cycles of vinblastine and cisplatin were completed by
34% of patients; the radiation therapy and concurrent
carboplatin was completed by 70% of patients. Grade
3 or 4 granulocytopenia occurred in 53% of patients
on regime 1 versus 17% on regime 2 (p \ 0.003);
grade 3 or 4 nausea/vomiting occurred in 20% of
those on regime 1 versus 7% on regimen 2
(p = 0.175). Response rates and survival were similar
for the two regimens, with approximately 30% of
patients surviving at 2 years. Nest study originated in
Japan were Furuse et al. (1999, 2000) reported on a
study of the West Japan Lung Cancer Group which
compared mitomycin, cisplatin, and vindesine che-
motherapy given as either induction followed by
continuous course radical radiation therapy (56 Gy)
with the same mitomycin, cisplatin, and vindesine
given concurrently with split-course radiation therapy
of the same total dose. First publication showed
superior results (the median survival time, 16.5 vs.
13.3 months; 5-year survival, 16% vs. 9%;
p = 0.039) for concurrent radiation therapy–chemo-
therapy (Furuse et al. 1999). Subsequent data analysis
showed that an improvement in local tumour control
(median time, 10.6 vs. 8.0 months; 5-year, 34% vs.
20%; p = 0.0462) is the reason for an improvement
in survival (Furuse et al. 2000). More recently, Curran
et al. (2000) and Komaki et al. (2000) reported on
Radiation Therapy Oncology Group 9410 study
which compared (1) induction chemotherapy fol-
lowed by radiation therapy, same as Cancer and
418
Leukemia Group B 8433 (Dillman et al. 1990) and
Radiation Therapy Oncology Group 8808/Eastern
Cooperative Oncology Group 4508 (Sause et al.
1995) with concurrent either (2) standard fraction
radiation therapy (60 Gy) and cisplatin/etoposide or
(3) hyperfractionated radiation therapy (69.6 Gy) and
cisplatin/etoposide. Both standard radiation therapy–
chemotherapy and hyperfractionated radiation ther-
apy–chemotherapy arm had better median survival
time than the induction arm (17.0 vs. 16.0 vs.
14.6 months), although only standard radiation ther-
apy–chemotherapy was statistically significantly bet-
ter than induction chemotherapy (Curran et al. 2000).
Pattern of failure analysis showed that the best local
control was in the hyperfractionated radiation ther-
apy–chemotherapy arm, confirming indirectly the
observations of Jeremic et al. (1995, 1996) that high-
dose hyperfractionated radiation therapy–chemother-
apy is an advantageous approach. Furthermore and
contrary to studies using low-dose chemotherapy
concurrently with high-dose radiation therapy, it was
shown again that high-dose chemotherapy bears a risk
of exceptional acute toxicity when given with high-
dose standard or hyperfractionated radiation therapy.
This finding is not just limited to Radiation Therapy
Oncology Group 9410 but was also seen in other
similar studies (Byhardt et al. 1995; Lee et al. 1996;
Komaki et al. 1997) as well. The next study was
aforementioned Turkish study of Ulutin et al. (2000),
designed as three-armed study (including the group 1
was split-course radiation therapy alone) to compare
the effects of sequential and concurrent radiation
therapy–chemotherapy in locally advanced non-small
cell lung cancer. Each treatment arm consisted of 15
patients with histologically confirmed stage III non-
small cell lung cancer. In group 2, 6 mg/sqm of cis-
platin was applied daily and concurrently with split-
course radiation therapy. In group 3, two cycles of
etoposide, ifosfamide, and cisplatin chemotherapy,
which ended 3 weeks before split-course radiation
therapy, was applied. Overall response rates were 40,
66, and 53% in groups 1–3, respectively. Median
survival was 10, 11, and 10 months for groups 1–3,
respectively. In France, Groupe Lyon-Saint-Etienne
d’Oncologie Thoracique-Groupe Français de
Pneumo-Cancérologie (Fournel et al. 2005) randomly
assigned 205 patients to receive either induction
chemotherapy with cisplatin (120 mg/sqm) on days 1,
29, and 57, and vinorelbine (30 mg/sqm/wk) from
B. Jeremić et al.
days 1 to 78, followed by thoracic radiation therapy at
a dose of 66 Gy in 33 fractions (2 Gy per fraction and
five fractions per week) or the same radiation therapy
(started on day 1) with two concurrent cycles of cis-
platin 20 mg/sqm/d and etoposide 50 mg/sqm/d (days
1–5 and days 29–33); patients then received consoli-
dation therapy with cisplatin 80 mg/sqm on days 78
and 106 and vinorelbine 30 mg/sqm/wk from days 78
to 127. There were six toxic deaths in the induction
arm and 10 in the concurrent arm. Median survival
was 14.5 months in the induction arm and
16.3 months in the concurrent arm (p = 0.24). Two-,
3-, and 4-year survival rates were better in the con-
current arm (39, 25, and 21%, respectively) than in
the induction arm (26, 19, and 14%, respectively).
Esophageal toxicity was significantly more frequent
in the concurrent arm than in the induction arm (32%
vs. 3%). Although not statistically significant, differ-
ences in the median, 2-, 3-, and 4-year survival rates
which were observed were clinically meaningful, with
a trend in favor of concurrent radiation therapy–che-
motherapy, suggesting that is the optimal strategy for
patients with locally advanced nonsmall cell lung
cancer. Finally, Belderbos et al. (2007) reported on
EORTC study in 158 patients which were randomised
to receive two courses of (induction) Gemcitabine
(1250 mg/sqm days 1, 8) and Cisplatin (75 mg/sqm,
day 2) prior to, or daily low-dose Cisplatin (6 mg/
sqm) concurrent with radiotherapy, consisting of 24
fractions of 2.75 Gy in 32 days, with a total dose of
66 Gy. Acute haematological toxicity grade 3/4 was
more pronounced in the induction arm (30% versus
6%), oesophagitis grade 3/4 more frequent in the
concurrent arm (5% versus 14%). Late oesophagitis
grade 3 was 4% (induction and concurrent), pneu-
monitis grade 3/4 14% (induction) and 18%
(concurrent). Because of the poor power of the study
no significant differences in median survival time
(induction, 16.2, concurrent, 165 months, respec-
tively), and 3-year overall survival (induction, 22%,
concurrent, 34%) could be detected.
Although discussed clinical trials have clearly
(though not always statistically significantly!) shown
that concurrent radiation therapy–chemotherapy may
be considered as standard treatment option in, at least
favorable (good performance status, less pronounced
weight loss) patients with locally advanced nonsmall
cell lung cancer, last decade was the time of contin-
uous discussions in this field. While proponents of
Radiochemotherapy in Locally Advanced Nonsmall-Cell Lung Cancer
concurrent radiation therapy–chemotherapy cited
high level evidence, opponents were usually using
various explanations and excuses for not using it in
daily practice. Some of these were showing ineffi-
ciency of administration matters at radiation oncology
departments, such as existing waiting lists and/or long
time to organize CT-scanning for treatment planning,
even in the leading institutions worldwide. To solve
major scientific and clinical question, but also to use
the opportunity to solve some, if not all of then-
existing uncertainties, three meta-analyses/systematic
reviews were performed.
O’Rourke et al. (2010) identified nineteen random-
ised studies (totaling 2728 participants) of radiation
therapy and concurrent chemotherapy versus radiation
therapy alone. Radiation therapy and concurrent che-
motherapy significantly reduced overall risk of death
(HR 0.71, 95% CI 0.64–0.80; I(2) 0%; 1607 partici-
pants) and overall progression-free survival at any site
(HR 0.69, 95% CI 0.58–0.81; I(2) 45%; 1145 partici-
pants). Incidence of acute oesophagitis, neutropenia
and anaemia were significantly increased with radia-
tion therapy and concurrent chemotherapy. Six trials
(1024 patients) of radiation therapy and concurrent
chemotherapy versus induction chemotherapy and
radiation therapy included. A significant benefit of
chemotherapy was shown in overall survival (HR 0.74,
95% CI 0.62–0.89; I(2) 0%; 702 participants). This
represented a 10% absolute survival benefit at 2 years.
More treatment-related deaths (4% vs. 2%) were
reported in the radiation therapy and concurrent che-
motherapy arm without statistical significance (RR
2.02, 95% CI 0.90–4.52; I(2) 0%; 950 participants).
There was increased severe oesophagitis with radiation
therapy and concurrent chemotherapy (RR 4.96, 95%
CI 2.17–11.37; I(2) 66%; 947 participants).
Liang et al. (2010) investigated whether current
clinical trials can clarify this schedule and offer further
bases for clinical decision making. They performed a
systematic review of 11 trials (2,043 patients; concur-
rent—1,019, induction—1,024) that compared radia-
tion therapy and concurrent chemotherapy with
induction chemotherapy followed with radiation ther-
apy in advanced nonsmall cell lung cancer patients.
Primary end point was overall survival. Pooled median
ratios and progression-free-survival ratios for median
survival and progression-free survival were calculated
using the weighted sum of the log ratio of pooled
median ratio and progression-free-survival ratios of
419
individual study. Pooled odds ratios for the objective
response rate, relapse control rate, and toxic events
were calculated using the Mantel–Haenszel estimate.
Results confirmed that radiation therapy and concur-
rent chemotherapy determined a statistically signifi-
cant increase in median survival time (16.3 vs.
13.9 months; pooled median ratios = 1.17, 95% CI
1.09–1.26), response rate (64.0% vs. 56.3%; odds
ratio = 1.38, 95% CI 1.10–1.72), and tumor-relapse
control (odds ratio = 0.82,95% CI 0.69–0.97), though
at the expense of increased hematological toxicity
(neutropenia and thrombocytopenia) and non-hema-
tological toxicity (nausea/vomiting, stomatitis, and
esophagitis). Similar results were obtained from the
sensitivity analysis of all Phase-III trials designed to
evaluate the primary end point of overall survival.
Subgroup analysis revealed that concurrent strategy
was mainly associated with improved loco-regional
control (odds ratio = 0.68, 95% CI 0.52–0.87). How-
ever, no difference in progression-free survival is
shown. While careful interpretation of their conclu-
sions is required because of potential bias, authors
concluded that further improvements will be obtained
by optimizing the conditions for a concurrent regimen.
Finally, Aupérin et al. (2010) used updated indi-
vidual patient data to address the same question.
Results from trials were combined using the stratified
log-rank test to calculate pooled hazard ratios. The
primary outcome was overall survival; secondary out-
comes were progression-free survival, cumulative
incidences of locoregional and distant progression, and
acute toxicity. Of seven eligible trials, data from six
trials were received (1,205 patients, 92% of all ran-
domly assigned patients). Median follow-up was
6 years. There was a significant benefit of radiation
therapy and concurrent chemotherapy on overall sur-
vival (pooled hazard ratio, 0.84; 95% CI 0.74–0.95;
p = 0.004), with an absolute benefit of 5.7% (from 18.1
to 23.8%) at 3 years and 4.5% at 5 years. For pro-
gression-free survival, the pooled hazard ratios was
0.90 (95% CI 0.79–1.01; p = 0.07). Radiation therapy
and concurrent chemotherapy decreased locoregional
progression (pooled hazard ratios, 0.77; 95% CI 0.62–
0.95; p = 0.01); its effect was not different from that of
induction treatment on distant progression (pooled
hazard ratios, 1.04; 95% CI 0.86–1.25; p = 0.69).
Radiation therapy and concurrent chemotherapy
increased acute esophageal toxicity (grade 3–4) from 4
to 18% with a relative risk of 4.9 (95% CI 3.1–7.8;
420
p \ 0.001). There was no significant difference
regarding acute pulmonary toxicity. Overall conclu-
sion of this meta-analysis was that radiation therapy
and concurrent chemotherapy, as compared with
induction chemotherapy and radiation therapy,
improved survival of patients with locally advanced
nonsmall cell lung cancer, primarily because of a better
locoregional control, but at the cost of manageable
increased acute esophageal toxicity.
With three meta-analyses the story of superiority
of radiation therapy and concurrent chemotherapy
over the induction chemotherapy followed by radical
radiation therapy seems to finally be over. Further
studies should attempt to optimize concurrent
approach only as it seems that there are still, however,
a number of unsolved issues.
While we are embarking on these efforts, one par-
ticular issue could easily be solved. Radiation therapy
and concurrent cemotherapy is still labelled as CHE-
MORADIATION. More appropriate, however, termi-
nology for a combination of radiation therapy and
concurrent chemotherapy is RADIOCHEMOTHER-
APY. If one gives 65–70 Gy of radiation therapy
and either daily low-dose chemotherapy or weekly
chemotherapy or even more protracted chemotherapy
(i.e. cisplatin, 100 mg/sqm, day 1 and etoposide,
120 mg/sqm, days 1–3, q 3 weeks) how this can be
called chemoradiation? Perhaps chemoradiation was
more appropriate term in ancient times, when one
started with chemotherapy. Since this sequencing is
inferior to one including radiation therapy from the
onset, the term ‘‘chemoradiation’’ should be put into the
museum of history of failures. Radiation therapy is
THE mainstay of the treatment and chemotherapy is
used to support these effects, this or that way. There-
fore, RADIOCHEMOTHERAPY should be preferen-
tially used as the term appropriate for all concurrent
regimens, deemed today as standard of treatment in
locally advanced nonsmall cell lung cancer, as recently
shown by tree meta analysis (O’Rourke et al. 2010;
Liang et al. 2010; Aupérin et al. 2010).
6 Optimization of Concurrent
Radiochemotherapy
In order to optimize combined modality approach in
patients with locally advanced nonsmall cell lung
cancer several new attempts have been undertaken.
B. Jeremić et al.
While Jeremic et al. (1998) tested the addition of
weekend carboplatin/etoposide to concurrent hyper-
fractionated radiation therapy (69.6 Gy) and low-dose
daily carboplatin/etoposide in phase II study leading
to promising median survival time of 29 months and
5-year survival in 25%, the results of their subsequent
prospective randomized trial showed no advantage for
weekend chemotherapy when compared to no week-
end chemotherapy (the median survival time, 22 vs.
20 months; 5-year survival, 23% vs. 20%; p = 0.57)
(Jeremic et al. 2001). In their continuous efforts to
address important questions in this disease and the
setting of radiation therapy and concurrent chemo-
therapy, Jeremic et al. (2005) (Table 1) recently
pioneered a combined modality approach consisting
of hyperfractionated radiation therapy and concurrent
low-dose daily paclitaxel and carboplatin. In order to
increase likelihood of successfully combating accel-
erated proliferation of tumour clonogens, they have
adapted their initial standard regimen (69.6 Gy in 58
fractions of 1.2 Gy given b.i.d) in 6 weeks to 67.6 Gy
in 52 fractions of 1.3 Gy given also bid, but in a
5-week total treatment time, saving approximately 1
week. Paclitaxel was given in a daily dose of 10 mg/
sqm, while carboplatin was given in a daily dose of
25 mg/sqm. In 64 patients with stage III nonsmall cell
lung cancer very promising median survival time of
28 months and a 5-year survival rate of 26% were
obtained, accompanied with low incidence of high-
grade toxicity. These results again reconfirmed
effectiveness and low toxicity of hyperfractionated
radiation therapy and concurrent low-dose daily
chemotherapy.
Last decade witnessed a particular approach aimed
to optimize radiation therapy and concurrent chemo-
therapy (Table 2). By adding more chemotherapy
after the end of concurrent radiation therapy and
chemotherapy, i.e. posterior, adjuvant, consolidation
chemotherapy, better treatment of microscopic dis-
ease is sought. Results of several available phase II
studies are given in table. First of such reports seem to
be that of Lau et al. (2001) who tried to address the
issue of somewhat poorer distant metastasis control
by increasing the dose of chemotherapy. They have
used concurrent radiation therapy (61 Gy) and che-
motherapy consisting of twice weekly paclitaxel for
6 weeks and once weekly carboplatin for 6 weeks.
Two cycles of consolidation paclitaxel and carbo-
platin were offered to patients who achieved a
Radiochemotherapy in Locally Advanced Nonsmall-Cell Lung Cancer
Table 2 Locally advanced nonsmall cell lung cancer consolidation chemotherapy studies
Study Year Concurrent RT-CHT
Lau et al. 2001 RT/TC
Albain et al. 2002 RT/PE
Gandara et al. 2003 RT/PE
Sakai et al. 2004 RT/DC
Sekine et al. 2006 RT/PV
Hanna et al. 2008 RT/PE
RT/PE
RT radiation therapy, CHT chemotherapy, MST median survival time, T paclitaxel, C carboplatin, P cisplatin, E etoposide, DOC
docetaxel, V vinorelbine
complete response (CR), partial response (PR), or
stable disease (SD). The median survival time was
17 months and 2-year actuarial survival rate was
40%. Another report comes also from Southwest
Oncology Group phase II study by Albain et al.
(2002) which used two cycles of cisplatin/etoposide
concurrently with conventionally fractionated 45 Gy
in pathologic Stage IIIB nonsmall cell lung cancer.
In the absence of progressive disease, additional
16 Gy was administered with two additional cycles of
cisplatin/etoposide. The median survival time was
15 months and 3- and 5-year survival was 17 and
15%, respectively. However, grade 4 neutropenia was
observed in 32% patients, grade 3–4 anemia in 28%
patients, and grade 3–4 esophagitis in 20% patients.
More recently, and quite encouragingly, the South
West Oncology Group reported a trial in which con-
current cisplatin/etoposide/radiation therapy was fol-
lowed by three cycles of adjuvant high-dose docetaxel
(Gandara et al. 2003). The median survival in this
phase II study was an extremely impressive
26 months, and this has become the basis for ongoing
South West Oncology phase III studies. Sakai et al.
(2004) also reported on a phase II study which
employed bi-weekly docetaxel and carboplatin with
concurrent radiation therapy (60 Gy in 30 daily
fractions) followed by consolidation chemotherapy
with docetaxel plus carboplatin in patients with stage
III unresectable nonsmall cell lung cancer. Among 32
evaluable patients, impressive response rate of 91%
was obtained. The median survival time was
27 months and a 2-year survival was 61%. High-
grade toxicity was low. Most recently, another phase
II study from Japan (Sekine et al. 2006) provided the
data on the use of docetaxel consolidation therapy
following thoracic radiation therapy and concurrent
421
Consolidation CHT MST (mo) Survival
TC 9 2 17 40% (2 yr)
PE 9 2 15 17% (5 yr)
DOC 9 3 26 29% (5 yr)
DC 9 2 27 61% (2 yr)
DOC 9 3 30 43% (3 yr)
No 23.2 26% (3 yr)
DOC 9 3 21.2 27% (3 yr)
cisplatin and vinorelbine in patients with unresectable
stage III non-small cell lung cancer. The median
progression-free survival was 12.8 (CI 10.2–15.4)
months, and median survival was 30.4 (CI 24.5–36.3)
months. The 1-, 2-, and 3-year survival rates were
80.7, 60.2, and 42.6%, respectively. The most com-
mon reason for discontinuation was pneumonitis,
which developed in 14 (24%) of the 59 patients.
During consolidation therapy, grade 3 or 4 neutro-
penia, esophagitis, and pneumonitis developed in
51, 2, and 4 patients, respectively. A total of four
patients died of pneumonitis.
Promising results of several phase II studies dis-
cussed above clearly called for verification in a phase
II study design. In such an attempt, Hosier Oncology
Group (Hanna et al. 2008) enrolled eligible patients
with stage IIIA or IIIB nonsmall cell lung cancer,
baseline performance status of 0–1, forced expiratory
volume in 1 s C 1 L, and less than 5% weight loss.
Patients received cisplatin 50 mg/sqm intravenously
(IV) on days 1, 8, 29, and 36 and etoposide 50 mg/
sqm IV on days 1–5 and 29–33 concurrently with
chest radiation therapy to 59.40 Gy. Patients who did
not experience progression were randomly assigned to
docetaxel 75 mg/sqm IV every 21 days for three
cycles versus observation. Grade 3–5 toxicities during
docetaxel included febrile neutropenia (10.9%) and
pneumonitis (9.6%); 28.8% of patients were hospi-
talized during docetaxel (vs. 8.1% in observation
arm), and 5.5% died as a result of docetaxel.
The median survival time for all patients (n = 203)
was 21.7 months; the median survival time was
21.2 months for docetaxel arm compared with
23.2 months for observation arm (p = 0.883). Based
on these results, authors concluded that consolidation
docetaxel after radiation therapy and concurrent
422
cisplatin/etoposide results in increased toxicities but
does not further improve survival compared with
radiation therapy and concurrent cisplatin/etoposide
alone in patients with stage III inoperable nonsmall
cell lung cancer. Finally, Kelly et al. (2008) reported
on a study that used targeted agents in consolidation
phase. Untreated patients with stage III nonsmall cell
lung cancer, a performance score of 0–1, and ade-
quate organ function were eligible. All patients
received cisplatin 50 mg/sqm on days 1 and 8 plus
etoposide 50 mg/sqm on days 1–5, every 28 days for
two cycles with concurrent thoracic radiation (1.8- to
2-Gy fractions per day; total dose, 61 Gy) followed
by three cycles of docetaxel 75 mg/sqm. Patients
whose disease did not progress were randomly
assigned to gefitinib 250 mg/day or placebo until
disease progression, intolerable toxicity, or the end of
5 years. An unplanned interim analysis conducted
rejected the alternative hypothesis of improved sur-
vival. The study, therefore, closed, and preliminary
results were reported. The median survival time was
23 months for gefitinib (n = 118) and 35 months for
placebo (n = 125; two-sided p = 0.013). The toxic
death rate was 2% with gefitinib compared with 0%
for placebo. Authors concluded that in this unselected
population, gefitinib did not improve survival.
Decreased survival was a result of tumor progression
and not gefitinib toxicity. This study showed not only
inefficiency of targeted agent gefitinib, but recon-
firmed inefficiency of consolidation chemotherapy
approach in locally advanced nonsmall cell lung
cancer.
These disappointing results largely stopped the use
of consolidation chemotherapy in this disease. While
reasons for such inefficiency may be multiple, it is
challenging to disclose some basic aspects that may
have adversely influenced the outcome from the
onset. Indeed, by virtue of the intervention, this
approach has two parts, a concurrent one and a con-
solidation one. In various studies, the same or dif-
ferent drugs were administered during the latter part
of combined treatment. Regardless of the underlying
principle for such an intervention, these studies nicely
outlined overall results, relapse-free-survivals and
clearly documented toxicity. The latter was divided
between the concurrent and the consolidation part and
we have all been able to learn more about exact
toxicity the first or the second part of the treatment
were leading to. Unfortunately, this did not happen
B. Jeremić et al.
with the patterns of failure. While these studies pre-
sented very detailed pattern of failure in general, this
was done for the whole time period of the study
(treatment plus follow-up). This way we only learned
about the total patterns of failure and not about which
type of failure was observed when, i.e. after concur-
rent or after consolidation part, and particularly in
which patients after the concurrent part, although
some studies mandated consolidation chemotherapy
in non-progressing patients.
One may, therefore, ask why exact pattern of
failure is important? It is important from several
standpoints, some of which are briefly outlined here.
First, there are several types of patients after the ini-
tial (concurrent) part of radiochemotherapy and they
can easily be separated regarding the response. While
it is extremely unlikely that those achieving a SD
would benefit from the consolidation chemotherapy,
those with either a CR or a PR seems as likely can-
didates (although not all of them) to benefit from the
consolidation chemotherapy. Separation, therefore, of
pattern of failure occurring in likely (CR and PR) and
unlikely (SD) candidates could be used for further
studies using similar design with respect to, e.g. eli-
gibility criteria. Second, and more importantly,
among likely candidates (CR and PR) to benefit from
consolidation chemotherapy, a distinction should be
made between those achieving CR and those
achieving PR after concurrent radiochemotherapy.
This is so, since different mechanisms (precisely,
different location) of action of consolidation chemo-
therapy would be expected. In the CR patients, con-
solidation chemotherapy would target microscopic
disease both intrathoracically and extrathoracically,
while in the PR patients, it would have to deal with
clinically overt intrathoracic disease and a micro-
scopic one extrathoracically. It is obvious that pattern
of failure in these two distinct groups of patients
would then clearly show how and where consolidation
chemotherapy is actually acting and to what extent
(clinical versus subclinical). Of additional importance
is that with clear pattern of failure, we would be able
to open the door of investigating the determinants of
treatment outcome such as cross-resistance between
drugs or drugs and radiation therapy. This would also
lead to investigating more of the inherent nature of
these treatment modalities such as total dose or
fractionation (for radiation therapy) or one or more
drug(s) combination (e.g. the same or different drugs
Radiochemotherapy in Locally Advanced Nonsmall-Cell Lung Cancer
in the concurrent and the consolidation part of the
treatment), especially important due to forthcoming
generation of drugs waiting to widely enter clinical
practice.
Although identifying pattern of failure in patients
achieving different response after concurrent radio-
chemotherapy may require some additional measures
and likely place additional burden on investigators
and hospitals, this effort would be eventually
rewarding. This way we would be able to discriminate
between different patients and different options and to
proceed (or not) with a consolidation therapy in one
or more patient subsets, an approach which would
ultimately lead to better patient-tailored treatment
sequence, a must for a clinical research in lung cancer
in the future.
One of the unsolved question on ‘‘optimization’’ of
concurrent radiochemotherapy, particularly from the
standpoint of radiation oncology, is the type of frac-
tionation; conventional, once daily or altered frac-
tionation, employing multiple fractions per day
(hyperfractionation). The Radiation Therapy Oncol-
ogy Group 8311 study (Cox et al. 1990) showed a
possible advantage only for a hyperfractionated
radiation therapy dose of 69.6 Gy, 1.2 Gy b.i.d.
fractionation (but not beyond it) over standard 60 Gy
given in 30 daily fractions in a favourable subset of
locally advanced nonsmall cell lung cancer, Radiation
Therapy Oncology Group 9410, while not statistically
designed to directly compare standard vs. altered
fractionation, appeared to show no survival difference
between conventional, once daily and hyperfraction-
ated radiation therapy when both given with concur-
rent chemotherapy. Interestingly, when compared to
conventionally fractionated radiation therapy, hyper-
fractionated radiochemotherapy offered better local
control in the Radiation Therapy Oncology Group
9410, but this did not translate into a difference in
survival. Another study came to the same conclusion,
albeit of somewhat different treatment approach. In
the North Central Cancer Treatment Group/Mayo
Clinic phase III study (Schild et al. 2002) conven-
tionally fractionated radiation therapy (60 Gy) was
compared to split-course hyperfractionated radiation
therapy using 30 Gy given in 20 fractions in ten
treatment days in 2 weeks with a 2-week break after
which another 30 Gy were given using the same
fractionation. Both conventionally fractionated and
hyperfractionated radiation therapy groups received
423
concurrent cisplatin/etoposide. No difference in
toxicity was seen and no statistically significant dif-
ference in treatment outcome, although hyperfrac-
tionated radiation therapy offered numerically slightly
better survival, and local control.
Further attempts to optimize the treatment
approach in this disease include radiation therapy
given concurrently with ‘‘third generation’’ drugs.
While all ‘‘third generation’’ drugs have been tested in
this setting, prospective randomized phase III studies
are lacking. Regardless, it seems that paclitaxel/car-
boplatin combination has similar efficacy and likely
less toxicity than either cisplatin- or other multiagent-
based chemotherapy (Kelly et al. 2001; Schiller et al.
2002). A number of phase II studies tested this
combination (Choy et al. 1998; Choy et al. 2000; Lau
et al. 2001; Jeremic et al. 2005) with promising
results. The first prospective study comparing radia-
tion therapy/paclitaxel versus radiation therapy alone
showed advantage for radiation therapy/paclitaxel
(the median survival time, 15.2 vs. 12 months;
p = 0.027) (Ulutin and Pak 2003). Testing paclitaxel/
carboplatin combination and standard-fraction radia-
tion therapy (63 Gy) in three schedules, Choy et al.
(2002) used either pre-radiation therapy chemother-
apy followed by radiation therapy (arm 1), pre-radi-
ation therapy and concurrent radiochemotherapy (arm
2), and concurrent radiochemotherapy and post-radi-
ation therapy chemotherapy (arm 3). Although this
phase II randomized study was not designed to sta-
tistically compare treatment arms, nevertheless, the
best results were achieved in the arm 3 (the median
survival time, 16.1 months; 2-year survival, 33%).
Also, in the arm 2 there was suboptimal compliance
with concurrent radiochemotherapy after induction
chemotherapy in arm 2.
7 New Approaches in Radiation
Therapy and Chemotherapy
of Locally Advanced Nonsmall-Cell
Lung Cancer
Some of the newer approaches regarding the chemo-
therapy have been mentioned above. It is also
expected that more new drugs will become more
readily available in the future and that the process of
their initial clinical testing (phase I–III) include test-
ing for their radioenhancing potentials which would
424
go in parallel to its testing for anticancer chemo-
therapy purposes. This way, we would be able earlier
to learn about drug properties, both alone or in
combination with radiation therapy and to address
important issues of optimal sequencing radiation
therapy and chemotherapy in locally advanced
disease.
Regarding radiation therapy, wide application of
powerful computers made a substantial impact on
treatment planning and delivery. Three-dimensional
conformal radiation therapy is now increasingly being
practiced worldwide. With radiation therapy fields
tailored to include only detectable tumour, more
focused and escalated radiation therapy doses can be
given. Phase I/II studies have shown that radiation
therapy doses at the order of C80 Gy are being fre-
quently used with acceptable toxicity (Armstrong
et al. 1993, 1997; Robertson et al. 1997), and that the
radiation therapy concepts of the necessity of elective
nodal irradiation may be challenged. It should, how-
ever, be mentioned that with even with limited field
radiation therapy in three-dimensional conformal
radiation therapy, some incidental elective nodal
irradiation always occur, and may approach
45–50 Gy, considered as the radiation therapy dose
necessary for elective treatment (Martel et al. 1999;
Rosenzweig et al. 2001). In addition to increasing
target coverage and allowing radiation dose escala-
tion, the use of three-dimensional conformal radiation
therapy also allows more accurate prediction of tox-
icity of a given course of radiation therapy (Graham
1997; Kwa et al. 1998).
Intensity-modulated radiotherapy has also been
used in locally advanced nonsmall cell lung cancer
and potential advantages of intensity-modulated
radiation therapy became evident when one compares
the three-dimensional conformal radiation therapy
and intensity-modulated radiation therapy plans
(Yorke 2001). With intensity-modulated radiation
therapy, in majority of cases the prescription dose
could be increased. This was coupled with the
decreased lung dose and improved planning target
volume uniformity, as well as significantly reducing
cumulative radiation therapy dose to the oesophagus
while maintaining the same or higher dose to gross
disease (Giraud et al. 2001). While extracranial ste-
reotactic radiosurgery and stereotactic fractionated
radiation therapy were initially used only for small
(early stage) (Uematsu et al. 1998; Hara et al. 2002;
B. Jeremić et al.
Fukumoto et al. 2002; Nagata et al. 2002; Whyte et al.
2003; Hof et al. 2003; Timmerman et al. 2003;
Onimaru et al. 2003) tumours, its application is
slowly extending to tumours being classified as
locally advanced. It is not unrealistic to expect that
extracranial stereotactic radiosurgery and stereotactic
fractionated radiation therapy will play an important
role in metastatic nonsmall cell lung cancer, par-
ticularly in cases with favourable characteristics
(response to chemotherapy, single metastatic lesion,
small primary tumours, etc.). However, it should be
clearly emphasized that proper selection of patients
remains prerequisite for the use of these new tech-
nologies in locally advanced and/or metastatic non-
small cell lung cancer. On the other side, proper
selection of patients suitable for any form of com-
bined radiation therapy and chemotherapy, may
enable using the two modality approach in non-
curative approach. In such one study, Nawrocki et al.
(2010) reported on a of a randomized phase II study
using (A) palliative radiation therapy given alone
(30 Gy/10 fractions) versus (B) the same palliative
radiation therapy given with concurrent chemother-
apy (two cycles of cisplatin and vinorelbine followed
by radiation therapy together with third cycle) in
patients with stage IIIA to IIIB nonsmall cell lung
cancer not eligible for radical (tumor [8 cm and/or
forced expiratory volume B40%, performance status
0–2, and existing tumour-related chest symptoms) A
total of 99 patients were eligible for response, overall
survival, and progression-free survival evaluation.
Median age was 66 years (45–78 years). Response
rate was 27% vs. 53%, p = 0.08; median overall
survival was 9.0 vs. 12.9 months, p = 0.0342; and
median progression-free survival was 4.7 vs.
7.3 months, p = 0.046, in arm A versus arm B,
respectively. There were no deaths during treatment
in arm A and six deaths in arm B; no haematological
grade 3–4 toxicities in arm A and 14 toxicities in arm
B. Symptom control was high and similar in both
arms. Upfront chemotherapy combined with palliative
radiation therapy (30 Gy) may be a promising treat-
ment option in the subpopulation of patients with
stage IIIA to IIIB non-small cell lung cancer not
amenable for definitive radiochemotherapy and
deserves further investigation.
Although hardly termed as ‘‘new approach’’, the
use of radioprotectors faced renewed clinical interest
in a protection of radiation therapy-induced toxicity.
Radiochemotherapy in Locally Advanced Nonsmall-Cell Lung Cancer
Several studies reported on the use of amifostine
during radiation therapy and chemotherapy in lung
cancer. Antonodou et al. (2001) performed a ran-
domized phase III trial of radiation therapy with or
without daily amifostine in patients with advanced
stage lung cancer. The incidence of pneumonitis C2
was significantly lower in the amifostine group as
well as incidence of esophagitis Cgrade 2, and the
protective effect of amifostine enabled lower inci-
dence of late damage, too, with no effect on treatment
outcome. Further evidence came from Komaki et al.
(2002) who administered amifostine twice weekly
before treatment in patients with inoperable nonsmall
cell lung cancer treated with concurrent radioche-
motherapy. They observed that Morphine intake to
reduce severe esophagitis was significantly lower in
the amifostine arm as well as was the incidence of
acute pneumonitis in the treatment arm. Finally, a
randomized double-blind study (Leong et al. 2003)
showed a trend for fewer patients showing toxicity in
the amifostine group. The Radiation Therapy Oncol-
ogy Group has just reported preliminary results on
study Radiation Therapy Oncology Group 98-01,
which randomized patients to intensive chemoradia-
tion (Induction carboplatin/paclitaxel followed by
hyperfractionated radiation therapy to 69.6 Gy with
concurrent weekly carboplatin/paclitaxel) with or
without amifostine four times per week during radi-
ation therapy. Although there was no difference in the
rate of Grade 3 esophagitis, patient-reported area-
under-the-curve swallowing dysfunction scores were
significantly lower in the amifostine group (Movsas
et al. 2003) It is expected that more studies regarding
the issue of optimal protection with amifostine will
provide more data on further optimization before
becoming a standard adjunct to radiation therapy or
radiochemotherapy treatments in the future.
8 Conclusions
Locally advanced nonsmall cell lung cancer is one of
the major targets for clinical research in lung cancer.
While it was accounted for approximately 40% of all
cases, it is expected that widespread use of positron
emission tomography (leading to more precise staging
of patients) will likely decrease in the number of
patients falling into stage III nonsmall cell lung can-
cer. This is because patients clinically or even
425
pathologically staged as IIIB and a minority of those
staged as IIIA will actually have metastatic burden
from the outset, undiagnosed with current diagnostic
tools. This is supported by simple observation of the
natural history of this disease, regardless of the
treatment: there are always some patients who fail
distantly several months or a year after the diagnosis.
These patients are likely to be ones who would be
upstaged by the use of positron emission tomography
and moved to stage IV (metastatic disease). On the
other hand, it is expected that a proportion of patients
with early stages (I and II) nonsmall cell lung cancer
will also be upstaged, and will likely increase the
number of patients actually having stage III (locally
advanced) disease. Whatever predominates, locally
advanced nonsmall cell lung cancer will remain one
of the major focuses of clinical research in lung
cancer simply because major improvements occurred
here and they have occurred owing to optimized
combined modality treatments, notably combined
radiation therapy and chemotherapy. There is con-
tinued discussion regarding the role of surgery for
these patients (Taylor et al. 2004). Four randomized
studies note no overall survival differences comparing
operative vs. non-operative approaches in patients
with stage III lung cancer (Shepherd et al. 1998;
Johnstone et al. 2002; van Meerbeeck et al. 2007;
Albain et al. 2009). An unplanned subset analysis of
the most contemporary of these trials, Intergroup-
0139 (Albain et al. 2009), did suggest a difference on
survival based on surgical approach. That is, mortality
rates with pneumonectomy were excessively high,
while lobectomy patients appeared to have improved
outcomes. It remains nonetheless appropriate to con-
clude that the sum of the evidence to date supports the
proposition that a non-surgical approach constitutes
the ‘‘standard’’ for stage III patients. Radiation ther-
apy and chemotherapy will therefore, further evolve
in the near future and will bring us to the exiting era
of more successful clinical research, leading ulti-
mately to better outcome in this disease.
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 Tri-Modality Therapy in Locally Advanced
Non-Small-Cell Lung Cancer
Jan P. van Meerbeeck and Elke Vandenbroucke

Contents
1 Introduction.............................................................. 434
2 Stage III Without Mediastinal Lymph Node
Involvement .............................................................. 434
3 Stage III with Mediastinal Lymph Node
Involvement .............................................................. 437
4 Discussion and Future Directions.......................... 440
5 Conclusion ................................................................ 442
References.......................................................................... 442
Abstract
This review addresses recent evidence on the role
of surgery in different clinical subsets of so called
’potentially resectable’ stage III NSCLC. In some
selected subsets of stage III patients, in particular
those with T3-4N0-1, surgery plays a key role.
Resection has to be decided on by a multidisci-
plinary team and carried out in a high volume
institution by an experienced team. In all patients
who are being considered for resection, accurate
staging of the mediastinum and excluding occult
metastasis is recommended. Comorbidities of
patients have considerable influence on the overall
treatment plan in each individual patient. The
preferred mode of treatment for locally advanced
NSCLC with clinical mediastinal lymph node
invasion is a combined modality treatment with
concurrent chemo- and radiotherapy.

Keywords
Chemoradiotherapy
Combined modality
Non-
small cell lung cancer
Stage III
Surgery

Abbreviations
J. P. van Meerbeeck (&)
Department of Respiratory Medicine, NSCLC Non-small cell lung cancer
University Hospital Ghent, OS Overall survival
De Pintelaan 185, 9000 Ghent, Belgium PFS Progression-free survival
e-mail: jan.vanmeerbeeck@ugent.be SST Superior sulcus tumor
J. P. van Meerbeeck R0 Complete resection
Department of Respiratory Medicine, pCR Pathological complete response
Lung Oncological Network Ghent University Hospital,
Ghent, Belgium
E. Vandenbroucke
Department of Respiratory Medicine,
Monica Hospital, Antwerp, Belgium

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 433
DOI: 10.1007/174_2011_306, Ó Springer-Verlag Berlin Heidelberg 2011
434 J. P. van Meerbeeck and E. Vandenbroucke

Table 1 Definition of clinical subsets in stage III NSCLC according to the current and the proposed new TNM-classification
Description TNM (Mountain 1997) Stage Proposed TNM Stage
(Goldstraw et al. 2007)
Without mediastinal lymph node involvement
Chest wall invasion including SST or tumor T3N1 IIIA T3N1 IIIA
\2 cm distal to main carina
Central tumor with local invasion T4N0-1 IIIB T4N0-1 IIIA
Same lobe nodules T4N0-1 IIIB T3N0 IIB
T3N1 IIIA
Malignant pleural effusion T4N0-1 IIIB M1a IV
With mediastinal lymph node involvement
Ipsilateral mediastinal nodes T1-3N2 IIIA T1-3N2 IIIA
Same lobe nodules T4N2 IIIB T3N2 IIIA
Central tumor with local invasion T4N2 IIIB
Contralateral or supraclavicular nodes T1-4N3 IIIB T1-4N3 IIIB
TNM tumor-node-metastasis, SST superior sulcus tumor

1 Introduction 2 Stage III Without Mediastinal

Lung cancer has become the leading cause of death
among cancers worldwide. Non-small-cell lung
cancer (NSCLC) accounts for approximately 85% of
all cases and has a poor overall 5-year survival of
about 15% (Molina et al. 2008). At the time of pre-
sentation, at least 40% of patients are diagnosed in an
advanced stage and about one-third have locally-
advanced (stage III) disease, which is a heterogeneous
group of patients ranging from either T3N1 over
advanced T4 tumors, positive mediastinal lymph
nodes or malignant pleural effusion in the current
TNM-classification (Mountain 1997; Goldstraw et al.
2007). The standard of care for most patients is a
combined modality treatment, wherein the role of
surgery remains controversial.
This review addresses recent published evidence
on the role of surgery in different clinical subsets of
so-called ‘potentially resectable’ stage III NSCLC
(Table 1). A discussion of the different induction
regimens is beyond the limits of this review.
The evidence was retrieved from ‘PubMed’ using
the keywords (surgery), (non-small-cell lung cancer)
and limited to original reports published from 2007
onward. The articles were then selected manually for
further appropriateness.
Lymph Node Involvement
Superior sulcus tumors (SST) are a distinct group
among NSCLC because of their localization and
clinical presentation. A combined modality treatment
was first presented with the results of preoperative
radiotherapy followed by resection (Shaw et al.
1961). During the following decades, this approach
remained the standard of care with 5-year survival
rates up to 30%, but less than 10% for patients with
N2-disease. Loco-regional recurrence was the com-
monest cause of relapse, emphasizing the need for
better loco-regional treatment strategies.
Two multi-centric phase 2 trials (Rusch et al. 2007;
Kunitoh et al. 2008) have recently shown high
resectability, local control rates and survival using a
tri-modality regimen consisting of induction plati-
num-based chemoradiotherapy followed by surgery
(Table 2).
The Southwest Oncology Group (SWOG) (Rusch
et al. 2007) treated 110 patients with T3-4 SST without
mediastinal lymph node involvement with two cycles of
cisplatin-etoposide and concurrent radiation. After
induction, of 95 patients without progression, 88 under-
went thoracotomy. All patients, whether or not resected,
received two additional cycles of chemotherapy. Median
Table 2 Recent evidence for surgery in superior sulcus, central T4 and multifocal T4 NSCLC
Author Setting Stage Analyzed Regimen Pneumo- Exploratory Clinical R0 Pathological pCR Treatment Median 2-3-5-year PFS
populations nectomy thoracotomy response resection downstaging (%) mortality survival survival (%) (mo)
(n) (n) (%) (%) (%) (%) (mo)
Superior sulcus tumors
Rusch et al. Phase 2 trial cT3-4 ITT 2 cycles CE ? RT — — 42 76 — 29 4.5 33 NR-NR- 44 —
(2007) N0-1 (n = 110) (45 Gy) ? surgery
SWOG ? 2 cycles CE
PP 3 2 43 — 33 36 — 94 (R0) NR-NR- 55 —
9416
(n = 88) (R0)
Intergroup
trial 0160
Kunitoh Phase 2 trial cT3-4 ITT 2 cycles MVP ? RT — — 61 68 — 16 4 — NR-62-56 28
et al. (2008) N0-1 (n = 75) (45 Gy) ? surgery
JCOG ± boost RT (21.6 Gy) if
PP 0 1 — — 40 — — — NR-NR- 70 —
9806 unresectable disease
(n = 57) (R0)
Marra et al. Prospective cT3-4 ITT 3 cycles CE or — — 48 — — — 6 54 74-NR- 46 52
(2007) serie N0-3 (n = 31) CP ? 1 cycle (5-
CE ? 45 Gy year)
? surgery
PP 1 0 — 100 38 45 — — — —
(n = 29)
Pourel et al. Prospective cT3-4 ITT 2 cycles CE + 45 Gy ? — — NR — — — — 26.7 55-NR-40 15.2
(2008) serie N0-2 (n = 107) surgery
± adjuvant treatment
PP 21 1 — 90 60 39 6 36.4 62-NR-51 20.9
(n = 72)
Yildizeli Retrospective cT4 ITT Neoadjuvant — — NR — NR — 1 28 NR-NR- 37 —
et al. (2008) serie N0-1 (n = 126) treatment ? surgery
± adjuvant treatment
PP 3 0 — 90 — NR — — NR-NR- 39 —
(n = 126) (R0)
Tri-Modality Therapy in Locally Advanced Non-Small-Cell Lung Cancer

Author Setting Extension No. cN0-1 (%) cN2-3 Pneumo- Neoadjuvant Adjuvant R0 pCR 30 day Median 5-year survival according to nodal status
patients (%) nectomy (n) treatment (%) treatment resection (%) mortality survival
pN0-3 (%) pN0 (%) pN1 (%) pN2-3 (%)
(%) (%) (%) (mo)
Central T4 tumors
Yildizeli Retrospective Carina 92 87 23 29 98 — 6 28 42 40 47 18
et al. (2008) serie SVC 39 100 0 32 36 59 85 — 8 19 29
Mediastinum 14 12 43 64 86 — 7 37 61
De Leyn Prospective PA 5
et al. (2009) serie LA 5 100 0
Aorta 3 ITT n = 32 — 100 100 78 NR — NR 74 — — —
Mediastinum 3 PP n = 27 11 100 100 93 7 0 NR 77 (R0) — — —
Subclavian artery 1
SST 15
Misthos Retrospective Aorta 13 100 0 5 0 10 100 — 0 38 31 100 37 0
et al. (2007) serie SVC 9 100 0 0 0 100 NR — 0 31 11 NR NR NR
Farjah et al. Retrospective Not specified 1177 68 22 20 4–8 40–55 NR NR 10 NR 20 28 NR 8
(2008) serie
Wu et al. Retrospective PV or LA 46 93 7 30 22 100 NR NR 0 NR 22 29 28 18 (3-year)
(2009) serie
Anraku Retrospective Spine 23 NR NR 1 100 NR 83 43 9 47 58 (3-year) NR NR NR
et al. (2009) serie 72 (R0)
435

(continued)
 436 J. P. van Meerbeeck and E. Vandenbroucke

PFS progression free survival, R0 microscopically radical resection, pCR pathological complete response, CE cisplatin-etoposide, CP cisplatin-paclitaxel, RT radiotherapy, NR not reported, MVP mitomycin ? vindesine or vinblastine ? cisplatin,
survival for all eligible patients was 33 months versus

pN+
5-year survival

(%)

NR
94 months for the patients who underwent complete

—
30
47
according to
nodal status
pN0
resection (R0). Pathological complete response (pCR)
(%) was a significant prognostic factor for survival. Relapse

48
—
58

64
was predominantly distant with the brain as the
commonest site.
survival (%)

The Japanese Clinical Oncology Group (JCOG)

5-year

—
—
48

57
(Kunitoh et al. 2008) included 75 patients with T3-4
N0-1 tumors from 19 centers. Of the patients who
survival (mo)

started induction treatment, 57 (76%) underwent sur-

gical resection. Fiftyone (68%) patients had a R0
Median

PP per protocol (operated patients), ITT intention-to-treat population, PV pulmonary vein, LA left atrium, SVC superior vena cava, PA pulmonary artery, SST superior sulcus tumor, mo months
45.4
22.8

resection with pCR in 16%. In un-resected or incom-

44

68

pletely resected cases, boost radiotherapy was admin-

mortality (%)

istered. The 3- and 5-year overall and progression-free

survival rates were 61, 56, 49, and 45%, respectively.
30 day

NR

In contrast to the SWOG trial (Rusch et al. 2007),

4
0

subset analysis revealed that patients with clinical

pN2/3

T3-disease had a better outcome than those with clin-

(%)

100
49
0
7

ical stage T4. The clinical N-stage and histologic type

of the tumor did not significantly affect the overall
[1 satellite

survival (OS) or progression-free survival (PFS). As

lesion (%)

expected, the survival rate was good in patients in

NR
30
19

whom R0 resection could be achieved with a projected

5-year OS of 70% compared to 24% in incompletely
resected patients. For un-resected or incompletely
lesion (%)
1 satellite

resected cases, loco-regional relapse was predominant.

NR
32
81

91

For completely resected cases, relapse at distant sites

was the most frequent pattern of recurrence with some
R0 resection

patients only relapsing in the brain.

(%)

100
100

NR

The results of both trials have further been confirmed

86

by other recent prospective and retrospective series

(Table 2) (Marra et al. 2007; Pourel et al. 2008; Yildizeli
nectomy (n)
Pneumo-

et al. 2008; De Leyn et al. 2009). A tri-modality

NR
12

approach is feasible in most series with a reasonably low

0

mortality and tolerable morbidity rate. The survival data,

cT4
(%)

NR

with a 5-year OS rate in the intention-to-treat population

15

51
0

of 44% in the US trial and 56% in the Japanese trial, are

patients

clearly superior to the historical value of 30%. Most if

No.

56
67
53

35

not all series show the following factors to be predictive

of success: R0 resection, lobectomy, pCR and absence of
pT4N+
pT4N0
Stage

cT4/

cT4/
pT4

pT4

invasion in either the intervertebral foramina, subclavian

artery or brachial plexus. Ipsilateral supraclavicular
Retrospective
Retrospective

Retrospective

lymph node involvement, only specified in the JCOG,

Table 2 (continued)
Setting

was not prognostic. Other variables such as age, gender,

serie
serie

serie

performance status or histological subtype had no

Multifocal T4 tumors

influence on survival.
Trousse et al.

Although there are no formal randomized trials,

Port et al.

Rao et al.
Author

preoperative chemoradiotherapy followed by surgical

(2008)
(2007)

(2007)

resection is now regarded as the optimal management

Tri-Modality Therapy in Locally Advanced Non-Small-Cell Lung Cancer
for locally-invasive tumors of the superior sulcus in
carefully selected patients without mediastinal lymph
node involvement.
Patients with central T4 tumors have invasion of
either the heart, great vessels, trachea, esophagus or
vertebrae (Mountain 1997). Most patients have also
mediastinal lymph node involvement. They are often
considered unresectable and treated with chemoradia-
tion, as is generally recommended for patients with
stage IIIB NSCLC (Shen et al. 2007; Jett et al. 2007).
Although there are no randomized data, cumulative
evidence suggests that selected T4 tumors without
mediastinal lymph nodes can be resected with better
long-term outcome than historically-associated with
stage IIIB NSCLC as shown in Table 2 (Yildizeli et al.
2008; De Leyn et al. 2009; Misthos et al. 2007; Farjah
et al. 2008; Wu et al. 2009; Anraku et al. 2009). The
largest retrospective cohort study (Anraku et al. 2009)
reports on 1,177 operated patients with T4 tumors with
a 20% 5-year survival rate, although they were not
stratified according to their localization. The largest
experience of resection for central T4 tumors involves
carinal resection usually together with right pneumo-
nectomy. Yildizeli et al. (2008) performed 109 carinal
resections in patients with carinal (n = 92) or superior
vena cava (n = 17) involvement. Median OS time was
28 months and 5-year survival 42.5%. In patients with
N0/N1 disease 5-year OS was 50%. Wu et al. (2009)
reported 46 patients with tumors invading the base of
the pulmonary vein or the left atrium (LA). Partial LA
resection was performed in all patients with an overall
5-year survival rate of 22% and a worse prognosis with
N2-involvement. A retrospective analysis of 23 patients
undergoing radical vertebrectomy after induction che-
moradiation for NSCLC invading the spine (including
SST) reports a median OS of 47 months and 3-year
survival of 58% (Anraku et al. 2009). Patients who
achieved (near) pCR demonstrated significantly better
survival than those who did not (3-year survival 92
versus 20%).
NSCLC with multiple intralobar lesions represents
either a multi-focal origin or intralobar metastasis.
Several retrospective series have shown that , patients
in whom multi-focal T4 was found at resection
behave differently than T4 cases with other extension.
The following series confirm these findings (Table 2).
Port et al. (2007) reviewed 53 patients with resected
lung cancer containing intralobar satellite lesions
detected preoperatively (n = 8) or in the resected
437
specimen (n = 45). Patients with multi-centric bron-
cho-alveolar cancer (BAC) and those with different
histologies in the primary versus the satellite lesions
were excluded. Five-year OS was 48% for all patients
and 58% in patients without nodal involvement.
The number of satellite lesions in the resected lobe did
not appear as a prognostic factor.
Trousse et al. (2008) analyzed 56 patients with
postoperatively detected multi-focal NSCLC. Overall
5- and 10-year survival rates were 48 and 30%
respectively. The tumors with nodal involvement
(N1-3) had a 5- and 10-year survival of 30 and 18%.
The better results in the series from Rao et al. (2007)
may be related to the high percentage of BAC in this
study. Adenocarcinoma or BAC, R0 resection, node-
negative patients and the absence of vascular invasion
are frequently reported prognostic factors for better
survival in these surgical series of multi-focal T4.
Patients with intralobar multi-focal NSCLC hence
seem to have a more favorable prognosis after sur-
gical resection than might be predicted by their T4
stage. 5-year survival rates, especially in N0 patients,
approximate those with stages IB of II NSCLC. These
results support the proposal of the forthcoming new
TNM-classification wherein ipsilobar multi-focal T4
disease will be recoded as T3 (Goldstraw et al. 2007).
3 Stage III with Mediastinal Lymph
Node Involvement
Patients with positive mediastinal lymph nodes are
the largest group within stage III NSCLC. The extent
of mediastinal node involvement has an inverse cor-
relation with survival. Although the current staging
system does not divide the N2-category into subsets
based on the size of mediastinal disease, this factor
must be considered when evaluating the results of
clinical series. The subgroup with unforeseen
N2-involvement, incidentally found on final patho-
logic examination (IIIA-1) or recognized intra-oper-
atively (IIIA-2), accounts for 14 - 24% of patients.
However, the largest subgroup of stage IIIA (67%)
consists of patients with clinical single or multiple
level ipsilateral lymph node invasion (IIIA-3), or
‘bulky’ N2-disease at imaging (IIIA-4). Preopera-
tively proven stage IIIA-3 disease is variably con-
sidered ‘resectable’ with or without induction or
adjuvant therapy, whereas patients with stage IIIA-4
Table 3 Outcome of surgery as part of combined modality treatment in stage III-N2/3 NSCLC
438

Author Setting Stage Analyzed Regimen Pneumo- Exploratory Clinical R0 Nodal pCR Mortality Median 2-3-5- Median
populations nectomy thoracotomy response resection downstaging (%) rate (%) OS year PFS
(%) (%) (%) (%) (%) (months) survival (months)
(%)
PP/ITT PP PP ITT PP PP PP PP ITT ITT ITT

Garrido Phase 2 IIIA(N2) 46/69 Three cycles cisplatin- 39 11 56 72 27(R0) 3(R0) 8 15.6– NR-37- 9.9
et al. 2007 gemcitabine- 36.9 (R0) 21
(2007) docetaxel ? surgery
IIIB 44/67 43 23 56 66 – 24(R0) 7 16.8–
SLCG 9901
(T4N0-1) 60.6(R0)
Van Phase 3 III-N2 154/167 I: three cycles platinum- 47 14 612 50 41 5 9 16.4 35-NR- 9.0
Meerbeeck based combined 16
et al. CT ? surgery
(2007)
154/165 II: three cycles platinum- – – 612 – 0 – \1 17.5 41-NR- 11.3
EORTC
based combined CT ? RT 14
08941
(60 Gy)
Thomas Phase 3 IIIA/B 142/264 I: three cycles CE ? bid RT 35 8 50 37 46 60 9 15.7 NR-28- 9.5
et al. (45 Gy) ? carbo- 21
(2008) vindesine ? surgery
GLCCG
154/260 II: three cycles 35 8 46 32 29 20 5 17.6 NR-26- 10
CE ? surgery ? 18
conventional RT (54 Gy)
Gottfried Phase 3 IIB(T3N0) 107/155 I: three cycles 39 8 53 74 29 5 3 32.3 59-47- 16.8
et al. NIP ? surgery (n = 42) NR
(2008)1
IIIA- II: three cycles 31.8 62-49- 16.8
B(T4N0) NIP ? surgery ? 2 cycles NR
NIP (n = 37)
Uy et al. Retrospective IIIA(N2) 40 Two cycles CE ? RT 27 0 NR 92 NR 17 7 40 NR-52- 37.1
(2007) serie (45 Gy) ? surgery ? NR
2 cycles CE
Mansour Retrospective IIIA-N2 28 I: induction CT ? persistent 11 28 NR–NR- NS
et al. serie N2 ? surgery 32
(2008)
32 II: induction CT ? 100 0 NR NR NR NR 12 27 NR–NR- NS
pN0-1 ? surgery 35
93 III: surgery alone 10 15 NR–NR- NS
12
Carretta Retrospective IIIA/B 110 MVP ? surgery ? ± RT 27 0 84 100 NR 12 2 NR NR–NR- NR
et al. serie 50–56 Gy 46
(2008)
GC ? surgery ?
± chemotherapy
Yap et al. Retrospective IIIA/B 25/33 Three cycles PG ? RT 18 0 70 100 NR 24 \1 29.9 NR–NR- 18.3
(2008) serie (50 Gy) ? surgery 36
1
study was closed prematurely because of low inclusion rate;
2
n = 579
PFS progression-free survival, OS overall survival, R0 microscopically radical resection, pCR pathologic complete response, CT chemotherapy, CE cisplatin-etoposide, RT radiotherapy, NR not reported, NS not significant, MVP mitomycin ? vindesine
or vinblastine ? cisplatin, GC gemcitabin–cisplatine, NIP vinorelbine–ifosfamide–cisplatin, PG paclitaxel–carboplatin, PP per protocol (operated patients), ITT intention-to-treat population (registered/randomozed patients)
J. P. van Meerbeeck and E. Vandenbroucke
Tri-Modality Therapy in Locally Advanced Non-Small-Cell Lung Cancer
and IIIB-N3 are considered ‘primary unresectable’
(Jett et al. 2007; Robinson et al. 2007).
The recently published evidence with regard to the
surgical treatment in stage III NSCLC with medias-
tinal lymph node involvement is summarized in
Table 3. The Spanish Lung Cancer Group (SLCG)
performed a phase 2 trial of induction chemotherapy
with a cisplatin-based triplet followed by surgery for
stage III-N2 and selected IIIB (T4N0-1) (Garrido et al.
2007). 136 patients were included of whom 129 were
assessable for treatment. Only 90 patients (70%)
underwent thoracotomy and R0 resection was achieved
in 62 patients. Postoperative treatment was allowed in
patients with pathologically persistent N2-disease,
unresectable disease or incomplete resection. Median
OS for both stages III-A and III–B by intention-to-treat
analysis was 15.9 months and the median PFS was
9.9 months. There was no significant difference in
median OS between stage IIIA and IIIB. In this study
clinical response, R0 resection and nodal down-staging
in stage IIIA-N2 were significant prognostic factors for
survival. The type of surgical procedure (e.g. pneu-
monectomy) was not correlated with outcome.
Two large multi-center randomized phase 3 trials
have explored the role of surgery versus radiotherapy
after induction treatment for stage III-N2 NSCLC.
The first study was already reported by the North
American Intergroup in 2005, but is not published yet
(Albain et al. 2009).
In the EORTC 08941 trial (Van Meerbeeck et al.
2007), 582 patients with stage IIIA-3 and IIIA-4 were
included. ‘Un-resectability’ was defined as any
mediastinal lymph node invasion by a non-squamous
NSCLC or in case of squamous cell cancer,
involvement of more than one station. In case of
response on chest CT-scan after induction chemo-
therapy, patients were randomized between surgery
and radiotherapy. Postoperative radiotherapy was
allowed in the surgical arm when resection was not
radical. The primary endpoint was OS analyzed
according to the intention-to-treat principle. Overall
response rate to induction chemotherapy was 61%,
however this response was not pathologically con-
firmed. The R0 resection rate was 50 with 5% pCR.
Downstaging to N0-1 was obtained in 41%. Median
OS (17.5 versus 16.4 months) and 5-year survival
rates (14 versus 15.7%) as well as PFS for patients in
the surgery versus radiotherapy arm were similar. Site
of first relapse was more often loco-regional in the
439
radiotherapy arm and predominantly distant in the
surgery arm. Half of patients however received
postoperative radiotherapy, which may have influ-
enced the local relapse rate. In a post-hoc unplanned
subgroup analysis of the surgical arm, 5-year survival
was longer if there was a nodal downstaging to N0 or
if lobectomy was performed (Van Schil et al. 2005).
The authors concluded that, after a radiologic
response to induction chemotherapy, surgery was not
superior to radiotherapy. In the surgery arm, the
extent (lobectomy versus pneumonectomy) and
the type (R0 versus R1) of resection were prognostic.
In the radiotherapy arm, none of the patient charac-
teristics was prognostic. In view of its lower mortality
and morbidity, sequential chemoradiotherapy was
recommended to remain the standard of care in
patients with initially ‘unresectable’ IIIA-N2 disease.
The randomized phase 3 trial by the German Lung
Cancer Cooperative Group (Thomas et al. 2008) com-
pared the intensity of the induction regimen: neoadju-
vant concurrent chemoradiation versus chemotherapy
alone. In the latter surgery was followed by radiother-
apy up to 54 Gy. The severe toxicity and mortality rates
were significantly higher in the group of patients with
preoperative radiotherapy with almost a doubling in the
postoperative mortality rate (9 versus 4.5%) especially
after pneumonectomy. Despite the finding that the
more intense induction treatment resulted in a higher
pCR rate, this did not translate in a better outcome,
casting a doubt on the value of pCR as a surrogate
marker of outcome. In this study, 67% of patients had
stage IIIB. The criteria for ‘unresectable disease’
before and after induction treatment seemed not well
defined, and the comparison of the two induction reg-
imens—chemotherapy versus chemoradiotherapy—
may be blurred by several other differences between the
two groups: standard fractionation versus hyper-frac-
tionation and preoperative versus postoperative radio-
therapy. Additionally, the use of hyper-fractionated
radiotherapy in NSCLC has not been shown to improve
outcome (Belani et al. 2005).
The phase 3 trial by Gottfried et al. (2008),
assessing the role of adjuvant chemotherapy in
patients with stage IIB-IIIA/B, was closed prema-
turely because of a low inclusion rate. Of 107 patients
operated, 37 were randomized to the adjuvant treat-
ment arm and 42 to the observational arm. There were
no differences in outcome, although the data have to
be interpreted with caution as the study was not
440
stratified by stage. Response rates and pCR were
comparable to the above-mentioned results.
Impressive results of induction chemoradiation
before surgical intervention for selected patients with
stage IIIA-N2 NSCLC were recently published by Uy
et al. (2007), who adopted the protocol from the
surgical arm of the North American Intergroup trial.
Other retrospective surgical series confirm 5-year
survival rates ranging from 30–45% after induction
chemoradiotherapy (Table 3). The results from
Mansour et al. (2008) suggest that pneumonectomy is
justified even in patients with persistent N2-disease
after induction chemotherapy. Comparing the series
of Carretta et al. (2008) and Yap et al. (2008), there is
no benefit from chemoradiotherapy over chemother-
apy alone as induction treatment. As in previous
trials, patients with R0 resection, nodal down-staging
and pCR seemed to benefit most from surgery,
although there are no randomized data available in
these subgroups.
The role of surgery after induction chemotherapy
in patients with stage IIIB-N3 NSCLC remains
unclear. No phase 3 data has presently shown that a
neoadjuvant treatment followed by surgery results in
prolonged survival compared to adequate chemora-
diation only.
4 Discussion and Future Directions
According to recent guidelines (Shen et al. 2007; Jett
et al. 2007; Robinson et al. 2007; D’Addario and
Felip 2008; NCCN Clinical Practice Guidelines in
Oncology. Non-small cell lung cancer.V.2 2009),
there are now accepted indications for surgery in
selected subsets of patients with stage III NSCLC,
especially as part of a combined modality treatment.
Selected patients with SST with good performance
and without mediastinal lymph node involvement are
preferentially treated with combined chemoradiation
induction therapy followed by surgery. Recent
promising results confirm that tri-modality is feasible
with an acceptable low morbidity and mortality rate.
The resectablility depends on the localization and the
anatomical extension of the tumor—either in the
anterior, middle or posterior compartments—which
require a different surgical approach (Girard and
Mornex 2007; Shaw et al. 1961; Dartevelle et al.
1993; Grunenwald and Spaggiari 1997). As distant
J. P. van Meerbeeck and E. Vandenbroucke
metastasis, sometimes only the brain, is the com-
monest form of relapse in completely resected
patients, improved systemic therapy will be needed.
There is no real consensus about the length of induction
chemotherapy nor about the need of any adjuvant
treatment or not. Whereas in the SWOG trial every
patient received additional chemotherapy, postopera-
tive chemotherapy or radiotherapy was administered in
most studies in case of unresectability or incomplete
resection, without resulting in a better 5-year survival.
Even the role of postoperative radiotherapy in incom-
pletely resected patients is uncertain as the major
relapse is still locoregional. Prophylactic cranial irra-
diation is to be considered as part of clinical trials in
other subsets of locally-advanced NSCLC.
There are only limited data available, but in selected
patients with clinical T4 N0-1 NSCLC with either
multi-focal ipsilobar disease or with central extension
to the main carina, great vessels or vertebral column,
upfront surgery should be considered. There is cur-
rently no role for induction therapy. The SLCG
(Garrido et al. 2007) included patients with T4N0-1
NSCLC in a phase 2 trial but showed no survival benefit
in this subset of patients after post-induction surgery
compared to other series with central or multi-focal T4
tumors not receiving induction therapy (Misthos et al.
2007; Farjah et al. 2008; Wu et al. 2009). In the series of
Farjah et al. (2008), there was no apparent relation
between neoadjuvant therapy and short- or long-term
outcome. This finding is in contrast with the results
reported in SST. One explanation is that neoadjuvant
therapy may not improve the ability to achieve R0
resection in patients with T4 disease. Of interest is the
lack of data reporting the impact of any induction
treatment in lowering the pneumonectomy rate in these
series, which might well decrease their operative
mortality rate. Postoperative treatment should be
dictated by the pathological findings and include post-
operative radiotherapy in case of incomplete resection or
chemotherapy in case of unforeseen hilar or mediastinal
lymph node invasion. Due to their low prevalence, it is
highly unlikely that a randomized trial will ever be
conducted comparing the role of surgery to a non-sur-
gical approach only in these subsets of stage III NSCLC
without mediastinal lymph node invasion. As there are
no randomized controlled data available, the reported
role of surgery is mainly based on the centers’ expertise.
It is hence crucial that these patients are evaluated and
treated by expert multi-disciplinary teams.
Table 4 Ongoing phase 3 clinical trials including surgery in stage III NSCLC
Title of study Design Schedule Primary Estimated Start Study Collaborators Country
objective No. status
Patients
Surgery versus no surgery
Neoadjuvant Phase I: chemotherapy ? radiotherapy Overall 406 January Recruiting Rigshospitalet Denmark
chemotherapy ± surgery in 3 survival 1998 Denmark
NSCLC stage IIIA-N2 II: chemotherapy ? surgery ?
(Scandinavian Neoadjuvant Phase radiotherapy
III Study of Induction 2009)
Standard definitive boost Phase I: chemotherapy (paclitaxel- Overall 500 July Recruiting Essen Germany
radiotherapy versus surgery 3 cisplatin) ? radiochemotherapy survival 2003 Paris
following induction chemotherapy (cisplatin-vinorelbine ? 45 Gy Tübingen
and neoadjuvant bid) ?boost radiotherapy ?
radiochemotherapy based on chemotherapy
hyper-fracionated accelerated II: chemotherapy (paclitaxel-
Tri-Modality Therapy in Locally Advanced Non-Small-Cell Lung Cancer

radiotherapy in NSCLC IIIA-N2/ cisplatin) ? radiochemotherapy

III-B ESPATÜ-trial-GCS 2.1 (cisplatin-vinorelbine ? 45 Gy
bid) ? surgery
Sequential chemoradiotherapy versus chemotherapy as induction treatment
Chemotherapy ± radiation Phase I: chemotherapy (cisplatin- Event-free 120 April Recruiting SAKK Switzerland
therapy before surgery in treating 3 docetaxel) ? surgery survival 2001 NCI
patients with NSCLC stage IIIA- II: chemotherapy (cisplatin- Operability
N2 (Preoperative docetaxel) ? radiation ? surgery after
Chemoradiotherapy versus chemotherapy
Chemotherapy Alone 2009)
441
442
In stage III-N2/3 NSCLC, the role of surgery
compared to radical and adequate modern thoracic
radiotherapy for local control after induction treat-
ment is still a challenge. There is no consensus on the
intensity of induction therapy. In patients receiving
induction chemoradiation, early toxicities (e.g.
esophagitis and hematotoxicity) are increased and in
those undergoing surgery, post-operative mortality
rate is higher especially when a pneumonectomy is
performed. Further randomized controlled trials are
needed to show the superiority of neoadjuvant treat-
ment followed by surgical resection for patients with
stage III-N2/3 NSCLC. Two large randomized con-
trolled trials (Table 4) are on-going in stage IIIA-N2
(Scandinavian Neoadjuvant Phase III Study of
Induction 2009) and IIIA/B NSCLC (ESPATÜ,
Eberhardt, personal communication). Whether che-
moradiation is superior to chemotherapy alone as
induction therapy, is currently investigated in a
Swiss trial (Preoperative Chemoradiotherapy vs.
Chemotherapy Alone 2009).
R0 resection, nodal down-staging and pCR are all
prognostic factors for survival in patients with stage III
NSCLC. However, these are post hoc variables deter-
mined on resection specimen, and they are not helpful
to the clinician’s preoperative decision-making. Whe-
ther surgery should be reserved only for patients with
mediastinal clearance after induction chemotherapy is
unclear. FDG-PET/CT-scan is of great interest, how-
ever the sensitivity in the detection of residual medi-
astinal lymph node disease is low. Post-induction
mediastinoscopy has been reported to have a disap-
pointing low sensitivity (De Leyn et al. 2006).
5 Conclusion
The preferred standard of care for most locally-
advanced NSCLC is a combined modality treatment
with chemotherapy and radiotherapy. However, there
are some selected subsets of stage III patients, in
particular those with T3-4N0-1, in whom surgery
plays a key role. In all patients who are being
considered for resection, accurate staging of the
mediastinum and excluding occult metastasis is rec-
ommended. Comorbidities of patients have consider-
able influence on the overall treatment plan in each
individual patient. Resection has to be decided on by
J. P. van Meerbeeck and E. Vandenbroucke
a multi-disciplinary team and carried out in a high
volume institution by an experienced team.
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 Prophylactic Cranial Irradiation
Jason Francis Lester
Contents
1 Introduction.............................................................. 445
2 Risk Factors for Brain Metastases
Development .............................................................
2.1 Disease Stage.............................................................
2.2 Histological Subtype .................................................
2.3 Age .............................................................................
2.4 Neoadjuvant Chemotherapy ......................................
3 Randomized Controlled Trials of PCI
in NSCLC .................................................................
3.1 VALG Trial ...............................................................
3.2 Umsawasdi Trial........................................................
3.3 RTOG 84-03 ..............................................................
3.4 SWOG Trial...............................................................
3.5 RTOG 0214 ...............................................................
4 Incidence of Brain Metastases ............................... 448
5 Time to Brain Metastases....................................... 449
6 Survival ..................................................................... 449
7 Toxicity...................................................................... 450
8 Quality of Life.......................................................... 450
9 Neurocognitive Function......................................... 450
10 What is the Most Effective PCI Regimen? .......... 451
11 Summary................................................................... 451
References.......................................................................... 451
J. F. Lester (&)
Velindre Cancer Centre, Cardiff, UK
e-mail: jason.lester@velindre-tr.wales.nhs.uk
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_252, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
The incidence of brain metastases following loco-
regional treatment for locally advanced non-small
cell lung cancer (LA-NSCLC) is high. Brain
446 metastases impair quality of life and are associated
446 with a poor prognosis. The rationale behind
446
prophylactic cranial irradiation (PCI) is to control
446
447 or eradicate undetectable micrometastases before
they become clinically significant without inducing
447 severe adverse effects. Given the profound detri-
447 mental effect on survival, treatment that reduces
447 the incidence of brain metastases in patients with
448 LA-NSCLC might reasonably be expected to
448
448 prolong life and improve quality of life. This
chapter reviews the role of PCI in LA-NSCLC
with specific reference to the five randomized
controlled trials carried out in this field.
1 Introduction
The incidence of brain metastases following locore-
gional treatment for locally advanced non-small cell
lung cancer (LA-NSCLC) is high; in up to 30% of
cases, the brain is the first site of relapse (Stuschke
et al. 1999). In addition, studies have shown that brain
metastases will occur in up to half of patients during
the course of their disease (Strauss et al. 2005; Law
et al. 1997). Brain metastases can result in debilitating
symptoms, significantly impair quality of life (QOL)
and dramatically shorten life expectancy (Nussbaum
et al. 1996; Gaspar L et al. 1997).
A study comparing two cranial radiotherapy (RT)
regimens in patients with solid tumors starkly illustrates
445
446
the poor prognosis of NSCLC patients with brain
metastases; the subgroup of patients in the trial with
NSCLC had a median survival of just 69 days (Priest-
man et al. 1996).
Adjuvant chemotherapy has been shown to prolong
survival after potentially curative resection for NSCLC
(Arriagada et al. 2010). It is unlikely, however, that
adjuvant chemotherapy decreases the incidence of brain
metastases as the normal brain is considered a sanctuary
site for chemotherapy. This is supported by the findings of
the international adjuvant lung cancer trial (IALT)
(Dunant et al. 2005). IALT was designed to assess the
potential benefit of adjuvant cisplatin-based chemother-
apy after complete resection of NSCLC. The incidence of
local recurrence and distant metastases was better in the
chemotherapy arm, but there was no reduction in the
incidence of brain metastases; brain as the first site of
metastases was seen in 18.1% of patients in the adjuvant
chemotherapy arm compared to 16.3% in the control arm.
In small cell lung cancer (SCLC), prophylactic
cranial irradiation (PCI) has been shown to signifi-
cantly reduce the incidence of brain metastases and
prolong survival. For SCLC patients treated with
curative intent achieving complete or near-complete
remission with chemotherapy, survival is increased by
5.4% at three years and the cumulative rate of brain
metastases reduced by 25.3% (PCIOCG 2002).
Despite the high incidence of brain metastases in
patients with LA-NSCLC, the role of PCI has not
been established (Lester et al. 2005).
There have been five published randomized con-
trolled trials (RCTs) of PCI versus no PCI in patients
with LA-NSCLC following locoregional treatment
(Cox et al. 1981; Umsawasdi et al. 1984; Russell
et al. 1991; Miller et al. 1998; Gore et al. 2011).
This chapter will review the literature on PCI for
LA-NSCLC with specific reference to these trials and
other relevant publications.
2 Risk Factors for Brain Metastases
Development
The risk of developing brain metastases after loco-
regional treatment for LA-NSCLC depends on several
factors. In order to minimize the number of patients
treated unnecessarily, it would be beneficial to iden-
tify a high risk population which might derive more
benefit from PCI.
J. F. Lester
2.1 Disease Stage
The incidence of brain metastases depends on the
initial disease stage. Salbeck et al. (1990) reported
no cases of brain metastases on initial CT staging in
patients with stage I and II NSCLC. In the same
study, CT scanning detected brain metastases in
17.5% of patients thought to have stage III disease.
The rate of brain metastases as a first site of relapse
in stage III disease is reported to be as high as 30%
at four years (Stuschke et al. 1999). Indeed, there is
some evidence that patients with stage IIIB disease
may have a higher incidence of brain metastases
than those with stage IIIA disease (Robnett et al.
2001). Therefore, it would seem PCI should be more
beneficial in stage III as opposed to early stage
disease.
2.2 Histological Subtype
Studies have suggested brain metastases occur in a
higher proportion of patients with adenocarcinoma or
large cell carcinoma (Figlin et al. 1988; Perez et al
1987; Salbeck et al. 1990). For example, Perez et al.
(1987) reported on patterns of failure in 551 patients
with inoperable NSCLC treated with definitive RT.
The brain was the initial site of relapse in 7%
of patients with squamous carcinoma, 13% with
large cell carcinoma and 19% with adenocarcinoma.
During the entire course of the disease, 16% of
squamous patients and 30% of adenocarcinoma and
large cell carcinoma patients developed brain metas-
tases. It would be expected that any benefit from PCI
would be more pronounced in patients with the latter
two histological subtypes.
2.3 Age
There is some evidence that younger patients may be
at higher risk of developing brain metastases as the
first site of failure. Carolan et al. (2005) reported on
patients with LA-NSCLC treated with curative intent.
Patients aged less than 60 had a 25.6% risk of brain
metastases compared to an 11.4% risk for patients
aged 60 and over. This trend has been reported by
several other authors (Ceresoli et al. 2002; Westeel
2003).
Prophylactic Cranial Irradiation 447

Table 1 Published RCTs of PCI in LA-NSCLC

RCT No. Thoracic PCI Brain met Survival
treatment dose incidence (PCI vs no)
(PCI vs no)
VALG 410 RT: 50 Gy/25F/5 weeks or 42 Gy/15F/3 weeks 20 Gy/10F 6 vs 13% 35.4 vs
(S) 41.4 weeks
(NS)1
Umsawasdi 100 Chemo-RT (50 Gy/25F/5 weeks), or 30 Gy/10F 4 vs 27% 22 vs 23.5% at
combinations of surgery, RT and chemo (S) 3 years
RTOG 84-03 187 RT: 55–60 Gy/30F/6 weeks Post op: 50 Gy/ 30 Gy/10F 9 vs 19% 8.4 vs
25F/5 weeks (NS) 8.1 months
(NS)1
SWOG 254 Primary RT: 58 Gy/29F or Neoadjuvant chemo 37.5 Gy/15F Or 1 vs 11% 8 vs 11 months
then RT and adjuvant chemo 30 Gy/15F (S) (S)1
RTOG 0214 356 RT alone ([30 Gy) or combinations of surgery, 30 Gy/15F 7.7 vs 18% 75.6 vs 76.9%
RT and chemo (S) (S) at 1 year
No number of patients, RT radiotherapy, PCI prophylactic cranial irradiation, F fractions, chemo chemotherapy, S significant,
NS not significant
1
Median survival

2.4 Neoadjuvant Chemotherapy
Some authors have suggested that the risk is higher
when chemotherapy is given prior to definitive local
therapy. Andre et al. (2001) reported on relapse pat-
terns in 109 patients with N2 disease treated with
neoadjuvant chemotherapy prior to surgery compared
to 185 patients treated with primary surgical resec-
tion. Brain metastases occurred in 22% of patients
given neoadjuvant chemotherapy and 11% having
primary surgery.
One possible explanation for this is that neoadjuvant
chemotherapy delays definitive local therapy and
allows more time for the primary tumor to metastasize.
There are factors then, which are associated with
an increased risk of brain metastases. The strongest
association is with disease stage, and all five pub-
lished RCTs of PCI in NSCLC mainly or exclusively
included patients with locally advanced disease.
widely in the local therapy used and PCI dose-
fractionation schedules. All five trials required histo-
logical confirmation of the diagnosis. In four trials,
patients were randomized to PCI or observation irre-
spective of thoracic response to treatment; in RTOG
0214, patients needed to have non-progressive disease
after local treatment (Gore et al. 2011). The trial
designs are outlined below:
3.1 VALG Trial
The VALG trial randomized 410 evaluable male
patients not considered suitable for surgical resection
with no spread beyond the regional nodes to one of two
radical RT regimens; 50 Gy in 25 fractions over 5 weeks
or 42 Gy in 15 fractions over 3 weeks (Cox et al. 1981).
Overall, 323 patients were evaluable. In the PCI arm,
patients received 20 Gy in 10 fractions over 2 weeks.

3 Randomized Controlled Trials 3.2 Umsawasdi Trial

of PCI in NSCLC
There have been five published RCTs of PCI versus
no PCI in patients with LA-NSCLC following loco-
regional treatment which are summarized in Table 1
(Cox et al. 1981; Umsawasdi et al. 1984; Russell et al.
1991; Miller et al. 1998; Gore et al. 2011). The five
studies included different patient groups, and varied
One hundred patients with LA-NSCLC of any cell
type were randomized and 97 patients were evaluable
(Umsawasdi et al. 1984). Of these, 87% were stage III
and 13% were stage I to II. The thoracic treatment
received was not clearly stated for all patients. Sixty-
three patients received radical chemo-RT (thoracic
RT dose 50 Gy in 25 fractions over 5 weeks) and
448
34 patients received differing combinations of sur-
gery, RT and chemotherapy. PCI patients received
30 Gy in 10 fractions over 2 weeks.
3.3 RTOG 84-03
RTOG 84-03 randomized 187 patients with inopera-
ble or unresectable adenocarcinoma or large cell
carcinoma confined to the chest and resected carci-
nomas of the same cell types (Russell et al 1991).
Patients received primary RT 55–60 Gy in 30 frac-
tions over 6 weeks or 50 Gy in 25 fractions over
5 weeks to the mediastinum and hilar areas following
surgical resection. PCI patients received 30 Gy in 10
fractions over 2 weeks.
3.4 SWOG Trial
The SWOG trial randomized 254 patients with inop-
erable stage III NSCLC (Miller et al. 1998). Patients
were first randomized to either chest RT (58 Gy in 29
fractions) or neoadjuvant chemotherapy followed by
chest RT and adjuvant chemotherapy. The first 34
patients in the PCI arm received 37.5 Gy in 15 frac-
tions, but this was changed to 30 Gy in 15 fractions
soon after the trial began recruiting due to concerns
about early deaths in the PCI arm.
3.5 RTOG 0214
RTOG 0214 randomized 356 patients with stage III
NSCLC without disease progression after surgery and/
or RT with or without chemotherapy (Gore et al. 2011).
Local treatment was extremely variable; patients could
have RT alone ([30 Gy) or RT with neoadjuvant,
concurrent or adjuvant chemotherapy, surgery alone or
surgery with pre- or post-operative chemotherapy, RT
or both. RTOG 0214 had planned to recruit 1058
patients but closed early due to poor recruitment. The
PCI schedule used was 30 Gy in 15 fractions.
4 Incidence of Brain Metastases
PCI significantly reduced the incidence of brain
metastases in four of the five published randomized
trials (Cox et al. 1981; Umsawasdi et al. 1984; Miller
J. F. Lester
et al. 1998; Gore et al. 2011). The results from RTOG
8403 although not statistically significant, also
strongly support the effectiveness of PCI in reducing
the incidence of brain metastases.
In the VALG study, the two thoracic RT schedules
used were combined for statistical analysis (Cox et al
1981). The incidence of brain metastases was signif-
icantly lower in the PCI arm compared to the obser-
vation arm (6 vs 13%, P = 0.038). Subgroup analysis
showed the only specific cell type in which PCI was
significantly more effective in reducing the incidence
of brain metastases was adenocarcinoma (0 vs 29%,
P = 0.04).
It might be expected that any benefit from PCI is
more likely to be seen in patients with adenocarci-
noma, as these patients have a higher incidence of
brain metastases (Perez et al. 1987).
In Umsawasdi et al. (1984) the incidence of brain
metastases in the PCI arm was 4% compared to 27%
in the observation arm (P = 0.02). Multivariate
analysis suggested the beneficial effect of PCI was
only significant in females, patients with a good
performance status, weight loss less than 6%, squa-
mous histology and stage III disease. The benefit for
squamous cancers only is counter-intuitive as brain
metastases are more common in patients with ade-
nocarcinoma (Perez et al. 1987). Only 97 patients in
total were evaluable, so sample sizes in the subgroup
analysis may have been too small to reliably estimate
differences.
In the SWOG trial the incidence of brain metas-
tases in the PCI arm was 1% compared to 11% in the
observation arm (P = 0.003) (Miller et al. 1998). No
Subgroup analysis was published.
RTOG 0214 was the only trial to include regular
brain imaging as part of the follow-up protocol (Gore
et al. 2011) CT head was required at 6 and 12 months
then yearly after RT. The incidence of brain metas-
tases was lower in the PCI arm compared to the
control arm at 6 months (3.3 vs 10.7%, P = 0.004)
and 1 year (7.7 vs 18%, P = 0.004). No subgroup
analysis was published.
In RTOG 84-03, PCI did not significantly reduce
the incidence of brain metastases compared to the
observation arm (9 vs 19%, P = 0.10) (Russell et al.
1991). The prevalence of brain metastases at
24 months for PCI was 15 versus 31% in the obser-
vation arm. Again, this result was not statistically
significant but RTOG 84-03 results strongly suggest
Prophylactic Cranial Irradiation
PCI reduces the incidence of brain metastases and
that this benefit is maintained two years after PCI.
Looking at the results of all five RCTs together, it
is clear that PCI is effective at reducing the incidence
of brain metastases in patients with LA-NSCLC given
locoregional treatment for their disease. Attempts to
define particular subgroups which may derive pro-
portionally more benefit from PCI have been largely
unsuccessful due to the relatively small size of the
trials carried out.
5 Time to Brain Metastases
In the VALG trial, the median time to development of
brain metastases was 34 weeks in the PCI group and
29 weeks in the observation group (Cox et al. 1981).
The statistical significance of this result was not
reported, but the difference is clearly not a large one. In
Umsawasdi et al. (1984), PCI significantly prolonged
the median time to brain metastases (50.5 vs 23 weeks,
P = 0.002). The SWOG, RTOG 84-03 and RTOG
0214 trials did not report on time to brain metastases.
The only RCT to show a significant benefit was the
smallest of the 5 trials, so it remains unclear as to
whether PCI delays time to brain metastases.
6 Survival
To date, no trial has reported a survival advantage with
PCI over observation despite impressive reductions in
the incidence of brain metastases in all published
RCTS. The median survival figures for PCI versus
observation in the VALG trial were 35.4 weeks
versus 41.4 weeks (P = 0.5), and in RTOG 84-03,
8.4 months versus 8.1 months (P = 0.36) (Cox et al.
1981; Russell et al. 1991). RTOG 84-03 also reported
no significant difference between PCI and observation
in one and two-year survival (40 vs 44% and 13 vs 21%,
P = 0.36) (Russell et al. 1991).
In Umsawasdi et al. (1984), three-year survival in
the PCI and control groups was 22 and 23.5%,
respectively. No statistical analysis of the survival
data was reported but it is highly unlikely there was a
real difference between the arms.
In the SWOG trial, median survival was actually
significantly shorter in the PCI arm (8 vs 11 months,
P = 0.004) (Miller et al. 1998). In this study, the first
449
34 patients in the PCI arm received 37.5 Gy in 15
fractions, but this was changed to 30 Gy in 15 frac-
tions soon after the trial began recruiting due to
concerns about early deaths in the PCI arm. The
remaining patients randomized to PCI received 30 Gy
in 15 fractions, but had a similar median survival to
the 37.5 Gy group. It was not clear to the investiga-
tors why there was a shorter life expectancy in the
PCI arm, but PCI was given concurrently with
thoracic RT and it may be that the subsequently
increased toxicity contributed to the reduced survival.
The only RCT to mandate patients needed to
have at least stable disease after locoregional treat-
ment was RTOG 0214 (Gore et al. 2011). It is
reasonable to assume that any survival advantage
with PCI is far more likely to be seen in patients
with controlled thoracic disease. Patients who have
progressive or metastatic disease after locoregional
treatment will have a short life expectancy and are
likely to die from extracranial disease complications
before any benefit from PCI can be seen. Despite
this, there was no difference in 1-year overall sur-
vival in RTOG 0214 (75.6% for PCI vs 76.9% for
controls). The lack of survival advantage in RTOG
0214 and the other RCTs is not necessarily sur-
prising. RTOG 0214 initially planned to randomize
1058 patients; this was the number of patients
needed to detect a 20% difference in overall survival
with 80% statistical power. The trial closed early
due to poor recruitment with only 340 evaluable
patients enrolled, so any true benefit is unlikely to
have been seen. Applying the same statistical logic
to the other four RCTs, it is clear that none of the
studies was large enough to detect a survival benefit
from PCI if one truly exists - the largest study was
the VALG study and this only included 410 evalu-
able patients.
The experience with PCI in SCLC is also
important to consider. Several trials suggested a
reduction in the incidence of brain metastases with
PCI, but no convincing improvement in survival.
As a consequence, PCI was not considered a stan-
dard of care in SCLC. A subsequent meta-analysis
of seven RCTs including 987 patients did however,
demonstrate a small but significant increase in three-
year survival of 5.4% with PCI (PCIOCG 2002). It
is not logical to extrapolate these results to NSCLC
patients as SCLC is a more radiosensitive disease
with a higher incidence of brain metastases, but it
450
may be that a large enough RCT would demonstrate
a survival advantage not seen in the relatively small
trials reported to date.
In addition, the locoregional treatment for many
patients in the five RCTs would not be considered
optimal by today’s standards. For example, even in
RTOG 0214, the most contemporary of the trials,
patients were eligible having had as little as 30 Gy RT
to the chest. This is not a tumoricidal RT dose and is
unlikely to achieve long–term local disease control.
Patients would then be at risk of disease relapse and
early death before any PCI benefit could be seen. The
disease-free survival at 1 year was not significantly
different between the two arms in RTOG 0214 despite
a significant decrease in the incidence of brain
metastases with PCI suggesting patients are relapsing
systemically and dying, possibly before any PCI
benefit can be seen.
Summarizing then, no RCT had shown a survival
benefit from PCI in LA-NSCLC despite all showing a
reduction in the incidence of brain metastases. The
reasons for this may in part be down to trial design;
individual trials had relatively few participants,
included some patients with early stage disease, and
locoregional treatment was suboptimal and varied.
7 Toxicity
Toxicity data collection and subsequent publication
was poor in four of the five trials. Only RTOG 0214
included detailed prospective toxicity data collection
(Gore et al. 2011). The VALG trial did not report on
PCI-related toxicity (Cox et al. 1981). RTOG 84-03
reported no acute toxicity other than epilation and
skin reactions and no late toxicity (Russell et al.
1991). The Umsawasdi and SWOG trials reported no
excessive toxicity with PCI compared to the obser-
vation arm, but it was not stated in either trial what
data was collected or how this data was collected
(Umsawasdi et al. 1984; Miller et al, 1998).
RTOG 0214 reported that PCI resulted in generally
mild toxicity (Gore et al. 2011). Grade 3 and 4 tox-
icities occurred in 4 and 1% of patients, respectively.
The grade 3 toxicities reported were acute fatigue,
dyspnoea, ataxia, and depression. One patient repor-
ted acute grade 4 mood alteration/depression. Four
patients reported grade 3 late toxicity including
dyspnoea, syncope, weakness, and fatigue.
J. F. Lester
It is difficult to draw any definitive conclusions
regarding PCI-related toxicity due to the relative
paucity of data. It does seem that from the RTOG
0214 results, PCI at a dose of 30 Gy in 15 fractions is
generally well tolerated.
8 Quality of Life
Prospective QOL assessments were carried out in
RTOG 0214—none of the other randomized trials
included QOL data collection. QOL was assessed
using the EORTC QLQ-C30 and BN20 question-
naires. In total, 340 patients were evaluable in RTOG
0214. At baseline, 95% of patients completed QOL
assessments but compliance to testing declined rap-
idly during the study. At 3 months, only 43% of
potentially evaluable patients completed the assess-
ments and this fell further to 34% at 12 months. There
were no significant differences between the two arms
in change in QOL scores from baseline at 6 and
12 months. In the trial, subgroup analysis was carried
out to try and identify patients at higher risk of
experiencing a decline in QOL. No clear differences
emerged in any of the subgroups tested.
Two trials have evaluated the effect of PCI on QOL
in SCLC patients (Arriagada et al. 1995; Gregor et al.
1997). Neither study reported any difference in QOL
between patients in the PCI arm and control arm.
Given the relatively small number of patients
evaluated in RTOG 0214 and the lack of data from
other trials, definitive conclusions cannot be drawn on
the effect of PCI on QOL. It does seem that any effect
on QOL is unlikely to be substantial within the first
12 months, but confirmatory research is needed and
longer follow-up data is essential.
9 Neurocognitive Function
RTOG 0214 was the only RCT to collect detailed
prospective data on the long-term effects of PCI on
neurocognitive function (NCF) (Gore et al. 2011).
NCF was assessed using the Mini-Mental Status
Examination (MMSE), Hopkins Verbal Learning Test
(HVLT) and Activity of Daily Living Scale (ADLS).
The MMSE change scores from baseline at
3 months showed significantly more patients reported
a decline in the PCI arm than in the control arm (36 vs
Prophylactic Cranial Irradiation
21%, P = 0.04). A similar trend was seen in the
HVLT, with significantly more patients in the PCI
arm reporting deterioration in immediate recall (45 vs
13%, P \ 0.001) and delayed recall (44 vs 10%,
P \0.001). At the 6 month time point, the differences
in both MMSE and HVLT had disappeared. Intrigu-
ingly, at the 12 month time point there remained no
difference in the MMSE scores, but immediate recall
(26 vs 7%, P = 0.03) and delayed recall (32 vs 5%,
P = 0.008) in the HVLT were again significantly
worse in the PCI arm.
It is likely that the decline in recall is a conse-
quence of PCI; the differences seen in the tests may be
because HVLT has a better sensitivity than the
MMSE for detecting early dementia (Wade 1992).
What is not known is whether this decline stabilizes
or continues to deteriorate. Longer term NCF data
from the RTOG 0214 may become available in future
to help answer this question.
It is worthwhile considering the data on PCI in
SCLC when attempting to define the effect of PCI on
NCF. Two trials have evaluated the effect of PCI
on NCF in SCLC patients. In Arriagada et al. (1995)
patients in the PCI group received 24 Gy in 8 frac-
tions over 12 days. There were no significant differ-
ences between patients receiving PCI and those in the
observation group in terms of NCF. In Gregor et al.
(1997) the majority of patients randomized to PCI
received 30 Gy in 10 fractions over two weeks.
In both groups, there was an impairment of NCF before
PCI, and further impairment at 6 and 12 months, but no
additional impairment in the PCI group compared to the
control group. It is reasonable to assume that any effect
on NCF with a given PCI regimen would be similar in
SCLC and NSCLC patients.
It is likely, therefore, that there is an acute
reversible decline in NCF after PCI which improves
by 6 months. Longer term follow-up data is lacking,
but it is probable that deterioration in NCF can occur
12 months after PCI. It is not yet known whether this
decline is progressive.
RT techniques are being developed that may
reduce the late cognitive sequelae of treatment. The
Hippocampus is a structure that is crucial to NCF and
hippocampal metastases are rare. Sparing of this
region with PCI is feasible using advanced RT plan-
ning and delivery systems (Marsh et al. 2010, Hsu
et al. 2010). The hope is that these technical advances
translate into meaningful benefits for patients.
451
10 What is the Most Effective PCI
Regimen?
Four different PCI regimens were used in the five
RCTs (Table 1), but the small number of patients in
each trial, differences in inclusion criteria and loco-
regional treatment make any comparison between the
trials inappropriate. In addition, no randomized trial
has compared these (or any other) PCI regimens head-
to-head. Therefore, it is not possible to establish
which PCI regimen is superior.
11 Summary
There is insufficient evidence to support the routine
use of PCI in the management of patients with
LA-NSCLC having undergone locoregional treat-
ment. All five published RCTs show a reduction in the
incidence of brain metastases in patients receiving
PCI, but this did not translate into a survival advan-
tage. The patient population most likely to benefit is
not clear, nor is the most beneficial RT schedule.
Unlike in SCLC, the trials are too heterogenous for
meta-analysis to be useful, and the poor recruitment
to the RTOG 0214 trial means the role of PCI in
LA-NSCLC may never fully be established.
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 Palliative External Beam Thoracic Radiation
Therapy of Non-Small Cell Lung Cancer
Stein Sundstrøm
Contents
1 Introduction.............................................................. 454
2 Symptoms.................................................................. 454
3 Palliative Radiotherapy: Definition ....................... 454
4 Prognostic Factors for Selecting Treatment ........ 454
5 Radiotherapy Technique......................................... 455
6 Defining the Radiotherapy Volume ....................... 455
7 Dose and Fractionation ........................................... 455
8 Phase III Studies...................................................... 456
9 Interpretation ........................................................... 457
10 Treatment Recommendations ................................ 457
11 When Should Palliative Radiotherapy be
Delivered? ................................................................. 458
12 Summary................................................................... 458
References.......................................................................... 458
S. Sundstrøm (&)
St Olav University Hospital, Trondheim, Norway
e-mail: Stein.Sundstrom@stolav.no
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_316,  Springer-Verlag Berlin Heidelberg 2011
Abstract
About two-thirds of patients with non-small cell
lung cancer are diagnosed with incurable disease
and are usually treated with a palliative intent.
Palliative radiotherapy is defined as radiotherapy
given with less than radical doses. Although a
large variation in treatment schedules considering
dose, fractionation, and overall treatment time are
used, usually a dose 50 Gy is considered as
palliative. Given the palliative intent of the radio-
therapy with the goal of reducing tumour-related
symptoms, the radiotherapy should be simple to set
up, to perform, and less time-consuming for the
patient. If high-dose palliative fractionated radio-
therapy is planned a normal setup margin defining
GTV and CTV/PTV is recommended including the
tumour and disease-related nodes. When low-dose
radiotherapy is planned, the treated volume should
include the symptomatic part of the tumour.Most
studies show that the effect on symptoms and
palliative effect is similar regardless of dose and
fractionation. A trend of more rapid relief of
symptoms in favour of hypofractionation is
observed. Though no major difference in median
survival is observed, some patients with localised
stage III disease may have better survival with a
protracted high-dose schedule. Acute toxicity with
dysphagia is mild, temporary, and manageable.
Late toxicity is rare and sporadic with low severity.
Palliative thoracic radiotherapy should not be
administrated to patients without symptoms
present.
453
454
1 Introduction
The majority of patients with non-small lung cancer
are diagnosed with advanced disease, either localised
stage III or metastatic stage IV disease. Approxi-
mately 40% have stage III disease and 40% have
stage IV disease. Of stage III localised disease, only
one-third have tumours considered to be candidate for
a curative strategy. This leaves about two-thirds of the
non-small population diagnosed with incurable dis-
ease and should be treated with a palliative intent.
Most of these patients will have symptoms from
intrathoracic tumour at diagnosis or the propensity to
develop symptoms in the near future. In this setting,
any intervention should have the goal of effective
palliation avoiding unacceptable toxicity.
2 Symptoms
The most common symptoms from tumours in the chest
are dyspnoea, cough, and hemoptysis. Other symptoms
are chest pain, compression of large vessels (superior
vena cava syndrome), nerve infiltration causing
hoarseness or Horners syndrome, and dysphagia due to
compression of oesophagus. These latter symptoms are
related with infiltrative tumours beyond any curative
strategy. About 70% of patients with advanced disease
have one or more symptoms from intrathoracic tumour
at diagnosis requiring treatment intervention (Hopwood
and Stephens 1995; Lutz et al. 2001).
3 Palliative Radiotherapy: Definition
Palliative radiotherapy is defined as radiotherapy given
with less than radical doses. Usually a dose\50 Gy is
considered as palliative. A large variation in treatment
schedules considering dose, fractionation, and overall
treatment time are used. The various regimes in use are
often based on tradition, preference of the responsible
physician and radiotherapy capacity (Maher et al.
1992). The selection for technique and total dose
should be based on a thorough clinical evaluation of the
patient before start of radiotherapy. In this setting a
discrimination of the patient in good prognostic or poor
prognostic group should be elucidated.
S. Sundstrøm
4 Prognostic Factors for Selecting
Treatment
Stage of the disease, spontaneous weight loss over the
last 3–6 months, and performance status are the most
robust prognostic factors in non-small cell lung can-
cer (Brundage et al. 2002).
Disease stage is the most powerful prognosticator
in lung cancer. Patients with metastatic disease have
shorter survival than stage III disease. Some good
prognostic stage III patients can be treated with a
curative intent, but even with the aim of high dose
chemo-radiotherapy the survival is limited. Patients in
stage III with poor prognostic factors will have sur-
vival equal to stage IV disease.
Performance status is a strong prognostic factor in
non-small cell lung cancer regardless of stage.
Patients with WHO PS status 0–1 will experience a
meaningful effect of treatment, both for chemotherapy
and radiotherapy. Patients in WHO PS 2 are a bor-
derline group; they will achieve less effect of che-
motherapy, often with intolerable toxicity. Patients
with WHO PS status of 3–4 should routinely not be
offered chemotherapy. If treatment is required, palli-
ative radiotherapy is probably a better strategy for
relieving symptoms.
Weight loss is common and is categorised
according to the normal body weight before diagnosis
and to the time interval over which the weight loss
has developed (none versus \5–10% vs. C10% of
normal body weight) over the last 3–6 months.
Weight loss is a consistent and strong prognosticator.
A weight loss C10% over the last 3 months is a strong
negative prognostic factor, and the patient should be
treated with a palliative intent regardless of other
prognostic factors.
Tumour size is important regarding the possibility
of eradication of a tumour by radiotherapy. There is
no general accepted consensus for the maximum
tumour size or volume that precludes a radical strat-
egy. The pivotal study from RTOG in 1982 showed a
clear relation to less effect in tumours [6 cm in
diameter (Perez et al. 1982). Several other studies
show the same trend (Bradley et al. 2002; Dehing-
Oberije et al. 2008), and a tumour larger than [8–
10 cm is considered by most clinicians to be treated
with a palliative intent.
Palliative External Beam Thoracic Radiation Therapy of Non-Small Cell Lung Cancer
Table 1 Prognostic factors Good prognostic factors
in stage III patients
WHO PS status 0–1
Tumour size \8 cm in largest diameter
Weight loss \10% last 3 months
Overall, in the heterogeneous stage III group of
patients, selection of either a curative or palliative
schedule should be based on a thorough clinical
evaluation of the factors outlined in Table 1. Occur-
rence of one or more of the poor prognostic factors
should conduct a palliative treatment strategy.
Patients in stage IV disease should in almost all cases
be treated with a palliative intent.
5 Radiotherapy Technique
Given the palliative intent of the radiotherapy with
the goal of reducing tumour-related symptoms, the
radiotherapy should be simple to set up, to perform,
and less time-consuming for the patient.
Radiotherapy planning involves consideration of
patient positioning, localization of tumour, and criti-
cal organs. A supine positioning is usually preferred
with the arms adducted or above the head if oblique
field is planned. A conventional two-dimensional
radiotherapy (2DRT) technique is sufficient in most
cases based on an X-ray beam simulator. Parallel
opposed anterior-posterior fields are used. Shielding
of uninvolved lung tissue should be made reducing
side effects. If high-dose treatment is planned, oblique
fields after maximal tolerable dose to the spine are
advocated. Previously, 40 Gy/20 fractions were con-
sidered as the maximal spinal cord tolerance. Recent
updates designate 50 Gy using conventional frac-
tionation as safe to the thoracic spine (Kirkpatrick
et al. 2010). If a more protracted schedule with higher
palliative dose is planned, a three-dimensional con-
formal radiotherapy (3DCRT) technique based on CT
scan should be preferred. This will better define the
tumour volume and organs at risk and assure a more
precise encompassing of tumour. High energy photon
beams in the rage of 5–15 MeV is recommended.
Most radiotherapy units will in the near future
become simulator-less, basing all planning also for
palliative purposes on CT scan. This is more convenient
for patients and time sparing for the treatment units.
455
Poor prognostic factors
WHO PS status C2
Tumour size [8 cm in largest diameter
Weight loss C10% last 3 months
6 Defining the Radiotherapy Volume
In situations where curative intended radiotherapy is
planned there is consensus for including enlarged
and disease-related lymph nodes in field planning.
Including elective lymph nodes will add toxicity
with no increase in local control or survival (Yan
et al. 2007).
If high-dose palliative fractionated radiotherapy is
planned a normal setup margin defining GTV and
CTV/PTV is recommended including the tumour and
disease- related nodes. According to international
guidelines a setup margin of 1 cm from GTV to CTV,
and 0.5 cm from CTV to PTV is recommended.
Larger margins in the cranio-caudal direction due to
respiration movements might be necessary. Reduced
margins are desirable if the treated volume enlarge to
[200 cm2 in field size.
When low-dose radiotherapy is planned, the treated
volume should include the symptomatic part of the
tumour. In most cases this can confine the volume to the
symptomatic area avoiding unnecessary radiotherapy
to non-symptomatic lung tissue even though these parts
may include tumour spread. The central airways with
mediastinum and hilus on the affected side will often be
an adequate volume. Margins from the tumour border
to CTV and PTV should not be emphasized. Close
margins or even margins set up in the tumour are
acceptable if the volume becomes large.
Considering the palliative intent of the treatment,
focus on radiotherapy side effects should be kept in
mind. In that respect smaller volumes are more
desirable than large volumes encompassing the
complete tumour extension.
7 Dose and Fractionation
A large variety of fractionation schemes and radio-
therapy schedules are in use for palliative treatment,
from single fraction of 8–10 Gy up to subradical
456 S. Sundstrøm

Table 2 Different phase III trials using low dose hypofractionated palliative TRT in advanced NSCLC
Study N Regimens Stage III/IV WHO Palliation Survival
(%) PS
MRC I (1991) 369 17 Gy/2 versus 30 Gy/10 68/32 0–2(3) Equal Equal
MRC II (1992) 235 10 Gy/1 versus 17 Gy/2 71/29 2–4 Equal Equal
MRC III (1996) 509 17 Gy/2 versus 39 Gy/13 100/0 0–2 Equal 39 Gy
better
Rees et al. (1997) 216 17 Gy/2 versus 22.5 Gy/5 Not reported 0–3 Equal Equal
Bezjak et al. (2002) 230 10 Gy/1 versus 20 Gy/5 76/24 0–3 Equal 20 Gy
better
Sundstrøm et al. (2004) 407 17 Gy/2 versus 42 Gy/15 versus 78/22 0–3 Equal Equal
50 Gy/25
Erridge et al. (2005) 148 10 Gy/1 versus 30 Gy/10 Not reported 0–3 30 Gy Equal
better
Kramer et al. (2005) 297 16 Gy/2 versus 30 Gy/10 52/48 0–3(4) 30 Gy 30 Gy
better better
Senkus-Konefka et al. 100 16 Gy/2 versus 20 Gy/5 84/16 1–3(4) Equal 16 Gy
(2005) better

doses of 50–60 Gy. These differences in treatment
policy are probably due to marginal radiotherapy
capacity favouring low-dose irradiation. Until the first
study from the Medical Research Council UK was
published in 1991 (MRC Lung Cancer Working Party
1991), a typical course was 30 Gy in ten fractions.
8 Phase III Studies
Since the MRC I (MRC Lung Cancer Working Party
1991) study was published, eight other randomised
phase III trials (Medical Research Council Lung
Cancer Working Party 1992; Medical Research
Council Lung Cancer Working Party 1996; Rees et al.
1997; Bezjak et al. 2002; Sundstrøm et al. 2004;
Erridge et al. 2005; Kramer et al. 2005; Senkus-
Konefka et al. 2005) comparing a strict hypofrac-
tionated schedule with a normal-fractionated regimen
have been published, outlined in Table 2. More than
2,500 patients are included in these trials. All trials
have either a single (8 or 10 Gy) or two large frac-
tions (17 or 16 Gy/2) as the short-course experimental
arm. The comparative arms were fractionated sched-
ules with a range of 20–50 Gy. The trials included
patients up to WHO PS 3 with a majority of stage III
patients. One trial (MRC II) (Medical Research
Council Lung Cancer Working Party 1992) included
poor performance status patients only (WHO PS 2–4)
comparing a single fraction versus 17 Gy/2 fractions.
All trials (MRC Lung Cancer Working Party 1991,
1992, 1996; Rees et al. 1997; Bezjak et al. 2002;
Sundstrøm et al. 2004; Erridge et al. 2005; Kramer
et al. 2005; Senkus-Konefka et al. 2005) reported the
effect on symptoms assessed by patients through self-
reported questionnaires and physicians’ evaluation of
symptoms, as well as overall survival. Except in two
trials (Erridge et al. 2005; Kramer et al. 2005) where
the effect on symptoms is in favour of the higher dose,
the effect on disease-related symptoms are equal.
In three trials (Medical Research Council Lung
Cancer Working Party 1996; Bezjak et al. 2002;
Kramer et al. 2005) the survival is in favour of the
high-dose arm; 39 Gy/13 fractions, 30 Gy/10 frac-
tions, and 30 Gy/10 fractions, respectively. One trial
(Senkus-Konefka et al. 2005) reports a survival ben-
efit for the low-dose arm; 16 Gy/2 fractions versus
20 Gy/5 fractions. In one three-armed trial
(Sundstrøm et al. 2004) comparing 17 Gy/2 fractions
(n = 143) with two high-dose arms; 42 Gy/15 frac-
tions (n = 140) and 50 Gy/25 fractions (n = 124), no
difference in median survival was found.
Five randomised phase III studies (Simpson et al.
1985; Teo et al. 1987; Abratt et al. 1995; Reinfuss et al.
1999; Nestle et al. 2000) have compared different
normal to high-dose regimens, including more than
1,000 patients, as shown in Table 3. Nearly all had
stage III localised disease with a reasonably good
Palliative External Beam Thoracic Radiation Therapy of Non-Small Cell Lung Cancer 457

Table 3 Different phase III trials using normal-high dose palliative TRT in advanced NSCLC
Study N Regimens Stage III/ WHO Palliation Survival
IV PS
Simpson et al. 316 20 Gy/20 versus 30 Gy/10 vs 40 Gy/20 split 100/0 0–2 Equal Equal
(1985)
Teo et al. (1987) 291 31.2 Gy/4 versus 45 Gy/18 90/3 0–3 45 Gy Equal
better
Abratt et al. 84 35 Gy/10 versus 45 Gy/15 100/0 0–2 Equal Not reported
(1995)
Reinfuss et al. 240 40 Gy/10 (split 4 week) versus 50 Gy/25 vs 100/0 0–2 Not Better 40/
(1999) wait and see reported 50 Gy
Nestle et al. 152 32 Gy/16 (twice/day) versus 60 Gy/30 79/21 1–2 Equal Equal
(2000)

performance status WHO PS 0–2. Four of five studies
have assessed the effect on symptoms. One has used
patient self-reported questionnaires (Nestle et al.
2000), in the other studies the effect on symptoms were
assessed by the physicians. One study reported better
palliation in the high-dose arm (Teo et al. 1987). Four
studies have data on survival, equal in three, better in
one in the high-dose arms (Reinfuss et al. 1999). This
study by Reinfuss et al. (1999) is special since one arm
in this three-armed trial was a ‘‘wait and see’’ arm;
40 Gy10 (split) versus 50 Gy/25 versus ‘‘wait and
see’’. The survival in this ‘‘wait and see’’ arm was
inferior compared to the two actively treated arms.
All studies reporting side effects show that esoph-
agitis and dysphagia was most frequent in the high-
dose arms, although dysphagia was also detectable in
the hypofractionated low-dose arms. Onset and dura-
tion of dysphagia was earlier and shorter in the hyp-
ofractionated arms compared to high-dose arms. Rare
cases of radiation-induced myelopathy are reported,
usually mild and temporary (MacBeth et al. 1996;
Reinfuss et al. 2011). The incidence is estimated to 2%
at 2-year survival for hypofractionated schedules.
9 Interpretation
dose schedule. As seen in Tables 2 and 3, the majority
of patients in the trials had localised stage III disease.
In one trial (MRC Lung Cancer Working Party 1991)
there was some evidence that a higher dose could give
some long-term survivors in stage III, even though
median survival was equal. Therefore, MRC III study
(Medical Research Council Lung Cancer Working
Party 1996) was set up including only stage III dis-
ease and good performance patients, comparing
17 Gy/2 fractions (F1) with high-dose 39 Gy/13
fractions (F2). The median survival increased from 7
to 9 months in the F2 arm, although not significant,
with a 1- and 2-year survival of 31 and 9% with 36
and 12% in the F1 and F2 arms, respectively. In the
other study (Sundstrøm et al. 2004) comparing a strict
low-dose with high-dose schedules, a trend in better
survival in the high-dose arms was found. Later
exploration of this study restricted to stage III patients
only (Sundstrøm et al. 2006) reveal a 3- and 5-year
survival in the three arms (17 Gy/2, 42 Gy/15, 50 Gy/
25) of 1, 8, and 6%, against 0, 4, and 3%, respec-
tively. Patients with metastatic disease can safely be
treated with a hypofractionated schedule.
Side effects: acute toxicity with dysphagia is mild,
temporary, and manageable. Late toxicity is rare and
sporadic with low severity.

Palliation: most studies show that the effect on

symptoms and palliative effect is similar regardless of
dose and fractionation. A trend of more rapid relief of
symptoms in favour of hypofractionation is observed.
Survival: no major difference in median survival is
observed. Some patients with localised stage III dis-
ease may have better survival with a protracted high-
10 Treatment Recommendations
Systematic reviews including a Cochrane analysis
have been carried out focusing palliative thoracic
radiotherapy in lung cancer (Lester et al. 2006;
Fairchild et al. 2008). Due to large heterogeneity
458
concerning dose and fractionation no formal meta-
analysis has been initiated. The conclusion is that
there is no substantial strong evidence that a higher
dose gives a better outcome concerning symptom
relief and survival, and that a hypofractionated regi-
men is an option for most patients. However, patients
with stage III disease with a reasonable performance
status and less weight loss should be treated with a
protracted fractionated regimen 30–45 Gy. Self-
reported appetite loss can help in selecting patients
for short- or long-course palliative radiotherapy
(Sundstrøm et al. 2006). Stage IV patients can be
treated safely with a hypofractionated technique in
almost all cases. Some selected cases with single
metastasis can be treated more radically providing a
radical strategy for the metastatic site. Before treat-
ment decision is made, a thorough clinical evaluation
of the individual patient should be mandatory in all
cases, elucidating the patient into a good or poor
prognostic group as outlined in Table 1.
Of special interest is the fact that palliative radio-
therapy in lung cancer can unexpectedly generate
some long-term survivors (Sundstrøm et al. 2006;
Mac Manus et al. 2005). Approximately 1–3% of
patients with localised disease have been found with
5-year survival after palliative high-dose radiother-
apy. This can be explained by unpredictable high
radiotherapy sensitivity of some lung tumours.
11 When Should Palliative
Radiotherapy be Delivered?
In the last two decades the effect of chemotherapy in
advanced non-small cell lung cancer is recognised
(NSCLC Meta-analysis collaborative group 2008).
Numerous studies show the effect on survival and
improvement in quality of life and disease-related
symptoms. Treatment with chemotherapy should be
restricted to patients with a reasonably good perfor-
mance status (WHO PS B 2). Most patients with
advanced non-small cell lung cancer will therefore be
offered chemotherapy as the first-line treatment.
However, chemotherapy can generate toxicity and not
all patients are considered fit. For these patients pri-
mary palliative thoracic radiotherapy is a good option.
Palliative radiotherapy can also be offered to patients
S. Sundstrøm
progressing during or after chemotherapy with less
toxicity.
Palliative thoracic radiotherapy is administered
with the intention of treating symptoms from intra-
thoracic tumours. Patients evaluated to have less or no
disease-related symptoms will have minimal effect of
immediate treatment (Falk et al. 2002; Sundstrøm
et al. 2005). Immediate treatment is likely to give
unnecessary side effects like dysphagia in otherwise
symptom-free patients and do not prevent the devel-
opment of later symptoms. A wait and see procedure
is therefore advocated until the patient develops dis-
ease-related symptoms.
12 Summary
• Hypofractionated and moderately high-dose palli-
ative radiotherapy give equal effects on symptoms
and survival in advanced non-small cell lung
cancer.
• Stage III patients not candidates for a curative
strategy with favourable prognostic factors should
be treated with a fractionated schedule to a dose of
30–45 Gy.
• Stage IV patients can safely be treated with a strict
hypofractionated schedule.
• Palliative thoracic radiotherapy should not be
administrated to patients without symptoms present.
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 Intraoperative Radiotherapy in Lung
Cancer: Methodology (Electrons
or Brachytherapy), Clinical Experiences
and Long-Term Institutional Results
Felipe A. Calvo, Javier Aristu, Sergey Usychkin, Leire Arbea,
Rosa Cañón, Ignacio Azinovic, and Rafael Martinez-Monge

Contents 8 Montpellier Regional Cancer Centre

Experience ................................................................ 466

1 Introduction.............................................................. 462 9 The Allegheny University Hospital

2 Tissue Tolerance Studies of IORT ........................ 462
3 Technical Considerations: IOERT ........................ 463
4 Clinical Indications: IOERT .................................. 464
5 International Intraoperative Electron
Radiotherapy (IOERT) Clinical Experiences
and Results ............................................................... 464
6 National Cancer Institute Experience................... 464
7 University Medical School of Graz Experience... 465
of Philadelphia Experience..................................... 467
10 Madrid Institute of Oncology (Grupo IMO)
Experience ................................................................ 467
11 USP Hospital San Jaime Experience .................... 467
12 The University Clinic of Navarra Experience ..... 468
13 International LDR-IORT and
HDR-IORT Clinical Experiences and Results ..... 470
14 Stage I–II Disease .................................................... 471
15 Stage III Disease ...................................................... 472
16 Superior Sulcus Tumors (SST) .............................. 472
17 Summary and Final Considerations...................... 473
References.......................................................................... 475

F. A. Calvo (&)
Abstract
Department of Oncology,
University Hospital Gregorio Marañón, Intraoperative radiotherapy is a feasible technical
University Complutense, Madrid, Spain modality to improve precision and dose-escalation
e-mail: fcalvo.hgugm@salud.madrid.org in high-local risk lung cancer patients. Methodology
J. Aristu  L. Arbea is described regarding the use of high-energy
Department of Oncology, University Clinic, electron beams or brachytherapy. Results of normal
University of Navarre, Pamplona, Spain
tissue tolerance in experimental animal models and
S. Usychkin in clinical experiences are analyzed in detail.
Department of Radiotherapy,
Instituto Madrileño de Oncología,
Characteristics of clinical experiences using IORT
Madrid, Spain electrons or brachytherapy are reported and clinical
R. Cañón  I. Azinovic
outcome results are discussed. Ten IORT brachy-
Department of Radiation Oncology, therapy and six electron-based publications are
Hospital San Jaime, Torrevieja, Spain identified proving the adaptability of IORT to the
R. Martinez-Monge clinical-therapeutic scenario of lung cancer, its
Department of Radiation Oncology, feasibility and the promotion of high local control
Clinica Universitaria de Navarra, rates in the context of dose-escalation trials.
Pamplona, Spain

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 461
DOI: 10.1007/174_2011_286, Ó Springer-Verlag Berlin Heidelberg 2011
462
1 Introduction
Lung cancer is the leading cause of cancer-related
mortality worldwide, with nearly 1.4 million deaths
each year (Jemal et al. 2010). Lung cancer is diag-
nosed at an advanced stage in a majority of patients,
which is the primary reason behind the high mortality
rate associated with this disease (Ramalingam et al.
2011). At present 5-year overall survival in operable
or marginally operable locally advanced disease is
about 20–25% (Hansen and Roach 2010).
There is a well-known dose response relationship
in non-small-cell lung cancer (NSCLC). In a study of
Rengan et al. (2004) the median survival time for
patients treated with 64 Gy or higher was 20 months
versus 15 months for those treated with less than
64 Gy and a 10 Gy increase in dose resulted in a
36.4% decreased risk of local failure. A phase I–II
RTOG 9311 study confirmed a safety of dose-esca-
lation to 83.8 Gy with three-dimensional conformal
techniques (Bradley et al. 2005). In a recently pub-
lished study (Dong-Soo et al. 2011) showed that
clinical tumor response after concurrent chemoradia-
tion in locally advanced, recurrent and postoperative
gross residual NSCLC was the only significant
prognostic factor for overall survival.
Pattern of failure data show that 40–70% of
the patients with non-small-cell lung cancer stages
II–IIIB are expected to relapse locally (Kumar et al.
1996). Recently dose-dependent pattern of failure in a
NSCLC was demonstrated. In a study of Sura et al.
(2008) 75% of patients with NSCLC who received
\60 Gy had failure within GTV and 25% had disease
relapse at the GTV margin while among patients who
received C60 Gy 33 and 61% had relapse within
GTV and at the margin of GTV, respectively.
Local control in NSCLC continues being an
unresolved issue and the introduction of new radiation
techniques to intensify the local dose is justified.
Intraoperative radiation (IORT) is a sophisticated
radiation modality well explored in the treatment
of abdominopelvic tumors but is scarcely used in
thoracic tumors. The therapeutic gain in IORT pro-
cedures is obtained with the displacement of radio-
sensitive organs away from the electron beam or with
the shielding of fixed structures with lead sheets.
Target definition is done after the surgical resection
jointly with the thoracic surgery team.
F. A. Calvo et al.
IORT has been integrated into multi-disciplinary
programs as a boosting modality that completes the
total dose given with fractionated external beam
radiation therapy (ISIORT 1998). This treatment has
the advantage of the radiobiological effects of frac-
tionation over the primary volume that includes the
primary tumor and the draining areas while the tumor
bed is boosted with single-dose electrons.
The current review describes methodology and
clinical results of retrospective analyses including the
prognostic factors related with local control and sur-
vival in large institutional experiences generated in
NSCLC patients treated with IOERT component
within a multi-disciplinary treatment program.
2 Tissue Tolerance Studies of IORT
The tolerance of mediastinal structures to IORT with
high-energy electron beams (IOERT)ental animal
studies. In a dose-escalation study (Barnes et al. 1987)
delivering 20, 30 and 40 Gy to two separated intra-
thoracic IOERT fields which included collapsed right
upper lobe, esophagus, trachea, phrenic nerve, right
atrium and blood vessels, pathologic changes were
observed at 30 Gy in the trachea and esophagus, with
severe ulceration and peribronchial and perivascular
chronic inflammation in the normal lung. At dose of
20 Gy medial and adventitial fibrosis, obliterative
endarteritis of the vasa vasorum, and severe coagu-
lative necrosis were observed. Acute pneumonitis was
seen at all doses, and changes in the contralateral lung
were detected using 12 MeV electrons.
De Boer et al. (1989) studied the effects of 20, 25
and 30 Gy in mediastinal structures. The bronchial
stump healed in all dogs. Severe tissue damage was
seen at all doses and included bronchovascular and
esophagoaortic fistulas and esophageal stenosis.
At the National Cancer Institute, an experimental
program evaluated the tolerance of surgically
manipulated mediastinal structures to IOERT in 49
adult foxhounds. Tolerance of normal tissues was also
evaluated in a limited phase I clinical trial (four
patients with stage II or III NSCLC). Normal healing
of the bronchial stump was found after pneumonec-
tomy at IOERT doses of 20, 30 and 40 Gy, but there
were late changes with tracheobronchial irradiation
damage at all doses (5–10 months after treatment).
Two out of four patients receiving 20 Gy developed
Intraoperative Radiotherapy in Lung Cancer
Table 1 Clinical and pathologic findings observed in animal experimental models (Barnes et al. 1987; De Boer et al. 1989;
Tochner et al. 1992; Sindelar et al. 1992; Zhou et al. 1992; Kritskaia et al. 2006)
IORT doses Bronchial stump Esophageal damage
20 Gy Normal healing Transient mild dysphagia
30 Gy Normal healing Chronic ulcerative esophagitis
40 Gy Normal healing Esophageal perforation
Esophageal stricture
esophageal ulceration at 6 months without late stric-
ture. In dogs given 30 and 40 Gy, esophageal damage
was severe (esophagoaortic fistula and stenosis) and
one dog developed carinal necrosis. The same insti-
tution reported the results of five dogs reserved for
long-term studies and one stage II NSCLC patient
alive at 5 years. They conclude that IOERT in the
mediastinum may be safe at dose levels that do not
exceed 20 Gy (Tochner et al. 1992).
Additional experimental analysis of canine esoph-
agus tolerance to IOERT has been reported by the
NCI investigators (Sindelar et al. 1992). After right
thoracotomy with mobilization of the intrathoracic
esophagus, IOERT was delivered to include a 6 cm
esophageal segment using a 9 MeV electron beam with
escalating single doses of 0, 20 and 30 Gy. Dogs were
followed clinically with endoscopic and radiologic
studies and were electively sacrificed at 6 weeks or 3,
12 or 60 months after treatment. Transient mild dys-
phagia and mild esophagitis was observed in all dogs
receiving 20 Gy, without major clinical or pathological
sequelae except in one dog that developed achalasia
requiring a liquid diet. At a dose of 30 Gy, changes in
the esophagus were pronounced with ulcerative
esophagitis and chronic ulcerative esophagitis inducing
gross stenosis after 9 months.
Zhou et al. (1992) analyzed the acute responses of
the mediastinal and thoracic viscera in nine canines that
were sacrificed after they received single IOERT doses
of 25, 35 and 45 Gy. No pathological changes were
found in the spinal cord and vertebra. Microscopic
examination of trachea, esophagus and lung showed
mild or severe histological changes at 30 days at the
level of 25 Gy versus 35–45 Gy, respectively. Severe
and unrepaired histologic changes were found in the
heart and aorta receiving 35–45 Gy.
Morpho-functional changes in the bronchial
mucosa were studied in 33 patients with stage III
NSCL treated with 15 Gy IORT with or without
463
Lung damage Pathologic changes in
heart and vessels
Mild Moderate
Moderate Moderate-severe
Severe Severe
cisplatin (Kritskaia et al. 2006). No degenerative
changes in the bronchial epithelium were found
2 weeks after IORT. Basal cell proliferation was
observed, goblet cells were reduced in size and the
basement membrane was thickened and twisted.
Epithelial reparation due to pronounced local basal
cell proliferation was observed 3 months later. A year
later, the mucosa was covered with the multi-nuclear
cylindrical epithelium and the cover of ciliated cells
was preserved. The functional activity of goblet cells
was in the normal range and scanty lympho-plasmo-
cytic infiltration was found in the stroma. In patients
treated with IORT without radiosensitization, the
damaged epithelium was regenerated due to the
reserved cells coming from the damaged margins with
the formation of an epidermoid regenerative layer and
subsequent cell differentiation. Moderate sclerosis
occurred in the stroma. A year later the bronchial
epithelium was characterized by moderate goblet cell
hyperplasia with preserved functional activity. The
authors concluded that IORT caused mucosal damage
as alteration, dystrophy and desquamation of the
epithelium. Subsequently, the bronchial epithelium
recovered through reparative regeneration.
Based on these data, active clinical programs using
thoracic IOERT agree that 20 Gy is the upper single-
dose limit that can be safely tolerated by mediastinal
and thoracic viscera (Table 1) with IOERT alone.
There are no reported experimental normal-tissue
tolerance studies of IOERT used in combination with
EBRT.
3 Technical Considerations: IOERT
IOERT requires the adaptation of linear accelerator
with multi-energetic electron beam capability (ener-
gies recommended from 6 to 20 MeV), through the
development of specially designed applicators for
464
Fig. 1 Equipment used in a IOERT procedure: gantry adapter
with mirror-carrier (A); intermediate element (B) transparent
methacrylate applicator with a metric reference (C); distal
section of a beveled applicator (D)
electron-beam conformation (cone sizes recommended
from 5 to 12 cm diameter) (Fig. 1). The clinical pro-
gram combines the efforts of surgeons, anesthesiolo-
gists, physicists and radiation oncologists to adequately
select patients for IOERT indications, perform the
surgical procedure (tumor resection plus normal-tissue
protection), transport and monitor the patient during
intraoperative irradiation and finally decided the radio-
therapeutic parameters for treatment prescription
(Figs. 2, 3). In general, IOERT during lung cancer
surgery involves the coordination of 10–15 health
professionals, prolongs the surgical time approxi-
mately 30–45 min (depending upon transportation
time), and induces a 2 h gap of time availability in the
linear accelerator for outpatient treatment.
Miniaturized and mobile linear accelerator such as
the Mobetron operates at energies of: 4–12 MeV,
using two different dose rates: 2.5 and 10 Gy/min.
These energies are sufficient to achieve a 4 cm depth
of relative uniform beam penetration with acceptable
dose homogeneity (±5%) (Merrick and Dobelbower
2003) (Fig. 4).
The unit is mounted on a gantry and cantilevered
with a beam after it passed through the patient. This is
the principal feature that allows this unit to be used in
any operating room without additional shielding.
In addition to C-arm rotation the unit can rotate in and
out and in orthogonal planes. This design increases its
versatility in setting up patients for treatment and
reduces the amount of time needed to align the radiation
field with the applicator (Biggs et al. 2003) (Fig. 5).
F. A. Calvo et al.
4 Clinical Indications: IOERT
IOERT at the time of thoracotomy for a surgical
approach to lung cancer has been employed in three
different situations:
– Treatment of unresectable hiliar and/or mediastinal
disease
– Treatment of postresected residual disease (chest
wall, mediastinum and/or bronchial stump)
– Adjuvant treatment of mediastinum.
Conceptual indications for IOERT in thoracic
surgery have been the treatment of residual disease at
the primary site and/or nodal regions, or adjuvant
treatment of high risk of recurrence without proven
cancer residue after induction therapy and surgery.
IOERT is a super-selective radiation boost component
available for integration in conventional radiotherapy
programs for lung cancer. Lung parenchyma is the
normal tissue that may benefit the most from IOERT.
Esophagus, trachea, aorta and heart are difficult to
displace from the IOERT beam, particularly in the
treatment of mediastinal regions or left lower chest
cavity. In the case that the bronchial stump is included
in the IOERT field, tissue coverage with a vascular-
ized pleural or pericardial flap is recommended to
promote bronchial healing.
5 International Intraoperative
Electron Radiotherapy (IOERT)
Clinical Experiences and Results
The clinical experience of IOERT in lung cancer is
still limited and the available data regarding treatment
of NSCLC were obtained in phase I–II trials in a
small series of patients. Abe and colleagues in the
initial Japanese experience did not use IOERT in lung
neoplasms because of the early systemic dissemina-
tion of disease (Abe and Takahashi 1981).
6 National Cancer Institute
Experience
Based on a previous canine experimental model
involving the use of pneumonectomy and IOERT
doses of 0, 20, 30 and 40 Gy, a limited phase I
National Cancer Institute (NCI) clinical trial
Intraoperative Radiotherapy in Lung Cancer
Fig. 2 Different general
views of thoracic IOERT with
electrons in superior sulcus
tumor (1, 2), upper
mediastinum tumor (3) and
left hilum tumor (4).
demonstrated considerable toxicity with 25 Gy of
IOERT to two separated fields encompassing the
superior and inferior mediastinum following pneu-
monectomy (Pass et al. 1987). Early complications
were described in three out of four patients: one case
of bronchial stump dehiscence, one broncho-pleural
fistula and one case of reversible esophagitis. Three
patients with late complications showed one case of
irreversible radiation esophagitis. Only one long-term
survivor is free from disease (more than 3 years). The
retrospective analysis of toxic events detected over-
lapping of the fields in one toxic case. This study
recognized the feasibility of IOERT during lung
cancer surgery and recommended a decrease in the
IOERT dose to 15–20 Gy.
7 University Medical School of Graz
Experience
Combined IOERT (10–20 Gy) and postoperative
EBRT (46–56 Gy) were used in 21 inoperable tumors
at the University Medical School of Graz (Austria)
(Jeuttner et al. 1990). The analysis included 12 patients
465
with N0 disease. The radiosensitive mediastinal
structures such as the heart, spinal cord, esophagus and
large vessels could be mobilized or protected from the
IOERT beam by shielding maneuvers.
The response rates in 14 evaluable patients
18 weeks after they completed IOERT and EBRT were
excellent with three complete responses (21%) and 10
partial responses (71%). Ten patients are alive and well
at a range of 5–20 months (median 12 months).
The same institution updated the results of this
program in two consecutive studies (Arian-Schad
et al. 1990; Smolle Juettner et al. 1994). The IOERT
procedure was generally well tolerated, but fatal intra-
bronchial hemorrhage related to IOERT occurred in
two cases with tumor involvement of the pulmonary
artery. Local failure was seen in three patients and the
5-year overall and recurrence-free survival rates were
15 and 53%, respectively.
An expanded series from the University of Graz has
been recently published (Jakse et al. 2007). Fifty-two
patients with predominantly pathological stage I
NSCLC (76%) with limited pulmonary reserve (med-
ian FEV1: 1,3) were treated with surgery, IORT
(median dose 20 Gy) and EBRT (median dose 46 Gy).
466
Fig. 3 Simulation for applicator selection (size, beveled angle,
positioning and maneuvers for normal-tissue protection) after
right superior lobectomy. The IOERT target volume includes right
mediastinum and bronchial stump; the remaining normal lung is
mobilized out of the electron field (1). Postresection simulation for
Fig. 4 Mobetron mobile linear accelerator in the operating room
The actuarial overall survival and disease-specific
survival at 3 years were 37 and 48%, respectively.
Females had a significantly better disease-specific
F. A. Calvo et al.
a Pancoast’s tumor. The target volume includes the tumor bed
region (posterior and superior chest wall and paravertebral space),
and the remaining normal lung is mobilized out of the intraop-
erative field (2). IOERT applicator positioning during exploratory
thoracotomy for an unresectable right-lobe NSCLC (3)
survival than males. Causes of death were unrelated to
tumor in 17% and tumor related in 54% patients.
Two patients died from second cancers and 25% are
alive without evidence of tumor progression. Overall
loco-regional tumor control was 73% at 12 months and
68% at 24 and 36 months, respectively. IORT and
EBRT were well tolerated without serious treatment
related acute or late side effects.
8 Montpellier Regional Cancer
Centre Experience
The Centre Regional De Lutte Contre Le Cancer In
Montpellier (France) reported results in 17 patients:
three stage I, seven stage II and seven stage IIIA (Carter
et al. 2003). The treatment protocol involved the use of
IOERT with doses in the range of 10–20 Gy and 45 Gy
Intraoperative Radiotherapy in Lung Cancer
Fig. 5 Mobetron set-up for intraoperative irradiation
EBRT in 20–25 fractions with or without a 3 week rest
period following a complete surgical excision. Micro-
scopic residual disease in the mediastinal nodes or
pleura-chest wall was seen in 12 and 5 patients,
respectively. The median follow-up time for the entire
group of patients alive was 59 months, with follow-up
ranging from 40 to 120 months.
Disease control and survival results were as follow.
Local control was obtained in 13 out of 17 patients
(76%) and central recurrence in the IOERT field has
been demonstrated in four patients. Three patients are
alive without disease at 5.5, 8 and 11 years. Fourteen
patients are dead: seven from distant metastases, four
from loco-regional recurrence, one patient developed
a second cancer, and two patients had a local recur-
rence in the EBRT field. The median survival time for
the entire group was 36 months and the actuarial
survival rate is 18% projected at 11 years.
9 The Allegheny University Hospital
of Philadelphia Experience
This unique experience in the United States was pre-
liminarily reported in 1994 (Fisher et al. 1994). The last
update (Aristu et al. 1999) includes 21 patients treated
from 6/92 to 9/97 as a part of a pilot feasibility expe-
rience for stage I (n = 1), II (n = 2) and III (n = 18)
NSCLC patients managed by surgical resection,
IOERT (10 Gy), and EBRT (45.0–59.4 Gy, 16 preop-
eratively and 5 postoperatively). Chemotherapy was
administered to all patients. The median survival time
467
for the alive patients is 33 months. Patterns of relapse
have shown 3 (14%) thoracic and 12 (55%) systemic.
Actuarial 5-year survival was 33%.
10 Madrid Institute of Oncology
(Grupo IMO) Experience
In the Instituto Madrileño de Oncología (Grupo IMO)
in Madrid from February 1992 to July 1997, 18 patients
with stage III non-small-cell lung cancer (11 Pancoast’s
tumors) received IOERT as a part of a multi-disci-
plinary program including surgical resection in all
cases, chemotherapy in 13, preoperative EBRT in 7,
and postoperative EBRT in 7. Tumor residue at the time
of surgery was macroscopic (gross) in eight cases. The
median survival time for the entire series is 14 months.
Intra-thoracic recurrence has been identified in two
patients. Five-year actuarial survival is projected
as 22% (cause-specific 33%). Long-term toxicity
observed included neuropathy (two cases) and esoph-
ageal structure (one case) (Calvo et al. 1999).
11 USP Hospital San Jaime Experience
Between June 2004 and October 2008 in the USP
Hospital San Jaime in Torrevieja, Spain, eight patients
have been treated with IORT using the Mobetron
mobile linear accelerator: two woman and six men,
with a median age of 53 years (range 45–66 years). All
patients had locally-advanced non-small-cell lung
468
cancer (NSCLCs): stage IIA (n = 1), stage IIIA
(n = 1), stage IIIB (n = 4), stage IV (n = 1, a woman
with T2N2 and brain metastases) and one patient with
local relapse after surgery and radiotherapy.
All patients received preoperative radiochemo-
therapy: 50 Gy with conventional fractionation,
except two patients: one patient with local relapse
after radiochemotherapy and then treated with hypo-
fractionation (10 Gy for four sessions, 2 days a week)
and one patient stage IV, who received 66 Gy with a
radical intention and systemic chemotherapy. There
were three ypT0, five ypTmicroscopic, five ypN0, one
ypNmicro and two ypN1 pathologic responses in the
surgical specimens.
The median dose of IORT administered was 10 Gy
(range 6–10 Gy), using a cone of 4.5 cm of diameter
(range 3.5, 6 cm), 9 meV (range 4–9 MeV) electron
beam and with a median time for the procedure of
35 min, range: 15–60 min.
At a median follow-up of 36.5 months (range
2–66 months): one patient is lost for follow-up, two
died free of disease, one died with local and brain
relapse, three are alive free of disease 36, 37 and
53 months after the IORT, and one is alive with
pleural and mediastinal relapse 2 years after the IORT
and 1 year after suprarenalectomy for metastasis.
Two patients died 1.5 months after the IORT were:
the first patient who had received 66 Gy of radio-
therapy died for lung complication, and the second
patient with local relapse after radiochemotherapy
and treated with hypofractionation died from massive
bleeding.
The median overall survival is 22 months and the
disease-free survival is 12 months. Patterns of failure
are: one patient with local relapse was rescued with
reirradiation. Six months after he progressed with
brain metastases and died with disease. The second
patient had adrenal gland metastases 11 months after
surgery which were rescued with suprarenalectomy
and 13 months after he developed pleural and medi-
astinal relapse.
12 The University Clinic of Navarra
Experience
During the period from November 1984 to November
1993 104 patients with histologically confirmed non-
small-cell lung cancers stage III were treated with
F. A. Calvo et al.
IOERT as a treatment component of multidisciplinary
management at the University Clinic of Navarra in
Pamplona (Spain) (Calvo et al. 1990, 1991, 1992;
Aristu et al. 1997, 1999; Martínez-Monge et al. 1994).
Twenty-two patients were treated with surgery,
IOERT and postoperative EBRT, 82 patients received
neoadjuvant chemotherapy and were treated depend-
ing on tumor response as follows: 46 responders with
respectable tumor were managed with surgery, IO-
ERT and postoperative EBRT, non-responders with
unresectable disease (17 patients) or Pancoast’s tumor
(19 patients) received preoperative chemoradiother-
apy, surgery and IOERT boost.
The neoadjuvant chemotherapy consisted of cis-
platin 120 mg/m2 i.v. on day one, mitomycin C 8 mg/
m2 i.v. day one and vindesine 3 mg/m2 (maximum
dose 5 mg/m2) i.v. on days one and fourteen (MVP)
or the same treatment regimen where the cisplatin
administration was replaced by intraarterial carbo-
platin 150 mg/m2. The cycles of chemotherapy were
repeated every 28 days for 3–5 treatments until
achieved maximum response (3–5 cycles). Patients
who documented a clinical response or with stable
disease and considered resectable were referred to
surgical resection including the primary tumor and
mediastinal lymphadenectomy 4–5 weeks after the
last cycle of neoadjuvant chemotherapy. The bron-
chial stump was protected with a pleural or pericardial
flap in order to prevent anastomotic leak. After sur-
gical resection IOERT was applied over the surgical
bed, hiliar and mediastinal regions depending on the
tumor location. Total dose administered varied
between 10 and 15 Gy depending on the amount of
residual tumor. A detailed description of the IOERT
methodology for thoracic tumors has been published
previously (Calvo et al. 1990, 1992; Aristu et al.
1997; Martínez-Monge et al. 1994). Postoperative
external beam radiation therapy was started four to
5 weeks after surgical resection. Treatment was
delivered with a linear accelerator employing AP–PA
technique to encompass the treatment volume which
included bronchial stump, ipsilateral hilum, the
bilateral mediastinal and supraclavicular lymph
nodes. A dose of 46 Gy in 23 fractions was applied.
Tumors that were not considered resectable after
neoadjuvant chemotherapy were treated with preop-
erative external beam radiation therapy using the
same total dose and fractionation than with postop-
erative external beam radiation therapy described
Intraoperative Radiotherapy in Lung Cancer
Table 2 Patterns of failure Surgical residue
according to disease stage and
surgical residue in the Micro/Absent
University Clinic of Navarra IIIA
Experience
IIIB
Pancoast’s tumors
Macroscopic/Unresected
IIIA
IIIB
Pancoast’s tumors
a
No local or distant failure
b
Distant failure alone or distant and local failure
above. All patients received concurrent chemotherapy
with preoperative radiation using the same chemother-
apy combination used as neoadjuvant or with cisplati-
num 20 mg/m2 or carboplatinum 55 mg/m2 combined
with five fluorouracil 1,000 mg/m2 (maximum daily
dose 1,500 mg) during three to five days over the first
and last week of external beam radiation therapy. Four
to six weeks after the completion of the preoperative
chemoradiation course the patients were referred for
surgical resection and IOERT, when feasible.
The local control rates observed in patients with
\microscopic residual disease (R0 or R1 resection)
were 18/24 (75%), 4/14 (29%) and 11/12 (92%) for
stage IIIA, IIIB and Pancoast’s tumors, respectively.
Local control in patients with macroscopic residual
disease (R2 resection) were 3/7 (43%), 7/30 (23%)
and 5/5 (100%) for stage IIIA, IIIB and Pancoast’s
tumors, respectively. Table 2 describes the patterns of
failure according to the treatment group.
At the time of analysis 16 patients (15%) were alive
and free of disease. Five-year OS for the entire group
was 40% for stage IIIA and 18% for stage IIIB patients
(P = 0.01). Five-year disease free survival (DFS)
regarding amount of residual disease is as follows: 69%
and 42% for microscopic (R1) or no residual disease
(R0) for stages IIIA and IIIB, respectively and 58 and
41% for macroscopic (gross) residual disease (R2) for
stages IIIA and IIIB, respectively. Anecdotally, 19
patients survived more than 5 years after IOERT with a
follow-up range from 64 to 107 months. Among
patients surviving more than 5 years there were
3 second tumors (colon, esophagus and head and neck)
and one cancer-unrelated death.
Regarding treatment toxicity and complications,
four patients died in the postoperative period due to
possible IOERT-related toxicity: two broncho-pleural
469
Local controla Distant failureb
18/24 (75%) 7/24 (29)
4/14 (29%) 4/14 (29)
11/12 (92%) 2/12 (17)
3/7 (43%) 6/7 (86)
7/30 (23%) 12/30 (40)
5/5 (100%) 1/5 (20)
fistulas and two pulmonary hemorrhages. The first
broncho-pleural fistula occurred in a lobectomized
patient, in whom the bronchial stump was not included
into the IOERT field. Another patient died 3 months
after surgery due to a broncho-pleural fistula in a
microscopically tumor involved bronchial stump.
One patient developed fatal massive hemoptysis at
2 months following IOERT because of pulmonary
artery rupture. This latter patient had prior hemoptysis
and a left hiliar unresected tumor treated by tumor
exposure and 15 Gy (20 MeV) IOERT plus 46 Gy
postoperative EBRT. The autopsy study showed a
necrotic cavity in the primary tumor with no viable
residual tumor cells and a fistulous tract communicat-
ing between the pulmonary artery and the bronchial
tree. A non-resected patient treated with three cycles of
MVP regimen, preoperative EBRT (44 Gy) and IORT
of 15 Gy died early in the postoperative period from
pulmonary hemorrhage.
Esophagitis grade 3–4 was noted in 26 (25%)
patients and esophageal damage with ulcerated or
necrotic tissue was observed in two patients. One out of
two patients who developed esophageal ulcer died
8 months after surgery from fatal hemorrhage. This
patient had a T4 tumor infiltrating the descending
portion of the aorta and the esophagus. He was treated
with three cycles of MVP chemotherapy regimen,
preoperative EBRT (46 Gy), surgery (atypical resec-
tion plus chest wall resection), and 10 Gy IORT boost
(12 MeV). No viable microscopic tumor was encoun-
tered in the resected specimen and the necropsy find-
ings revealed a connection between the esophagus and
the aorta without histological evidence of tumor cells.
Symptomatic radiation acute pneumonitis was
observed in six patients. Seven patients were diag-
nosed with severe long-term fibrosis and required
470 F. A. Calvo et al.

Table 3 IOERT international clinical experiences in NSCLC

Authors (reference) Number Stage Treatment protocol Local 5-year
of control survival
patients
University Medical School of Graza 24 12 I IORT 10–20 Gy 19/23 15%
(Smolle Juettner et al. 1994) 1 II + (83%)
10 EBRT 46–56 Gy
IIIA
Montpellier Regional Cancer Centre 17 3I S ? IORT (10–20 Gy) 13/17 18%
(Carter et al. 2003) 7 II + (76%)
7 IIIA EBRT 45 Gy
University Clinic of Navarra in 104 19 Multidisciplinary treatment (see text) 48/92 40% (IIIA)
Pamplona IIIA with IORT 10–20 Gy ? EBRT (52%) 18% (IIIB)
(Calvo et al. 1990, 1991, 1992; Aristu (N0) (46 Gy) + CT
et al. 1997, 1999; Martínez-Monge 29
et al. 1994) IIIA
(N2)
56
IIIB
The Allegheny University Hospital of 21 1I Neoadjuvant CT ± preop EBRT 18/21 33%
Philadelphia 2 II + (86%)
(Aristu JJ, Fisher S, Calvo FA et al. 15 S ? IORT ± postop EBRT
1999) IIIA
3 IIIB
Madrid Institute of Oncology (Grupo 18 11 Neoadjuvant CT ± preop EBRT 16/18 22%
IMO) (Calvo et al. 1999) IIIA + (90%)
6 IIIB S ? IORT ± postop EBRT
1IV
USP Hospital San Jaime in Torrevieja 8 1 IIA Preoperative EBRT 50 Gy 6/8 Median OS
(Cañon R et al. 2008) 1 IIIA + (75%) 22 m, DFS
4 IIIB S ? IORT 6–10 Gy 12 m
1 IV
1 local
relapse
CT Chemotherapy
a
Inoperable patients

chronic cortico-therapy administration. Neurologic

toxicity was noted only in patients treated with
IOERT which included the thoracic apex or chest
wall. Six patients developed transient neuropathy
(four Pancoast’s tumors) with pain and paresthesia in
the superior ipsilateral extremity or chest wall. Severe
infectious complications were seen in 11 patients. Six
of these patients were diagnosed with simultaneous
thoracic tumor progression coexisting with an
abscess.
A summary of NSCLC IOERT clinical experi-
ences from different institutions is presented in
Table 3.
13 International LDR-IORT and
HDR-IORT Clinical Experiences
and Results
Intraoperative brachytherapy using low-dose rate
(LDR-IORT) or high-dose rate (HDR-IORT) is a
radiation treatment alternative in lung cancer patients
who are technically operable but cannot tolerate the
operative procedure and the expected reduction in
lung function after resection or conventional EBRT.
LDR-IORT/HDR-IORT can be also used as a radia-
tion boost technique in patients with residual disease
Intraoperative Radiotherapy in Lung Cancer
after chemoradiation or in previously irradiated
patients diagnosed with recurrent disease.
The LDR-IORT/HDR-IORT technique to be used
depends on tumor location and the volume of residual
disease after resection (R0, R1 and R2). Resectable
but inoperable tumors, R2 resections and recurrent
tumors may be treated by a permanent implant using
Iodine-125 (I-125) or Palladium-103 (Pd-103) seeds.
Unresectable chest wall lesions and R1 resections
may be treated intraoperatively by either a temporary
Iridium-192 (Ir-192) implant or a permanent I-125
implant imbedded in absorbable polyglactin (vicryl)
sutures and directly sutured onto the target area
(d’Amato et al. 1998) or it may be treated by employing
I-125 seeds imbedded into an absorbable gelatine
sponge (Gelfoam) plaque (Nori et al. 1995a). Periop-
erative high-dose-rate brachytherapy (PHDRB) using
Ir-192 administered over the immediate postoperative
period has been mainly used in R0–R1 tumor resec-
tions. Intraoperative implantation of plastic catheters
into the tumor bed after surgical resection for PHDRB
has several theoretical advantages over other types of
radiation boosting techniques, including: (i) accurate
real-time definition of the clinical target volume (CTV)
surrounding the tumor bed and other high risk areas
(with the assistance of the surgical team); (ii) CT scan-
based treatment planning; (iii) risk-adapted brachy-
therapy dose selection based upon the amount of
residual disease described in the final pathology report;
and (iv) early delivery of fractionated radiation during
the immediate postoperative period.
14 Stage I–II Disease
The largest experience with IOBT has been published
in patients with stage I–-II lung cancer who are unfit
for surgery and radical EBRT. The majority of the
studies are retrospective and come from single insti-
tutions. The MSKCC experience has been reported by
(Hilaris and Mastoras 1998). The study included 55
patients treated with thoracotomy, intersticial I-125
implantation ± moderate doses of EBRT. There were
no operative or postoperative deaths. Locoregional
control at 5 years was 100% in T1N0 lesions, 70% of
patients with T2N0 tumors and 71% in T1-2N1
tumors. The 5 year OS was 32% and DFS was 63%.
The median survival was better in patients with
cancer in the right lung but no difference in survival
471
could be demonstrated among patients with squamous
versus adenocarcinoma, T1 versus T2 tumors or those
who did or did not receive postoperative EBRT.
Fleischman et al. (1992) have published the results
of 14 medically inoperable stage I patients treated
with I-125 implantation at thoracotomy. Doses ranged
from 80 Gy at the periphery to 200 Gy at the
center. There was one operative mortality and two
postoperative complications. With a minimum fol-
low-up of 1 year, the local control was 71% and the
median survival was 15 months.
A retrospective multi-center study of 291 patients
with T1N0 disease was done comparing the outcomes
after sub-lobar resection (124 patients) and lobar
resection (167 patients) (Fernando et al. 2005).
Brachytherapy (100 Gy to 120 Gy to a 0.5 cm depth)
was used in 60 patients with sub-lobar resection. With
a mean follow-up of 34.5 months, brachytherapy
decreased the local recurrence rate significantly
among patients undergoing sub-lobar resection from
17.2 to 3.3%. There was no difference in survival
between sub-lobar resection and lobar resection in
tumors smaller than 2 cm. However, for tumor rang-
ing from 2 to 3 cm, median survival was significantly
better in the lobar resection group.
The experience of the New England Medical
Center in Boston is based on the implantation of
radioactive I-125 seeds along the resection margin in
35 patients with stage I lung cancer treated with
limited resection (not candidates for lobectomy) (Lee
et al. 2003). Two patients developed local recurrence
at the resection margin and six patients developed
regional recurrences in the mediastinun or chest wall.
The 5 year OS was 67 and 39% for patients with
T1N0 and T2N0 tumors, respectively.
Investigators of the University of Pittsburgh
Cancer Institute reported a trial exploring the feasi-
bility and outcomes of 125-I Vicryl mesh brachy-
therapy after sub-lobar resection (open or video-
assisted thoracoscopic procedure) in stage I non-
small-cell lung cancer patients with poor pulmonary
function (Chen et al. 1999; Voynov et al. 2005). The
implant was introduced through the surgical incision
and sutured to the visceral pleura. A prescribed dose
of 100–120 Gy was delivered to a volume within
0.5 cm from the plane of the implant. There were four
local recurrences in the 110 patients treated and the
estimated 5 year local control, locoregional control,
and OS rates were 90, 61, and 18%, respectively.
472
15 Stage III Disease
In the University of Navarra investigators initiated a
prospective, nonrandomized, controlled Phase II
clinical trial to determine whether perioperative
high-dose-rate brachytherapy (PHDRB) using Ir-192
administered over the immediate postoperative period
is feasible and tolerable and may improve locore-
gional control rates in lung cancer patients with
residual disease after chemoradiation or recurrent
disease after previous radiation therapy (Valero et al.
2007). In R0/R1 lung cancer resections the tumor bed
was implanted with plastic catheters for PHDRB. The
brachytherapy dose was 4 Gy b.i.d. x 4–10 fractions
(16–40 Gy total dose). Selected technically unfeasible
cases for PHDRB were treated using a silicone mold
in which plastic catheters are inserted and a single
dose of 10–12.5 Gy was administered. Macroscopic
residual unresectable tumors (R2 resections) were
implanted with I-125 or Pd-103 seeds to deliver a
minimum tumor dose of 90–110 Gy. Between 2001
and 2006 period, 20 patients have been treated, 15
patients had residual disease and 5 patients had recur-
rent disease. Two patients developed grade three
complication with thoracic abscess. Nine patients are
alive, seven without disease, one without disease after
radiosurgery for brain metastases and one patient is
alive with disease. The local, locoregional and systemic
control rates are 89, 84 and 70%, respectively. After a
median follow-up of 20 months (6–78 months) the
6 year OS and DFS are 36 and 27%, respectively.
The MSKCC treated 322 patients considered
unresectable at thoracotomy and treated with brachy-
therapy (Hilaris and Nori 1987). Patients without
mediastinal nodes metastases achieved 71% local
control versus 63% in patients with affected mediasti-
nal nodes. The 2 and 3 year OS in N0 and N2 patients
were 20/15% and 10/3%, respectively. A subgroup of
100 patients with positive mediastinal nodes were
treated with surgical resection when feasible, brachy-
therapy (temporary Ir-192 implantation in patients with
close or positive margins or I-125 implantation in
patients with residual gross disease) and postoperative
EBRT (median dose 40 Gy). There was no postoper-
ative mortality and local control obtained in 76% of
patients (77% for patients with no residual disease and
72% in patients who had incomplete or no resection)
(Hilaris et al. 1983, 1985).
F. A. Calvo et al.
The same institution presented a later experience
including 225 patients with thoracotomy and IOBT
when need in primary non-small-cell lung invading
only the mediastinum (T3-4N0-2) (Burt et al. 1987).
The authors encountered a positive correlation
between prolongation of survival and extent of
resection/IORT. Forty-nine patients had complete
resection without IORT and fared no better than a
cohort group of 33 patients underwent pulmonary
resection with simultaneous iodine-125 interstitial
implantation or iridium-192 delayed afterloading to
areas of unresectable primary or nodal disease. The
median survival, 3 and 5 year survival was
17 months, 21 and 5%, respectively, with incomplete
resection; and 12 months, 22 and 22% with incom-
plete resection and brachytherapy. One hundred and
one patients underwent interstitial implantation
without resection, with a median survival of
11 months, 3 year survival of 9%, and no 5 year
survivors. The perioperative mortality was 2.7% and
the nonfatal complication rate 13%.
Researchers in the New York Hospital Medical
Center of Qeens in New York investigated the safety,
reproducibility and effectiveness of intraoperative
I-125 or Pd-103 Gelfoam plaque implant technique in
12 patients as a treatment complement for resected
stage III patients with positive surgical margin. All
patients received preoperative or postoperative EBRT
(45–60 Gy) and four patients received chemotherapy.
There were no early or late complications due to
brachytherapy or EBRT. The local control and 2-year
OS and cause-specific survival were 82, 45 and 56%,
respectively (Nori et al. 1995b).
16 Superior Sulcus Tumors (SST)
The Erasmus Medical Cancer Center Experience in
SST has been recently reported (van Geel et al. 2003).
Twenty-six patients with cytologically or histologi-
cally proven NSCLC (T3N0-1 or T4N0) arising in the
pulmonary apex were treated with preoperative EBRT
(46 Gy in 23 fractions, 2 Gy per fraction, 5 fractions
per week), surgery and HDR-IORT using a flexible
intraoperative template (FIT). FIT is a 5 mm thick
silicone mold in which after loader catheters are
inserted parallel to each other at a fixed distance of
1 cm and is used to deliver a homogeneous dose to a
surface to which the shape of the mold is adjusted.
Intraoperative Radiotherapy in Lung Cancer 473

Table 4 LDR- HDR-IORT international clinical experiences in stage I–II NSCLC

Authors (reference) Number of Stage Treatment protocol Local control Time point
patients
Hilaris and Mastoras 55 T1-2N0- S ? I-125 (160 Gy) 100% 32% 5 year
(1998) 1 ± (T1N0) OS
EBRT 70% (T2N0)
71% (T1-
2N1)
Fleischman et al. (1992) 14 T1N0 S ? I-125 10/14 (71%) MS 15.1 m
(80–200 Gy)
Fernando et al. (2005) 291 T1N0 Lobar resection (LR) 96.5% (LR)a MS
versus 95.6% (SR)a 68.7 m (LR)a
Sublobar resection (SR) ± I- 50.6 m (SR)a
125
(100–120 Gy)
Lee et al. (2003) 33 T1-2N0 Limited resection 31/33 (94%) 5 year OS
+ 67% (T1N0)
I-125 39% (T2N0)
Voynov et al. (2005) 110 T1-2N0 Limited resection 106/110 5 year OS
+ (96%) 22% (T1N0)
I-125 (100–120 Gy) 5-y LC 90% 12% (T2N0)
S surgery, EBRT external beam radiation therapy, MS median survival, OS overall survival
a
Local recurrence and survival rates for the 2–3 cm tumors

A single radiation fraction of 10 Gy was administered
specified in a plane parallel to the surface of the FIT
at 1 cm distance with HDR Ir-192. EBRT
(12 9 2 Gy) was indicated for unresectable tumors
during thoracotomy. Three patients progressed during
the preoperative treatment and were excluded. In two
patients HDR-IORT was not considered because the
tumors had no chest wall invasion. Finally, 21
patients underwent the entire programmed treatment
protocol. One patient (4%) died in the postoperative
period due to a cardiac failure. Another patient died
7 weeks after surgery with a broncho-pleural fistula
and sepsis. Two patients had a prolonged hospital stay
of more than 3 weeks because of ARDS and pleural
empyema recovering after intensive conservative
treatment. With a median follow-up of 18 months, 8
patients were alive (37%), of which 7 had no evidence
of disease and 18 patients (85%) were free from
locoregional relapse. The median survival for patients
without and with distant failure was 14 months and
6 months, respectively.
Hilaris et al. (1974, 1987) presented the results of
129 patients with SST treated with thoracotomy (in
bloc excision of the involved lung and chest wall
when feasible) interstitial IORT using either perma-
nent implantation of I-125 seeds or temporary
implantation of Ir-192, and postoperative EBRT in
patients who had received no preoperative EBRT or
when the implant presented unacceptable dose dis-
tribution requirements. The authors describe a 0.8%
of postoperative deaths and 17 patients (13%) pre-
sented nonfatal complications including wound
infection, empyema with or without broncho-pleural
fistula, bleeding, atelectasia or pneumonia and phle-
bitis. The 5 year OS was 25% and patients with
negative mediastinal nodes fared better than patients
with positive mediastinal nodes showing a 5 year OS
of 29 and 10%, respectively.
A summary of NSCLC LDR-IORT and HDR-
IORT clinical experiences from different centers is
presented in Tables 4 and 5.
17 Summary and Final Considerations
The modern developments in the treatment of local-
ized NSCLC confirm the oncology tendency to
intensify systemic and local treatment to promote
disease control. Although a large number of patients
with stage III NSCLC die of systemic disease, local
failure remains a substantial problem. CALGB
reported patterns of disease failure in stage IIIA
patients treated with induction chemotherapy, surgery
and thoracic irradiation (Kumar et al. 1996). The
474 F. A. Calvo et al.

Table 5 LDR- HDR-IORT international clinical experiences in stage III NSCLC

Authors Number of Stage Treatment protocol Local Time point
(reference) patients control
Valero et al. 20 III S ? PHDRB (16–40 Gy) or IOBT (10.12.5 Gy) 89% 36% 6 year
(2007) or I-125/Pd-103 seeds (90–110 Gy) OS
Burt et al. 225 III S ± I-125a/Ir-192 10/14 MS 12 mb
(1987) (71%) 22% 5 year
OSb
Hilaris and 322 Unresectable Thoracothomy ? I-125 (160 Gy) 71%(N0) 15% 3 year
Nori (1987) 63% OS (N0)
(N2) 3% 3 year
OS (N +)
Hilaris et al. 100 IIIN2 I-125 (160 Gy)/Ir-192 (30 Gy) 89% 22% 5 year
(1985) ± S ? EBRT (30-40 Gy) (R0) OS
53% 22% 5 year
(R1) OS (R2)
72%
(R2)
Nori et al. 12 III ± EBRT (45–60 Gy) + S 82% 45% 2 year
(1995a) (PSM) + OS
I-125/Pd-103 Gelfoam implant
± EBRT (45–60 Gy)
S surgery, EBRT external beam radiation therapy, MS median survival, OS overall survival PHDRB Perioperative high-dose-rate
brachytherapy, IOBT Intra-operative brachytherapy using a silicone mold in which plastic catheters are inserted, PSM Gross o
microscopic positive surgical margins
a
125-I in patients with incomplete resections
b
Patients with incomplete resection and brachytherapy

study found that 52 out of 74 patients had failures and
the thorax was the first site of isolated or combined
local failure in 36 patients (69%).
Unfortunately, less than 20% of stage III patients
have disease that is resectable for cure at diagnosis
and the optimal management of patients with
unresectable disease remains controversial. In spite
of improvement in resectability rates with neoad-
juvant approaches, stage III NSCLC patients have a
high incidence of local recurrence. Based on these
observations, higher tumor doses may result in
improved local control, and several trials have
emerged in an attempt to promote thoracic control
by escalating total radiation doses exploring altered
fractionation or three-dimensional radiation planning
(Rengan et al. 2004; Bradley et al. 2005; Sura et al.
2008).
IORT/IOBT has been integrated into the multi-
disciplinary management of NSCLC in several small
prospective single-institution pilot trials as a sophis-
ticated electron, LDR or HDR boost of radiation,
confirming the feasibility of IORT procedure during
surgical exploration of NSCLC patients. IORT doses
between 10 and 15 Gy combined with EBRT
(46–50 Gy) induce acute and late toxic events at a
clinically acceptable level. Tables 3, 4 and 5 show
summarized international IORT clinical trials
regarding local control and survival data in NSCLC.
Definitive conclusions based on the available
experiences discussed in this chapter cannot be
established. In stage I or II NSCLC, IOERT and
IOBT have been used for medically inoperable
patients with excellent rates of local control
(70–100%). Alternatively, stereotactic body radio-
therapy (SBRT) has emerged as a well-tolerated
technique in this subgroup of patients with high rates
of local control (Fakiris et al. 2009; Lo et al. 2008).
IOBT may be reserved to complex central T1-2
tumors or unsuspected surgical findings.
Thoracic control seems to be related to tumor stage
and location, surgical residue and neoadjuvant treat-
ment in locally-advanced NSCLC. Remarkable local
control rates in Pancoast’s and stage IIIA tumors with
microscopic residual disease have been detected.
Intraoperative Radiotherapy in Lung Cancer
The effect of IORT on the group of patients pre-
senting with stage IIIB appear to be favorable. This
point is illustrated by the fact that patients with
macroscopic residual disease or unresected disease
achieved modest rates of local control (23%), but a
few long-term survivors are identified. The high rates
of metastatic disease in locally-advanced NSCLC
may conceal the definitive long-term local control but
the introduction of novel systemic agents generating
more long-term survivors will clarify this question.
Further confirmatory trials will be necessary to define
the implication of IORT/IOBT in thoracic control and
survival of patients with NSCLC. IORT/IOBT as a
component of treatment can be integrated in phase III
trials with treatment strategies that may include surgical
thoracic exploration. This effort will require interna-
tional cooperation among expert IORT institutions.
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 Brachytherapy for Lung Cancer
A. Polo, M. Castro, A. Montero, and P. Navı́o

Contents Abstract
Brachytherapy is the direct placement of a radio-
1 Introduction.............................................................. 478 active source inside or close to a tumor mass. The
2 Procedure for Lung Brachytherapy...................... 478 use of endobronchial brachytherapy for broncho-
2.1 Endobronchial High-dose Rate Brachytherapy ........ 478 genic carcinoma is not new, being the initial use
2.2 Interstitial Brachytherapy .......................................... 479 reported back in the early 1920s. Brachytherapy
3 Clinical Results: Tumor Control for lung cancer can be done either by implanting
and Palliation ........................................................... 480 the source directly via the upper airway (endolu-
3.1 Endobronchial Brachytherapy (EBB) with Curative minal brachytherapy) or by placing the source
Intention ..................................................................... 480
3.2 EBB with Palliative Intention ................................... 482 interstitially during tumor resection (intraoperative
3.3 Interstitial Brachytherapy .......................................... 484 interstitial brachytherapy) or using a percutaneous
technique (interstitial brachytherapy). Endolumi-
4 Clinical Results: Toxicity........................................ 484
nal high dose rate brachytherapy is largely used for
5 Conclusion ................................................................ 486 the curative and palliative treatment of endobron-
References.......................................................................... 486 chial tumors. Endoluminal brachytherapy can be
used to treat patients with respiratory symptoms
which are predominantly due to the endobronchial
component of their disease. Brachytherapy can
obtain palliation with less morbidity than external
irradiation. Endoluminal brachytherapy can be
used in combination with external beam radiother-
apy for dose escalation as a part of a more radical
approach. Finally, brachytherapy may be given to
patients who require further palliation having
relapsed after previous treatments, including high
dose external beam irradiation. Interstitial brachy-
therapy has been described for the treatment of
A. Polo (&)
A. Montero malignant thoracic tumors. Intraoperative perma-
Department of Radiation Oncology, nent radioactive 125-I seed implantation can be
Ramon y Cajal University Hospital, used in the treatment of lung cancer when resec-
Madrid, Spain
e-mail: alfredo.polo@mac.com tion margins are close or involved with tumor or
for palliation of inoperable disease. Percutaneous
M. Castro
P. Navío
Department of Pneumology, implantation of radioactive seeds has also been
Ramon y Cajal University Hospital, reported for the management of stage T1N0M0
Madrid, Spain

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 477
DOI: 10.1007/174_2011_311, Ó Springer-Verlag Berlin Heidelberg 2011
478
medically inoperable NSCLC with CT-guided
brachytherapy. During the last two decades, tech-
nological advances helped the development of
brachytherapy and now it is a safe and effective
standard procedure in the treatment of lung cancer.
1 Introduction
Brachytherapy is the direct placement of a radioactive
source inside or close to a tumor mass. This can be
done either by implanting the source directly via the
upper airway (endoluminal brachytherapy) or by
placing the source interstitially during tumor resection
(intraoperative interstitial brachytherapy) or using a
percutaneous technique (interstitial brachytherapy).
Endoluminal high-dose rate brachytherapy is lar-
gely used for the curative and palliative treatment of
endobronchial tumors. Endoluminal brachytherapy can
be used to treat patients with respiratory symptoms
which are predominantly due to the endobronchial
component of their disease. Brachytherapy can obtain
palliation with less morbidity than external irradiation.
Endoluminal brachytherapy can be used in combina-
tion with external beam radiotherapy for dose escala-
tion as a part of a more radical approach. Finally,
brachytherapy may be given to patients who require
further palliation having relapsed after previous treat-
ments, including high-dose external beam irradiation.
Interstitial brachytherapy has been described for
the treatment of malignant thoracic tumors (Stewart
et al. 2009). Intraoperative permanent radioactive 125I
seed implantation can be used in the treatment of lung
cancer when resection margins are close or involved
(R1, R2) with tumor or for palliation of inoperable
disease. Percutaneous implantation of radioactive
seeds has also been reported by Martinez-Monge
(2008) for the management of stage T1N0M0 medi-
cally inoperable NSCLC with CT-guided brachy-
therapy. The use of permanent seed brachytherapy has
the potential to improve local control through the
delivery of a high conformal dose. Due to the low
energy of 125I, the falloff in the dose allows optimal
sparing of normal tissues surrounding the implant.
The initial use of endobronchial brachytherapy for
bronchogenic carcinoma was reported in the early
1920s by Yankauer (1922), who implanted radium
capsules into an endobronchial tumor using a rigid
A. Polo et al.
bronchoscope. Iodine-125 and gold-198 have also
been used for permanent interstitial transbronchial
implantation. These early techniques were not very
popular due to several logistical reasons, the risk of
severe complications, and the poor control over the
dosimetric outcome. The development of the after-
loading techniques during the 1950–1960s was
essential for the widespread application of brachy-
therapy (Henschke et al. 1964). Other new radioactive
sources were developed, such as iodine and cesium.
New rules of implantation and dose calculation
were established. These developments introduced
new possibilities for implantations. Afterloading
techniques were developed to facilitate intraluminal
brachytherapy using cesium-137, cobalt-60, or
iridium-192. A modern technique for endoluminal
brachytherapy (enclosing the brachytherapy source
within a polyethylene catheter and implanting it via a
flexible fiberoptic bronchoscope) was described in the
1980s (Moylan et al. 1983; Mendiondo et al. 1983).
Iridium-192 became the isotope of choice for brach-
ytherapy around this time. Although this led to the
more frequent use of this treatment, it was still of
limited application because of the large size and low
activity of the radioactive sources, prolonged treat-
ment times because of the low-dose rate, and the
exposure of staff to significant radiation doses.
In addition, both permanent interstitial implantation
and temporary intraluminal brachytherapy required
general anesthesia for insertion of the sources or
their carrying applicators. During the last two
decades, technological advances solved some of the
inconveniences of brachytherapy for lung cancer
(Schray et al. 1988, 1985; Seagren et al. 1985). High
activity, miniaturized 192Ir sources and computerized
planning and afterloading developed. Intraluminal
catheter positioning using local anestesia and flexible
bronchoscopy is a safe and effective standard proce-
dure (Mehta et al. 1992; Lo et al. 1995).
2 Procedure for Lung Brachytherapy
2.1 Endobronchial High-dose Rate
Brachytherapy
It requires the insertion of one or several plastic
vectors (usually, a 5–6F closed end plastic tube) into a
patient’s airway. Plastic tubes can be connected to an
Brachytherapy for Lung Cancer
afterloader device holding a miniature iridium or
cobalt source able to travel to the desired position
thanks to a computerized dosimetric system. Per-
formed by an experienced bronchoscopist, HDR
brachytherapy has a few acute side effects as routine
fiberoptic bronchoscopy and can therefore be easily
applied in an outpatient setting.
This procedure may be performed under intrave-
nous conscious sedation typically used in standard
bronchoscopic procedures. After topical anesthetic is
carefully applied to the nasal cavity and the naso-
pharynx, the pulmonologist inserts the bronchoscope
through the nose, the vocal cords, and into the
affected bronchus. If there is subtotal stenosis of the
bronchi due to submucosal or exophytic tumor
growth, it is sometimes necessary to perform recan-
alization methods like laser, cryotherapy, or balloon
dilatation for better applicator placement. When the
bronchoscope is in position near the tumor, a thin
(5–6 French) polyethylene catheter is inserted through
the bronchoscope working channel. The pulmonolo-
gist can see the catheter as it emerges from the distal
end of the bronchoscope and is advanced distal to the
tumor area (Gross Tumor Volume—GTV) under
direct visualization.
Endoluminal irradiation should be delivered with a
‘‘safety margin’’ at both ends of the GTV to account
for microscopically disease (Clinical Target
Volume—CTV) and catheter movement (Planning
Target Volume—PTV). External marks in the cathe-
ter’ surface help in the definition of the different
volumes related to the end. As the distal end of the
tumor cannot always be seen, the distal endpoint must
be estimated from previous chest X-rays or CT scans
and controlled during bronchoscopy by fluoroscopy.
The use of multiple catheters to enlarge the treated
volume and cover complex tumor shapes and local-
izations (bulkier tumors involving more than one of
the bronchi) may be necessary. If additional catheters
are needed to encompass the tumor, the procedure is
repeated. Once the first tube is in place, the bron-
choscope is then withdrawn, leaving the catheter in
place. The bronchoscope can be again introduced in
parallel to check the catheter position and replace it if
necessary. Finally, the catheters are carefully fixed
and referenced.
Acute side effects of the placement procedure
include more or less severe coughing, which could be
minimized by thorough topical anesthesia and given a
479
codeine pill to the patient before the procedure.
Severe acute effects such as massive bleeding or
pneumothorax induction are very rare.
HDR is usually delivered with 1–6 fractions/
treatment at an interval of 1–3 weeks. Prescription
doses range between 3 and 20 Gy/fraction (at 0.5–
1 cm from the source axis). In patients previously
treated with external beam radiation therapy and in
the palliative setting, a regimen of 7–10 Gy (HDR)/
fraction and a total of 2–3 fractions/treatment can be
used. However, the optimal dosage and fractionation
schemes for the tumor therapy are still unknown and
the selection of the treatment schedule depends on the
approach (palliative, exclusive brachytherapy with
curative intent or boost to external beam radiother-
apy) and the tradition of the team.
2.2 Interstitial Brachytherapy
The techniques of interstitial implantation vary
depending on the type of implantation used. Perma-
nent implants are interstitial implants in which the
radioactive sources are permanently left in the tissue.
Temporary implants are interstitial implants in which
the radioactive sources are removed after the desired
dose has been delivered.
Seeds can be placed directly into a tumor as a
volume implant, or mesh in a grid pattern in a planar
implant (Stewart et al. 2009). Volume implants are
often done through a thoracotomy approach. The first
step of the procedure consists of delineating the area
to be treated (GTV) and the margins to obtain the
CTV. The second step consists of determining the
number of sources required using a previsional
dosimetry. Next, hollow needles are inserted, and then
is the afterloading with radioactive seeds using the
Mick applicator or preloaded needles.
In the surgical treatment of large tumors, negative
margins are often unattainable. In tumors adhering to
critical vessels or bone or other visceral structures,
resection is often incomplete. To cover the post-
surgical bed, a planar implant can be custom-made
intraoperatively. The target region is measured and a
planar implant is prepared. The mesh can be done
using permanent vycril suture, gelfoam, or other
platform custom-sized to cover the region of interest,
and embedding 125I or 103Pd seeds. The mesh is then
sutured to the region of interest to prevent slippage.
480
While permanent seed implantation has been used
with some success in the intraoperative treatment of
unresectable, residual, or medically inoperable
NSCLC its use in a percutaneous CT-guided approach
is merely anecdotal (Martinez-Monge et al. 2008;
Sider et al. 1988; Heelan et al. 1987). This fact may
be explained in part by the lack of tradition even in
the most experienced brachytherapy centers, the small
number of suitable candidates that probably stands for
less than 20% of those referred for radical radiation
due to a poor surgical risk and the fear of acute
complications associated with the procedure. The
implant is performed in a standard CT room under
general anesthesia, allowing patient immobilization
and limited lung motion, decreasing the risk of
pneumothorax. CT imaging determined the coordi-
nates of the skin entry point and permitted adjustment
of depth and angle of needle placement. After target
volume determination, interstitial needles are inserted
into the tumor and then seeds are inserted through
each needle. Once the implant is completed, a final
CT scan is obtained for postplanning.
Temporary implants using HDR are useful in the
treatment of some clinical situations. A hollow
stainless needle is passed through the chest skin of the
patient. The closed end of a plastic catheter is threa-
ded through the needle until it emerges from the
opposite end of the needle. The needle is then
removed while the plastic tube is held in the chest.
The process is repeated for the planed number of
afterloading catheters constituting the planar implant.
Each catheter is placed in the desired situation
according to the defined target volume and secured
with suture material. The afterloading catheters are
secured to the skin with buttons and silk sutures.
Prescription doses ranges between 125 Gy for
103
Pd and 100–160 Gy for 125I, depending on the
approach (adjuvant vs. exclusive), type of implant
(planar vs. volumetric) and the tradition of the team.
3 Clinical Results: Tumor Control
and Palliation
3.1 Endobronchial Brachytherapy (EBB)
with Curative Intention
Unresectable tumors with a significant intraluminal
component and obstructive symptoms can benefit
A. Polo et al.
from EBB as a component of treatment associated
with radiotherapy, or as exclusive treatment. Lung
cancers in very early stages, confined to the trachea/
bronchus and without evident lung parenchymal
involvement, the so-called hidden lung carcinomas
(pure endobronchial carcinoma not visible on CT) are
most likely to benefit from exclusive brachytherapy
with curative intent. Occasionally, EBB has also been
associated with surgery in a postoperative setting as a
boost to the surgical bed in cases of close or micro-
scopically affected bronchial resection margins.
There are no prospective, randomized studies
evaluating the effect of endobronchial brachytherapy
alone in the treatment of very early lung cancer, but
numerous retrospective studies have reported the
results of EBB in this context. Table 1 shows the
results observed by different groups using exclusively
EBB with curative intent (Hilaris et al. 1987;
Schraube et al. 1993; Sutedja et al. 1994; Tredaniel
et al. 1994; Perol et al. 1997; Taulelle et al. 1998;
Stout et al. 2000; Peiffert et al. 2000; Marsiglia et al.
2000; Hennequin et al. 2007; Aumont-le Guilcher
et al. 2011). Nevertheless, it is necessary to keep in
mind the enormous heterogeneity between studies,
both in the characteristics of the patients enrolled, and
in terms of the total dose, fractionation scheme, and
overall treatment time. In spite of this, a benefit of
EBB can be inferred from the analysis of these
studies, mainly in terms of local disease control, that
always must be balanced according to the risk of
complications.
In patients with tumors considered unresectable,
brachytherapy has also been used in conjunction with
external beam radiation therapy as a boost. Higher
combined doses of EBRT and brachytherapy have
been associated with increased overall response,
although this was not found by all published studies.
The observed results are less clear, probably due to
the heterogeneity of the series and the different
schemes used. Table 2 lists the clinical outcomes
observed in studies in this field (Aygun et al. 1992;
Cotter et al. 1993; Nori et al. 1993; Speiser and
Spratling 1993a; Kohek et al. 1994; Fuwa et al. 2000;
Nomoto et al. 1997; Huber et al. 1997; Furuta et al.
1999; Muto et al. 2000; Saito et al. 2000; Langendijk
et al. 2001; Ozkok et al. 2008). In a prospective,
randomized trial performed by Huber et al. (1997)
including a total of 98 patients, two groups were
compared. One group was treated with external
Brachytherapy for Lung Cancer 481

Table 1 Definitive brachytherapy alone: clinical results

Author n EBRT (Gy) BT Total dose MFU LC (%) CSS (%) OS (%) MST
Technique (dose per (months)
fraction/
number
of fractions)
Hilaris 55 44% EBRT LDR/HDR 54 63 NA 32 NA
et al. mediastinum
(1987)
Schraube 13 – HDR 5–30 NA NA NA NA 9 months
et al. (3–5/1–6)
(1993)
Sutedja 2 – HDR 30 (10/3) 40 NA 100 NA NA
et al. (1994)
Tredaniel 29 – HDR 42 (7/6) 23 NA NR NA Not reached
et al.
(1994)
Perol et al. 19 – HDR 35 (7/5) 28 75 78 NA 28 months
(1997) (1 years) (1 years)
58
(2 years)
Taulelle 23 – HDR 24–40 32 NA 46 NA 17 months
et al. (8–10/3–4) (2 years)
(1998)
Stout et al. 49 – HDR 15 (15/1) NA NA NA 2 250 days
(2000) 50 30 – – 10 287 days
P = 0.04 P = 0.04
Peiffert 33 No EBRT HDR 30 (5/6) 14 NA 53 80 23 months
et al. (18p) (2 years) (2 years)
(2000) 50–60 (15p) HDR 10–20 (5/2–4)
Marsiglia 34 – HDR 30 (5/6) 29 85 NA 78 NA
et al. (2 years) (2 years)
(2000)
Hennequin 106 – HDR 30–42 (5–7/6) 48 60.3 67.9 47.4 21.4 months
et al. (2 years) (2 years) (2 years)
(2007) 51.6 48.5 24
(5 years) (5 years) (5 years)
Aumont-le 226 – HDR 24–35 30.4 68 81 57 28.6 months
Guilcher (2 years) (2 years) (2 years)
et al. (5–7/4–6) 50 56 29
(2011)
(5 years) (5 years) (5 years)
EBRT: external beam radiotherapy; BT: brachytherapy; HDR: high-dose rate; LDR: low-dose rate; MFU: median follow-up;
LC: local control; CSS: cancer-specific survival; OS: overall survival; MST: median survival time; NA: not available

radiotherapy alone (planned dose 60 Gy), the second
group received an additional boost of HDR brachy-
therapy (4.8 Gy scheduled, at 10 mm from the source
axis) before and after external irradiation. In patients
with squamous cell carcinoma, the HDR brachyther-
apy group showed a borderline advantage in median
survival and a better local tumor control.
Finally, EBB has been also used as adjunctive
treatment to radical surgery. The presence of micro-
scopic disease in the surgical resection margin of the
bronchial stump is a known risk factor for local
recurrence. The study by McKenna et al. (2008)
discusses their experience in the use of EBB as
adjuvant treatment after surgery.
482 A. Polo et al.

Table 2 Definitive brachytherapy boost with external beam radiotherapy: clinical results
Author n EBRT BT Total dose MFU LC (%) CSS (%) OS (%) MST
(Gy) Technique (dose per (months)
fraction/
number
of fractions)
Aygun et al. 62 50–60 HDR 15–25 (5/3–5) 18 months NA NA NA 13
(1992)
Cotter et al. 65 55–66 LDR 6–35 NA NA 23 8
(1993) (2 years)
Nori et al. 17 *50 HDR 15 (5/3) 14.5 months 88 NA NA 17.5
(1993) (6 months)
Speiser and 50 60 HDR 22.5–30 NA NA NA NA 11
Spratling (7.5–10/3)
(1993a)
Kohek et al. 39 50–70 HDR 5–25 (5/1–5) NA NA NA NA 13
(1994)
Fuwa et al. 41 50 LDR 22 0– NA NA 61 (CR) NA
(2000) 60 months
Nomoto 9 40–60 HDR 18 (6/3) NA NA NA 64 NA
et al. (1997) (3 years)
Huber et al. 56 60 HDR 9.6 (4.8/2) 2.5 years 12 weeks NA 25 10
(1997) (1 year)
42 60 – – 21 weeks 19 8
(1 year) (P = 0.09)
Furuta et al. 5 40 HDR 18 (6/3) 36 months 100 (CR) 80 (CR) 60 (CR) NA
(1999)
Muto et al. 320 60 HDR 10–15 5– NA NA NA 11
(2000) (5–10/1–3) 36 months
Saito et al. 64 40 LDR 25 44 months 87 96 72 NA
(2000) (5 years) (5 years) (5 years)
Langendijk 48 30–60 HDR 15 (7.5/2) 12 months NA NA 9 (CR) 7
et al. (2001)
47 30–60 – – 15 (CR) 8.5
Ozkok et al. 43 60 HDR 15 (5/3) NA NA NA 25.5 11
(2008) (2 years)
BT and Surgery
McKenna 48 Wedge HDR 24.5 (3.5/7) 13.5 92 (CR) NA 83 (CR) NA
et al. (2008) resection
EBRT: external beam radiotherapy; BT: brachytherapy; HDR: high-dose rate; LDR: low-dose rate; MFU: median follow-up;
LC: local control; CSS: cancer-specific survival; OS: overall survival; MST: median survival time; CR: crude rate; NA: not available

3.2 EBB with Palliative Intention
As mentioned above, one of the main indications for
endobronchial brachytherapy is the palliation of
symptoms due to uncontrolled bronchial tumor
growth. EBB is a relatively simple and quick method
to relieve bronchial obstruction and ensure the
viability of the airway for a long time.
The American Brachytherapy Society (ABS)
should consider EBB as a good palliative treatment in
patients with tumors with significant endobronchial
component that result in symptoms of shortness of
breath, persistent cough, hemoptysis, or signs of
obstructive pneumonitis (Nag et al. 2001; Gaspar
1998). Patients should be able to withstand the proce-
dure, should not present a significant active bleeding,
Brachytherapy for Lung Cancer 483

Table 3 Palliative brachytherapy: clinical results

Author n Prior BT BT schedule Symptomatic response
treatments technique
Lo et al. (1992) 77 laser LDR 45–60 Gy Overall: 54%
Gollins et al. (1996) 322 EBRT, HDR 15 Gy 9 1 Stridor: 92%;
laser 20 Gy 9 1 hemoptysis 88%;
cough: 62%;
dyspnea: 60%;
pain: 50%;
pulmonary collapse: 46%
Speiser and 109 laser HDR 7.5 Gy 9 3 Overall: 70%;
Spratling (1993a) 5 Gy 9 3 hemoptysis: 99%;
pneumonia: 99%;
dyspnea: 86%;
cough: 85%
Delclos et al. (1996) 81 EBRT HDR 15 Gy 9 2 Overall: 84%
Ornadel et al. 117 EBRT, HDR Cough: 62–77%;
(1997) laser dyspnea: 32–56%;
hemoptysis: 78–97%
Stout et al. (2000) 50 None EBRT 30 Gy Improved symptom palliation for EBRT (83%)
(3.75 9 8) versus HDR (59%), P = 0.03
49 HDR 15 Gy 9 1
Kelly et al. (2000) 175 EBRT, HDR 15 Gy 9 1 Overall: 66%
laser
Celebioglu et al. 95 EBRT HDR 7.5 Gy 9 3 Overall: 100%
(2002) 10 Gy 9 2
Mallick et al. (2007) 95 NA HDR 10 Gy 9 1 Dyspnea: 92.5%;
8 Gy 9 2 cough: 81%;
hemoptysis: 97%;
15 Gy 9 1 pneumonia: 91%
Kubaszewska et al. 270 EBRT, BT HDR 8 Gy 9 1 Overall: 80%;
(2008) 10 Gy 9 1 dyspnea: 76%;
cough: 77%;
hemoptysis: 92%;
pneumonia: 82%
Skowronek et al. 648 EBRT HDR 7.5 Gy 9 3 Overall:88%; no differences between schedules
(2009) (303p)
10 Gy 9 1
(345p)
EBRT: external beam radiotherapy; BT: brachytherapy; HDR: high-dose rate; LDR: low-dose rate; NA: not available

and should have tumors that still protruding into the
bronchial lumen, allow the passage of the endobron-
chial catheter. However, EBB is not always indicated
in patients with obstructive symptoms. Tumors that
cause bronchial luminal narrowing by endobronchial
growth are more likely to respond than those with an
extrinsic component and obstruction secondary to
compression exerted on bronchus or trachea.
Multiple studies have analyzed the role of EBB as a
palliative treatment of lung cancer, either exclusively
or in combination with other therapies such as EBRT,
Nd: YAG laser, cryotherapy or photodynamic therapy.
Again, the huge disparity of criteria for inclusion in the
studies, the different treatment regimens used and the
aspects considered when assessing the effect of palli-
ation obtained, makes it difficult to establish firmly and
definitively the role of EBB. Table 3 shows the results
of symptomatic improvement observed in studies
involving more than 50 patients using EBB as
palliative treatment (Speiser and Spratling 1993a;
484
Lo et al. 1992; Gollins et al. 1996; Delclos et al. 1996;
Ornadel et al. 1997; Kelly et al. 2000; Celebioglu et al.
2002; Mallick et al. 2007; Kubaszewska et al. 2008;
Skowronek et al. 2009).
To our knowledge, there is only one controlled,
randomized study to evaluate the effect of dose rate,
overall radiation dose, fractionation, and localization
of the afterloading catheter to survival rate, local
control and complications (Huber et al. 1995). In this
study, two treatment regimens with a comparable total
irradiation dose of 15 Gy (at 1 cm from the source
axis), but different doses per fraction (four fractions of
3.8 Gy on a weekly basis, and two fractions of 7.2 Gy
at a 3-week interval) were compared. They found no
disadvantages for the shorter fractionation regimen.
Similar survival time (19 weeks) and local control time
was achieved in both groups. The complication rate
was also similar with fatal hemorrhage occurring in
21% of all patients.
Globally, it is estimated that the symptomatic relief
of brachytherapy ranges between 38 and 90% of cases
with hemoptysis, between 50 and 66% of cases with
persistent cough and between 43 and 64% cases with
dyspnea, with an average duration of symptomatic
response of 4–6 months after treatment (Marsiglia
et al. 2000).
Two systematic reviews have been published on this
topic. Ontario Cancer Care clinical guidelines analyzed
29 trials involving the use of EBB with palliative
intentions. The authors concluded that in previously
untreated patients, EBRT alone is more effective than
EBB. In patients who have previously received EBRT,
EBB is a good option to consider according to the
patient’s condition (Ung et al. 2006). Similarly, a
Cochrane Review in 2008 reviewed 13 trials, but
without carrying out a meta-analysis due to the wide
heterogeneity in terms of patients enrolled and their
treatments. The authors concluded that EBRT is more
effective than EBB and there is no conclusive evidence
for recommending the combination of EBRT and EBB
versus EBRT alone (Cardona et al. 2008).
Finally, the American Society for Radiation
Oncology (ASTRO) has recently published an evi-
dence-based clinical practice guideline regarding
palliative thoracic radiotherapy. The role of EBB is
discussed. The authors recognise that there are no
randomized trials assessing the role of EBB in the
routine initial palliative management of endobron-
chial obstruction resulting from lung cancer. In spite
A. Polo et al.
of this fact, EBB remains a reasonable option in the
palliative management of a patient with endobron-
chial lesion causing obstruction or hemoptysis who
has previously received thoracic EBRT (Rodrigues
et al. 2011).
3.3 Interstitial Brachytherapy
Patients are referred for brachytherapy by the surgeon
preoperatively when there is a concern for incomplete
tumor resection or close or positive margins. In other
cases, tumor may be stripped off vital structures, such as
blood vessels or nerves. On the other hand, in patients
with poor cardiopulmonary reserve, a sublobar resection
may be considered, but retrospective data have shown
that in these patients the rates of local recurrence is
higher. Addition of interstitial seed implantation can
result in a better local control. This hypotheses is being
tested in the ACOSOG Z4032 randomized trial, where
patients with tumors\3 cm maximal diameter stage IA
or selected stage IB (visceral pleural involvement), node
negative NSCLC and not fit for lobar resection are
randomized to sublobar resection alone or sublobar
resection with 125I seeds placed at the suture line.
Table 4 shows the results observed using interstitial
brachytherapy in lung cancer.
4 Clinical Results: Toxicity
Acute complications of the endoluminal brachyther-
apy procedure are not more frequent than those
occurring during routine diagnostic flexible bron-
choscopy. The placement of the catheter and the
irradiation procedure are normally well tolerated. The
commonest acute effect which can be attributed to
endoluminal brachytherapy is a transient exacerbation
of cough, usually within 2–3 weeks after treatment.
The most important potential side effect of end-
oluminal brachytherapy is fatal hemoptysis. Massive
haemoptysis is usually a fatal event which occurs in
lung cancer whether or not radiotherapy has been
given. The incidence of this complication ranges
between 0 and 32% of patients treated with a
prevalence of approximately 10% (Vergnon et al.
2006; Bedwinek et al. 1992). Despite numerous
attempts, a direct relationship between the occur-
rence of massive hemoptysis and the type of
Brachytherapy for Lung Cancer 485

Table 4 Interstitial brachytherapy: clinical results

Author n Disease stage BT Technique Total dose LC (%) OS (%)
(AJCC) (Gy)
125
Hilaris and Martini 470 I–III I 160 80 (5 years, 7 (5 years)
(1979) stages I, II)
80 (5 years, stage
III)
125
Hilaris and Martini 88 T1–3 N2 I; HDR 160; 30 76 (2 years) 51 (2 years)
(1988) 225 T3N0 22 (2 years)
125
Ginsberg et al. 102 I–III, close/positive I 160 NA 41 (5 years)
(1994) margins HDR 10–20
Brach et al. (1994) 20 I, tumor \2 cm HDR 10–20 NA 75% (CR,
3–30 months)
125
Chen et al. (1999) 23 I I 100–120 100 (CR) 83 (CR)
125
Santos et al. (2003) 203 IA–B I (101p) 100–120 98 (CR) 60 (4 years)
–(102p) – 81 (CR) 67 (4 years)
125
Lee et al. (2003) 33 I I 125–140 94 (5 years) 47 (5 years)
125
Voynov et al. 118 IA–B I 85–129 87 (5 years) 18 (5 years)
(2005)
Birdas et al. (2006) 167 IB Sublobar 100–120 95.2 (CR) 54 (4 years)
resection ? – 96.8 (CR) 52 (4 years)
125
I (41p)
Lobectomy
(126p)
125
Colonias et al. 145 IA–B I 120 NA 35 (5 years)
(2011)
BT: brachytherapy; HDR: high-dose rate; LC: local control; OS: overall survival; CR: crude rate; NA: not available

implants, tumor location, volume or treatment dose
has not been clearly found. Some authors noted a
higher incidence of bleeding in the treatments of
tumors that settled in the bronchus of right upper
lobe against the left upper lobe, connecting this to
the proximity of the brachytherapy catheter to the
pulmonary artery (Aygun and Blum 1995). Some-
times the occurrence of fatal hemoptysis is related to
the disease progression, and not to the treatment.
Gollins et al. (1996) reported 8% massive fatal
haemoptysis in a large retrospective series of 406
patients. Associated treatment factors increasing the
likelihood of massive fatal haemoptysis were a
brachytherapy dose greater than 15 Gy, prior laser
treatment, brachytherapy used for reirradiation and
concurrent external beam radiotherapy. Stout et al.
reported a UK randomised trial where brachytherapy
(15 Gy) as a sole primary treatment was compared
directly with a palliative course of fractionated
external radiotherapy (30 Gy in eight fractions). The
incidence of massive fatal haemoptysis was the same
in both arms of the trial, occurring in only 7% of the
patients overall (Stout et al. 2000).
Other complications related to endoluminal brach-
ytherapy are pulmonary bronchitis in 4–12% of patients
(Speiser and Spratling 1993b; Gauwitz et al. 1992) and
bronchial stenosis in 11% (Speiser and Spratling
1993b). Histological changes consist of mild mucosal
inflammation to severe bronchial fibrosis. Speiser and
Spratling (1993b) have proposed a grading system from
grade 1 (mild mucosal inflammation, thin, circumfer-
ential membrane, no significant luminal obstruction) to
grade 4 (greater degree of fibrosis with circumferential
stenosis). Therapy of these postradiation effects
consists of conventional treatment, including admin-
istration of steroids, oxygen, balloon dilatation, laser
resection, or endobronchial prosthesis placement in
case of severe stenosis (Vergnon et al. 2006).
486
Overall, endobronchial brachytherapy must be
considered a well tolerated, with a gentle toxicity
profile. It is a not very aggressive treatment option,
especially in patients with poor performance status.
5 Conclusion
Endoluminal HDR brachytherapy with Iridium-192
has an established role in the treatment of lung cancer
when used alone or with external irradiation as
described above. Symptomatic improvement can be
achieved in a large proportion of patients, and
sometimes brachytherapy alone can cure small
tumors. Brachytherapy can be combined with all other
modalities of tumor therapy, including external beam
radiotherapy, local therapies (cryotherapy, photody-
namic therapy, laser resection) and chemotherapy.
However, the optimal dosage and fractionation
schemes for the tumor therapy still have to be defined.
Furthermore, the risk of severe complications could
perhaps be avoided through better scheduling and
dosing of the HDR brachytherapy. Rigorous appraisal
in controlled clinical trials is needed to document the
potential benefits and identify the risks when multi-
modality treatment is employed. Endoluminal brach-
ytherapy is a permanent exercise of multidisciplinary
venture, and there is a need for close contact between
radiation oncologists and chest specialists.
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 Limited-Disease Small-Cell Lung Cancer
Branislav Jeremić, Željko Dobrić, and Francesc Casas
Contents
1 Introduction.............................................................. 492
2 General Treatment Concepts ................................. 492
3 Chemotherapy .......................................................... 493
4 Thoracic Radiation Therapy .................................. 495
5 Conclusions ............................................................... 500
References.......................................................................... 500
B. Jeremić (&)
Ž. Dobrić
Institute of Lung Diseases, Sremska Kamenica, Serbia
e-mail: nebareje@gmail.com
F. Casas
University Clinic, Barcelona, Spain
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_253, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
About one-third of all patients with small cell lung
cancer present with their disease confined to
thorax. In the last two decades, combined radiation
therapy and chemotherapy have been considered
standard treatment option in this disease. This
particularly became evident when radical thoracic
radiation therapy was combined with concurrent
platinum-etoposide chemotherapy. Prophylactic
cranial irradiation was also shown to be important
part of the overall treatment approach and is
suggested as standard treatment option in the last
decade. Several questions, however, remained in
focus of clinical investigations in the recent
decades with no clear answers provided. In partic-
ular, investigators embarked on evaluating the
timing of administration of radiation therapy and
chemotherapy in combined modality approach.
Several prospective randomized trials and several
meta-analyses showed that there is an advantage
for early administration of the two modalities,
especially using concurrent approach. While land-
mark Intergroup study clearly showed benefit of
BID fractionation over QD fractionation, two
ongoing studies further built on the question of
optimization of dose and fractionation issue in this
setting. Finally, issue of tumor volumes to be used
during the radiation therapy course remain subop-
timally investigated due to lack of clinical studies
investigating it and, therefore, poor guidelines for
daily clinical practice.
491
492
1 Introduction
Small-cell lung cancer is highly aggressive carcinoma
representing approximately 15–20% of all lung can-
cer cases (Greenlee et al. 2000). It is an entity of lung
cancer that is biologically and clinically different
from non-small-cell lung cancer. The world health
organization (WHO) classification of lung tumor,
revised in 2004 (Travis et al. 2004) remains the cor-
nerstone for lung cancer nomenclature.
Of all potential risk factors which may cause this
disease, cigarette smoking has long been considered as
the primary risk factor for its occurrence. This occurs in
[90% cases (Mulshine et al. 1993; Ihde et al. 1993).
Cough, hemoptysis, dyspnoea, hoarseness, and
dysphagia are the most frequent clinical signs and
symptoms. The paraneoplastic syndromes are more
common than in non-small-cell lung cancer. They
occur frequently in a variety of presentations, including
the syndrome of inappropriate antidiuretic hormone,
ectopic Cushing’s syndrome, and Lambert-Eaton
Myastenic Syndrome. Rare neurologic syndromes can
also occur, such as subacute spinal or peripheral neu-
ropathy, cerebellar ataxia, limbic encephalopathia, and
retinal degeneration (Curran 2001).
More than 4 decades ago, the Veterans Adminis-
tration Lung Group had proposed dividing all small-
cell lung cancer cases into the two-stage system:
limited-disease and extensive disease (Green et al.
1969). Majority of clinicians and investigators still
use it nowadays. The vast majority of patients
(approximately two-thirds) fall into the extensive
disease category while limited-disease occurs in
approximately one-third of all small-cell lung cancer
cases. Limited-disease small-cell lung cancer is
defined as the disease confined to the hemithorax of
origin along with the involved regional lymph nodes
(hilar and mediastinal), with or without ipsilateral
supraclavicular lymph nodes. It can also be consid-
ered as a disease which can be incorporated within a
single, tolerable radiation therapy treatment field, and
may include patients with contralateral, mediastinal,
or hilar lymph nodes. What has created a confusion
and still does it is the term ‘‘tolerable radiation ther-
apy treatment field’’. It was not always easy to denote
and compare it between clinicians, especially radia-
tion oncologists. This, however, may be more easily
solved nowadays due to normal lung constraints and
B. Jeremić et al.
available computer-enabled volumetric analysis. The
most recent staging classification of small-cell lung
cancer (Shepherd et al. 2007) and stage grouping
differentiated tumors with different prognoses. The
TNM classification and staging system was recom-
mended for small-cell lung cancer and stratification
by stage I–III was also recommended in clinical trials
of early-stage (i.e., limited) disease.
2 General Treatment Concepts
Chemotherapy is the mainstay of the treatment for
several decades now. With chemotherapy alone,
however, intrathoracic failure occurs in up to 80%
leading to a median survival of 10–14 months
(Cohen et al. 1979). Radiation therapy has great
potential in decreasing locoregional failures and it
was increasingly practiced in the seventies and the
eighties of the last century. However, radiation
therapy was eventually introduced as a necessary
part of the combined modality approach owing to
results of two meta-analyses that appeared almost
two decades ago
(Pignon et al. 1992; Warde and Payne 1992). Small
but significant improvement in 2-year and 3-year
survival, averaging 5–7% and an improvement in
local control rates in 25% cases with the addition of
thoracic radiation therapy was shown. Importantly,
the widespread use of cisplatin/etoposide regimen,
and its lower toxicity (than that observed with the
cyclophosphamide, doxorubicin, vincristin) when
combined with thoracic radiation therapy, made
more effective use of concurrent thoracic radiation
therapy and platinum-based chemotherapy, which is
nowadays considered as the standard treatment in
limited-disease small-cell lung cancer. While recent
meta-analysis (Auperin et al. 1999) confirmed the
necessity for prophylactic cranial irradiation, details
of it will be dealt with in another chapter in this
book.
A number of questions requesting further studies in
this disease remain. These include, but are not limited
to optimization of both chemotherapy (choice of
drugs and its schedule/timing/dosing) and thoracic
radiation therapy (timing of thoracic radiation therapy
and dose/volume/fractionation). Some of them will be
addressed below.
Limited-Disease Small-Cell Lung Cancer
3 Chemotherapy
Due to its pronounced chemosensitivity, there are
many chemotherapeutic agents which achieve
response rates of [30% in small-cell lung cancer.
They include cisplatin, carboplatin, etoposide, cyclo-
phosphamide, doxorubicin, methotrexate, and vin-
cristine (Sandler, 2003). While cyclophosphamide/
doxorubicin/vincristin regimen was mostly used in
early studies, studies done in the last three decades
started more frequently employing cisplatin/etopo-
side, since it became known as not only less toxic, but
also very active (Einhorn et al. 1988). These results
were subsequently reconfirmed by Fukuoka et al.
(1991) who alternated cyclophosphamide/doxorubi-
cin/vincristin and cisplatin/etoposide which were
shown to be superior to either cyclophosphamide/
doxorubicin/vincristin alone or cisplatin/etoposide
alone (median survival: 16.8 vs. 12.4 vs. 11.7 months).
The regimen containing cisplatin/etoposide has
become the standard therapy for patients with small-
cell lung cancer, especially when combined with
radiation therapy. In a Phase III study, the cisplatin/
etoposide appeared superior to cyclophosphamide,
epirubicin, and vincristine in 436 patients randomized
to either cisplatin/etoposide or cisplatin/etoposide/
vincristin. The 5-year survival rates were between 5
and 2% in the cisplatin/etoposide and cisplatin/eto-
poside/vincristin arms, respectively (p = 0.0004). In
subgroup analysis done for 214 patients with limited-
disease, this benefit was even more pronounced
(5-year survival; 10 vs. 3%; p = 0.0001), while for
patients having extensive disease this benefit
remained unreported (Sundstrøm et al. 2002).
The use of cisplatin/etoposide in this disease has
been additionally supported by a systematic review
using 36 randomized trials which have tested single
agent either cisplatin or etoposide or both (doublet)
against regimens not containing these agents. The
significant improvement with use of these drugs in
comparison with chemotherapy with neither was
demonstrated (Mascaux et al. 2000). Furthermore, a
meta-analysis of 19 trials that investigated the effects
of chemotherapy with or without cisplatin in more
than 400 patients. Patients receiving cisplatin had sur-
vival advantage of 4.4% at 1 year (Pujol et al. 2000).
However, a recent systematic review of 29 trials
involving 5530 patients compared platinum-based
493
(cisplatin or carboplatin) with nonplatinum-based
regimens and did not reveal any difference in survival
for the compared arms. Subgroups (stage, radiation
therapy use) analysis also showed no difference
(Amarasena et al. 2008). Given these conflicting
results, many consider that the optimal chemotherapy
schedule for small-cell lung cancer has not yet been
confirmed. Contrasting these ambiguities are the long-
known facts about favorable toxicity profile of cis-
platin/etoposide regimen (Pignon et al. 1992) in
combination with radiation therapy, no evidence of
improvement with any other schedule and the best
results so far obtained with this schedule which all
make this combination of chemotherapy a standard
for fit patients undergoing thoracic radiation therapy.
Since it was well documented that cisplatin/etoposide
had less cardiac and lung toxicity when compared
to cyclophosphamide/doxorubicin/vincristin, it was
preferentially used with thoracic radiation therapy,
providing 2-year survivals of [40% (Turrisi et al.
1999; Takada et al. 2002). Although majority of
investigators continue to consider cisplatin/etopop-
side and thoracic radiation therapy as the mainstay
of concurrent treatment today, carboplatin was
sometimes used instead of cisplatin (Kosmidis et al.
1994; Jeremic et al. 1997). It was used in combi-
nation with etoposide (i.e., carboplatin/etoposide)
due to a similar response and survival as cisplatin/
etoposide but with less kidney and ear toxicity than
cisplatin/etoposide (Kosmidis et al. 1994; Jeremic
et al. 1997). Other drugs were also attempted to
incorporate into the treatment plan (Woo et al.
2000; Hanna et al. 2002).
In an attempt to provide sustained and prolonged
duration of response and control of existing symp-
toms, some advocated to treat patients for the duration
of their life. Of a number of randomized trials which
have investigated this issue, only one study demon-
strated a survival advantage for limited-disease small-
cell cancer patients (Maurer et al. 1980). This is in a
sharp contrast to numerous studies showing either no
advantage at all (Woods and Levi, 1984; Cullen et al.
1986; Bleehen et al. 1989; Lebeau et al. 1992;
Giaccone et al. 1993; Beith et al. 1996; Sculier et al.
1996) or even showing detrimental effects of contin-
uous chemotherapy (Byrne et al. 1989). The lack of
survival improvement and increased toxicity of pro-
longed treatment, made this approach having no role
in the treatment of limited-disease small-cell lung
494
cancer patients nowadays. Additionally, some studies
investigated the optimal number of induction che-
motherapy courses. Here, no survival benefit was seen
for 8 cycles of cyclophosphamide/etoposide/vincris-
tine compared to 4 cycles, if there was an option of a
second line chemotherapy (Spiro et al. 1989). This
was indirectly confirmed as early as in 1996 by pre-
liminary results of an intergroup 0096 study which
produced convincing results with only 4 cycles of
cisplatin/etoposide and thoracic radiation therapy
(Johnson et al. 1996a, b). It is, therefore, that current
standard chemotherapy protocol is four cycles of a
platinum-based regimen, although advocates of more
chemotherapy courses (e.g., six) continue to try to
obscure existing highest level of evidence by intro-
duction of data other than that coming from prospective
randomized clinical trials using combined (mostly
concurrent) radiation therapy and chemotherapy.
Another approach was to intensify the dose of
chemotherapy which was tested in randomized trials
including either doxorubicin or alkylating-based
chemotherapy in the 1970s and 1980s (Cohen et al.
1977; Mehta et al. 1982; Figueredo et al. 1985), or
cisplatin-based in the 1990s (Arriagada et al. 1993),
occasionally including granulocyte colony-stimulat-
ing factor support (Ardizzoni et al. 2002). Improved
survival was noted in the dose-intensive arm in 3
studies, with two trials showing significant improve-
ment. This was, however, accompanied with more
severe toxicity, which influenced that the dose
intensification did not become standard treatment
approach. The issue of the increase of the dose
intensity is also attempted by decreasing the interval
between the cycles of chemotherapy. Two trials
demonstrated an improvement in survival (Steward
et al. 1998; Thatcher et al. 2000) but again, unfortu-
nately, accompanied by increased toxicity. Most
recently, Leyvraz et al. (2008) randomly assigned
patients who had limited or extensive small-cell lung
cancer with no more than two metastatic sites to high-
dose or standard-dose chemotherapy with ifosfamide,
carboplatin, and etoposide. High-dose chemotherapy
cycles included bone marrow support. The primary
outcome was 3-year survival. The 3-year survival rates
were 18 and 19% in the high-dose and standard-
dose chemotherapy arms, respectively. No differences
were observed between the two arms in overall
response and complete response, respectively. High-
dose treatment was predictably associated with severe
B. Jeremić et al.
myelosuppression, and five patients (8%) died from
toxicity.Taken all together, the data from literature do
not support any intensification of chemotherapy as
worthwhile further investigation nowadays.
Last decade also brought investigation of the place
and the role of the third generation drugs. In a Japan
Clinical Oncology Group, phase III study in extensive
disease small-cell lung cancer, only (Noda et al. 2002)
irinotecan was combined with cisplatin and compared
to cisplatin/etoposide, with irinotecan/cisplatin arm
achieving significant survival advantage (the median
survival time, 390 vs. 287 days; 1-year survival, 58 vs.
38%; p = 0.002). Overall response rates were also
significantly higher in the irinotecan/cisplatin arm
(83 vs. 63%). Although high-grade diarrhea was seen
only in irinotecan/cisplatin arm, high-grade hemato-
logical toxicity was seen more frequently in the cis-
platin/etoposide arm. Since topotecan was initially
shown to be effective in relapsed small-cell lung cancer
patients, it was then evaluated in maintenance therapy
after initial cisplatin/etoposide in chemonaive exten-
sive disease small-cell lung cancer patients and com-
pared to no maintenance therapy. The addition of
topotecan led to improvement in progression-free
survival but with no impact on survival (8.7 vs.
9.0 months, p = 0.71) (Schiller et al. 2001). Of tax-
anes, only paclitaxel was tested in a phase III study.
With chemotherapy alone two recently published
studies compared cisplatin/etoposide with cisplatin/
etoposide/paclitaxel. Both Mavroudis et al. (2001) and
Niell et al. (2002) found no difference in response rates,
median, and overall survival, but observed more
treatment-related deaths in the cisplatin/etoposide/
paclitaxel regimen. Gatzmeier et al. (2000) showed no
difference in toxicity between paclitaxel, carboplatin,
and etoposide vs. carboplatin, etoposide, and vincris-
tine in limited-disease and extensive disease small-cell
lung cancer. Finally, a preliminary analysis of another
study (Birch et al. 2000) showed only modest
improvements in the overall response rate with a trend
toward improvement in survival when paclitaxel was
added to carboplatin, and etoposide and compared to
carboplatin and etoposide in patients with extensive
disease small-cell lung cancer. Data from four phase II
trials in small-cell lung cancer showed only moderate
success when paclitaxel was added to concurrent
cisplatin/etoposide and thoracic radiation therapy
(Levitan et al. 2000; Ettinger et al. 2005; Sandler et al.
2000; Bremnes et al. 2001), with complete response
Limited-Disease Small-Cell Lung Cancer
rates of 13–81% and median survival times of about
22 months. Finally, recent analysis of the Southwest
Oncology group phase II study 9713 provided another
set of the data on the use of paclitaxel in 87 patients with
limited-disease small-cell lung cancer (Edelmen et al.
2004). Concurrent cisplatin/etoposide/radiation ther-
apy part of the combined modality program was fol-
lowed by three cycles of consolidation paclitaxel/
carboplatin. The response rate was 86%, the median
survival time was 17 months and a 2-year survival rate
was 33%, while the progression-free survival at 2 years
was only 21%. This prompted authors to conclude that
paclitaxel is inactive against small-cell lung cancer and
suggested its abandoning in further investigation,
confirming previously disappointing results of the
Eastern Cooperative Oncology Group (Sandler et al.
2000). Contrary to these results, European Organiza-
tion for research and treatment of Cancer (Reck et al.
2003) found an advantage for paclitaxel-containing
arm in patients with small-cell lung cancer. In limited-
disease small-cell lung cancer patients it achieved the
median survival time of 17.6 months, which was quite
similar to that of the Southwest Oncology group study
cited above as well as those achieved during the
Intergroup study (Turrisi et al. 1999), and somewhat
lower than achieved in other prospective randomized
studies which used only cisplatin/etoposide combina-
tion (Jeremic et al. 1997; Takada et al. 2002).
As a summary, there is no firm basis to recommend
either dose intensification or the integration of new
drugs into actual regimens, due to the risk of severe
toxicity and the lack of clearly demonstrated
improvement in overall survival. This is especially so
when one considers lack of the data for chemotherapy
combined with thoracic radiation therapy. Targeted
agents are now widely under testing in this disease in
chemotherapy-only setting. If proven beneficial, it is
reasonable to expect their testing within the concur-
rent radiation therapy-chemotherapy approach.
4 Thoracic Radiation Therapy
Among several important issues investigated in recent
decades, prophylactic cranial irradiation seems to
have been settled. It will be a matter of another
chapter of this book. In addition, treatment volumes
will also be a subject of another chapter of this book.
495
Of the remaining issues in thoracic radiation therapy,
timing of combined radiation therapy and chemo-
therapy, and total dose and fractionation used, have
attracted most of the attention of researchers. When
timing of combined radiation therapy and chemo-
therapy is considered, it is usually defined as either
concurrent, or sequential or alternating. While some
of the initial studies showed promising results for
alternating radiation therapy and chemotherapy, this
type of combined approach is mostly abandoned
today. The main question with the remaining two
modes of administration is simply whether any por-
tion of thoracic radiation therapy and chemotherapy
overlaps and, if this is the case, when overlapping
occurs. Early concurrent thoracic radiation therapy
and chemotherapy studies used non-platinum regi-
mens, or alternated it with cisplatin/etoposide, while
more recent ones were exclusively platinum-based
regimens. Some studies (Perry et al. 1987; Schultz
et al. 1988; Work et al. 1997) suggested that thoracic
radiation therapy delayed until the fourth cycle of
chemotherapy (Perry et al. 1987) or until day 120
(Schultz et al. 1988) may be superior to initial radi-
ation therapy or suggested no difference when com-
pared to early thoracic radiation therapy and
chemotherapy (Work et al. 1997). Likely the expla-
nation lies in marked reduction of chemotherapy dose
in the Cancer and Leukemia Group B (Perry et al.
1987) and the Danish trial when thoracic radiation
therapy was applied early. It is important to note that
the Danish trial (Work et al. 1997) can not really be
considered as a concurrent study because sequential
radiation therapy was used before and after chemo-
therapy. More recent studies using cisplatin/etoposide
(Jeremic et al. 1997; Takada et al. 2002) or cisplatin/
etoposide alternating with cyclophosphamide/doxo-
rubicin/vincristin (Murray et al. 1993) showed clear
superiority for early administration of thoracic radi-
ation therapy (concurrently given during the first or
the second cycle of chemotherapy). Overview of
existing trials is presented in Table 1. These studies
have also reconfirmed in clinical practice an original
Goldie and Coldman (1979) theoretical consider-
ations that an early administration of both treatment
modalities lead to the best outcome on both local and
distant level (Table 1). Early concurrent thoracic
radiation therapy and cisplatin/etoposide chemother-
apy was capable of achieving 5-year survival of
[20%, while late thoracic radiation therapy usually
496 B. Jeremić et al.

Table 1 Randomized phase III trials investigating optimal timing of combined thoracic radiation therapy and chemotherapy in
limited-disease small-cell lung cancer
Author Year N CHT RT RT timing MST Survival Outcome
(weeks) (months) (5 year) (%) (p)
Perry 1987 125 CEVA 50 Gy/24 fr/ 1 13.04 7
et al. QD
145 same Same 9 14.54 13 0.08
Murray 1993 155 CAV/PE 40 Gy/15 fr/ 3 21.2 20
et al. QD
153 same 15 16.0 11 0.008
Work 1997 99 PE ? CAV 40–45 Gy/22 1 10.7 11
et al. fr/QD
100 same same 18 12.9 12 0.4
Jeremic 1997 52 PE (CpE with 54 Gy/36 fr/ 1 34 30
et al. RT) BID
51 same same 6 26 15 0.052
Takada 2002 114 PE 45 Gy/30 fr/ 1 27.2 24
et al. BID
114 same same 15 19.7 18 0.097
Spiro 2006 159 CAV/PE 40 Gy/15fx/ 3 13.7 16*
et al. QD
166 same same 15 15.1 22* 0.23
CEV cyclophosphamide, etoposide, vincrstine; CAV cyclophosphamide, doxorubicin, vincristine; PE cisplatin, etoposide; CpE
carboplatin, etoposide; fr fraction; RT radiation therapy;* at 3 years

Table 2 Timing/scheduling of RT and CHT in LD SCLC: systematic reviews/meta-analyses

Author Year Time (year) OS RR 95% CI p
Fried et al. 2004 2 1.17 1.021.35 0.03
3 1.13 0.92–1.39 0.2
Huncharek/McGarry 2004 2 1.60 1.29–1.99 \0.01
3 1.49 1.15–1.93 \0.01
Pijls-Johannesma et al. 2005 2–3 0.84 0.56–1.28 0.4
5 0.80 0.47–1.38 0.4
OS overall survival, RR risk ratio, CI confidence interval

obtained only about 10%. Therefore, it became a
common practice to offer as early as possible (cycle
one or two of chemotherapy) thoracic radiation ther-
apy with curative doses worldwide. Others have also
proved that this is indeed the fact even outside the
clinical trial, e.g., in an institutional setting. Kamath
et al. (1998) showed in a small study on 48 patients
that early concurrent thoracic radiation therapy/cis-
platin/etoposide offers advantage over sequential
chemotherapy and thoracic radiation therapy in terms
of overall survival and decreased distant metastasis in
patients with limited-disease small-cell lung cancer.
Recently, several meta-analyses and systematic
reviews addressed this issue by putting all existing
evidence into a perspective of timing of combined
radiation therapy and chemotherapy in limited-dis-
ease small-cell lung cancer (Table 2). (Huncharek
and McGarry 2004) observed significantly superior
survival at both 2- and 3-years for early radiation
therapy and chemotherapy. Fried et al. (2004)
observed a significantly higher 2-year survival in
the early group and there was a suggestion of a
similar trend at 3 and 5 years. Contrary to these,
Pijls-Johannesma et al. (2005) did not find any
Limited-Disease Small-Cell Lung Cancer
advantage for early radiation therapy and chemo-
therapy. Finally, Spiro et al. (2006) found no differ-
ence between the early and the late administration of
the two regimens. However, they have disclosed that
test for heterogeneity was significant (p = 0.0002),
which indicated that hazard ratios estimates likely
differ from overall estimates. To correct these ambi-
guities, they have performed Forrest plot analysis for
treatment effect. When they focused on cases which
received all chemotherapy cycles, they have found
better survival for patients in early group if patients
received similar percentage of chemotherapy in both
arms, contrary to cases when there was less percent-
age in early arm, leading to better survival in late
group. Similarly, positive effect of hyperfractionated
radiation therapy was found in early group, but not in
late, as well as when platinum based chemotherapy
was used, early group was better and when not, late
was better. These 4 analyses (Huncharek and
McGarry 2004; Fried et al. 2004; Pijls-Johannesma
et al. 2005; Spiro et al. 2006) brought somewhat
conflicting results which were result of: (a) different
definition of limited-disease small-cell lung cancer,
(b) different definition of ‘‘early’’ and ‘‘late’’ admin-
istration, (c) inclusion of ‘‘grey literature’’, (d) dif-
ferent patient number, and (e) lack of individual
patient data. In an attempt to resolve the matter,
Jeremic (2006) performed ‘‘meta analysis’’ of the
meta-analyses, identifying common findings in
existing analyses. The finding included the following:
(a) there was more leucopoenia in late group, (b) there
was a favorable effect of short (B30 days) overall
treatment time, (c) there was a favorable effect of
hyperfractionation, (d) there was a favorable effect of
platinum-etoposide chemotherapy, and (e) there was
negative effect of split-course radiation therapy.
Overall, prevailing evidence is that nowadays, using
‘‘standard’’ approach consisting of hyperfractionated
radiation therapy and 4 courses of chemotherapy
based on cisplatin-etoposide, early administration
seems favorable and should be practiced as standard
approach. Reports showing that prolonged (e.g., 4–6
cycles) sequential administration of chemotherapy
followed by radical thoracic radiation therapy is
inferior treatment approach when compared to early
and concurrent radiochemotherapy is unfortunately
still occurring nowadays (El-Sharouni et al. 2009;
Yilmaz et al. 2010).
497
Regarding thoracic radiation therapy dose and
fractionation, total doses used for limited-disease
small-cell lung cancer were usually about 50 Gy,
standard fractionation. They have, however, been as
low as 30 Gy and as high as 70 Gy. In addition, many
recent studies have used some form of hyperfrac-
tionation (b.i.d.). Whichever fractionation regimen
one uses, even in the era of concurrent thoracic
radiation therapy and chemotherapy, one major site of
recurrence continues to be in-field (about 30% are
isolated and additional 20% are combined with sys-
temic progression). Majority of available studies are
retrospective in nature, with one study (Choi and
Carry 1989) observing a better local control for doses
40–50 Gy than with doses \40 Gy ([50 vs. 30%),
indicating, therefore, potential dose–response rela-
tionship. Another study indicated excellent local
control after 60 Gy, being 97% (Papac et al. 1987).
The Cancer and Leukemia Group B (Choi et al. 1998)
performed a trial to identify at least 70 Gy (using
standard fractionation) as the maximum tolerated
dose for combination with chemotherapy. Subse-
quently, they (Bogart et al. 2004) reported that 70 Gy
was feasible and effective when given concurrently
with 3 cycles of carboplatin and etoposide, following
an induction with 2 cycles of paclitaxel and topotec-
an, with the median overall survival of 19.8 months
with a 1-year survival rate of 70% the median failure-
free survival was 12.9 months. Group study results
were also confirmed in a single-institutional setting.
Miller et al. (2003) retrospectively evaluated the data
of 65 patients from the Duke University in which
58–66 Gy, standard fractionation was used with either
concurrent (n = 32) or sequential (n = 33) chemo-
therapy. Somewhat lower (30%) 2-year survival rate
was explained by less than one-half of patients
receiving concurrent thoracic radiation therapy and
chemotherapy and only 26% received prophylactic
cranial irradiation. The toxicity of their regimen was
low. Similarly, Roof et al. (2003) observed that
overall survival, local control, and disease-free sur-
vival obtained with [50 Gy compared favorably with
the historic controls which were using lower doses.
Most recently, Komaki et al. (2003) reported on
Radiation Therapy Oncology Group 9712 study
which was a phase I dose-escalation study of thoracic
radiation therapy with concurrent cisplatin/etoposide
in limited-disease small-cell lung cancer. Thoracic
498
radiation therapy was given 1.8 Gy daily to 36 Gy
followed by boost delivered with escalations of
1.8 Gy b.i.d. during the final days which permitted
doses of up to 64.8 Gy to be given. The maximum
tolerated dose was determined to be 61.2 Gy in 34
fractions of 1.8 Gy when given concurrently with 2
cycles of cisplatin/etoposide and followed by 2
additional cycles of cisplatin/etoposide.
Besides hyperfractionation and conventional frac-
tionation, hypofractionated radiation therapy regi-
mens were also used, which was thought to cause
more damage to small-cell lung cancer cells (Murray
et al. 1993; Spiro et al. 2006). Interestingly, shifting
from such hypofractionated to conventionally frac-
tionated thoracic radiotherapy did not alter outcomes,
the survival, local control, and toxicity rates were all
similar (Videtic et al. 2003). Of altered fractionated
regimens, accelerated hyperfractionation was the
logical choice due to a high sensitivity of small-cell
lung cancer to radiation therapy, sparing effect of
twice-daily fractionation and possible effect of the
dose acceleration to combat rapid proliferation
thought to occur in small-cell lung cancer. In the
Intergroup study (Johnson et al. 1996a, b; Turrisi et al.
1999), 45 Gy given in 30 fractions in 3 weeks
(1.5 Gy b.i.d. fractionation) was compared with the
same dose given once-daily, both with concurrent
cisplatin-etoposide chemotherapy. While a survival
was significantly better in the b.i.d. arm (5-year, 26
vs. 19%), this was, however, achieved with somewhat
higher incidence of acute toxicity. Another study
investigating this issue was a North Central Cancer
Treatment Group study which compared concurrent
two cycles of cisplatin/etoposide with either b.i.d.,
split-course thoracic radiation therapy (48 Gy in a
total of 5.5 weeks) or once-daily thoracic radiation
therapy (50.4 Gy), both given after 3 cycles of cis-
platin/etoposide (Bonner et al. 1999). There was no
difference in a 3-year overall and locoregional con-
trol. After 5 years (Schild et al. 2003), the median and
5-year survival were 20.4 months and 22% for b.i.d.
versus 20.5 months and 21% for once-daily thoracic
radiation therapy, respectively (p = 0.7). Having
these two studies together, possible explanation may
lie either in inferiority of split-course regimen (which
undermined the effect of hyperfractionation) or effects
of acceleration outweighing those of hyperfractiona-
tion (To put it in other words, hyperfractionation
given with a split equals conventional, once-daily
B. Jeremić et al.
fractionation, providing total dose and treatment
duration being similar if not the same). Extending
overall treatment time, therefore, which allows tumor
cell regeneration, may have been the reason for this
finding due to a delay in thoracic radiation therapy
either by long lasting induction chemotherapy or by
split-course protocol for thoracic radiation therapy. A
quality-adjusted reanalysis of a that phase III trial
(Bonner et al. 1999; Schild et al. 2003) comparing
once-daily thoracic radiation versus twice-daily
thoracic radiation in patients with limited-stage small-
cell lung cancer using Quality Time Without Symp-
toms or Toxicity methodology showed no difference
in survival after adjusting for toxicity and progression
(Sloan et al. 2002).
While accelerated hyperfractionated thoracic
radiation therapy was practiced with increasing evi-
dence in the last two decades, the accumulated data
show different outcome (Johnson et al. 1996a, b; Ali
et al. 1998; Mennecier et al. 2000; Segawa et al.
2003) and toxicity profile. The future studies directly
comparing b.i.d. to once-daily fractionation will bring
definitive answers about optimal total dose and frac-
tionation regimen preferentially used. Currently, two
major clinical trials investigating this issue are
recruiting patients. In a CONVERT trial, EORTC is
evaluating 66 Gy using standard fractionation with
the bid fractionation as used in the Intergroup study
(45 Gy in 30 fractions in 15 treatment days in
3 weeks). Similarly, joint CALGB 30610/RTOG
0538 is directly comparing the same control Inter-
group regimen with two experimental arms, either
conventional (QD) or concomitant boost regimen
(CB). The better of the two experimental arms (CB) is
then directly compared to hyperfractionated regimen.
Mature data from the two trials should supplement
existing ones and hopefully give better perspective
about fractionation issue. Recent single-institutional
report (Watkins et al. 2010a) compared two radiation
therapy regimens with planned doses of (1) [59.4 Gy
at 1.8–2.0 Gy per once-daily fraction or (2) [45 Gy
at 1.5 Gy b.i.d. with concurrent platinum-based che-
motherapy. A total of 71 patients were included in the
study with patient, tumor, staging, and treatment
factors being similar between the two treatment
groups. Acute toxicities were similar between the
groups. The 2-year overall survival estimates were
similar at 43 and 49% for the once-daily versus twice-
daily groups, respectively. Isolated in-field failures
Limited-Disease Small-Cell Lung Cancer
were similar between the two groups. While this
analysis did not detect a statistically significant
difference in acute toxicities, disease control, or sur-
vival outcomes in limited-stage small-cell lung cancer
patients treated with concurrent chemotherapy and
once-daily versus twice-daily radiation therapy, it
should not be forgotten that other regimens of b.i.d.
irradiation (e.g., 54 Gy in 36 fractions in 18 treatment
days in 3.5 weeks) have been successfully imple-
mented in practice concurrently with low-dose che-
motherapy in both limited-disease (Jeremic et al.
1997) and extensive disease small-cell lung cancer
(Jeremic et al. 1999), providing not only excellent
results, but also leading to low toxicity. Finally, it is
not unreasonable to expect that novel drugs eagerly
await its place and time in this disease and the data
slowly emerge (Sandler et al. 2000).
There are two important issues one must take into
account when considering the irradiation volume for
limited-disease small-cell lung cancer patients. The
first is related to the irradiation of the pre- or post-
chemotherapy disease volume and the second one is
related to the elective nodal irradiation. When radia-
tion therapy starts concurrently with the first cycle of
chemotherapy this issue simply does not exists and
one treats what available imaging says. The question
of including or not (in the radiation therapy field)
regions where the visible tumor involvement was
presumably sterilized with chemotherapy arises as a
problem in cases of delayed radiation therapy, when it
is given concurrently with 2 or 3 cycles of chemo-
therapy. Only one randomized clinical trial has
examined the issue of radiotherapy treatment volume
in small-cell lung cancer. This study, performed by
southwest oncology group (Kies et al. 1987), involved
466 patients and randomized patients with a partial
response or stable disease after four cycles of non-
platinum-based chemotherapy to radiation therapy
fields based either on the pre- or on post-chemother-
apy volume of disease. No statistical differences in
survival or recurrence patterns were noted as a func-
tion of volume treated. Postchemotherapy volumes
were, therefore, judged appropriate for target delin-
eation, not risking higher incidence of marginal fail-
ures. Several retrospective analyses have assessed
pre- versus post-chemotherapy tumor volumes with
contrasting results (Perez et al. 1981; White et al.
1982). In 17 limited-disease small-cell lung cancer
patients treated with postchemotherapy volumes,
499
Mira and Livingston (1980) found that the majority
who failed in the chest also failed at outside the field
(lung periphery) but not within nodal structures. It
suggested that prechemotherapy volumes would pro-
vide improved local control and, therefore, be pref-
erentially used in this setting. In contrast to it, in the
study of Liengswangwong et al. (1994) the use of
postchemotherapy volumes was supported. Of a total
of 59 patients studied, 28 were treated with postche-
motherapy tumor volumes and 31 with prechemo-
therapy tumor volumes. Of a total group, 10 of 31
patients treated with radiation therapy fields that
encompassed pre- chemotherapy tumor volumes and
9 of 28 patients treated with radiation therapy fields
that encompassed postchemotherapy tumor volumes
had locoregional failures, suggesting no difference for
choice of irradiation volume. These results indicate
that in cases of bulky disease within pulmonary
parenchyma shrinking after chemotherapy one may
use radiation therapy fields to encompass postche-
motherapy findings in order to reduce the treatment
toxicity, especially in frail patients and/or those with
limited pulmonary reserve. None of the landmark
trials on thoracic radiotherapy in limited-disease
small cell-lung cancer provide a consistent basis for
drawing conclusions on the role of elective nodal
irradiation in small-cell lung cancer. Some were using
elective nodal irradiation (Jeremic et al. 1997; Takada
et al. 2002; Turrisi et al. 1999), while some were not
(Murray et al. 1993; Work et al. 1997; Spiro et al.
2006). Ongoing studies, the CONVERT and Inter-
group randomized Phase III trials, are addressing a
question of dose but not the use of elective nodal
irradiation. To date, we have only one prospective
Phase II study directly addressing the issue of elective
nodal irradiation in limited-disease small-cell lung
cancer (de Ruysscher et al. 2006). The authors pro-
spectively evaluated the patterns of recurrence when
elective nodal irradiation was not used. In total, 27
patients received hyperfractionated thoracic radiation
therapy of 45 Gy in 30 fractions concurrent with
carboplatin and etoposide. Only the primary tumor
and the positive lymph nodes on the pretreatment CT
scan were irradiated. After a median follow-up of
18 months, seven patients developed a local recur-
rence. Three patients developed an isolated nodal
failure, all of them in the ipsilateral supraclavicular
fosse. The authors concluded that omission of elective
nodal irradiation on the basis of CT scans in patients
500
with limited-disease small-cell lung cancer resulted in
a higher rate than expected rate of isolated nodal
failures in the ipsilateral supraclavicular fosse and the
intentional omission of elective nodal irradiation may
not be safe and should not be practiced outside the
clinical trials. Contrary to that, recent retrospective
study of Watkins et al. (2010b) showed that involved-
field thoracic radiation therapy given with concurrent
chemotherapy did not appear to have an adverse
impact on the anticipated patterns of failure, disease
control, or overall survival in patients with limited-
disease small-cell lung cancer. In the most compre-
hensive review of the use of elective nodal irradiation
in limited-disease small-cell lung cancer, authors
recently noted the absence of strong evidence sup-
porting omission of elective nodal irradiation. They
have suggested that clinicians must carefully balance
the increased failure risk, expected to occur with
omission of elective nodal irradiation with the reduc-
tion of treatment-related toxicities with involved fields
in the decision-making process (Videtic et al. 2008).
5 Conclusions
The standard treatment for the majority of patients
with limited-disease small-cell lung cancer is com-
bination of thoracic radiation therapy and cisplatin/
etoposide, given concurrently, with thoracic radiation
therapy being started early. While majority of insti-
tutions worldwide use 4 cycles of cisplatin/etoposide,
numerous thoracic radiation therapy and chemother-
apy issues remain unsolved. Ongoing studies will help
clear these important issues in optimizing the treat-
ment approach and outcome in this disease. The les-
sons we have learned from optimization of the
treatment approach in limited-disease small-cell lung
cancer also served as an attempt to optimize the
treatment in extensive disease small-cell lung cancer.
As we have recently shown in a prospective ran-
domized trial, thoracic radiation therapy can play an
important role in extensive disease small-cell lung
cancer, providing that suitable patients are identified
(Jeremic et al. 1999). We have focused on those
patients who have the most favorable prognosis after
induction chemotherapy, i.e., those achieving com-
plete response at distant sites accompanied with either
complete response or partial response intrathoraci-
cally. They were chosen as a subject of our study
B. Jeremić et al.
because they resembled limited-disease small-cell
lung cancer patients at most. In them, after 3 initial
cycles of cisplatin/etoposide, accelerated hyperfrac-
tionated thoracic radiation therapy offered survival
advantage over that achieved with chemotherapy
alone (the median survival time : 17 vs. 11 months;
5 year survival rates : 9.1 vs. 3.7%, respectively;
p = 0.041) sue to an improvement in the local
recurrence-free survival (p = 0.062). Patients treated
with thoracic radiation therapy achieved better results
than those treated with chemotherapy only regarding
both median time to first relapse (13 vs. 9 months,
respectively) and 1–5 year first relapse-free survival
(p = 0.045). Interestingly, after initial 3 cycles of
cisplatin/etoposide, thoracic radiation therapy offered
higher response rate than additional cisplatin/etopo-
side. When further response was evaluated, additional
cisplatin/etoposide (in both groups) offered nothing
but a few percent of additional response, an indirect
evidence of the necessity of limiting of the number of
chemotherapy cycles to 4–6. Results of this study
await further verification, an important task for the
future endevors in small-cell lung cancer.
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 Radiation Therapy in Extensive Disease
Small Cell Lung Cancer
Branislav Jeremić and Luhua Wang

Contents
1 Introduction.............................................................. 505
2 Trial of Radiation Therapy in Extensive Disease
Small Cell Lung Cancer ......................................... 506
3 Other Existing Studies ............................................ 509
4 Ongoing Studies ....................................................... 510
References.......................................................................... 510
Abstract
Approximately two-thirds of all patients with
small-cell lung cancer have the disease that spread
beyond confines of the thorax, including as well
patients whose disease has traditionally been
described as ‘‘too large to be encompassed with a
tolerable radiation port’’. For these patients, che-
motherapy has been considered standard treatment
option for many decades. However, patterns of
failure after chemotherapy alone in this disease
reveals substantial percentage of patients failing in
the chest. It is, therefore, that curative, high-dose
thoracic radiation therapy could offer improvement
in chest disease control and, hence, improved
survival. However, in spite of these observations,
thoracic radiation therapy has mostly been used in
palliative setting. In a landmark trial, Jeremic et al
have shown that in a suitable patients, those with
best prognosis, radical chest radiation therapy can
indeed offer an improvement in local control and
overall survival over that obtained with the same
chemotherapy given alone. This was achieved at
the expense of low toxicity. recent single-institu-
tional studies from Canada and China seem to
confirm this, while two ongoing prospective stud-
ies should help further refine radiation therapy
approach in this disease.

B. Jeremić (&)
Institute of Lung Diseases, Sremska Kamenica, Serbia 1 Introduction
e-mail: nebareje@gmail.com
L. Wang For decades, clinicians and investigators considered
Department of Radiation Oncology,
chemotherapy as the standard treatment option for
Chinese Academy of Medical Sciences,
Beijing, China patients with extensive disease small cell lung cancer.

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 505
DOI: 10.1007/174_2011_208, Ó Springer-Verlag Berlin Heidelberg 2011
506
Given alone, it can offer the median survival time of
9–12 months and 5-year survivals of 1–3% (Bunn
et al. 1977; Beck et al. 1988; Jeremic et al. 1999).
While up to 90% of patients eventually experience
objective response following initial courses of che-
motherapy, extensive disease small cell lung cancer
remains the disease with very poor prognosis. This is
so because most of patients unfortunately relapse;
leading to outcomes virtually unchanged since che-
motherapy based on platinum-etoposide combination
was introduced several decades ago. It is not hard,
therefore, to see this disease as one of the most
frustrating challenges in thoracic oncology. To com-
bat poor prognosis in patients with this disease when
treated with chemotherapy alone, various approaches
aiming intensification of the treatment were attemp-
ted. Unfortunately, maintenance chemotherapy after
4–6 cycles of initial chemotherapy (Splinter 1989;
Bunn 1992; Schiller et al. 2001) and higher doses of
chemotherapy (Ihde et al. 1994; Leyvraz et al. 2008)
did not prove to be beneficial in this setting. Accu-
mulated evidence of patterns of failure in patients
with extensive disease small cell lung cancer treated
with chemotherapy alone shows that besides distant
progression, local progression remains very frequent
event. Brain relapses, similarly to limited disease, are
frequent event, too. It is therefore that thoracic radi-
ation therapy and/or prophylactic cranial irradiation
could be of a benefit in suitable patients with exten-
sive disease small cell lung cancer. Those would
likely be the ones who experience some form of
response to chemotherapy, preferably complete
response as to enable meaningful prolongation of life,
which in turn, should allow enough observation time
to prove beneficial effects of either thoracic radiation
therapy and/or prophylactic cranial irradiation.
Although the place and the role of thoracic radia-
tion therapy in limited disease small cell lung cancer
are well established (Murray et al. 1993; Jeremic et al.
1997; Takada et al. 2002), the usefulness of thoracic
radiation therapy in extensive disease small cell lung
cancer is still open to debate. Almost 30 years ago, in
a large retrospective review of literature thoracic
radiation therapy was shown to be able to reduce the
frequency of initial chest failure. Nevertheless, com-
plete response rates, overall response rates, the med-
ian survival time, and 2-year disease-free survival
were identical for patients treated with chemotherapy
alone and those treated with chemotherapy and
B. Jeremić and L. Wang
thoracic radiation therapy (Bunn and Ihde 1981). It
should be clearly noted, however, that the majority of
studies from that report were performed and pub-
lished in 1960s and 1970s. Therefore, major charac-
teristics of radiation therapy course such as total
tumor dose, dose per fraction, and timing as well as
rather primitive treatment planning cannot be con-
sidered as the optimally defining modern thoracic
radiation therapy today. Not to be forgotten, also, is
that when one attempts to explore the effectiveness of
thoracic radiation therapy in extensive disease small
cell lung cancer, it must be taken into account the
systemic character of extensive disease small cell
lung cancer (Ou et al. 2009). It may obscure possible
effects of thoracic radiation therapy on survival
(established on a local level), especially in adequately
chosen subgroup of patients suitable for ‘curative’
role of thoracic radiation therapy. Simply said,
patients with extensive disease small cell lung cancer
may have systemic progression so fast that any pos-
sible effect on local control and, subsequently, sur-
vival may not be observed due to short life span of
these patients. Other issues concerning radiation
therapy, like irradiation to sites of systemic tumor
metastasis or the role of prophylactic cranial irradia-
tion, were also controversial until recent EORTC
study confirmed effectiveness of prophylactic cranial
irradiation in these patients (Slotman et al. 2007).
Trying to focus on the issues of possible
improvement in local (intrathoracic) tumor control
and its subsequent impact, if any, on overall survival
in favorable patient population, the role of thoracic
radiation therapy was evaluated in a prospective
randomized trial designed in late 1987 which con-
tinued from 1988–1993 (Jeremic et al. 1999).
2 Trial of Radiation Therapy
in Extensive Disease Small Cell
Lung Cancer
Included in this trial were treatment-na patients with
biopsy-proven extensive disease small cell lung can-
cer defined as the tumor beyond the confines of the
hemithorax, mediastinum, and ipsilateral or contra-
lateral supraclavicular nodes. Patients with tumors
that could not be encompassed within a tolerable
thoracic radiation therapy field as well as those having
an ‘isolated’ pleural effusion with positive cytology
Radiation Therapy in Extensive Disease Small Cell Lung Cancer
were also considered as having extensive disease
small cell lung cancer. Patients with negative cytol-
ogy in an ‘isolated’ pleural effusion were considered
ineligible for this study. Other eligibility criteria
included a Karnofsky performance status score of
C70, age 18–70 years, and adequate haematological,
renal, and hepatic function (unless due to liver
metastases). Excluded were patients with recent or
concurrent severe, uncontrolled cardiovascular or
pulmonary disease as well as those with central ner-
vous system metastases or other abnormality when
substantially impairing mental status. For staging
purposes chest X-rays and tomography, bronchos-
copy, bone marrow biopsy, brain, bone and liver
radionuclide scans, and abdominal ultrasonography
were done. Computerized tomography scans of the
thorax, brain, and abdomen were highly recom-
mended as well as pulmonary function tests and
actually became mandatory in all patients treated
from 1989. Treatment started with three cycles of
standard-dose cisplatin-etoposide regimen given at
3-week intervals: cisplatin, 80 mg/m2, day 1, and
etoposide, 80 mg/m2, days 1–3. After this portion of
the treatment schedule, complete patient reevaluation
and restaging were performed, using the procedures
outlined above. Patients achieving complete response
at local and distant levels and those achieving partial
response within the thorax accompanied with the
complete response elsewhere were then randomized
to receive either (a) accelerated hyperfractionated
radiation therapy and concurrent low-dose daily
chemotherapy consisting of carboplatin and etoposide
50 mg each, given on each radiation therapy treat-
ment day, followed by prophylactic cranial irradiation
and then by additional two cycles of cisplatin-etopo-
side (group I) or (b) four additional cycles of cis-
platin-etoposide and prophylactic cranial irradiation
(group II). Remaining patients (achieving worse
response) were not a part of randomization procedure.
Patients achieving worse response, i.e. those achiev-
ing complete response or partial response within
thorax, but only a partial response elsewhere (group
III and group IV), were offered two additional cis-
platin-etoposide cycles followed by the same accel-
erated hyperfractionated radiation therapy/
carboplatin-etoposide and in case of complete
response at distant level, also prophylactic cranial
irradiation. Patients achieving either stable disease or
progressive disease (group V) were either observed
507
until death (treated with supportive care only) or
treated with oral etoposide, 50 mg/m2, days 1–21,
every 28 days to a total of six cycles or further until
further progression.
Thoracic radiation therapy was performed using
6–10 MV photons from linear accelerators. Target
volume included all gross disease and ipsilateral
hilum with a 2 cm margin, and the entire mediasti-
num with a 1 cm margin and both supraclavicular
fosse were routinely irradiated. Anteroposterior-pos-
teroanterior treatment fields were used to deliver
36 Gy in 24 fractions in 12 treatment days over
2.5 weeks, after which various combinations of
treatment fields were used to give additional 18 Gy in
12 fractions in six treatment days. Therefore, the total
tumor dose was 54 Gy in 36 fractions in 18 treatment
days in 3.5 weeks. Normal tissue dose limits included
the maximum dose of 36 Gy to the spinal cord and the
entire heart, 54 Gy for the oesophagus, and 18 Gy for
the contralateral lung. Two daily fractions of 1.5 Gy
were used. During accelerated hyperfractionated
radiation therapy, on each thoracic radiation therapy
treatment day 50 mg of carboplatin and 50 mg of
etoposide were both given between the two daily
fractions (3–4 h after the first one, i.e. 1–2 h before
the second one). Prophylactic cranial irradiation was
administered with tumor dose 25 Gy in ten daily
fractions in 2 weeks to the whole brain via two par-
allel—opposed lateral fields in groups I and II.
Patients in groups III and IV also received prophy-
lactic cranial irradiation, but only in cases achieving
complete response at distant level. When appropriate,
palliative radiation therapy with 30 Gy in ten daily
fractions in 2 weeks was offered to patients with
metastatic lesions. Follow-up consisted of the fol-
lowing: patients were fully examined at the end of
their treatment (groups I–IV), every month for
6 months after the end of the treatment,
every 2 months for 2 years thereafter, and every
4–6 months thereafter. By using the diagnostic tools
outlined above restaging was made at time of pro-
gression. Patients were evaluated for response at the
prespecified time points: (1) after three cycles of
cisplatin-etoposide (week 9), then (2) after either
accelerated hyperfractionated radiation therapy or two
additional cisplatin-etoposide cycles (week 15), and
(3) at the end of treatment (week 21). The Eastern
Cooperative Oncology Group and the Radiation
Therapy Oncology Group/European Organization for
508
the Research and Treatment of Cancer toxicity criteria
were used in combination to address the issue of
chemotherapy- and radiation therapy-induced
toxicity.
A total of 210 patients entered this study. Four
patients were excluded from analysis due to various
reasons, making, therefore a total of 206 patients fully
evaluable for toxicity and survival. There was no
difference in the distribution of various variables
between the five treatment groups. For all 206
patients, the median survival time was 9 months, and
survival rates at 1, 2, 3, 4, and 5 years were 38, 19,
9.7, 4.9 and 3.4%, respectively. Further data and the
discussion are limited to patients in the randomized
part of the study (groups I and II).
Patients in group I (radiochemotherapy) achieved
the results that were significantly better than those in
group II (chemotherapy alone): the median survival
time was 17 vs. 11 months (p = 0.041), and 5-year
survival rates were 9.1 and 3.7% for groups I and II,
respectively. Local recurrence-free survival was also
better in group I than in group II, with median time to
local recurrence of 30 and 22 months, respectively,
and 5-year local recurrence-free survival of 20 and
8.1%, respectively (p = 0.062). Distant metastasis-
free survival was similar between the two groups.
Although group II patients treated with chemotherapy
only achieved longer median time to distant metas-
tasis than group I patients treated with combined
chemotherapy/thoracic radiation therapy (16 vs.
14 months, respectively), they had 5-year distant
metastasis-free survival half of that observed in the
combined group (14 vs. 27%), the difference being
insignificant (p = 0.35). Because local recurrence-
free survival rate was only marginally insignificant
and distant metastasis-free survival rate was not sig-
nificantly different between groups I and II, first
relapse-free survival analysis was done next and
showed significant superiority of patients in group I
(median time to first relapse, 13 vs. 9 months,
respectively; 1–5 year first relapse-free survival rate;
(p = 0.045)).
Analysis of response rates provided the local
complete response rates in groups I and II at weeks 9,
15, and 21. At week 9 (i.e., after three cycles of
induction cisplatin-etoposide, before randomization),
there was no difference between the two groups in the
local response rate (47 vs. 44%, p = 0.77). At
week 15 (when either accelerated hyperfractionated
B. Jeremić and L. Wang
radiation therapy/carboplatin-etoposide (group I) or
two additional cycles of PE (group II) were admin-
istered), the complete response rate was significantly
higher in group I than in group II (96 vs. 61%,
p = 0.000007), and it persisted until week 21 when
actual response rates for the groups I and II were 96
and 66%, respectively (p = 0.00005). Looking at
both absolute increase in percent responders and the
tempo of its achievement, the 4th and the 5th cycles
of chemotherapy add nothing to the response
achieved in group I patients after accelerated hyper-
fractionated radiation therapy had been added to three
cycles of cisplatin-etoposide. Furthermore, the 6th
and 7th cycles of cisplatin-etoposide in the chemo-
therapy alone group brought only a few percent
increase in response rates. Therefore, it seems that
after three cycles of induction chemotherapy followed
by thoracic radiation therapy, no additional gain was
observed with additional chemotherapy in the group
(I). Similarly, addition of 6th and 7th cycle of che-
motherapy in chemotherapy alone group (II) added no
visible gain in response rates. These data altogether
question the duration (number of cycles) of chemo-
therapy as it is practiced nowadays. They also set up
the stage and scene for possible clinical trial in the
future using standard-dose chemotherapy (e.g., cis-
platin-etoposide) with or without thoracic radiation
therapy.
Haematological high-grade ([3) toxicity (leuco-
poenia, thrombocytopenia, and anaemia) was more
frequent in chemotherapy-only (group II) than in
radiochemotherapy (group I), though not significant.
There was no difference between groups I and II
regarding incidence of high-grade infection
(p = 0.64). Nausea and vomiting were significantly
more frequent in group II than in group I
(p = 0.0038), due to more cycles of chemotherapy
administered to patients in group II. Similar was
observed in case of alopecia (p = 0.000003). High-
grade kidney toxicity was observed only in group II.
Acute high-grade (C3) radiation therapy-induced
oesophagitis was observed only in patients who
received thoracic radiation therapy. Due to a few
cases of radiation therapy-induced high-grade bron-
chopulmonary toxicity, the difference between the
two groups was not significant (p = 0.082).
Study of Jeremic et al. (1999) was the very first
prospective randomized study that evaluated curative
thoracic radiation therapy in extensive disease small
Radiation Therapy in Extensive Disease Small Cell Lung Cancer
cell lung cancer. It showed that thoracic radiation
therapy may have an important place and may have a
substantial role in overall treatment of patients with
extensive disease small cell lung cancer. In an effort
to gain more insight in the study results and perhaps
additional information for future studies, a multivar-
iate analysis of the most common pretreatment
prognostic factors in these patients was performed.
Karnofsky performance status score and weight loss
were strong prognosticators of improved treatment
outcome. Of particular importance, the number of
metastases significantly and independently predicted
improved overall survival. Patients with only one
metastasis had better outcome than those with C2
metastases, showing that metastatic tumor burden
should be taken into account in future studies. Finally,
overall good results should be attributed, at least in a
part, to the fact that approximately 90% of all patients
in that study had 1–2 metastases. It is therefore that
subsequent discussion of the study results including
prognostic factors analysis was frequently done using
the term limited extensive disease trying to emphasize
low tumor burden in these patients.
3 Other Existing Studies
Recently, preliminary data from two studies became
available. In a Canadian trial, Yee et al. (2010) found
eligible patients had biopsy-proven extensive disease
small cell lung cancer and attained an objective
radiologic disease response after receiving at least one
chemotherapy cycle. Study patients were also offered
prophylactic cranial irradiation (25 Gy in ten daily
fractions in 2 weeks) which was given simultaneously
with thoracic radiation therapy (40 Gy in 15 daily
fractions in 3 weeks) 4–6 weeks after completing
chemotherapy. Target volume in thoracic radiation
therapy was post-chemotherapy residual disease and a
margin. Endpoints in this study included overall sur-
vival, disease-free survival, local control, and toxic-
ity. Thirty-two of 33 accrued patients were evaluable.
Seventeen patients had \3 metastases, while 2
patients had at least three metastases. Bulky intra-
thoracic disease was present alone in 3 patients, and it
was accompanied by \3 metastases in 1 patient.
Pleural/pericardial disease was alone present in 3
patients and was accompanied with \3 metastases in
6 patients. All but three patients completed radiation
509
therapy with no delays. One patient received one
cycle of chemotherapy, three received three cycles
and 28 received four cycles. There were four com-
plete and 28 partial responses to chemotherapy. All
study patients received prophylactic cranial irradia-
tion. The median time to disease progression was
8.4 months and the median overall survival time was
13.7 months. There have been 13 distant-only recur-
rences and six combined distant-local recurrences.
There were no treatment-related deaths. Maximal
radiation therapy-induced toxicity was grade 2
oesophagitis in 18 patients which resolved in all
patients.
In another study, also only preliminarily reported
(Zhu et al. 2010), of a total of 154 patients 89 patients
received combined radiochemotherapy and 65
patients received chemotherapy alone. Chemotherapy
regimens were either cisplatin-etoposide or carbo-
platin-etoposide. Thoracic radiation therapy dose
ranged 40–60 Gy given in 1.8–2.0 Gy per fraction.
No prophylactic cranial irradiation was planned for
this patient population as it was not standard treat-
ment option in the study period (January 2003–
December 2006). For the whole group, the medians
survival time was 13.7 months and the 2- and 5-year
survival rates were 27.9 and 8.1%, respectively.
Corresponding figures for chemotherapy-alone group
were 9.3 months, 16.9 and 4.6%, respectively, while
for radiochemotherapy group were 17.2 months, 36
and 10.1%, respectively (p = 0.0001). The incidence
of thoracic failures in two treatment groups was 70 vs.
29.6% (p \ 0.001). What these two studies have
shown is, albeit of some shortcomings, that thoracic
radiation therapy indeed can decrease the incidence of
chest failures and leads to promising survival data. In
addition, as an important factor in understanding
therapeutic benefit, toxicity of combined radioche-
motherapy in patients with extensive disease small
cell lung cancer was low.
Studies of Zhu et al. (2010) and Yee et al. (2010)
should also not only be seen as a confirmatory data of
the study of Jeremic et al. (1999) but also as confir-
matory of existing institutional practices among
radiation oncologists and medical oncologists
involved in the treatment of extensive disease small
cell lung cancer since the time study of Jeremic et al.
(1999). This was recently brought to the evidence by
the study of Ou et al. (2009) who retrospectively
analyzed the data from the Cancer Surveillance
510 B. Jeremić and L. Wang

programs of Orange, San Diego, and Imperial coun- Table 1 Basic comparison RTOG 0835 vs. CREST
tries in southern California covering an area with Trial Nature Diagnosis Patients Sequencing
estimated population of 6.2 million. Small cell lung (classic/ (n mets) Rt-chemo
cancer patients diagnosed between 1991 and 2005 pet)
who had complete follow-up data were included in RTOG Curative More More Sequential
the study. Extensive disease was defined as distant precise favorable
disease stage according to Surveillance, Epidemiol- CREST Palliative Less Less Sequential
ogy, and end results summary staging. There were precise favorable
3,428 such patients. Of them, radiation therapy was
given in 1,204 (35.1%) patients. A number of
with brain restaging done and with 0–1 residual sites
clinicopathologic characteristics were analyzed upon
of extrathoracic disease present at the time of re-
their influence on the outcome. The 1-year, 2-year,
staging. Radiotherapy part of the study includes tho-
and median overall survival of extensive disease
racic radiation therapy dose of 45 Gy in 15 fractions,
small cell lung cancer patients who received radiation
prophylactic cranial irradiation of 25 Gy in 10 frac-
therapy were 27.8, 9.3%, and 8 months and were
tions, while 45 Gy in 15 fractions will be given to
significantly better than extensive disease small
metastatic lesions. Major objectives of the trial
cell lung cancer patients who did not receive
included (1) overall median and 1-year survival (2)
radiation therapy (16.2, 3.8%, and 4 months, respec-
recurrence patterns and time to failure, as well as (3)
tively; p \ 0.0001). Cox multivariate analysis of
acute and late toxicity. Similarly, the Dutch Lung
potential prognostic factors confirmed independent
Cancer Study Group is executing a chest radiotherapy
positive influence of delivered radiation therapy on
in extensive disease small cell lung cancer trial
treatment outcome (HR, 0721; 95% CI, 0-670-0.776;
(CREST) with the primary endpoint being overall
p \ 0.001). Unfortunately, other important charac-
survival. Secondary endpoints include pattern of
teristics of radiation therapy (e.g., curative vs. palli-
relapse and toxicity. In CREST trial, patients with
ative, time-dose-fractionation patterns, sequencing of
extensive disease small cell lung cancer without brain
chemotherapy and radiation therapy) were not pro-
metastasis or pleural metastasis undergo chemother-
vided as to enable better insight into patterns of
apy. Those achieving any response to 4–6 cycles of
practice of radiation therapy in this disease. Never-
chemotherapy are randomized to prophylactic cranial
theless, these data suggest that radiation therapy is
irradiation and no thoracic radiation therapy versus
practiced in about 1/3 of these patients improving
those treated with prophylactic cranial irradiation and
survival. These may be a good starting point for more
thoracic radiation therapy (30 Gy in 10 fractions)
practicing in the near future, especially once we have
given only if the toxicity of the required fields will not
more solid data from ongoing trials.
be prohibitive. These two trials are different in many
characteristics, and some of major strategic charac-
teristics are briefly outlined in a Table 1. It is
4 Ongoing Studies expected that these two studies will bring additional
substance to the data of Jeremic et al. (1999) and help
After a gap of almost 10 years following the publi-
optimize both treatment approach with thoracic radi-
cation of this landmark study (i.e., 20 years since its
ation therapy and identification of suitable patients for
start!), investigators over the world finally started
thoracic radiation therapy.
with preparations for additional prospective random-
ized trials of thoracic radiation therapy in extensive
disease small cell lung cancer. The Radiation Therapy
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Oncol Radiol 72, Abstract 2211
 Prophylactic Cranial Irradiation in Small-Cell
Lung Cancer
Michael C. Stauder and Yolanda I. Garces

Contents
1 Introduction.............................................................. 514
2 Studies Evaluating Prophylactic Cranial
Irradiation ................................................................
2.1 Retrospective Studies ................................................
2.2 Randomized Trials.....................................................
2.3 Meta-Analyses ...........................................................
2.4 Extensive Stage Small-Cell Lung Cancer ................
3 Treatment Schedule................................................. 516
3.1 Dose and Fractionation ............................................. 516
3.2 Timing of PCI............................................................ 516
4 Neurotoxicity and Quality of Life .........................
4.1 Retrospective Studies ................................................
4.2 Prospective Trials ......................................................
4.3 Extensive Stage Small-Cell Lung Cancer ................
5 Patterns of Care....................................................... 518
6 Future Directions..................................................... 519
7 Conclusions ............................................................... 519
References.......................................................................... 519
Abstract
Prophylactic cranial radiation (PCI) has been used in
the management of small-cell lung cancer given the
propensity of disease relapse in the brain. Several
514 studies have shown that PCI reduces the rate of brain
514 metastases and improves survival. However, the use
514
of PCI in the management of small-cell lung cancer
515
516 has been controversial due to conflicting evidence of
efficacy and toxicities. For example, the most
effective radiation dose and fractionation regimen
is not known. Also, conflicting reports on the
neurotoxicity of PCI make it difficult to make
517
517 definitive conclusions regarding the side-effects of
517 treatment. As the survival of patients with SCLC
518 improves, the controversies regarding the neuro-
toxic effect of PCI may become more defined.
Certainly, well-designed prospective clinical
trials addressing these issues are needed and are
ongoing.

Abbreviations

Gy Gray
Fx Fractions
BID Twice-daily
LS Limited stage
ES Extensive stage
SCLC Small-cell lung cancer
NSCLC Non-small-cell lung cancer
M. C. Stauder
Y. I. Garces (&)
Radiation Oncology, Mayo Clinic College of Medicine,
Charlton Building, 200 First Street SW, Rochester,
MN 55905, USA
e-mail: garces.yolanda@mayo.edu

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 513
DOI: 10.1007/174_2011_270, Ó Springer-Verlag Berlin Heidelberg 2011
514
1 Introduction
Small-cell lung cancer (SCLC) comprises 15–25% of
all lung cancer cases. A complete response to treat-
ment can be seen in 50–80% of patients undergoing
chemoradiotherapy for limited stage disease (Turrisi
et al. 1999; Levitan et al. 2000; Bremnes et al. 2001),
and in 40–50% of patients with extensive disease
(Jeremic et al. 1999). Unfortunately, disease relapse
within the central nervous system (CNS) is common.
Radiotherapy directed at the brain for prevention of
CNS relapse, or prophylactic cranial irradiation (PCI)
has been used in an attempt to decrease the incidence
of brain metastasis. However, the use of PCI in the
management of small-cell lung cancer has been con-
troversial due to conflicting evidence of efficacy and
toxicities. SCLC has a propensity to metastasize to
the brain and incidence of brain metastasis can be up
to 15% at diagnosis. Also, approximately 50–70% of
small-cell lung cancer patients who do not receive
PCI will ultimately develop clinical evidence of brain
metastases. Autopsy series report an even higher
incidence of 80% at 2 years (Nugent et al. 1979). The
introduction of PCI in SCLC was first proposed in
1973 by (Hansen et al. 1973) due to the dissatisfaction
with the high rate of brain metastasis following pro-
longed survival after the use of novel chemothera-
peutic agents in patients with limited and/or extensive
stage disease.
2 Studies Evaluating Prophylactic
Cranial Irradiation
2.1 Retrospective Studies
One of the early retrospective studies evaluating the
role of PCI in the management of SCLC was per-
formed in the mid 1970s by Komaki and colleagues.
A total of 131 patients were analyzed for the inci-
dence of brain metastasis of patients when PCI was
included as part of their small-cell lung cancer ther-
apy. Of these patients, 57 received PCI and 74
patients did not. The incidence of CNS failure at 12
and 24 months was significantly decreased in the
patients receiving PCI versus those not receiving PCI
(11 vs. 28%, and 11 vs. 58%, respectively; p \ 0.01)
(Komaki et al. 1981).
M. C. Stauder and Y. I. Garces
Similarly, other trials from the 1970s also con-
cluded that PCI decreased the incidence of brain
metastases but did not improve overall survival
(Jackson et al. 1977; Cox et al. 1978). However, when
restricted to patients experiencing a complete
response to chemoradiotherapy, other more modern
trials suggest that there may indeed be a survival
benefit with the use of PCI (Ohonoshi et al. 1993;
Shaw et al. 1994; Arriagada et al. 1995; Gregor et al.
1997; Laplanche et al. 1998). Several randomized
trials have been performed in an attempt to better
define the role of PCI in the management of SCLC.
Several of these trials are listed in Table 1.
2.2 Randomized Trials
A French prospective randomized trial (PCI-85) was
performed to evaluate the effect of PCI on the inci-
dence of brain metastases, overall survival, and late
toxic effects of treatment. A total of 300 patients with
SCLC in complete remission were enrolled at 21
centers from March 1985 to March 1993. Patients
with extensive stage SCLC comprised 20% of the
sample population. Randomization was done to PCI at
a dose of 24 Gy/8 Fx (n = 149) or no PCI (n = 151).
PCI was given at the time of determination of com-
plete remission and no chemotherapy was allowed
during PCI or one week before and after (Arriagada
et al. 1995). The incidence of brain metastasis at
2-years was decreased in the arm receiving PCI
(40 vs. 67%, p \ 10-13) which translated into a non-
statistically significant improvement in 2-year overall
survival (29 vs. 21.5%, p = 0.14). A follow-up study
(PCI-88) was closed early based on the interim
analysis showing such a significant decrease in the
incidence of brain metastasis that most investigators
felt that PCI should be administered to all patients
(Laplanche et al. 1998).
A Japanese trial evaluating 46 patients with SCLC
in complete remission showed a significant decrease
in the rate of brain metastasis with the use of PCI
(Ohonoshi et al. 1993). The incidence of CNS relapse
in the group receiving PCI was 22 versus 52% in
those where it was omitted. A trend for an improved
median overall survival (21 vs. 15 months) was also
seen in the group receiving PCI. The 5-year overall
survival rate was 22 and 13% in the patients where
PCI was delivered and not delivered, respectively.
Prophylactic Cranial Irradiation in Small-Cell Lung Cancer 515

Table 1 Characteristics of trials examining the role of PCI in SCLC

Brain metastasis Overall survival
Study N PCI dose* PCI No-PCI PCI No-PCI
Arriagada et al. (1995) 300 24 Gy/8 Fx 40% 67% 29% 21.5%
2 years 2 years 2 years 2 years
Laplanche et al. (1998) 211 24 Gy/8 Fx 44% 51% 22% 16%
4 years 4 years 4 years 4 years
Ohonoshi et al. (1993) 46 40 Gy/20 Fx 22% 52% 22% 13%
5 years 5 years
Gregor et al. (1997) 314 30 Gy/10 Fx 30% 38% 25% 19%
2 years 2 years 2 years 2 years
Aupérin et al. (1999) 987 24–25 Gy/8–12 Fx 33.3% 58.6% 20.7% 15.3%
3 years 3 years 3 years 3 years
Slotman et al. (2007) 286 20 Gy/5 Fx 14.6% 40.4% 27.1% 13.3%
1 year 1 year 1 year 1 year
*
Most common dose
PCI prophylactic cranial radiation, Gy Gray, Fx fractions

A three-arm trial performed by the UKCCCR and 2.3 Meta-Analyses

EORTC was designed to randomize 314 patients to
either PCI at a dose of 36 Gy/18 Fx or 24 Gy/12 Fx
versus no PCI (Gregor et al. 1997). The trial was
remarkable for a very poor accrual rate so it was
redesigned to allow the physician to choose a PCI
dose regimen. Most physicians chose 30 Gy/10 Fx
(n = 61) and 8 Gy/1 Fx (n = 25). Results from this
study revealed that with PCI, a significant reduction
in brain metastases was seen (38 vs. 54%, HR = 0.44,
95% CI 0.29–0.67), as well as an improvement
in metastasis-free survival (HR = 0.75, 95% CI
0.58–0.96). No difference in overall survival was
observed between the group receiving PCI and those
not receiving PCI with a median survival of 305 days
and 300 days, respectively.
As in SCLC, the use of PCI after complete remission
in patients with non small-cell lung cancer (NSCLC)
has shown to be effective in preventing brain metasta-
ses. Recently, a randomized trial by RTOG has been
reported which compared PCI versus observation in
patients with stage III NSCLC without progression
after definitive therapy (Gore et al. 2011). The use of
PCI decreased the 1-year rate of brain metastasis
compared to the group that did not receive PCI (7.7 vs.
18%, respectively (p = .004)). No difference was
observed in overall survival between groups.
Given the suggestion of improved survival with PCI,
a meta-analysis was performed, which included 7
trials consisting of 987 patients with limited stage
SCLC in complete remission after primary chemora-
diotherapy (Aupérin et al. 1999). The use of PCI
improved the incidence of brain metastasis at 3-years
(33.3 vs. 58.6% at 3 years, p \ 0.001). An absolute
3-year overall survival benefit of 5.4% was also seen
(15.3 vs. 20.7%, p = 0.01) favoring the use of PCI.
However, there have been some criticisms of the
methodology employed in this analysis. Over half of
the trials included (4 of 7) enrolled less than 100
patients and approximately 15% of patients had
extensive stage disease. Also, the dose-fractionation
regimens were not uniform among the trials but as
in the UKCCCR/EORTC trial, this analysis also
suggests that higher doses of RT led to a greater
reduction in the incidence of brain metastasis.
Another meta-analysis which included 12 ran-
domized trials and 1547 patients had a similar con-
clusion (Meert et al. 2001). Only 5 of the 12 trials
consisted exclusively of patients known to be in
complete remission after primary therapy. In the other
trials, 5 included patients given PCI at the time of
induction chemotherapy, and 2 included patients
516
given PCI at end of induction chemotheraphy without
any restaging. A decrease in the incidence of meta-
static brain lesions was seen for all patients given PCI
(HR 0.48 (95% CI: 0.39–0.60)) and an improvement
in overall survival was seen for patients in complete
remission given PCI (HR 0.82; 95% CI: 0.71–0.96).
2.4 Extensive Stage Small-Cell Lung
Cancer
While several randomized studies have been per-
formed in limited stage SCLC to evaluate the effect of
PCI on brain metastasis and survival, data is much
more limited in extensive stage SCLC. One large
randomized trial included patients with extensive
stage SCLC and any response to 4–6 cycles of che-
motherapy (Slotman et al. 2007). The patients in this
trial received either PCI (20/5 Fx or 30/12 Fx) or no
radiotherapy. The results show that the cumulative
risk of brain metastasis at one year was decreased
in the group that received PCI (14.8 vs. 40.4%,
p \ 0.001) as was the progression-free survival (14.7
versus 12 weeks, respectively, p = 0.02). Although,
not a primary end point of the trial, overall survival at
1 year was also improved in the patients receiving
PCI compared to the no radiotherapy group (27 vs.
13%, respectively, p = 0.003).
3 Treatment Schedule
3.1 Dose and Fractionation
One of the important findings of the UKCCCR/
EORTC study is that a suggestion of a dose response
was seen due to the fact that those receiving 24 Gy/12
Fx PCI had no difference in the incidence of brain
metastasis compared to those patients not receiving
any PCI and the patients who appeared to benefit the
most from PCI were those who received 36 Gy in 18
Fx (Gregor et al. 1997). This relationship was also
seen in the meta-analysis performed by the Prophy-
lactic Cranial Irradiation Overview Collaborative
Group (Aupérin et al. 1999).
Conflicting data comes from Canadian investiga-
tors who reported the results of a retrospective review
of 163 patients with limited stage SCLC given PCI
(Tai et al. 2003). No difference in dosing schedule
M. C. Stauder and Y. I. Garces
was seen among the patients in this study. Addition-
ally, a higher biologically equivalent dose (BED) did
not significantly decrease the incidence of brain
metastases. On further analysis, the 5-year overall
survival rate was improved in patients who received a
BED of \39 Gy10 compared to those receiving a
BED of [39 Gy10 (22.3 vs. 13.3%, p = 0.03). It is
worthwhile to note, however, that only a small num-
ber of patients (n = 6) in this review actually
received a dose [39 Gy.
A large Intergroup trial recently attempted to address
this question by enrolling 720 patients with limited
stage SCLC in a randomized trial looking at a standard
PCI dose (25 Gy/10 Fx) versus a higher dose of PCI
(36 Gy/18 Fx or 36/24 BID Fx). Patients in this trial
needed to have a documented complete remission prior
to inclusion. Patients from 157 different treatment
centers in 22 different countries were represented
(Le Pechoux et al. 2009). No significant difference was
seen in the 2-year incidence of brain metastasis between
the high and low-dose groups (23 and 29%, respectively
(p = 0.18)). Paradoxically, a decreased 5-year overall
survival rate was seen in the high-dose arm compared to
the low-dose arm (42 vs. 37%, respectively (p = 0.05)),
but of note, survival was not the primary endpoint of the
trial. The authors concluded that 25 Gy in 10 fractions
should remain the standard of care.
Altered fractionation has also been evaluated as a
potential method to improve control of brain metas-
tasis and promote improved survival. A single insti-
tution Phase II trial comparing twice-daily PCI to
observation reported a 2-year disease-free and overall
survival of 54 and 62%, respectively in the 15 patients
who received PCI (Wolfson et al. 2001).
Based on the lack of evidence for increased effec-
tiveness of a higher PCI dose or altered fractionation, a
25 Gy/10 fraction regimen, corresponding to the stan-
dard-dose arm of the intergroup trial, has become a
commonly adopted PCI regimen. The currently open
RTOG 0937 trial examining PCI alone versus PCI and
consolidative extracranial RT for extensive stage
SCLC uses this regimen. (NCT01055197).
3.2 Timing of PCI
The large meta-analysis conducted by Aupérin et al.
(1999) suggests that control of brain metastases
improves as the delay to receiving PCI is decreased.
Prophylactic Cranial Irradiation in Small-Cell Lung Cancer
On sub-group analysis, a significant reduction in the
risk of brain metastasis was seen as the time between
the start of induction therapy decreased. The relative
risk of developing brain metastases compared to a
control group was 0.27 in the patients receiving
PCI \ 4 months from the start of induction therapy,
0.50 in the 4–6 month group, and 0.69 in the
[6 month group (p = 0.01) (Aupérin et al. 1999).
In another study, the rate of brain metastases was
decreased in patients receiving PCI after 2–3 cycles
of chemotherapy compared to after 5–6 cycles. The
group of patients having PCI delayed an average of
170 days had a 15% rate of developing overt metas-
tases before PCI started (Lee et al. 1987).
A radiobiologic analysis was performed to evalu-
ate the effect of increased dose on brain relapse rate in
patients with SCLC (Suwinski et al. 1998). Using data
from 42 trials which report the incidence of brain
metastases both with and without the use of PCI, these
investigators calculated that in patients not receiving
PCI, the cumulative incidence of brain metastases was
32%. In the group of patients receiving PCI within
60 days of starting primary therapy, a linear dose–
response was established up to a dose of 35 Gy when
delivered daily as 2 Gy fractions. The same rela-
tionship was not seen, however, if PCI was delayed
and delivered after 60 days. Also, in patients receiv-
ing early PCI (\60 days), the dose of radiation nee-
ded to produce a 50% reduction in the rate of brain
metastases that was less than in those receiving late
PCI (20 vs. 27 Gy, respectively).
4 Neurotoxicity and Quality of Life
4.1 Retrospective Studies
In the large meta-analyses showing improved brain
control and survival in the patients who received PCI,
the neurotoxicity experienced is not well described and
data regarding the extent of neurotoxicity induced by
PCI is inconclusive (Aupérin et al. 1999; Meert et al.
2001). Data from the Mayo Clinic and North Central
Cancer Treatment Group report a 2- and 5-year risk of
severe neurotoxicity at 3% and 10%, respectively in
patients receiving PCI (Shaw et al. 1994).
A retrospective study of 30 patients performed at
MD Anderson Cancer Center attempted to better
characterize the risks of neurotoxicity from PCI
517
(Komaki et al. 1995). The patients analyzed had a
complete response (1 PR) to primary therapy and were
administered a panel of widely used standardized
neuropsychological tests. On initial evaluation, 97% of
patients had evidence of cognitive dysfunction prior to
receiving PCI. The most common deficiencies were in
verbal memory, frontal lobe dysfunction, and fine
motor coordination. Excluding the patients with
underlying medical conditions such as stroke, mild
mental retardation, learning disability , or alcohol
abuse, 20 of 21 patients still displayed abnormal test-
ing. Additional testing of 11 patients at 6–20 months
after PCI revealed no significant difference in any of the
tests compared to baseline. A dose of 25 Gy delivered
in 10 fractions was used in all patients analyzed.
A corollary study published in 2008 confirms these
results (Grosshans et al. 2008). In the 17 patients with
extended follow-up (mean 1.5 years), early declines in
executive function and expressive language tests were
observed. When controlling for disease progression, no
differences were seen from pre-PCI testing. Testing at
later time points ([450 days) revealed significant
improvements in expressive speech and motor coordi-
nation. In another study which showed improved brain
control and survival in the group of patients treated with
PCI, late neurotoxicity was observed infrequently with
only 1 patient experiencing mild neurological deterio-
ration (Ohonoshi et al. 1993).
4.2 Prospective Trials
The results regarding neuropsychological testing,
global health status, and quality of life outcomes in
patients enrolled in randomized trials are also mixed
(Arriagada et al. 1995; Gregor et al. 1997; Slotman
et al. 2007).
In the PCI-85 study, patients underwent neuro-
psychological testing which included temporo-spatial
orientation, memory, judgment, language, praxis, and
mood status (Arriagada et al. 1995). The tests were
performed at randomization and at 6, 18, 30, and
48 months later if neurological symptoms appeared.
At 2 years, no test showed any significant difference
from baseline.
In the UKCCCR/EORTC trial, 136 patients par-
ticipated in extensive psychometric testing that was
performed at randomization and every six months
(Gregor et al. 1997). Up to 41% of patients analyzed
518
had significant abnormalities on individual tests
before PCI and additional impairment was seen at
6 months and 1 year. There were no notable differ-
ences, however, between the group receiving PCI and
the group that did not. The most common symptoms
reported at follow-up were tiredness, lack of energy,
irritability, decreased sexual interest, shortness of
breath, and cough. These symptoms were as moderate
or severe more frequently in the group of patients who
did not receive PCI.
Based on the increased local control in the brain
with the use of PCI in SCLC, recent trials have also
focused on patients with NSCLC. A prematurely
closed, prospective randomized trial enrolled 340
patients without disease progression after completing
definitive therapy for NSCLC and was randomized to
PCI (30 Gy/15 Fx) or observation (Sun et al. 2011).
Patients had neurocognitive function assessed with
Mini-Mental Status Exam (MMSE), Hopkins Verbal
Learning Test (HLVT), and Activity of Daily Living
Scale (ADLS) and used the same quality of life tools
as the patients described in the EORTC extensive
stage SCLC study (Slotman et al. 2007, 2009). No
significant differences in quality of life, MMSE, or
ADLS were observed at 1 year, but patients receiv-
ing PCI had decreased scores for immediate and
delayed recall (p = 0.03 and 0.008, respectively) on
HVLT.
4.3 Extensive Stage Small-Cell Lung
Cancer
The effect of PCI on quality of life end points was
also addressed in patients with extensive stage lung
cancer (Slotman et al. 2007, 2009). Two quality of
life tools (EORTC-QLQ-C30 and BN20) were used to
analyze short and long-term changes in functioning.
In a preliminary report, the authors note significant
side-effects of PCI, including fatigue and hair loss,
which were significantly more severe in the group of
patients receiving PCI (Slotman et al. 2007). No
significant differences were seen in global health
status, role functioning, cognitive functioning, or
emotional functioning. A subsequent study showed a
limited effect of PCI on these factors, but none
reached the level of clinical significance as pre-
defined in the protocol design (Slotman et al. 2009).
Patients receiving PCI had an increased rate of severe
M. C. Stauder and Y. I. Garces
worsening in global health status (35 vs. 22%) from
base line up to 3 months. There was poor compliance
with follow-up assessments with a 94% participation
rate at baseline, but only 60 and 55% at 6 weeks and
3 months, respectively. Also, the median survival of
6 months seen in this cohort was shorter than
expected. Both of these factors may have contributed
to a lack of power to detect a difference between
groups. An exploratory analysis of other symptom
scale factors, however, showed significant differ-
ences, both statistical and clinical in appetite loss,
constipation, nausea and vomiting, social functioning,
future uncertainty, headaches, motor dysfunction, and
weakness of the legs favoring the control arm.
5 Patterns of Care
Using a complex decision-analytic model, and based
on a large cohort of simulated patients, an assessment
of the potential overall value of PCI was explored
(Lee et al. 2006). Assumptions such as a low (30%)
and moderate (50%) latent rate of neurotoxicity and a
5-year overall survival of a PCI and no-PCI group
derived from data published as part of a large Inter-
group SCLC trial (26 and 22%, respectively) were
used in the model during patient simulation (Turrisi
et al. 1999). This resulted in a 7.8 and 13% incidence
of observed neurotoxicity at the low and medium
rates, respectively. This was then translated to a
quality-adjusted life expectancy (QALE) for each
group of patients to incorporate the impact of chronic
neurotoxicity on patient quality of life. According to
the model, in all cases when the latent neurotoxicity
rate is less than 54% or 5-year survival is less than
46%, the group of patients receiving PCI has a greater
calculated QALE than those in the no-PCI group.
It is clear, however, that many patients who are
otherwise eligible to undertake PCI as part of their
treatment for SCLC, are not receiving it. A recently
published study of 207 patients without progressive
disease after chemotherapy and thoracic radiotherapy
shows that only 61% actually completed a PCI regi-
men (Giuliani et al. 2010). Of these patients, 37.5% of
patients refused PCI. In this cohort, over half (53%)
cited potential concerns about toxicity and another
20% of patients cited excessive toxicity of their prior
chemoradiotherapy as a reason to refuse PCI.
Prophylactic Cranial Irradiation in Small-Cell Lung Cancer
6 Future Directions
Recently, attempts have been made to decrease the
potential neuropsychological effects of whole brain
radiotherapy (WBRT). There is good evidence that
radiation disrupts the normal microvascular angiogenesis
of the hippocampus and decreases neurogenic cell pro-
liferation in vitro (Monje et al. 2002). Abnormal hippo-
campal function has been shown to correlate with
decreased memory in both humans and animals
(Abayomi 1996; Broadbent et al. 2004). As such, several
groups have published their experience with hippocam-
pal avoidance in WBRT for brain metastases (Gutierrez
et al. 2007; Gondi et al. 2010; Hsu et al. 2010). A Phase II
clinical trial evaluating the effect of hippocampal
avoidance in WBRT is scheduled to begin enrollment
soon and will evaluate delayed recall as assessed by the
HVTL at 4 months after hippocampal avoidance during
WBRT in patients with brain metastasis (RTOG 0933,
NCT01227954). Also, a Phase III cooperative group
trial is currently examining the role of the drug 3, 5-
dimethyladamantan-1-amine (Memantine) in preventing
neurocognitive dysfunction due to WBRT (RTOG 0614,
NCT00566852). These trials will provide important
additional information on the neuropsychological effects
of WBRT and suggest ways to minimize them.
7 Conclusions
Prophylactic cranial radiation should be recom-
mended for all limited stage SCLC patients in com-
plete remission or those who exhibit a good partial
response to chemoradiotherapy in order to decrease
brain metastasis and improve survival. In patients
with ES-SCLC, PCI should be recommended for all
patients with any response (partial or complete) to
chemotherapy. The optimal dose and fractionation
regimen is unknown, but a commonly accepted
standard is 25 Gy in 10 fractions for LS-SCLC and
20 Gy in 5 fractions for ES-SCLC patients. Good data
characterizing the neuropsychological effects of PCI
are ongoing and no definitive conclusions can be
made regarding long-term toxicity. As the survival of
patients with SCLC improves, the controversies
regarding the neurotoxic effect of PCI may become
more defined. Also, patients need to be better
informed of the potential risks and benefits of PCI as
519
part of comprehensive treatment for SCLC. Certainly,
well-designed prospective clinical trials addressing
these issues are needed and are ongoing.
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 Radiation Therapy for Lung Cancer
in Elderly
Branislav Jeremić and Željko Dobrić

Contents Abstract
Western world is rapidly aging, yet the exact threshold
1 Introduction.............................................................. 523 age for differentiating elderly versus non-elderly is not
2 Non-Small-Cell Lung Cancer................................. 525 widely adopted. Elderly are also underrepresented in
2.1 Early Stage Non-Small-Cell Lung Cancer ............... 525 clinical trials and level of evidence of preferred
2.2 Locally Advanced Non-Small-Cell Lung Cancer .... 529 treatment in both non-small-cell and small-cell lung
2.3 Metastatic Non-Small-Cell Lung Cancer ................. 532
cancer is basically lacking. From the existing evi-
3 Small-Cell Lung Cancer ......................................... 533 dence, however, it seems that radiation therapy is safe
4 Conclusions ............................................................... 538 and effective treatment modality in patients with early
stage non-small-cell lung cancer. It is so also in locally
References.......................................................................... 538
advanced non-small-cell lung cancer when combined
with radiochemotherapy, although caution should be
exercised when one attempts to combine high-dose
radiation therapy with high-dose chemotherapy. Sim-
ilarly, palliative radiation therapy is effective in
elderly with non-small-cell lung cancer unsuitable
for radical approach, with or without additional
chemotherapy. Finally, in small-cell lung cancer,
again, radiation therapy can successfully be employed
either alone or, most frequently, with chemotherapy in
treatment of both limited and extensive-disease small-
cell lung cancer. While largely unsubstantiated fear
has governed our approaches in elderly with lung
cancer in recent decades, novel radiation therapy
technologies and novel drugs should provide suitable
framework for embarking on more clinical trials
in elderly.

1 Introduction

Epidemiologic data are clearly showing that the

B. Jeremić (&)
Ž. Dobrić
Institute of Lung Diseases, Sremska Kamenica, Serbia Western world is rapidly ageing. Individuals over the
e-mail: nebareje@gmail.com age of 65 years compose the fastest-growing segment

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 523
DOI: 10.1007/174_2011_254, Ó Springer-Verlag Berlin Heidelberg 2011
524
of the population. In the year 1930, 1 out of 15 per-
sons was[65 years of age, while in the year 1990 this
was 1 out of 8. It is estimated that by the year 2020,
they will constitute approximately 20% of all popu-
lation in the United States, and by the year 2030
they will constitute approximately 25% of all pop-
ulation in the United States. The group [75 years
old will triple by 2030, and those [85 years of age
will double in the same period (Yanick 1997).
Unfortunately, no widely-accepted and exact defini-
tion of an elderly person exists. Cut-off age thresh-
olds differentiating an elderly versus non-elderly
person vary between 60 and 80 years of age, many
studies using the cut-offs between 65 and 75 years.
Contrasting fixed thresholds are used to define elderly
persons, operational definition of geriatric oncology is
‘‘when the health status of a patient population begins
to interfere with the oncological decision-making
guidelines’’ (Extermann 2000). Hence, rather than an
arbitrarily established age limit, biological age should
be defined individually by performance status and
co-morbidities, the two ultimately influencing the
decision–making process.
Increasing age is direct consequence of improved
sanitation, use of antibiotics, reduced smoking, and
diet. It has, however, many consequences, among
which there is a particular one, directly-associated
increasing cancer occurrence rates: eleven fold
increase in the cancer incidence in persons [65 years
of age when compared to their younger counterparts
indicates that elderly population will soon become
one of the major targets in oncology requiring specific
managements for various cancers (Yanick 1997).
Indeed, when compared to the general population of
the year 1990, in the year 2010 it is estimated that
there will be a growth of 9% in the general, but
growth in cancer cases will be more than 30%. In the
year 2020, it is estimated that population growth
would be 12% while growth of cancer population
would be 60%. There are multiple reasons for such
growth in cancer incidence such as less resistance and
longer exposure to carcinogens, reduced immune
competence, altered anti-tumor defence, decreased
DNA repair, defects in tumor suppressor genes, and
biologic behavior differences.
Lung cancer, major cancer killer in both sexes, is a
typical disease of the elderly patient. More than 50%
of patients are over the age of 65 years and nearly
35% are over the age of 70 years. The median age of
B. Jeremić and Ž. Dobrić
incidence is 69 years in males and 67 years in
females. In patients with early/localized disease
treatment approaches with curative intention are fea-
sible. However, the widely accepted ‘‘evidence’’ is
usually based on studies which are performed with
selected patients, the elderly patients being under-
represented in clinical trials. Disturbing observation
from daily practice worldwide is that elderly are less
likely to be vigorously screened and staged, and fre-
quently less aggressively treated (Nugent et al. 1997;
Higton et al. 2010).
Importantly, though, when evaluated for the spe-
cific features they did not seem to have different
characteristics at presentation. This particularly
relates to the stage of the disease, performance status,
and histology, when compared to their non-elderly
counterparts, although other characteristics such as
type and number of co-morbidities and organ function
differ in the two groups of populations (Montella et al.
2002). Furthermore, there still may be a reduction in
functional organ capacity although not clinically overt
and undetected in many ‘‘healthy’’ elderly. With
increasing age kidney, lung, and heart as well as the
immune system may show a reduced organ function
(Balducci and Extermann 2000a).
To base patient selection on clinical judgement with
performance status and organ function parameters is a
common practice in oncology. When one consider
elderly this, however, may not be adequate, since there
is a need for a more comprehensive pre-treatment
assessment that would consider potential hazards in
treating elderly the same way as non-elderly. This may
help in predicting and avoiding such hazards
(Monfardini et al. 1995), since geriatric syndromes
widely recognized as potential threat to diagnosis and
treatment include dementia, depression, incontinence,
delirium, osteoporosis, and failure to thrive. A com-
prehensive geriatric assessment as an adjunct to general
and cancer-specific diagnostic procedures is therefore,
developed. It has been defined as a multidimensional,
interdisciplinary diagnostic process to determine the
medical, psychological, and functional capabilities of a
frail elderly person in order to develop a coordinated
and integrated plan for treatment and long-term follow-
up (Rubenstein 1995; Osterweil et al. 2000; Bernabei
et al. 2000). This assessment includes the medical
assessment, assessment of functioning, psychological
assessment, social assessment, and environmental
assessment (Balducci and Extermann 2000b).
Radiation Therapy for Lung Cancer in Elderly
Finally, to set up a stage and scene for further
discussions, one may start with recent analysis
(Owonikoko et al. 2007) which studied the burden
and outcome of lung cancer in elderly by focusing on
cancer outcomes in the period 1988–2003 from
Surveillance, Epidemiology, and End Results data-
base. Study subjects were split into those C80 years
old versus those 70–79 years old versus those
\70 years old. Data used included demographics,
stage, and 5-year relative survival, the latter one
investigated upon influence of histology, sex, race,
stage and treatment. Two temporal trends (1988–1997
and 1997–2003, respectively) were used. Distribution
by stage and histology was comparable for three
groups. Five year overall survival was lower in very
elderly (7.4 versus 12.3 versus 15.5%) (P \ 0.0001)
across sex, histology subtype, stage, and race. Patients
C80 years were less likely to receive local treatment
(no surgery or radiation therapy) than younger
patients: 47 versus 28 versus 19% (C80 versus 70–79
versus \70 years). Overall outcome for patients
receiving surgery or radiation therapy was compara-
ble across the three age groups, but elderly had a
poorer outcome when radiation therapy or surgery
were combined or when no therapy was instituted.
This chapter addresses some of the important issues
in radiation therapy of lung cancer in elderly. Widely
accepted clinical designation of non-small-cell lung
cancer and small-cell lung cancer as two separate
entities will here serve as well to enable suitable
framework for addressing these issues in elderly.
2 Non-Small-Cell Lung Cancer
Non-small-cell lung cancer accounts for approxi-
mately 80% of all lung cancer cases, with[50% of all
patients with non-small-cell lung cancer being
[65 years old with about one-third of all patients
being[70 years old at the time of diagnosis. Curative
approaches are feasible in patients with early Stage
(I–II) disease and in a proportion of patients with
locally advanced disease (Stage IIIA/IIIB), while
palliation is the goal for the remainder of locally
advanced and all metastatic (Stage IV) non-small-cell
lung cancer patients. This general concept should also
prove to be feasible in elderly with non-small-cell
lung cancer. Surgery is the treatment of choice for
patients in early Stage (I/II) non-small-cell lung
525
cancer, with or without additional chemotherapy,
whereas the standard treatment for locally advanced
non-small-cell lung cancer is not well-defined.
Although a minority of Stage IIIA non-small-cell lung
cancer patients can be treated with surgery alone,
there is no clear benefit for either surgery alone or
surgery preceded by radiation therapy and chemo-
therapy. In addition, the vast majority of patients with
Stage III non-small-cell lung cancer are unresectable,
and, therefore, best treated with concurrent radiation
therapy and chemotherapy.
2.1 Early Stage Non-Small-Cell Lung
Cancer
Nearly 25% of elderly with early stage non-small-cell
lung cancer do not undergo surgery (Bach et al.
1999). Among the reasons for not undergoing surgery,
besides their advanced age, elderly were frequently
discriminated due to existing co-morbidity and,
only occasionally, there was a refusal to undergo
surgery. In the last decade, two studies addressed the
issue of the survival of unresected patients treated
with and without radiation therapy, showing that
radiation therapy may improve survival of these
patients. In the first study, Wisnivesky et al. (2005),
however, used only a standard regression to correct
for potential selection bias and the analyses were not
adjusted for use of chemotherapy or co-morbidities.
As patients with higher number of co-morbidities
were less likely to receive radiation therapy and/or
chemotherapy, lack of adjustments of these factors
may have biased the analyses toward showing a sig-
nificant effect of radiation therapy on survival. These
observations may have prompted same group of
investigators (Wisnivesky et al. 2010) to undertake
similar analysis using now a propensity score and
instrumental variable analyses to minimize potential
biases. Authors have used Surveillance, Epidemiol-
ogy, and End Results data identifying a total of
[6,000 eligible patients. Overall, 59% patients
received radiation therapy. The overall and lung
cancer-specific survival of unresected patients treated
with radiation therapy was significantly better com-
pared with the untreated cases (P \ 0.0001 for both
comparisons). Both propensity score and instrumental
variable indicted improved outcomes among patients
treated with radiation therapy.
526
To further extend this issue, Palma et al. (2010a)
used prospective databases from British Columbia to
identify patients with Stage I non-small-cell lung
cancer treated curatively with either surgery or radi-
ation therapy between 2000 and 2006. Kaplan–Meier,
Cox regression, and competing-risk analyses were
used to assess overall survival and disease-specific
survival in the elderly, and the relationship between
age and survival outcomes. Of a total of 558 patients
with Stage I disease, 310 (56%) received surgery, and
248 (44%) received radiation therapy. Elderly patients
(age C 75 years) were less likely to undergo resection
than their younger counterparts (43 versus 72%,
P \ 0.0001). Actuarial overall survival after surgery
for elderly patients was 87% at 2 years and 69% at
5 years. On multivariate analysis, overall survival
after surgery was dependent on tumor stage (P =
0.034) and performance status (P = 0.03), but not age
(P = 0.87). After radiation therapy, actuarial overall
survival for elderly patients was 53% at 2 years and
23% at 5 years. On multivariate analysis, age did not
predict for overall survival after radiation therapy
(P = 0.43), whereas tumor stage (P = 0.033), sex
(P = 0.044), and dose (P = 0.01) were significant
predictors. This study reconfirmed earlier observa-
tions that survival after radical treatment for Stage I
non-small-cell lung cancer is dependent on factors
such as tumor stage, performance status, sex, and
radiation therapy dose, but not age. This has again
indicated that elderly patients who are sufficiently fit
should not be considered ineligible for radical treat-
ment based on age alone.
Data from the existing literature, accumulated over
several decades, clearly shows that radiation therapy
is effective in this setting. Aristizabal et al. (1976)
seems to be very first to show that elderly (C70 years)
had significantly better 2- year survival than
non-elderly (49–69 years) (35.7 versus 13.1%, P =
0.044), likely as a consequence of high local control
(70%) and a lower incidence of distant metastasis.
Similarly, Coy and Kennelly (1980) and Newaishy
and Kerr (1989) observed a significant tend toward
better survival in older patients with non-small-cell
lung cancer treated with radiation therapy alone. In
addition, Noordijk et al. (1988) found no difference in
the outcome of elderly patients treated with radiation
therapy alone or surgery. In radiation therapy alone
studies, Sandler et al. (1990) and Rosenthal et al.
(1992) found no significant difference in overall
B. Jeremić and Ž. Dobrić
survival, disease-specific survival or local progres-
sion-free survival in elderly versus non-elderly.
Wurschmidt et al. (1994) used multivariate analyses
as well as did Kaskowitz et al. (1993) to show no
difference in the treatment outcome between elderly
and non-elderly. The same observation was made by
Slotman et al. (1994), Gauden et al. (1995), and Krol
et al. (1996). In the two of studies of Jeremic et al.
(1997, 1999a) no difference in either survival or
relapse-free survival was observed between patients
\60 years old and those C60 years old with Stage I
and II non-small-cell lung cancer, respectively, trea-
ted with hyperfractionated radiation therapy alone
with a total dose of 69.6 Gy using 1.2 Gy b.i.d.
fractionation. Multi-variate analyses using both sur-
vival and relapse-free survival confirmed that age did
not play an important role in this setting.
In a study of Hayakawa et al. (1999) 97 patients
C75 years old (elderly) and 206 patients \75 old
(non-elderly) were treated with radiation therapy
doses C60 Gy (up to [80 Gy) for inoperable non-
small-cell lung cancer. Elderly were classified into the
two subgroups: A—75–79 years and B—C80 years.
No difference was found between the three age groups
(5-year survival: 12 versus 13 versus 4% for non-
elderly, elderly A, and elderly B, respectively), but a
multivariate analysis disclosed detrimental effect of
oldest age, due to 14% treatment-related deaths in
patients receiving 80 Gy. Unfortunately, no multi-
variate analysis was done using disease-specific sur-
vival as endpoint to give better insight into this
finding and help to identify predisposing factors
leading to more treatment-related deaths in elderly
group treated with high-dose radiation therapy.
Gauden and Tripcony (2001) investigated the
effect of age using either dividing study group into the
5-year subgroups or using a specified cut-off value
(\70 years versus C70 years) on treatment outcome
in patients with Stage I non-small-cell lung cancer.
The median survival times (22 versus 26 months) and
a 5-year survival (22 versus 34%), respectively for
non-elderly and elderly were observed. The same held
true for recurrence-free survival. Finally, both overall
survival and recurrence-free survival remained simi-
lar in various 5-year subgroups. The multivariate
analysis excluded age as an important prognostic
factor predicting either of these two endpoints.
In contrast, Morita et al. (1997) found a survival
advantage for patients \80 years old when compared
Radiation Therapy for Lung Cancer in Elderly
to those C80 years old (5-year survival rate: 25.2
versus 7.7%), but did not specify the outcome when
splitting \80 year old group into various subgroups
(e.g. \70 versus 70–80 years). Similarly, Sibley et al.
(1998) documented superior outcome in younger
(\60 years) patients with Stage I versus older
patients, unconfirmed, however, when local progres-
sion was used as an endpoint (P = 0.10).
While some studies attempted to evaluate toxicity,
in none of these series it was specified that these toxic
events have happened in elderly. In those studies
which specifically addressed elderly with early stage
non-small-cell lung cancer, no significant radiation
therapy-related complications were found and inci-
dence of both acute and late high-grade toxicity was
similar among all age groups (Gauden and Tripcony
2001). When radiation therapy-related deaths occurred,
again, there was no difference between elderly (5%)
treated with highest dose levels (80 Gy) and their
non-elderly counterparts (4%) treated the same way
(Hayakawa et al. 2001).
When these data are summarized, conventionally
planned external beam radiation therapy appears
capable of producing the median survival times of
20–27 months and 5-year survivals of 15–34% in
patients [70 years and event better results when the
cut-off of 60 years is used.
Results of studies published in recent years seem to
confirm these observations. In a study by San Jose
et al. (2005), covering a period between 1995 and
1999, a total of 33 male patients were treated with
radiation therapy alone. Radiation therapy doses
ranged 66–78 Gy (median, 70 Gy) using standard
fractionation (2.0 Gy per fraction). The age range was
71–97 years (median, 75 years) with 11 patients
being C80 years old. Twenty-two (67%) patients had
a squamous cell carcinoma. There were 24 (73%)
Stage I and nine (27%) Stage II patients. Radio-
graphic objective response rate was observed in 23
(70%) patients. The median survival time was
37.4 months and 3-year survival time was 50%, while
the median cause-specific survival time was
48.1 months and a 3-year cause-specific survival rate
was 55.3%. The median time to local recurrence was
36.8 months and a 3-year local recurrence-free sur-
vival rate was 50.2%, while the median time to distant
metastasis was not achieved yet at the time of that
report, the 3-year distant metastasis-free survival rate
being 71.4%. One (3%) patient died of radiation
527
therapy-induced acute lung toxicity, while only two
(6%) patients experienced late grade 3 lung toxicity.
No other high-grade toxicity was observed during this
study. Ahmad et al. (2010) treated patients aged
60 years and older with inoperable Stage I non-small-
cell lung cancer using a hypofractionated schedule.
Between 1991 and 2006, 75 such patients were
identified with median age of 74 years (range,
60–86). Patients received a median total dose of
65 Gy using median daily dose fractions of 2.5 Gy.
Median local failure free survival was 19.6 months
and median overall survival was 21.2 months. Anal-
ysis of competing risks showed that at 5 years, the
probability of local failure as the first detected event
was 22.1%, the probability of distal failure as the first
detected event was 14.5%, and the probability of
death without recording a failure was 48.6% Radia-
tion-related toxicity of grade 3 or greater was seen in
three patients and there were no treatment-related
deaths.
Confirmation of the importance of novel radiation
therapy technologies comes from the study of Park
et al. (2010) who investigated whether complex
radiation therapy planning was associated with
improved outcomes in a cohort of elderly patients
with unresected Stage I–II non-small-cell lung cancer.
Using the Surveillance, Epidemiology, and End
Results registry linked to Medicare claims, they
identified 1998 patients aged [65 years with histo-
logically confirmed, unresected Stage I–II non-small-
cell lung cancer. Patients were classified into an
intermediate or complex radiation therapy planning
group using Medicare physician codes. To address
potential selection bias, they used propensity score
modelling. Survival of patients who received inter-
mediate and complex simulation was compared using
Cox regression models adjusting for propensity scores
and in a stratified and matched analysis according to
propensity scores. Overall, 25% of patients received
complex radiation therapy planning. Complex radia-
tion therapy planning was associated with better
overall (hazard ratio 0.84; 95% confidence interval,
0.75–0.95) and lung cancer-specific (hazard ratio
0.81; 95% confidence interval, 0.71–0.93) survival
after controlling for propensity scores. Similarly,
stratified and matched analyses showed better overall
and lung cancer-specific survival of patients treated
with complex radiation therapy planning. The use of
complex radiation therapy planning in this study was
528
associated with improved survival among elderly
patients with unresected Stage I–II non-small-cell
lung cancer. These findings should be validated in
prospective randomized controlled trials.
Recent years also brought clinical data from
studies which used sophisticated treatment planning
and delivery in this population. In the study of Niibe
et al. (2003), 22 elderly with tumors up to 5 cm were
treated with fraction size of 3–4 Gy, five fractions per
week with a mean total dose of 65.3 Gy. Overall
survival rates at 1–3 years were 100, 83, and 56%,
respectively, while local control rates at 1–3 years
were 92, 83, and 83%, respectively. There was no
grade 2 or greater toxicity except in two patients.
These results showed that this tool, now widely
available worldwide, provide feasible and effective
radiation therapy treatment in elderly. Yu et al. (2008)
investigated the efficacy and safety of involved-field
radiotherapy in 80 patients who are 70 years old or
more with early Stage (I/II) non-small-cell lung
cancer using intensity modulated radiation therapy.
Intensity modulated radiation therapy plans were
designed to deliver 66.6 Gy to involved-field. The
objective response rate of all patients was 88.6% with
a median overall survival time of 38 months and the
1-, 2- and 5-year overall survival rates and local
progression-free survival rates were 65.8, 55.7, 25.3,
and 84.8, 59.5, and 34.2%, respectively. Twenty-nine
patients (36.7%) with elective nodal failures were
identified, with a median time to treatment failure of
55 months (range 49–61 months) after treatment.
There were no treatment-related deaths or grade 4
toxicity. Grade 3 toxicities were esophagitis (1.3%),
radiation pneumonitis (3.8%), and hematological
effects (2.5%).
Stereotactic radiation therapy also found a fruitful
soil in elderly with early, mostly Stage I non-small-
cell lung cancer. In a study from The Netherlands
(Palma et al. 2010b), the impact of introducing ste-
reotactic radiation therapy in patients 75 years of age
or older was studied using a population-based cancer
registry. Amsterdam Cancer Registry was assessed in
three eras: 1999–2001 (period A, pre-stereotactic
radiation therapy), 2002–2004 (period B, some
availability of stereotactic radiation therapy), and
2005–2007 (period C, full access to stereotactic
radiation therapy. A total of 875 elderly patients were
diagnosed with Stage I non-small-cell lung cancer in
the study period. Primary treatment was surgery in
B. Jeremić and Ž. Dobrić
299 patients (34%), radiation therapy in 299 patients
(34%), and neither in 277 patients (32%). Radiation
therapy use increased between periods A and C (26
versus 42%, P \ 0.01), corresponding to a decrease
in untreated patients. The percentage of radiation
therapy patients undergoing stereotactic radiation
therapy in periods B and C was 23 and 55%,
respectively. Median survival for all patients
increased from 16 months in period A to 21 months
in period C (log-rank P \ 0.01). The improvement in
overall survival was confined to radiation therapy
patients, whereas no significant survival improve-
ments were seen in the other groups. Stereotactic
radiation therapy introduction was associated with a
16% absolute increase in radiation therapy use, a
decline in the proportion of untreated elderly patients,
and an improvement in overall survival. Indeed, in the
study of Haasbeek et al. (2010), 203 tumors in 193
patients aged C75 years were treated using stereo-
tactic radiation therapy. The median patient age was
79 years, 80% of patients were considered medically
inoperable, and 20% of patients declined surgery.
Risk-adapted stereotactic radiation therapy regimens
were used with the same total dose of 60 Gy in 3
fractions (33%), 5 fractions (50%), or 8 fractions
(17% of patients), depending on the patient’s risk for
toxicity. All but one patient completed treatment.
Survival rates at 1 and 3 years were 86 and 45%,
respectively. The actuarial local control rate at
3 years was 89%. Acute toxicity was uncommon and
late Radiation Therapy Oncology Group grade C3
toxicity was observed in\10% of patients. This study
showed that, taking into account risks and existing co-
morbidities bring, elderly could achieve the same
outcome as their non-elderly counterparts when
treated with the same technique.
Most recently, however, the very first study com-
pared surgery with continuous hyperfractionated
accelerated radiation therapy in elderly with Stage I
non-small-cell lung cancer (Ghosh et al.2003). One-
hundred forty-nine patients underwent lobectomy, 47
had wedge resection, while 19 had radiation therapy
alone. Non-lobectomy patients had significantly lower
pulmonary function. Survival at 1 and 5 years was 97
and 68% versus 98 and 74% versus 80 and 39%,
respectively (P = 0.0484). While survival data
favored surgical approaches, this was associated with
a 2.7% 30 day operative mortality in the lobectomy
group. Importantly, the frequency of loco-regional
Radiation Therapy for Lung Cancer in Elderly
recurrence was similar between the groups, while no
other endpoints were used in that study (e.g. cause-
specific survival). This study showed again that
radiation therapy alone is a reasonable treatment
option for those who are not suitable candidates for
surgery.
2.2 Locally Advanced Non-Small-Cell
Lung Cancer
Some of the studies which included ‘‘inoperable
cases’’ also included a proportion of patients with
Stage III; other did not specify outcome regarding
age. Due to poor results of early studies, some
suggested prohibition of radiation therapy in patients
over 70 years (Aristizabal et al. 1976; Patterson et al.
1998). In a retrospective study of Nakano et al. (1999)
elderly patients with Stage III non-small-cell lung
cancer who had been treated with radiation therapy
alone were investigated. It resulted in a median sur-
vival time of 11.5 months in the younger group and
6.3 months in the elderly group (P = 0.0043). In
multivariate analysis not only a good performance
status, and good response but also age less than
75 years as well were significantly favorable and
independent predictors of survival. There were more
deaths due to respiratory infections and lower prog-
nostic nutritional indexes before and after radiation
therapy in elderly group patients. Hayakawa et al.
(2001) also reported on an inferior survival in sub-
group of elderly patients with Stage III disease.
However, this was noted only in patients[80 years of
age. Contrary to that, Kusumoto et al. (1986) inves-
tigated this effect in Stage III/IV non-small-cell lung
cancer where patients \70 years old (n = 64) and
those C70 years old (n = 36) achieved the median
survival time of 7 and 6 months, respectively, the
difference being insignificant.
Many studies, however, provided data on the
effectiveness of radiation therapy in elderly. Zachariah
et al. (1997) reported on radiation therapy with
59–66 Gy using standard fractionation used in lung
cancer in octogenarians. Response was observed in
43% patients, and only 24% had progressive disease.
Another study evaluated influence of the age on
treatment outcome as well as acute and late toxicity of
curative thoracic radiotherapy using the data of 1,208
patients enrolled in trials conducted by the European
529
Organization for Research and Treatment of Cancer
(Pignon et al. 1998). When adjusted for the primary
location of the tumor, survival was comparable in
each group. Distribution over age was similar for
acute nausea, dyspnoea, esophagitis, weakness, and
the World Health Organization performance status
alteration. Also, the minimal time for complication
was similar in all age groups. No difference between
age groups was found regarding the patients experi-
encing no complications at 4 years post-treatment.
Only grade 2 late esophagitis demonstrated a signifi-
cant trend to be more frequent in older patients
(P = 0.01), but this difference disappeared after
adjustment on study (P = 0.32). Gava (1999) repor-
ted on Italian Geriatric Radiation Oncology Group
study on outcome of radiation therapy alone in 38
elderly patients with Stage III non-small-cell lung
cancer in whom 1-year survival rate approached 44%.
Another Italian study provided data which confirmed
effectiveness of radiation therapy in 48 patients
C75 years with locally advanced non-small-cell lung
cancer (Lonardi et al. 2000). Radiation therapy alone
was used to give a median dose of 50 Gy. Overall
survival was 10% at 24 months. There seems to be a
dose-response observed in that study with elderly
treated with C50 Gy achieving a significantly better
survival than those treated with \50 Gy (the median
survival time, 8 versus 4 months; 2-year survival, 20
versus 4%, respectively; P = 0.03). Tombolini et al.
(2000) also analysed patients C70 years in Stage III
non-small-cell lung cancer treated with radiation
therapy alone using doses of 50–60 Gy (and a 10 Gy
boost to the gross tumor volume) in 1.8–2 Gy frac-
tions. Two-year overall and disease-free survival was
27 and 14.6%, respectively. More recently, Pergolizzi
et al. (2002) reported on radiation therapy alone in 40
elderly patients with Stage IIIA using a median dose
of 60 Gy, conventionally fractionated. No treatment-
related mortality was observed and no clinically sig-
nificant acute morbidity was scored. The median
survival time was 19 months and 5-year survival was
12%.
For many years now, radiochemotherapy is a
widely used approach in patients with locally
advanced non-resectable non-small-cell lung cancer
and good performance status. One may, therefore,
rightly wonder whether this is also true for elderly
with the same disease. Some of the available studies
provided retrospective subgroup (age) analyses of
530
patients enrolled into radiochemotherapy trials but
could not identify age as negative prognostic factor in
multivariate analyses (Schaake-Koning et al. 1992;
Jeremic et al. 1998a; Clamon et al. 1999; Furuse et al.
1999). Contrasting these results were the results of the
Radiation Therapy Oncology Group who reported on
a study which included 1999 patients treated
with radiation therapy with or without chemotherapy
in several prospective studies. Using a recursive
partitioning and amalgamation analysis they have
found a negative influence of older age on survival
(Werner-Wasik et al. 2000). These results recon-
firmed their earlier results (Movsas et al. 1999) where
a quality-adjusted survival was used to examine 979
patients with inoperable Stage II–IIIB non-small-cell
lung cancer patients treated with radiation therapy
with or without chemotherapy enrolled into six pro-
spective trials. Elderly patients had the best quality-
adjusted survival with radiation therapy alone, which
was in sharp contrast to their younger counterparts
who benefited mostly from more aggressive, com-
bined radiochemotherapy approaches. The third ret-
rospective analysis comprised of pooled data from
three trials at the same group (Langer et al. 2000)
which showed that patients [70 years did not benefit
from concurrent radiochemotherapy when compared
to those treated with radiation therapy alone. In spite
of the fact that these three large analyses unequivo-
cally stand unified against the more intensive treat-
ment approach in elderly, it must, however, be clearly
emphasized that they are difficult to interpret because
the compilation of patients treated on separate study
protocols implies a comparison between patients with
a variety of entry criteria used to define eligibility and
different treatment regimens administered, including a
single-modality radiation therapy in many of these
studies. Contrary to these, Rocha Lima et al. (2002)
analyzed older patients from a randomized Cancer
and Leukemia group B trial of induction chemother-
apy followed by either radiation therapy alone or
concurrent radiochemotherapy for locally advanced
non-small-cell lung cancer. Patients [70 years com-
pleted treatment to the same extent as younger
patients and attained similar response and survival,
but at the expense of increased toxicity, especially
high-grade ([3) nephrotoxicity and neutropenia.
A retrospective analysis of the data from the Radia-
tion Therapy Oncology Group 94–10 study by Langer
et al. (2001) investigated the influence of age on
B. Jeremić and Ž. Dobrić
treatment outcome. Patients [70 years (n = 104)
were compared to those younger \70 years
(n = 491). It was shown that elderly patients benefit
from concurrent, as compared to sequential radio-
chemotherapy in a similar magnitude as their younger
counterparts. Similar to the study of Rocha Lima et al.
(2002), the observation was that elderly people have
suffered from an increase in toxicity, especially severe
esophagitis. Recently, Schild et al. (2003) performed
a secondary analysis of the North Central Cancer
Treatment Group study which evaluated split-course
versus standard-fraction radiotherapy and cisplatin/
etoposide in Stage III non-small-cell lung cancer. The
two age groups (\70 versus C70 years) achieved
similar 2- and 5-year survival rates, but grade C4
toxicity occurred in 62% patients \70 years of age
versus 81% in those C70 years of age (P = 0.007).
Both grade C4 hematologic toxicity and grade C4
pneumonitis were significantly more frequent in the
elderly group. More recently, another retrospective
North Central Cancer Group study (Schild et al. 2007)
included the data from two prospective randomized
trials comparing radiation therapy alone with com-
bined radiochemotherapy. In patients [65 years of
age, combined radiochemotherapy was found to be
superior to radiation therapy alone. This was, how-
ever, achieved at the expense of higher incidence of
toxicity in the combined-modality group. In a sub-
group (age) analysis of the original Hoosier Oncology
Group study which showed the failure of use of
consolidation chemotherapy in locally advanced non-
small-cell lung cancer (Hanna et al. 2008, Sgroi et al.
2007) preliminarily reported that elderly had similar
median survival time when compared to their non-
elderly counterparts (17.2 versus 21.2 months,
P = 0.3255). There was, however, higher incidence
of esophagitis (23 versus 15%) and dehydration (15
versus 7%) in elderly. In addition, elderly patients
were more likely to discontinue treatment due to
toxicity (12 versus 2%).
Some authors provided the data on prospective
approaches addressing this issue. In one such attempt
between January, 1988 and June, 1993, Jeremic et al.
(1999b) enrolled a total of 58 patients into a phase II
study, of whom 55 were evaluable. Carboplatin
(400 mg/m2) was given intravenously on days 1 and
29, and etoposide (50 mg/m2) was given orally on
days 1–21 and 29–42. Accelerated hyperfractionated
radiation therapy was administered starting on day 1,
Radiation Therapy for Lung Cancer in Elderly
with a total dose of 51 Gy in 34 fractions over
3.5 weeks. A complete response rate was 27% and the
overall response rate was 65%. The median time to
local recurrence was 14 months and the 5-year local
control rate was 13%, while the median time to dis-
tant metastasis was 18 months and the 5-year distant
metastasis-free rate was 15%. The median time until
relapse was 8 months and the 1-, 2-, and 5-year
relapse-free survival rates were 45, 20, and 9.1%,
respectively. The median survival time was
10 months, and the 1-, 2-, and 5-year survival rates
were 45, 24, and 9.1%, respectively. Hematological,
esophageal, and bronchopulmonary acute grade 3/4
toxicities were observed in 22, 7, and 4% of the
patients, respectively. Neither grade 5 toxicity nor late
grade [3 toxicity was observed. The survival results
appeared to be comparable to those obtained in non-
elderly patients with Stage III non-small-cell lung
cancer treated by full-dose radiation. In another phase
II study, Atagi et al. (2000) used standard fraction
radiation therapy with 50–60 Gy and concurrent low-
dose daily carboplatin (30 mg/m2) to treat 38 patients
with locally advanced non-small-cell lung cancer, 26
of whom were Stage III. The median survival time
was 15.1 months and 2-year survival was 20.5%.
Nakano et al. (2003) also reported on a pilot study in
which low-dose cisplatin (6 mg/m2; days 1–5, 8–12,
29–33, and 36–40) was added to conventionally
fractionated radical radiation therapy (60 Gy given
via 2.0 Gy daily fractions) in elderly with locally
advanced unresectable non-small-cell lung cancer. Of
12 registered patients 11 were eligible for this anal-
ysis, 91% of whom were Stage III. The overall
response rate was 82%, the median overall survival
was 23 months and the 2-year survival rate was 53%,
respectively. The most common grade 3 toxicities
included grade 3 leukopenia and thrombocytopenia
occurring in 20 and 9%, respectively. No other high-
grade toxicity was observed during this study. In an
attempt to selectively target tumor cells with cisplatin
while decreasing the toxicity concurrent radioche-
motherapy may lead to, Karasawa et al. (2002) used
bronchial arterial infusion of cisplatin and concurrent
radiation therapy (dose 50.4–73.2 Gy; median,
60.8 Gy) in 31 elderly Stage III non-small-cell lung
cancer. The results obtained that way were compared
to that obtained in 30 elderly patients receiving no
cisplatin. Response rate in the cisplatin group was 90
and 83% in the non-cisplatin group. Two-year local
531
control, median survival time and 5-year survival were
all significantly improved in the cisplatin group (81%,
33.4 months, and 38.3 versus 38.1%, 9.8 months, and
4.2%, respectively; local control, P \ 0.01; survival,
P \ 0.001). Multivariate analysis showed that addition
of cisplatin via supra-selective way (bronchial artery
infusion) was the strongest predictor of improved sur-
vival achieved at no increase in life-threatening toxic-
ity. Most recently, a phase II study (Giorgo et al. 2007)
evaluated safety and efficacy of sequential platinum-
based chemotherapy followed by concurrent radio-
chemotherapy in 30 consecutive patients with locally
advanced non-small-cell lung cancer. Age ranged
70–76 years (mean, 73 years). The median survival
time was 15 months and the median progression-free
survival was 8.7 months. Grade 3–4 neutropenia
developed in 12 (40%) patients, while two patients
developed neutropenic fever. Grade 3 anemia and
grade 3 thrombocytopenia developed in three patients
each. Grade 3 esophagitis developed in six (20%)
patients during the concurrent radiochemotherapy part
of the treatment. No grade 5 toxicity was observed
during this study. In the first prospective randomized
trial comparing radiation therapy alone (60 Gy in 30
daily fractions) with the same radiation therapy and
concurrent carboplatin given days 1–20 of the radiation
therapy course, Atagi et al. (2005) observed better
median survival time (554 versus 428 days) and 1-year
survival (65 versus 61%) for combined-modality
approach. However, this difference did not reach sta-
tistical significance. Four patients died of treatment-
related toxicity (three in radiochemotherapy arm), 60%
patients had protocol violations, 7% patients had vio-
lation in dose constraint to lung (two died of radiation
pneumonitis). This trial stopped early due to poor
accrual and, therefore, effectiveness of concurrent
radiochemotherapy approach as used in this study
remained unclear. Most recently, Jatoi et al. (2010)
reported on a phase II study of cetuximab and radiation
therapy in elderly and/or poor performance status
patients with locally advanced non-small-cell lung
cancer. Older patients [C65 years with an Eastern
Cooperative Oncology Group performance status of 0,
1, or 2] or younger patients (performance status of 2)
received cetuximab 400 mg/m2 i.v. on day 1 followed
by weekly cetuximab 250 mg/m2 i.v. with concomitant
radiation of 60 Gy in 30 fractions. Patient median age
(range) was 77 years (60–87), and 12 (21%) had a
performance status of 2. The median survival was
532
15.1 months [95% confidence interval (CI)
13.1–19.3 months], and the median time to cancer
progression was 7.2 months (95% CI 5.8-8.6 months).
No treatment-related deaths occurred, but 31 patients
experienced grade 3+ adverse events, most commonly
fatigue, anorexia, dyspnea, rash, and dysphagia, each of
which occurred in\10% of patients.
In most of the studies the toxicity of the combined
treatment was tolerable (Jeremic et al. 1999b; Lonardi
et al. 2000; Jatoi et al. 2010), with both acute and late
high-grade toxicity not different from that observed
with similar approaches in non-elderly. Contrary to
that, occasional study (Atagi et al. 2000) observed
high-grade hematological toxicity in 34.2–71.1% of
patients. Non-hematological toxicity was mild, with
no patient developing grade [3 esophagitis, although
two (5%) grade 4 pulmonary toxicities occurred.
It was also shown that co-morbidity and/or poor
performance status and/or pronounced weight loss,
rather than age, can influence patient selection for a
combined treatment. In one such study (Firat et al.
2006), 102 patients with Stage III non-small-cell lung
cancer having a Karnofsky Performance Status score
C70 were retrospectively evaluated for co-morbidity.
While all patients received thoracic radiation therapy,
57 (56%) patients also received either sequential or
concurrent chemotherapy. Multivariate analysis iden-
tified the use of radiation therapy alone (P \ 0.01) and
presence of grade 4 co-morbidity (P = 0.02) were both
independent prognosticators of inferior overall sur-
vival. Contrary to that, Stage IIIB, age C70 years,
radiation therapy dose[63 Gy and weight loss of[5%
were not. Similarly, more recent and retrospective
study of Semarau et al. (2008) in 66 inoperable
non-small-cell lung cancer patients also confirmed
independent and adverse influence of cardiac and
pulmonary co-morbidity on treatment outcome in a
multivariate analysis. Finally, Coate et al. (2011)
performed a retrospective review of 740 Stage III
non-small-cell lung cancer patients who were classified
by treatment plan: palliative (palliative chemotherapy
or radiation therapy [B40 Gy]); non-surgical multim-
odality ([40 Gy radiation therapy ± chemotherapy);
or surgical multimodality (chemotherapy, radiation
therapy, and surgery). Patients [65 years of age were
more likely to have poor performance status
(P \ 0.0001), multiple co-morbidities (P \ 0.0001),
and to receive palliative therapy only (P \ 0.0001).
Older and younger patients treated with curative intent
B. Jeremić and Ž. Dobrić
with non-surgical bimodality therapy or tri-modality
therapy including surgery had similar rates of grade 3/4
toxicity (P = 0.18) and toxic death (P = 0.76). Sur-
vival was worse with increasing age (P \ 0.0001),
likely due to greater use of palliative treatment in the
elderly. There was no difference between age groups
for non-surgical (P = 0.32) or surgical (P = 0.53)
therapy when survival was analyzed for patients treated
with curative intent. This study again reconfirmed
previous observations that in select fit elderly patients,
combined-modality therapy is tolerable and is associ-
ated with survival similar to that of younger patients.
2.3 Metastatic Non-Small-Cell Lung
Cancer
In spite of the fact that it is frequently used to treat
intrathoracic or distant spread in Stage IV (metastatic)
non-small-cell lung cancer, there is extreme paucity
of data on the feasibility and effectiveness of radiation
therapy in this setting. Recently, Hayman et al. (2007)
embarked on a study with the objective to examine
the utilization patterns of palliative radiation therapy
among elderly patients with Stage IV non-small-cell
lung cancer and, in particular, to identify factors
associated with its use. A retrospective population-
based cohort study was performed using linked Sur-
veillance, Epidemiology, and End Results-Medicare
data to identify 11,084 Medicare beneficiaries aged
C65 years who presented with Stage IV non-small-
cell lung cancer in the 11 Surveillance, Epidemiology,
and End Results regions between 1991 and 1996. The
primary outcome was receipt of radiation therapy and
logistic regression analysis was used to identify
factors associated with receipt of radiation therapy.
A total of 58% of these patients received radiation
therapy, with its use decreasing over time (P = 0.01).
Increasing age was negatively associated with receipt
of treatment (P \ 0.001), as was increasing co-mor-
bidities (p \ 0.001). Factors positively associated
with the receipt of radiation therapy included income
(P = 0.001), hospitalization (P \ 0.001), and treat-
ment with chemotherapy (P \ 0.001). Although the
use varied across the Surveillance, Epidemiology, and
End Results regions (P = 0.001), gender, race/
ethnicity, and distance to the nearest radiation therapy
facility were not associated with treatment. The
authors concluded that elderly patients with
Radiation Therapy for Lung Cancer in Elderly
metastatic non-small-cell lung cancer frequently
receive palliative radiation therapy, but its use varies,
especially with age and receipt of chemotherapy.
Additional research is needed to determine whether
this variability reflects good quality care.
In order to define ‘‘optimal’’ treatment approach in
these patients, Jeremic et al. (1999c) designed and
performed a phase II study evaluating short-term
chemotherapy given concurrently with palliative
radiation therapy. A total of 50 patients entered into a
phase II study that used two cycles of carboplatin,
300 mg/m2, days 1 and 29 and oral etoposide, 50 mg/m2,
days 1–21 and 29–42. Radiation therapy was admi-
nistered with the total radiation dose of 14 Gy given
in 2 fractions administered with 1 week split (days
1 and 8). There were 47 patients evaluable for the
response, of which there were three (6%) complete
responses, and 10 (21%) partial responses. Response
duration ranged 2–8 months (median, 5 months;
mean, 5 months). Median survival time-based on
intent-to-treat analysis, for all 50 patients was
7 months and 1–3 year survival rates were 31, 4.1,
and 2%, respectively. There were nine (19%) patients
experiencing hematological grade 3 toxicity, and all
other chemotherapy-induced toxicity was either grade
1 or grade 2. Of radiation therapy-induced high-grade
toxicity (according to the Radiation Therapy Oncol-
ogy Group), grade 3 esophageal was observed in nine
(19%) patients while only four (9%) patients experi-
enced grade 3 bronchopulmonary toxicity. No grade 4
or 5 toxicity occurred during this study. This study
showed that short-course chemotherapy and palliative
radiation therapy in elderly patients with Stage IV
non-small-cell lung cancer can be well-tolerated with
mild to moderate toxicity. Together with results
obtained this way, they warrant further studies eval-
uating the effectiveness of this approach and possible
chemotherapy- and/or radiation therapy dose escala-
tion in elderly patients with Stage IV (metastatic)
non-small-cell lung cancer.
3 Small-Cell Lung Cancer
Small-cell lung cancer represents 15–20% all lung
cancers cases. Its chemosensitivity and great meta-
static potential makes it a good candidate for che-
motherapy. However, with chemotherapy alone the
outcome of small-cell lung cancer is poor. Although
533
the initial response rates are high, only approximately
5% of patients survive 3 years. Of all small-cell lung
cancer cases, only about 20–30% of all patients pre-
sent with a tumor confined to the hemithorax of ori-
gin, the mediastinum or the supraclavicular lymph
nodes, designated as having ‘limited disease’ small-
cell lung cancer. All other patients present with dis-
seminated, extended disease. Since they have a dismal
prognosis and are, therefore, treated mostly with
palliative intention, this section focuses on limited
disease small-cell lung cancer in elderly.
Importance of active treatment in elderly with
limited disease small-cell lung cancer was shown by
Shepherd et al. (1994) who undertook a retrospective
review of elderly patients with small-cell lung cancer
in an attempt to assess the effect of age on treatment
decisions, response, survival, and toxicity. There were
123 patients with age [70 years. There were 74
patients aged 70–74, 35 aged 75–80, and 14 aged
80 years or older. No significant differences existed
between the groups in sex, stage, performance status,
or presence of co-morbid disease. Median survivals
for patients with limited and extensive disease were
11.9 and 5.2 months, respectively (P \ 0.0001), with
no significant difference for patients in any age group
(P = 0.4). For both limited and extensive disease,
survival correlated strongly with the treatment
received. Twenty-five patients received no treatment
(median survival time, 1.1 months), 20 had radiation
therapy only (median survival time, 7.8 months), and
27 patients had \3 cycles of chemotherapy (median
survival time, 3.9 months). Median survival time for
the 50 patients who had 4–6 cycles was 10.7 months
(limited disease 15.0 months, extensive disease
8.61 months). Results of this retrospective study
showed that active treatment should not be withheld
from elderly patients with small-cell lung cancer on
the basis of age. The survival of patients who receive
active treatment was significantly longer than that of
untreated patients even though frequent dose reduc-
tions for toxicity may be required. The survival ben-
efit was due to treatment effect and was not due to a
selection bias in the cohort of patients chosen for
therapy. Similarly to this, Noguchi et al. (2011) ret-
rospectively studied outcome of 45 patients 80 years
or older with small-cell lung cancer, comparing it
with those of 38 patients aged 70–79 years. Twenty-
four (53%) of the 45 patients were treated with
combination chemotherapy and/or thoracic radiation
534
therapy, which resulted in significant survival benefit
compared with those left untreated (P \ 0.01). The
main reasons for not administrating anti-cancer
treatments were advanced age ([85 years), poor
performance status, and severe co-morbidities. Med-
ian survival time and 1-year survival of the treated
patients were 13.0 months and 57% for limited dis-
ease and 10.3 months and 40% for extensive disease,
respectively. Despite a lower chemotherapy dose
being administered, survivals were similar to those of
patients aged 70–79 years. Survival benefit was
observed even in the treated patients with perfor-
mance status 2–3 or a moderate degree of co-
morbidity compared with those left untreated. The
frequency of grade 3–4 hematologic toxicities was
similar between the two age groups. The authors
concluded that the standard chemotherapy regimen
with or without thoracic radiation therapy seems to be
feasible for patients older than 80 years with small-
cell lung cancer, even for those with performance
status 2–3 and/or moderate co-morbidity, although
frequent dose adjustment is necessary.
Standard treatment for limited disease small-cell
lung cancer nowadays is combined radiation therapy
and chemotherapy. This practice has been widely
accepted after the survival benefit of thoracic radia-
tion therapy has been confirmed by two meta-analyses
published in 1992 (Pignon et al. 1992; Warde and
Payne 1992). The most widely used approach in
limited disease small-cell lung cancer consists of four
cycles of cisplatin/etoposide and thoracic radiation
therapy. Due to findings of a meta-analysis demon-
strating that prophylactic cranial irradiation improves
survival for limited disease small-cell lung cancer
patients in complete remission after radiochemother-
apy (Auperin et al. 1999), prophylactic cranial irra-
diation routinely follows in case of complete
remission. There are, however, initiatives to include
patients with ‘‘good partial response’’ in the group of
patients suitable for prophylactic cranial irradiation.
Importantly, this meta-analysis (Auperin et al. 1999)
did not show detrimental effect of age on treatment
outcome.
Owing to the lack of specifically designed clinical
trials addressing this issue in elderly, evidence for the
standard treatment for the vast majority of elderly
patients having limited disease small-cell lung cancer
is derived from phase III trials in which elderly are
largely under represented. It is still unclear to what
B. Jeremić and Ž. Dobrić
extent these results were biased by eligibility criteria
of the trials which restricted the entry of elderly
patients, since one of meta-analyses showed that the
survival benefit from thoracic radiation therapy was
restricted to younger patients (Warde and Payne
1992), possibly due to toxicity. Therefore, careful
selection of elderly suitable for full dose of radiation
therapy and chemotherapy is an important issue.
Randomized phase III studies investigating various
issues of radiation therapy and chemotherapy in
elderly patients with limited disease small-cell lung
cancer are lacking, and the prognostic significance of
age in small-cell lung cancer is not well-defined.
While some like Southwest Oncology Group and
Cancer and Leukemia Group B had demonstrated an
influence of age in limited disease small-cell lung
cancer (Spiegelman et al. 1989; Albain et al. 1990),
others did not confirm these observations (Osterlind
and Andersen 1986; Sagman et al. 1991). Some had
also investigated the relationship between the age and
toxicity and outcome among elderly treated with
combined thoracic radiation therapy and chemother-
apy in small-cell lung cancer. Findlay et al. (1991)
observed significantly more toxicity in the intensively
treated group (cyclophosphamide, doxorubicin, vin-
cristin) than in the less intensive group of patients
(single agents, planned dose reductions, or radiation
therapy alone), which was accompanied by a higher
response rate in the intensively treated group. How-
ever, in the subgroup of patients with limited disease
small-cell lung cancer intensive treatment did not lead
to an improved in overall survival.
Several studies investigated the influence of age
among various prognostic factors in small-cell lung
cancer (Table 1) (Siu et al. 1996; Dajczman et al.
1996; Nou 1996; Jara et al. 1999; Yuen et al. 2000).
As expected, due to various cut-off values used with
regard to age as prognostic factor, conflicting results
were observed. Importantly, in all of the studies fre-
quent dose emissions/reduced number of chemother-
apy cycles (Siu et al. 1996; Dajczman et al. 1996;
Nou 1996; Yuen et al. 2000) or dose reductions/less
intensive chemotherapy (Jara et al. 1999) or less
frequent use of radiation therapy occurred. This
reconfirmed previous observation that elderly was not
only the group receiving less intensive treatment, but
less likely to be included in clinical trials as well. The
situation seems to remain the same nowadays. In the
retrospective analysis of 174 patients with limited
Radiation Therapy for Lung Cancer in Elderly 535

Table 1 Retrospective studies in patients with limited disease small-cell lung cancer treated with radiation therapy and
chemotherapy
Author year Age/n RR (%) survival Toxicity Comments
Siu et al. 1996 \70: 580 78%; n.s. 5 yr.OS: 8%; Only cardiac grade 3/ All LD; CAV/
70: 88 82%; n.s. n.s. 4 toxicity More PE ? TI ? PCI (if CR) age
5 yr.OS: 11%; frequent in patients 70 not a prognostic factor in
n.s. multivariate
Dajczman 1996 \60: LD 49%; n.s. 2 yr. OS: 45 Fewer high-grade N = 123 LD, N = 89 ED;
et al. 45, ED 52%; n.s. 2 yr. OS: 48 toxicity and the mean CAV or PE ? TI;
55 51%; n.s. 2 yr. OS: 43 number of toxicities in No separate analysis for
60–60: elderly LD ? ED [70: only 23%
LD 48, received optimal treatment
ED (compared to 43%/50% in
73 70: the younger groups)
LD 43,
ED 57
Nou 1996 70: 243 All: 72% (n.s.) 5 yr.OS: 5%; No difference between 50% LD 50% ED; (85% of
[70: 110 n.s. 70 and [70 LD and 15% of ED treated
5 yr.OS: 1,3%; with CHT (various) ? TI
n.s.
Jara et al. 1999 \70: 25 46%; n.s. MST: 12.3 mo. No difference Only LD evaluated; PE or
70: 12 50%; n.s. MST: 14.9 mo. between 70 and [70 cPE ? TI
Yuen et al. 2000 \70: 80%; n.s. 5 yr.EFS: 19%; Grade 3/4 All LD, except data for LD
271 88%; n.s. n.s. hematological toxicity (N = 37) ? ED (N = 57)
70: 50 5 yr.EFS: 16%; higher in the elderly
n.s. group, all other
adverse effects: no
difference
Ludbrok 2003 \65: 55 91% MST: 17 mo. No difference in the Age not significant
et al. 65–74: 79% 2 yr OS: 37% incidence of acute or prognosticator in
76 74% MST: 12 mo. late grade 3/4 toxicity multivariate analysis since
[75: 43 2 yr OS: 22% elderly were less frequently
MST: 7 mo. treated with RT/CHT,
2 yr OS: 19% intensive CHT, and PCI
p = 0.003
Schild 2005 \70: 209 n.a 2 yr: 48%;5 yr Of all non-grade 5 Grade 5 toxicity occurred in
et al. [70: 54 n.a : 22% toxicity, only grade 4 6% of those [70 yrs, and in
2 yr: 33%;5 yr pneumonitis more 0.5% of those \ 70 yrs
: 17% frequent in group [70 (p = 0.03)
RR response rates; n.s. not significant; LD limited disease; CAV cyclophosphamide, doxorubicine, vincristin; PE cisplatin, eto-
poside; TI thoracic irradiation; PCI prophylactic cranial irradiation; CR complete response; OS overall survival; ED extensive
disease; MST median survival time; CHT: chemotherapy; cPE carboplatin, etopsoide; Hfx Ac RT hyperfractionated accelerated
radiotherapy

disease small-cell lung cancer, Ludbrok et al. (2003)
recently reconfirmed that during the 1990s of the last
century elderly continued to be under diagnosed and
undertreated, resulting in lower median and overall
survival rates. Interestingly, toxicity and pattern of
failure showed no differences when elderly were
compared to their non-elderly counterparts. When,
however, multivariate analysis was done in some
studies, age was not shown to be an independent
prognosticator of treatment outcome. It is more than
interesting, however, to observe that none of the
studies observed significantly inferior response rate,
overall or event-free survival for elderly. If therapy is
administered, therefore, the outcome in elderly
patients is the same to that observed in non-elderly
patients. Siu et al. (1996) observed that age influenced
survival in the univariate analysis, but not in a mul-
tivariate analysis. It is possible that rather than age
536
itself, factors frequently associated with age, such as
co-morbidity, performance status or less intensive
treatment may have influenced the prognosis.
In a re-analysis of original North Central Cancer
Group (Bonner et al. 1999), focused on the influence of
age on treatment outcome (Schild et al. 2005), a total of
263 patients with limited disease small-cell lung cancer
and an Eastern Cooperative Oncology Group perfor-
mance status of B2 who were randomized to receive
once-daily radiation therapy or split-course hyper-
fractionated radiation therapy. The outcomes of the 209
(79%) younger patients (age \70 years old) were
compared with the 54 (21%) elderly patients (age
C70 years old). Elderly patients were presented with
significantly greater weight loss and poorer perfor-
mance status. The 2- and 5-year survival rates were 48
and 22% for younger patients compared with 33% and
17% for older patients (P = 0.14). No difference was
also found when using local control, distant metastasis
control and freedom from progression. Grade C4
pneumonitis occurred in 0% of those patients age
\70 years compared with 6% of older patients
(P = 0.008). Grade 5 toxicity occurred in 1 of 209
(0.5%) patients age\70 years compared with three of
54 (5.6%) older patients (P = 0.03). Despite having
more weight loss, poorer performance status, increased
pulmonary toxicity, and more deaths due to treatment,
survival was not found to be significantly worse in older
individuals. Fit elderly patients with limited disease
small-cell lung cancer can receive combined-modality
therapy with the expectation of relatively favorable
long-term survival.
This was also an observation of several investi-
gators reporting on institutional experience in limited
number of patients (Shimizu et al. 2007; Okamoto
et al. 2010) treated with concurrent radiation therapy
and chemotherapy. Median progression-free survivals
of approximately 15 months and median overall sur-
vivals of approximately 25 months have been
achieved with acceptable toxicity.
Some studies also investigated the influence of age
on toxicity. While some observed fewer elderly
patients with high-grade toxicity (P = 0.0001), and
similar incidence of treatment-related deaths due to
less intensive treatment (Dajczman et al. 1996), other
reported on similar toxicities in both age groups. In
studies where a higher rate of hematological toxicity
and fatal toxicities occurred in the elderly group,
other toxicities were similar compared to non-elderly
B. Jeremić and Ž. Dobrić
patients (Nou 1996; Jara et al. 1999; Yuen et al.
2000).
Few prospective studies (Table 2) specifically
addressed the issue of optimizing the treatment
approach in elderly patients with limited disease
small-cell lung cancer. In one such attempt (Westeel
et al. 1998), a regimen of cisplatin, doxorubicin,
vincristine, and etoposide was designed for patients
older than 65 years with small-cell lung cancer and
compared with standard chemotherapy regimens to
maintain efficacy, diminish toxicity, enhance com-
pliance, and improve chemotherapy administration
convenience at an acceptable cost. Patients with
limited-stage disease and selected patients with
extensive-stage disease received thoracic radiation
therapy delivered concurrently with cisplatin/etopo-
side at the time of the second chemotherapy cycle.
There were 25 patients with limited-stage disease and
41 patients with extensive-stage disease. Median
survival was 70 weeks and 5-year survival was 25%
for limited-stage disease. Only one treatment-related
death occurred and severe toxicity was infrequent.
The median delivered dose-intensity was according to
protocol and the mean delivered total dose was 80%
of intended. The treatment outcome achieved with
this treatment approach in a phase II study of elderly
patients compared favorably with published results of
standard regimens in patient populations with better
prognostic factors. Murray et al. (1998) tailored an
approach for elderly, infirm or non-compliant patients
using only two cycles of chemotherapy (cyclophos-
phamide/doxorubicin/vincristin and cisplatin/etopo-
side) and radiation therapy (20 Gy in 5 fractions or
30 Gy in 10 fractions). Toxicity was low, except three
treatment-related deaths, two of which were due to
cardiac toxicity, with likely ischemic cause. The
median time to progression was 40 weeks and 2-year
progression-free survival was 25%. The median sur-
vival time was 54 weeks and 5-year survival rate was
18%. The median survival time and 5-year survival
were similar for 18 patients \70 years and for the 37
patients C70 years. In another study, Jeremic et al.
(1998a) also administered only two courses of che-
motherapy (carboplatin, 400 mg/m2, days 1 and 29
and oral etoposide 50 mg/m2, days 1–21 and 29–49)
concurrently with accelerated hyperfractionated
radiation therapy (45 Gy in 30 fractions in 15 treat-
ment days using 1.5 Gy b.i.d. fractionation) in 75
patients C70 years with a Karnofsky performance
Radiation Therapy for Lung Cancer in Elderly
Table 2 Phase II studies of radiation therapy and chemotherapy in elderly and/or frail patients with LD-SCLC
AUTHOR (yr) N CHT
Westeel et al. (1998) 25 PAVEx3, PEx1
Murray et al. (1998) 55 CAVx1, PEx1
Jeremic et al. (1998a) 72 CBDCA/oral Ex2
Matsui et al. (1998) 16 CBDCA/oral Ex4
CHT chemotherapy, RT radiation therapy, Gy Grey, fx fraction, PS performance status; not available, P cisplatin, A doxorubicin,
V vincristine, E etoposide, C cyclophosphamide, CBDCA carboplatin, BID two fractions a day
status score of [60% and with no major concomitant
diseases. The median survival time was 15 months
and 5-year survival was 13%. Good pre-treatment
patient characteristics led to 83% patients receiving
therapy on an outpatient basis and low toxicity. Grade
4 thrombocytopenia occurred in 1.4% of all patients,
thrombocytopenia grade 3 in 11%, grade 3 leucopenia
in 8.3%, grade 3 anemia in 2.8%, infection in 4.2%,
and nausea and vomiting in 4.2% of all patients. No
high-grade bronchopulmonary toxicity was observed
and grade 3 esophagitis occurred in only 2.8% of the
patients. Additional advantage of this approach was
its short duration, resulting in more time spent at
home, and therefore, a good quality of life. In
addition to these two studies, Matsui et al. (1998)
reported on 16 patients with limited disease small-
cell lung cancer [70 years for whom four cycles of
carboplatin and oral etoposide (40 mg/m2, days
1–14) were followed by chest radiation therapy
(45 Gy). The median survival time was 15.1 months
and a 2 year survival rate was 21.8%. For patients
C75 years the median survival time was
10.3 months and 2 year survival rate was 11.3%.
Grade 3 and 4 leucopenia occurred in 36 and 14% of
patients, respectively, and grade 3 and 4 thrombo-
cytopenia occurred in 39 and 14% of the patients,
respectively. Grade 3/4 anemia occurred in 50% of
patients. Non-hematological toxicity was rare. What
these three prospective studies have shown is that
well-tailored treatment approaches, in a well-selected
patient population, carefully balancing between
‘‘optimal’’ thoracic radiation therapy and chemother-
apy elderly can tolerate while avoiding unnecessary
toxicity, may lead to high treatment success and
toxicity profile not very different to that usually
observed in non-elderly patients.
537
RT (Gy/fx) N Age [ 70 (yrs) (%) PS [ 2 (%)
20/5 25 med. 72 28
30/10
40/5
20/5 55 67 45
30/10
45/30 72 100 17
(BID)
45/24 16 100 n.a.
What summary of retrospective and prospective
studies also showed is a similar outcome of elderly
and non-elderly patients with limited disease small-
cell lung cancer, despite elderly frequently receiving
less-intensive chemotherapy and/or thoracic radiation
therapy. Additionally, despite less compliance in
elderly, no difference in either response rates or sur-
vival was detected between them and their non-
elderly counterparts (Kelly et al. 1991; Siu et al. 1996;
Dajczman et al. 1996; Tebbutt et al. 1997; Yuen et al.
2000). Although the reason for this finding is still
unclear, possible explanation may lie in a different
metabolism of drugs. This may lead to a need for
lower doses of various drugs in elderly (Montamat
et al. 1989; McKenna 1994; Joss et al. 1995), since
different biological behavior of tumors in elderly is
not very likely cause of this observation (Matsui et al.
1998). As pointed out (Yuen et al. 2000), there may
be a threshold above which a significant benefit can
be realized. The delivery of ‘‘adequate enough’’
treatment to achieve a positive effect could, perhaps,
still be achieved with the modest dose reductions.
This threshold will be hard to specify and document,
but it seems that studies of Jeremic et al. (1998b) and
Murray et al. (1998) supported this statement:
although chemotherapy was limited to only two
cycles given concurrently with thoracic radiation
therapy, it was possible to obtain results which are not
substantially inferior to those obtained with more
intensive approaches. However, every caution should
be suggested in this patient population, particularly
regarding hematological toxicity.
In extensive disease small-cell lung cancer, stan-
dard treatment for patients with extensive disease
small-cell lung cancer is chemotherapy. The addition
of thoracic radiation therapy did not improve survival
538
in the past, and thoracic radiation therapy was applied
only for palliation of local symptoms when chemo-
therapy alone was not efficient (Livingston et al.
1984). However, a recent prospective randomized
trial by Jeremic et al. (1999d) showed an advantage
for three cycles of platinum-etoposide chemotherapy
followed by accelerated hyperfractionated thoracic
radiation therapy given concurrently with low-dose,
daily carboplatin/etoposide over chemotherapy with
platinum/etoposide (five cycles) alone. Important
finding of that study was survival advantage being
observed for patients [60 years old. This finding was
confirmed by the multivariate analysis identifying the
age as an independent prognosticator of survival in
patients with extensive disease small-cell lung cancer
(unpublished observations; drawn from Jeremic et al.
1999d).
4 Conclusions
Accumulated evidence identifies radiation therapy as
an important treatment modality in elderly patients
with lung cancer. This is so irrespective of the con-
sideration of cut-off age, histology or stage or whether
radiation therapy had been used alone or in combi-
nation with chemotherapy. Encouraging results were
obtained in both non-small-cell lung cancer and
small-cell lung cancer, although prospective studies,
especially randomized ones are basically lacking.
Unfortunately, current evidence also points out
that age alone is an uncertain prognostic criterion
when outcome including toxicity is considered. Bio-
logical age of each individual elderly seems to be
more important than chronological age. This requires
a specific geriatric assessment of each individual
patient, including detection of co-morbidities and the
functional capacity for performing activities of daily
living, the cognitive and nutritional status of the
patient. The decision- making of optimal treatment in
elderly patients with lung cancer should be based on
both disease and patient-specific criteria. Age itself is
not a contraindication for applying the standard
treatment. However, the individualized management
of the elderly must reflect the results of a compre-
hensive geriatric assessment.
Major issue in this field remains the lack of pro-
spective clinical studies investigating ‘‘optimal’’
treatments in this setting. This is especially so, since
B. Jeremić and Ž. Dobrić
accumulated evidence clearly show that ‘‘fit’’ elderly
may tolerate the treatments considerably well, regard-
less of its intensity. The starting point may well be
inclusion of more of elderly in clinical studies as well as
designing of specific clinical trials exclusively dedi-
cated to elderly. In addition, every caution should be
undertaken in order not to over emphasize the results of
recent studies which are, unfortunately, mostly retro-
spective. It said that, inherent biases and underlying
problems, unsolved so far, may hamper future
endeavors having the same goal: enabling elderly with
lung cancer equal diagnostic and treatment approach as
their younger counterparts receive, on or off the pro-
tocol. While this should be continuous reminder to all
wishing to engage in this setting, definite solution
remains within the domain of more clinical studies in
elderly with lung cancer and we need it now.
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 Radiation Therapy for Recurrent Disease
Branislav Jeremić, Jai Prakash Agarwal, and Sherif Abdel-Wahab

Contents Abstract
Recurrence is still a dominating and bitter event
1 Introduction.............................................................. 543 after the treatment of lung cancer regardless of
2 Surgery...................................................................... 545 histology, stage, or initial treatment. All recurrences
can be broadly divided into the local (e.g., lung
3 External Beam Radiation Therapy
in Locoregional Post-Surgical Recurrences parenchyma, bronchial stump, or chest wall),
of Non-Small-Cell Lung Cancer ............................ 545 regional (e.g., mediastinal lymph nodes), and distant
(e.g., brain, liver, or bones). Recurrent disease
4 External Beam Radiation Therapy
in Reirradiation of Locally Recurrent Lung almost always present as fatal event and only
Cancer ....................................................................... 546 anecdotal reports indicated potential for a treatment
5 Radiation Therapy in Reirradiation of Small-Cell to lead to cure. Beside surgery and chemotherapy,
Lung Cancer............................................................. 556 radiation therapy has been used in this setting and
6 Endobronchial Brachytherapy in Reirradiation
was shown that it was safe and effective way of
of Locally Recurrent Lung Cancer ....................... 556 retreating recurrent non-small-cell lung cancer after
initial radiation therapy. It achieved symptom
References.......................................................................... 557
control in substantial proportion of cases (overall,
approximately 80%). In many studies asymptomatic
patients were also included, indicating therefore,
intention of more ‘‘radical’’ approach of investiga-
tors. This had led to longer survivals, especially
when high-doses were successfully delivered, lead-
ing to the median survival time of 15 months and
2-year survival of 51%, not different from those
B. Jeremić (&) achieved with contemporary radiochemotherapy
Institute of Lung Diseases, Institutski Put 4, studies in treatment-naive locally advanced non-
21204 Sremska Kamenica, Serbia small-cell lung cancer. These results were obtained
e-mail: nebareje@gmail.com
at the expense of low toxicity.
B. Jeremić
Institute of Pulmonary Diseases,
Sremska Kamenica, Serbia
J. P. Agarwal
Department of Radiation Oncolgoy,
1 Introduction
Tata Memorial Center, Mumbai, India
Lung cancer remains one of the most prevalent and
S. Abdel-Wahab
Department of Oncology, Ain Shams University, deadliest malignancies worldwide. It was estimated
Cairo, Egypt that in the US in 2009 there were 219.440 new cases

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 543
DOI: 10.1007/174_2011_255, Ó Springer-Verlag Berlin Heidelberg 2011
544
and estimated 159.390 deaths of lung cancer (Jemal
et al. 2009), making it, therefore, the major cancer
killer in both sexes. The similar trend is seen on
global level. The most recent data from the Interna-
tional Agency for the Research of Cancer (IARC)
showed that in 2008 worldwide there was an esti-
mated total of 1.6 millions of lung cancer cases (1.095
million in men and 0.514 million in women) with
estimated 1.38 millions of deaths (0.95 million in men
and 0.43 million in women) (IARC 2010). As such, it
represents a huge burden and big challenge for health
care systems worldwide, which requests an orches-
trated approach in understanding and planning as to
enable successful prevention, early diagnosis, and
treatment.
In an attempt to optimize prevention and various
diagnostic and treatment approaches substantial
efforts were made in combating this disease. Recent
decades witnessed introduction of novel molecular
oncology approaches as well as positron emission
tomography, extensively used nowadays to diagnose
and stage lung cancer patients. It has also been used to
optimize radiotherapy treatment planning. In the
treatment domain, video assisted thoracoscopic sur-
gery, novel high-precision radiotherapy techniques
(three-dimensional conformal radiation therapy,
intensity modulated radiation therapy, stereotactic
radiation therapy), and novel chemotherapeutic agents
(third generation drugs, targeted drugs) have also
been used with increasing frequency, and, impor-
tantly, efficacy. Although became more effective in
diagnosing and treating lung cancer than ever, dismal
and frustrating results remain even nowadays. While
only a minority of lung cancer patients are those
falling into an early stage group, where surgery is
offering hopes of cure, the vast majority of non-small-
cell lung cancer patients and almost all with small-
cell lung cancer are considered ineligible for surgery.
There, radiation therapy and/or chemotherapy are
practiced in institutions all over the world.
In spite of promising novel biological and techno-
logical opportunities in diagnosis and treatment,
recurrence is still a dominating and bitter event after the
treatment of lung cancer regardless of histology, stage,
or initial treatment. While some failures are reported to
appear soon after the initial treatment, some manifest
years later. All recurrences can be broadly divided into
the local (e.g., lung parenchyma, bronchial stump, or
chest wall), regional (e.g., mediastinal lymph nodes),
B. Jeremić et al.
and distant (e.g., brain, liver, or bones). Again, any
combination of these may occur in a patient. Recurrent
disease almost always present as fatal event and only
anecdotal reports indicated potential for a treatment to
lead to cure. In addition, recurrence can also bring
substantial symptoms which request for additional
supportive treatment. An important issue to be
emphasized here is that the quality of life of such
patients is decreased and cost-effectiveness of diagno-
sis and/or treatment is always low.
Since some recurrences may appear in lung
parenchyma (ipsilateral or contralateral lung) alone, it
is important to recognize the distinct features of the
second metachronous primary lung cancer as opposed
to lung parenchyma recurrence occurring after the
initial treatment (Martini and Melamed 1975).
Once recurrent lung cancer has been diagnosed,
the dilemma one faces is to (re)treat or not? It is quite
clear that nowadays this question should be put aside
due to imperative in prolongation of patient’s life, and
maintaining or improving quality of remaining life,
unless other factors (existing serious comorbidities,
short anticipated remaining life, and patient’s wish)
reject such an idea. Aggressive approach has support
in studies which showed that active treatment offers
better outcome than purely supportive one (Hung
et al. 2009). Next issue to address is how to treat: with
curative or palliative intent? Here, decision-making
process needs to be put into the context of not only
the disease- and patient-related factors, but also the
level of evidence which currently exists. The data
available are from quite a few studies, all but one
being retrospective and with small number of sub-
jects, frequently without investigation of prognostic
factors which may have contributed to better under-
standing of both natural course of the disease and the
underlying reasons behind treatment choice. While
palliation was always specified as the major aim of
reirradiation of locally recurrent non-small-cell lung
cancer, recent studies also included somewhat higher
percentage of asymptomatic patients and with wide
introduction of novel technological appliances
enabled higher dose to be given to more conformal
volumes, leading perhaps to improved therapeutic
benefit in these cases. Hence, palliative versus cura-
tive intention is likely to be revisited, especially in
cases with isolated local recurrence of previously
irradiated non-small-cell lung cancer suitable for
more radical approach.
Radiation Therapy for Recurrent Disease
2 Surgery
As recurrences are documented after any treatment
modality used in lung cancer they can also be treated
by any of these as well. In cases of surgery
(re-operation) in the treatment for lung cancer recur-
rence, major determining factors were previous
complete resection, absence of other recurrent sites,
as well as the absence of concomitant diseases. Not to
be forgotten, site and stage of recurrent tumor were
considered important in decision-making process.
When several large surgical series were together
taken into account, it was observed that in more than
6,000 patients, mostly having intrapulmonary recur-
rence, reoperation with curative intent was managed
in 1–1.7% of patients (Gabler and Liebig 1980;
Dartevelle and Khalif 1985; Watanabe et al. 1992;
Voltolini et al. 2000). Not unexpectedly, results were
disappointingly poor with 2-year survival of 23%
(Pairolero et al. 1984) and the median survival times
ranging from 7 to 26 months (Becker et al. 1990;
Lesser et al. 1997; Voltolini et al. 2000; Westeel et al.
2000). More promising results, however, were
observed in the most recent studies (5-year survival,
15.5%), although in smaller patient population
(Voltolini et al. 2000). To further extend this, even
higher local control and overall survival rates can be
achieved by completion pneumonectomy, with 5-year
survival of about 50% in stage I and 40% in stage II
carcinoma (Regnard et al. 1999). Hung et al. (2009)
also reported on 1- and 2-year post-recurrence sur-
vival of 48.7 and 17.6%, respectively in patients with
initial stage I treated surgically. Although patients
who underwent complete resection for local only
recurrence survived longer than those who received
chemotherapy and/or radiotherapy and those who
received no therapy, post-recurrence survival in
patients with local only recurrence was not signifi-
cantly different from those with both local and distant
recurrences. Newer strategies, including alternative
treatment approaches, are clearly warranted in this
setting. Finally, recent years also brought qualita-
tively new evidence that surgery for recurrence
occurring after previous radiochemotherapy or
after highly-focused radiotherapy may be beneficial.
Bauman et al. (2008) reported on 24 patients under-
going previous radiotherapy, 22 of whom received
concurrent chemotherapy. The median overall
545
survival was 30 months and estimated 3-year survival
rate was 47%. Also, two recent case reports (Suzuki
et al. 2007; Neri et al. 2009) showed that lobectomy
may provide cancer-free survivals in excess of
12 months after initial radiotherapy for stage I non-
small-cell lung cancer using either three-dimensional
or stereotactic radiation therapy.
3 External Beam Radiation Therapy
in Locoregional Post-Surgical
Recurrences of Non-Small-Cell
Lung Cancer
Radiation therapy in locoregional post-surgical
recurrences of non-small-cell lung cancer was used to
treat various local/regional recurrences located intra-
thoracically. Common approach was to divide these
into chest wall/pleural, parenchymal, bronchial
stump, and mediastinal lymph node recurrences and it
also could include any combination of these. Radia-
tion therapy was shown to be effective and low toxic
in this setting (Green and Kern 1978; Kopelson and
Choi 1980; Law et al. 1982; Shaw et al. 1992; Curran
et al. 1992; Yano et al. 1994; Leung et al. 1995;
Emami et al. 1997; Kagami et al. 1998; Kono et al.
1998; Jeremic et al. 1999; Kelsey et al. 2006).
Observation coming from these studies is that there is
dose-response favoring higher doses. Another obser-
vation was that location of recurrence may influence
treatment outcome, bronchial stump recurrences far-
ing much better than recurrences located in chest
wall/pleura or mediastinal lymph nodes. When the
data from the literature on isolated bronchial stump
cases was pooled together (Jeremic and Bamberg
2002), the median survival time was estimated to be
approximately 28.5 months and a 5-year survival to
be about 31.5%. These results had clearly established
external beam radiation therapy as a treatment of
choice in this patient population. To extend this, in a
small subset of ‘‘early’’ (i.e., stage I: T2N0) bronchial
stump recurrences in the study of Jeremic et al. (1999)
an excellent survival (5-year: 57%) with high-dose
external beam radiation therapy (C60 Gy) was
achieved, which approached those obtainable with
surgery alone in newly diagnosed non-small-cell lung
cancer of the same stage (Mountain 1986; Naruke
et al. 1998). An intriguing fact, still unexplained
properly, is that their survival seems superior to that
546
of patients with newly diagnosed non-small-cell lung
cancer of a similar stage when treated with high-dose
standard or hyperfractionated radiation therapy (Ono
et al. 1991; Morita et al. 1997; Jeremic et al. 1997;
Sibley et al. 1998; Hayakawa et al. 1999; Jeremic
et al. 1999). Law et al. (1982) also provided the data
on patients having ‘‘more extensive’’ bronchial or
tracheal component of the disease. Their findings
further support the effectiveness of external beam
radiation therapy in bronchial stump recurrence.
These patients achieved the median survival time of
19 months and 1- and 3-year survival of 75, and
12.5%, respectively, showing that more extensive, but
ultimately localized (no nodes or other recurrent
tumor component present) may also benefit from
radiation therapy. When, however, tumor recurrence
located at bronchial stump was accompanied with
other intrathoracic sites, such as nodal, inferior sur-
vival was unequivocally documented (Curran et al.
1992; Jeremic et al. 1999; Kagami et al. 1998; Kono
et al. 1998). Contrary to these findings, Kelsey et al.
(2006) found superior survival for patients having
mediastinal recurrence. In their study on 29 patients,
the median radiation therapy dose was 66 Gy (range,
46–74 Gy). Elective nodal irradiation was used in
27/29 patients, while chemotherapy was given in
15/29 patients. In an interesting study, Cai et al.
(2010) have recently compared the survival of
postresection recurrent versus newly diagnosed non-
small-cell lung cancer patients treated with radiation
therapy or radiochemotherapy. The study population
consisted of 661 consecutive patients with non-small-
cell lung cancer registered in the radiation oncology
databases at two medical centers in the United States
between 1992 and 2004. Of the 661 patients, 54 had
postresection recurrent non-small-cell lung cancer
and 607 had newly diagnosed non-small-cell lung
cancer. The distribution of relevant clinical factors
between these two groups was similar. The median
survival time and 5-year overall survival rates were
19.8 months and 14.8% versus 12.2 months and
11.0% for recurrent versus newly diagnosed patients,
respectively (p = 0.037). For Stage I–III patients, no
significant difference was observed in the 5-year
overall survival (p = 0.297) or progression-free sur-
vival (p = 0.935) between recurrent and newly
diagnosed patients. For the 46 patients with Stage
I–III recurrent disease, multivariate analysis showed
that chemotherapy was a significant prognostic factor
B. Jeremić et al.
for 5-year progression-free survival (p = 0.027). This
study have shown that patients with postresection
recurrent non-small-cell lung cancer achieved sur-
vival comparable to that of newly diagnosed non-
small-cell lung cancer patients when they were both
treated with radiation therapy or radiochemotherapy.
These findings also suggested that patients with pos-
tresection recurrent chemo should be treated as
aggressively as those with newly diagnosed disease.
4 External Beam Radiation Therapy
in Reirradiation of Locally
Recurrent Lung Cancer
For patients recurring within previous radiation ther-
apy treatment field after initial treatment for either
early or locally advanced non-small-cell lung cancer,
reirradiation with external beam radiation therapy was
occasionally used. Radiation therapy was offered
aiming both increased survival and symptom control,
with expected improvement of the quality of
remaining life.
It seems that currently there are only eleven studies
clearly aiming to document the outcome of external
beam radiation therapy in reirradiation of locally
recurrent non-small-cell lung cancer (Green and
Melbye 1982; Jackson and Ball 1987; Montebello
et al. 1993; Gressen et al. 2000; Okamoto et al. 2002;
Wu et al. 2003; Kramer et al. 2004; Tada et al. 2005;
Poltninikov et al. 2005; Ebara et al. 2007; Cetingoz
et al. 2009). In addition, one case report was identified
on the use of intensity modulated radiation therapy as
pure planning study (Beavis et al. 2005). One study
also included several different tumor entities and did
not specify data for reirradiation of lung cancer using
either three-dimensional or stereotactic radiation
therapy (Jereczek-Fossa et al. 2008). Two additional
studies (Coon et al. 2008; Chang et al. 2008) included
patients reirradiated with sophisticated treatment
planning and stereotactic delivery in cases of locally
recurrent non-small-cell lung cancer, but focused on
different aspects of radiation therapy and failed to
produce some important patient, tumor and/or out-
come data which could have been meaningfully
included and compared with other studies.
It is, however, virtually unknown which proportion
of patients initially treated with chest radiation ther-
apy underwent reirradiation during the natural course
Radiation Therapy for Recurrent Disease
of the disease. One study that addressed the issue
(Estall et al. 2007) examined the proportion of
patients who received more than one radiation therapy
treatment for lung cancer. While the rate of initial
radiation therapy utilization has been estimated to be
76% (Delaney et al. 2003) accounting for the first
radiation therapy episode delivered, in the study of
Estall et al. (2007) it was 52%. Local disease in the
chest was treated with initial radiation therapy in most
cases (79%), while the second and third radiation
therapy treatment was administered in 22 and 21%,
respectively. With an increase in the number of
treatment episodes, the mean duration between each
episode decreased as was the case with the total dose
and number of fractions. It is likely that this occurred
as reflection of progressive decline in performance
status and poorer prognosis of patients in the end
stage of their disease and their life. Unfortunately, the
study findings are somewhat limited due to the fact
that it has covered the data from two years and not
prolonged periods of time. Unfortunately, no similar
study exists to provide detailed information from
other institutions and regions. This could have been
potential additional advantage of such an approach
and worldwide verification because it is more than
likely that different institutions/regions/countries
would have had both initial radiation therapy utili-
zation rate as well as reirradiation rate in lung cancer.
In general, there is both limited data in the avail-
able literature, vast majority of it being of retrospec-
tive nature. There is also great variety in not only
diagnostic tools used for both initial radiation therapy
and reirradiation, but patient and tumor characteristics
(Table 1), treatment (radiation therapy) specifications
(Table 2), and treatment outcome (Table 3) among
available studies which documented majority of these
important characteristics (7–16). Only three studies
(Green and Melbye, 1982; Jackson and Ball, 1987;
Gressen et al. 2000) provided actual number of
patients with non-small-cell lung cancer from which
reirradiated non-small-cell lung cancer cases were
drawn. As well, only three studies clearly defined
time interval for considering reirradiation appropriate
treatment option for actual/presumed (depending on
diagnostic tools used) locally recurrent non-small-cell
lung cancer. Interestingly, there was only one (Wu
et al. 2003) prospective phase I-II study. Finally,
many studies did not provide some important data at
all. In particular, of patient and tumor characteristics
547
(Table 1), five studies did not provide data on initial
staging (Green and Melbye, 1982; Jackson and Ball
1987: Gressen et al. 2000; Kramer et al. 2004; Ebara
et al. 2007), only three (Montebello et al. 1993;
Okamoto et al. 2002; Kramer et al. 2004) provided
data on initial performance status, and only two
studies (Okamoto et al. 2002; Tada et al. 2005) pro-
vided data on recurrent tumor staging, while five
studies did not provide data on performance status at
the time of reirradiation (Green and Melbye 1982;
Jackson and Ball 1987: Gressen et al. 2000; Kramer
et al. 2004; Cetingoz et al. 2009). Five studies did not
provide data on percentage of asymptomatic patients
reirradiated (Green and Melbye 1982; Jackson and
Ball 1987; Gressen et al. 2000; Wu et al. 2003;
Kramer et al. 2004). Of treatment characteristics,
three studies did not provide data on cumulative
radiation therapy doses (Wu et al. 2003; Tada et al.
2005; Cetingoz et al. 2009) probably due to a variety
of doses per fraction used during reirradiation course.
Only two studies used uniform radiation therapy
doses for reirradiation (Kramer et al. 2004; Tada et al.
2005). Two studies (Jackson and Ball 1987; Kramer
et al. 2004) did not provide data on field sizes and one
(Jackson and Ball 1987) did not provide data on
chemotherapy administration. Tumor motion control
was described in none of the eleven studies thor-
oughly discussed, but only in two most recent studies
(Coon et al. 2008; Chang et al. 2008). Similarly,
positron emission tomography-computerized scan-
ning was specified as done for the purpose of staging
and evaluation of response (not for treatment plan-
ning) in none of the eleven studies but only in two
most recent studies (Coon et al. 2008; Chang et al.
2008), while Wu et al. (2003) used positron emission
tomography for evaluation of response in follow-up
only. None of these studies or report tried to provide
radiobiological data that could perhaps help us more
clearly compare effectiveness of studies. In spite of
the fact that all studies provided data on time intervals
between initial radiation therapy and reirradiation,
only three studies (Montebello et al. 1993; Okamoto
et al. 2002; Cetingoz et al. 2009) provided survival
data from initial radiation therapy. It is therefore that
we are left short of an opportunity to have better
insight into an overall success of not only reirradia-
tion (as salvage radiation therapy) per se, but com-
bined initial radiation therapy and reirradiation and
perhaps compare it with the data obtained in patients
548 B. Jeremić et al.

Table 1 Patient and tumor characteristics

Author (year) N Sex Age range Initial tumor Histology PS at re-RT range Time interval from 1st
(M/F) (median) staging (%) (%) (median) to 2nd RT (median)
Green and 29 23/6 35–85 (57) n.s. SCC-66 n.s. 3–40 months (10)
Melbye ADC-14
(1982)
LC-14
SCLC-6
Jackson and 22 21/1 45–76 (62) n.s. SCC-50 n.s. 5.7–48.5 months (15)
Ball (1987) ADC-36
Other-14
Montebello 30 18/12 45–83 (62) I-II-23; SCC-53; KPS 40–100 (60) n.s. (12)
et al. (1993) IIIA-47 ADC-27
IIIB-30 LC-10
Other-10
Gressen et al. 23 13/10 47–87 (66) n.s. SCC-35 n.s. 3–156 months (15)
(2000) ADC-30
LC-9
Other-27
Okamoto et al. 34 29/5 38–85 (69) I-II-9 SCC-50 PS0-1 = 41% 5–87 months (23)
(2002) IIIA-29 ADC-18 PS C 2 = 59%
(PS2)
IIIB-53 LC-6
IV-9 Other-24
Wu et al. 23 21/2 43–79 (68) II-30 SCC-40 KPS 70–100 6–42 months (13)
(2003) III-70 ADC-30
SCLC-30
Kramer et al. 28 27/1 52–83 (68) n.s. All 6–72 months (17)
(2004) NSCLC
Tada et al. 19 17/2 49–84 (64) IIIA = 21 SCC-74 PS0-1 = 42% 5–60 months (16)
(2005) IIIB = 79 ADC-21 PS2-3 = 58%
LC-5
Poltinnikov 17 10/7 45–79 (66) n.s. SCC-35 KPS 60–90 (80) 2–39 months (13)
et al. (2005) ADC-59
Other-6
Ebara et al. 44 n.s. 49–86 (71) n.s. SCC-43 PS0-1 = 86% 5.8–47.2 months (12.6)
(2007) ADC-27 Other = 14%
SCLC-20
Other-10
Cetingoz et al. 38 35/3 33–80 (58) IIB = 5 SCC-61 n.s. 1–47 months (9)
(2009) IIIA = 10 ADC-13
IIIB = 84 Other-26
M male; F female: KPS Karnofsky performance status; RT radiotherapy; n.s. not stated; SCC squamous cell carcinoma;
ADC adenocarcinoma: LC large cell carcinoma; SCLC small cell lung cancer; other include at least two other histologies
Radiation Therapy for Recurrent Disease 549

Table 2 Treatment characteristics

Author Initial RT dose Re-RT dose Cumulative RT RT fields/volume RT field size CHT
Gy (median) Gy (median) dose Gy (median) cm2 (median) (%)
Green and 40–65 (53) 6–54 (35) 60–166* (82) Tumor only = 76% Average, 80 24
Melbye Uninvolved
(1982) mdstnm = 24%
Jackson and 50–61 (55) 20–30 (30) 70–90 (85) Volume encompassing the n.s. n.s.
Ball (1987) disease causing symptoms
Montebello 28–66 (60) 15–57 (30) 43–122* (88) Large fields** = 4–25 pts (96) 23
et al. (1993) Tumor = 30 pts (85)
Gressen et al. 25–66 (59) 6–40 (30) 60–101 (86) Tumor ? 1–2 cm 30–315 (81) 61
(2000)
Okamoto 30–80 (66) 10–70 (50) 56.5–150 (110) Radical = tumor only 20–238 (65) 47
et al. (2002) Palliative = affected region
Wu et al. 30–78 (66) 46–60 (51) n.s. Tumor ? 1.5–2.0 cm 42–210 (104) 100
(2003)
Kramer et al. 40–60 (n.s.) 16 (16) 56–76 (n.s.) ‘‘Limited RT’’ n.s. n.s.
(2004)
Tada et al. 50–70 (n.s.) 50–60 (50) n.s. ‘‘Limited RT’’ 30–204 (64) 6
(2005)
Poltinnikov 50–66 (52) 4–42 (32) n.s. GTV ? 5 mm 95 (30–189) 29
et al. (2005)
Ebara et al. 50–70-(60) 30–60 (40) 80–130 (102) Tumor ? 5–10 mm n.s. 57
(2007)
Cetingoz 29–67 (30) 5–30 (25) n.s. Tumor ? 1–2 cm 25–245 (89) 24
et al. (2009)
RT radiotherapy; CHT chemotherapy; n.s. not stated; mdstnm mediastinum; *includes patients reirradiated twice; **includes
various field sizes including ipsilateral hilum, contralateral hilum, mediastinum and ipsilateral supraclavicular fossa

with no reirradiation or those treated for an initial
tumor of the same histology and stage with radiation
therapy or radiochemotherapy. To extend this, only
two studies (Montebello et al. 1993; Okamoto et al.
2002) provided data on actuarial local progression-
free survival after reirradiation, while two studies
provided data as median distant metastasis-free sur-
vival (Montebello et al. 1993), although some studies
provided actual data on pattern of failure. Two studies
did not report on detailed symptomatic (per symptom)
relief (Okamoto et al. 2002; Wu et al. 2003), while
two studies did not use overall symptomatic relief as
surrogate for treatment success (Wu et al. 2003; Tada
et al. 2005), and one (Okamoto et al. 2002) reported
on only overall symptomatic relief. Only one study
(Montebello et al. 1993) provided symptom-free
duration. Finally, five studies attempted to evaluate
survival according to potential prognostic factors such
as interval between first and second radiation therapy
course, performance status, age, size, location, or
response (Green and Melbye 1982; Montebello et al.
1993; Tada et al. 2005; Cetingoz et al. 2009).
Due to existing limitations outlined above, avail-
able data may not be easy to interpret in order to
instantly establish the efficacy and therapeutic benefit
of this approach. This mostly concerns radiation
therapy characteristics that one may want to use in
daily clinic such as the adequate time, dose, and
fractionation pattern to achieve specific goal (cure,
palliation). In addition, there is also a legitimate
concern that reirradiation can cause significant tox-
icity, especially when previous high-dose radical
radiation therapy was used. Nevertheless, feasibility
and efficacy of reirradiation were clearly documented
in several early reports on treatment of recurrent lung
cancer (Green and Melbye 1982; Jackson and Ball
1987; Montebello et al. 1993; Gressen et al. 2000).
These studies were retrospective in nature with
inherent bias including patients with post-surgical
relapses, post-operatively irradiated patients, those
Table 3 Treatment outcomes (from reirradiation)
550

Author MST (range) OS Symptom improvement Toxicity (%)

months Hemoptysis Cough Chest pain Dyspnea Overall
(%) (%) (%) (%) (%)
Green and Melbye 5 (1–54) 1 yr = 14% 33 55 n.s. 44 48 Rib fracture-3
(1982) 5 yr = 3% pneumonitis-3
Jackson and Ball 5.4 (n.s) 1 yr = 38% 83 50 40 67 50 Myelopathy-5
(1987) 2 yr = 15%
Montebello et al. 5 (n.s.) n.s. 89 64 77 53 70 Esophagitis-20
(1993) skin-13
pneumonitis-3
Gressen et al. (2000) 4.9 (n.s.) 1 yr = 13% 100 60 80 73 72 Grade 5 (fatal)—4
Okamoto et al. (2002) 8 (n.s.) 1 yr = 43% n.s. n.s. n.s. n.s. 75 G2 pneumonitis-35
2 yr = 27% G3 pneumonitis-21
G2 esophagitis-12
G3 esophagitis-6
Wu et al. (2003) 14 (2–37) 1 yr = 59% n.s. n.s. n.s. n.s. n.s. G1-2 esophagitis-9
2 yr = 21% G1-2 pneumonitis-22
G3 late fibrosis-9

Kramer et al. (2004) 5.6 (n.s.) 1 yr = 18% 100 67 n.s. 35 71 G2 esophagitis-4

Tada et al. (2005) 7.1 (n.s.) 1 yr = 26% n.s. n.s. 80 100 n.s. G3 pneumonitis-5
2 yr = 11% G2 esophagitis-16
Poltinnikov et al. 5.5 (2.5–30) n.s. n.s. n.s. n.s. 65 G1 esophagitis-18
(2005) G2 esophagitis-24
G1 pneumonitis-6
Ebara et al. (2007) 6.5 1 yr = 27.7% n.s. n.s. n.s. 81 G2 pneumonitis-7
G3 pneumonitis-7
Cetingoz et al. (2009) 3 (n.s.) 1 yr = 8.7% 86 77 60 69 78 G1-2 esophagitis-77
2 yr = 5.8% G3 esophagitis-4
MST median survival time; OS overall survival; n.s. not stated; G grade
B. Jeremić et al.
Radiation Therapy for Recurrent Disease
with metastasis and those with second primary lung
cancer. Doses of the initial course of radiation therapy
ranged from 25 to 66 Gy, while those administered at
the time of recurrence ranged from 6 to 57 Gy.
Therefore, cumulative doses ranged from 43 to
122 Gy. Few patients underwent even third course of
radiation therapy (second reirradiation). Contrary to
radiation therapy treatment fields used during the
initial course of radiation therapy, which were usually
including more or less of uninvolved (prophylactic)
nodal regions, those used at the time of reirradiation
were obviously limited, in general only including
visible recurrence with a safety margin of 1–2 cm
(Green and Melbye 1982; Jackson and Ball 1987;
Montebello et al. 1993; Gressen et al. 2000). Fear of
excessive toxicity, which primarily may have occur-
red in lung and spinal cord, clearly governed the
choice of both total dose and treatment field used
during the reirradiation. Symptom relief was the main
goal of reirradiation. In a report of Gressen et al.
(2000), clinical data of existing articles were sum-
marized indicating a control of hemoptysis in 83%,
cough in 65%, dyspnoea in 60%, and pain in 64% of
cases. Reirradiation seemed to be less hazardous than
anticipated with a merely 3–5% complication rate
(Green and Melbye 1982; Jackson and Ball 1987;
Montebello et al. 1993; Gressen et al. 2000).
The last decade brought several studies which
provided additional evidence on effectiveness and low
toxicity of external beam radiation therapy in the
treatment of locally recurrent non-small-cell lung
cancer. Okamoto et al. (2002) reported on 29 males
and 5 females with initially irradiated stage I–IV non-
small-cell lung cancer that have been reirradiated
after a median time of 23 months (range,
5–87 months). Median initial radiation therapy dose
of 66 Gy (range, 30–80 Gy) was followed by median
reirradiation dose of 50 Gy (range, 10–70 Gy), lead-
ing to a median of 110 Gy total cumulative dose
(range 56.5–110 Gy). Authors clearly divided their
treatment into a radical and palliative, which affected
their treatment field design choice. Calculating from
the start of the initial radiation therapy, the median
survival time was 31 months and 2- and 5-year
overall survival rates were 65% and 33%,
respectively.
The study of Wu et al. (2003) was the first ever to
address the issue of reirradiation of 23 locoregionally
recurrent lung cancer patients after previous external
551
beam radiation therapy through a prospective phase
I–II study. After reirradiation, the median survival
time was 14 months and a 2-year survival rate was
21%, while 2-year locoregional progression-free sur-
vival was 42%. No acute grade C3 toxicity had been
reported during the follow up (median 15 months
after the end of reirradiation). Seventeen (74%)
patients had either grade 0 or 1 late toxicity. Six
(26%) patients had pulmonary fibrosis on computer-
ized tomography scan, of which symptomatic
(grade 3) was observed in 2 (9%) patients. Besides
promising results, this study also showed that its
prospective character may have enabled better
documentation of not only acute, but also late toxic-
ity. This may be especially important with expected
better results, including longer survivals newer tech-
nological tools may bring with successful dose esca-
lation owing to better imaging and dose conformation
deemed necessary for more curative approaches.
The prospective study of Kramer et al. (2004)
confirmed this observation, using 2 fractions of 8 Gy
given with one week split, a practical and comfortable
palliative regimen for both patients and hospitals. The
median survival time of 5.6 months was accompanied
with Karnofsky performance status score being
improved in 45% patients. The overall median dura-
tion of symptom relief was 4 months.
Contrary to Kramer et al. (2004), Tada et al. (2005)
used more radical approach with curative intent. They
have treated 19 patients with stage III non-small-cell
lung cancer with 50 Gy in 25 daily fractions,
including one patient treated with 60 Gy in 30 daily
fractions. Five patients could not receive the pre-
scribed reirradiation dose. Overall response rate was
43%. The overall 1-year and 2-year survival rates
were 26 and 11%, respectively, and the median sur-
vival time was 7.1 months.
Ebara et al. (2007) reported on a study with clearly
defined palliation as a goal. In the largest series
published so far, the authors included 44 patients with
in-field recurrent lung cancer after definitive radiation
therapy. Symptom relief was assessed according to
scoring system created by Kramer et al. (2004). While
initial radiation therapy doses ranged 50–70 Gy those
of reirradiation were 30–40 Gy. Chemotherapy was
initially given in 25 (57%) cases and at the time of
reirradiation in 16 (36%) cases. Size of radiation
therapy fields used at initial radiation therapy ranged
26–288 cm2 (median, 104 cm2), while those of
552
reirradiation ranged 16–100 cm2 (median, 48 cm2).
Symptom relief was observed in 74% of patients. The
median survival time was 6.5 months and 1-year
survival was 27.7% with only 3% patients experi-
encing Grade 3 pneumonitis. Distant metastasis at
reirradiation influenced survival favoring patients
without it (1- and 2-year rates, 31.3% and 31.3%
versus 25% and 0%, respectively; p = 0.02). Of all
variables investigated upon influence on survival,
only additional chemotherapy achieved statistical
trend toward improved survival in both univariate
(p = 0.067) and multivariate (p = 0.090) model.
The most recent report on the use of external beam
radiation therapy in reirradiation in non-small-cell
lung cancer is that of Cetingoz et al. (2009) who
reported the study comprising of 38 patients. Most of
the patients (81%) were previously treated with pal-
liative intent due to poor prognostic factors such as
advanced disease, poor performance status and pro-
nounced weight loss. Initial radiation therapy doses
ranged 28.8–67.2 Gy (median, 30 Gy) in 9–33
fractions (median, 10 fractions) with 2–3.2 Gy per
fraction. During reirradiation, a median total dose of
25 Gy (range, 5–30 Gy) in median of 10 fractions
(range, 1–10 fractions) with median of 3 Gy (range,
2–10 Gy) per fraction were delivered. The median
overall survival time (from the first irradiation) was
13.5 months (range, 4–65 months) and the median
survival time after reirradiation was 3 months (range,
0–65 months). One-year and two-year survival were
57.8 and 28.8%, respectively after initial diagnosis.
Recent years brought first reports on the use of
highly sophisticated radiation therapy planning and
execution in cases of reirradiation of mostly non-
small-cell lung cancer, such as stereotactic radiation
therapy or intensity modulated radiation therapy
(Beavis et al. 2005; Jereczek-Fosasa et al. 2008; Coon
et al. 2008; Chang et al. 2008). Beavis et al. (2005)
provided first report of the planning study on the use
of another novel radiation therapy technique, intensity
modulated radiation therapy, in the re-treatment of a
patient with non-small-cell lung cancer. Although
similar distributions were achieved for organs at risk
by intensity modulated radiation therapy versus con-
ventional technique, the target coverage given by the
conventional treatment option was clearly inferior to
that offered by the intensity modulated radiation
therapy plan. With the widespread use of intensity
modulated radiation therapy in cases when it can be of
B. Jeremić et al.
a significant advantage (e.g., shape and location of the
tumor as well as in cases of reirradiation), it is
expected that this technique plays an important role in
reirradiation of lung cancer in the future.
Poltinnikov et al. (2005) were the first to report on
the use of hypofractionated stereotactic fractionated
radiation therapy in 17 patients previously irradiated
to a median dose of 52 Gy (range, 50–66 Gy) deliv-
ered with concurrent chemotherapy in all cases. The
median time interval between completion of the first
course of radiation therapy and the start of reirradia-
tion was 13 months (range, 2–39 months). A median
dose of hypofractionated schedule was 32 Gy (range,
4–42 Gy), with a median fraction size of 4 Gy
(range, 2.5–4.2 Gy) delivered 3–5 times per week.
Five patients also received concurrent chemotherapy.
Radiologic response was observed in 5 (29%),
and stable disease in another 5 (29%) patients. The
median survival was from the start of reirradiation
was 5.5 months (range, 2.5–30 months). Symptom
resolution was observed in 11/13 (85%) symptomatic
patients, while no change was observed in the
remaining two (15%) patients. No Grade 3 or higher
side-effects were observed.
Three additional reports on the use of stereotactic
radiation therapy in recurrent non-small-cell lung
cancer were recently published. Chang et al. (2008)
used four-dimensional computerized tomography-
based planning to deliver 40–50 Gy to 14 patients
with isolated recurrent non-small-cell lung cancer
previously treated with definitive radiation therapy
with or without chemotherapy or surgical resection
before stereotactic radiation therapy. With a median
follow-up of 17 months (range, 6–40 months), the
crude local control at the treated site was 100% for
patients treated using 50 Gy. Four (29%) patients
developed Grade 2 pneumonitis, but no patient
experienced grade C3 toxicity. Coon et al. (2008)
reported on a similar fractionated stereotactic radia-
tion therapy but using novel technological tool called
Cyber Knife. For all (n = 12) patients with recurrent
tumors, a dose of 60 Gy was given in 3 fractions.
Importantly, in majority of patients pre-treatment
positron emission tomography-computerized tomog-
raphy scans were performed to aid in delineation of
tumor volume. Also, all patients received regularly
scheduled follow-up planned computerized tomogra-
phy or positron emission tomography-computerized
tomography imaging. Overall response rate was 75%,
Radiation Therapy for Recurrent Disease
while 17% of patients experienced stable disease. At a
median follow-up of 11 months, the local control rate
at the site treated was 92% and overall survival was
67%. Only one (2%) patient experienced Grade 2
pneumonitis. Most recently, Kelly et al. (2010) ret-
rospectively reviewed outcomes after stereotactic
radiation therapy for recurrent disease among patients
previously given radiation therapy to the chest at The
MD Anderson Cancer Center. There were 36 such
cases and the median follow-up time after stereotactic
radiation therapy was 15 months. Stereotactic radia-
tion therapy provided in-field local control for 92% of
patients; at 2 years, the actuarial overall survival rate
was 59%, and the actuarial progression-free survival
rate was 26%, with the primary site of failure being
intrathoracic relapse. Fifty percent of patients expe-
rienced worsening of dyspnea after stereotactic
radiation therapy, with 19% requiring oxygen sup-
plementation; 30% of patients experienced chest wall
pain and 8% grade 3 esophagitis. No grade 4 or 5
toxic effects were noted. This study confirmed pre-
vious, though limited, observations that stereotactic
radiation therapy can provide excellent in-field tumor
control in patients who have received prior radiation
therapy. Toxicity was significant but manageable. The
high rate of intrathoracic failure in this study indi-
cated the need for further study to identify patients
who would derive the most benefit from stereotactic
radiation therapy in this setting.
When overall results of external beam radiation
therapy in reirradiation of locally recurrent lung
cancer using different endpoints of studies are sum-
marized, the median survival times ranged from 3 to
14 months, while 1- and 2-year survival rates ranged
from 8.7–59 and from 5.8–27%, respectively. In
the series of Jackson and Ball (1987), 4-year rate
was 15 months. Interestingly, the three studies
that provided the longest median survival time
(7.1–14 months) and highest survival rates (Okamoto
et al. 2002; Wu et al. 2003; Tada et al. 2005) all used
reirradiation doses with median values of 50–51 Gy,
which was in contrast to studies using lower reirra-
diation doses which achieved the median survival
time of 4.9–5.6 months, indicating possible dose-
effect. Furthermore, in the study of Tada et al. (2005)
the median survival time for 14 patients who received
the prescribed dose was 10.5 months. Similarly, in the
study of Okamoto et al. (2002), while for the whole
group of patients, the median survival time was
553
8 months and a 2-year survival was 27%, for the
patients treated with curative intent and higher radi-
ation therapy doses, the median survival time was as
high as 15 months and 2-year survival was 51%.
Contrasting this is the observation of Jackson and Ball
(1987) who did not find difference between patients
retreated with 20 Gy and those retreated with 30 Gy,
possibly because both dose levels were relatively low.
Symptom relief varied between studies and
between symptoms investigated. Hemoptysis was
controlled in 33–100% cases, but when study of
Green and Melbye (1982) was excluded due to small
number of events (1 out of 3 responders), it became
rather uniform (83–100%). Cough was controlled in
43–77% cases, chest pain in 40–80% cases, while
dyspnea in 35–100% cases, the latter event having
greater range possibly again due to somewhat small
number of events reported in some studies. When,
however, overall symptom relief was considered,
except aforementioned studies of Green and Melbye
(1982) (48%) and Jackson and Ball (1987) (50%), it
became rather uniform, ranging 70–78% cases.
Reirradiation seemed to be less hazardous than
anticipated with a merely 5% complication rate
observed in initial studies (Green and Melbye, 1982;
Jackson and Ball, 1987; Montebello et al. 1993). The
most frequent event was esophagitis (20%), but
pneumonitis appeared in only 3% of cases, with
myelopathy and rib fracture being a rare and anec-
dotal event. These data may have suffered from both
underreporting and the lack of detailed scoring sys-
tems used in the past. When however, more recent
studies using scoring systems are taken into account,
grade 3 esophagitis was noted in only 4–6% cases,
and grade 3 pneumonitis was noted in 5–21% cases.
Somewhat higher incidence (21%) occurring in the
study of Okamoto et al. (2002) may have been the
consequence of the highest total cumulative and
highest median cumulative doses (150 and 110 Gy,
respectively) used. Additional support about possible
dose-effect for such an observation lies in the fact that
grade 2 pneumonitis occurred in that study in 35%
cases, while in other studies it was much less. Similar
total doses of initial radiation therapy and reirradia-
tion may have been the cause of grade 2–3 late lung
fibrosis occurring in 26% cases in the study of Wu
et al. (2003), of which only 2 (9%) was Grade 3. One
should not forget that, contrary to other studies which
largely lacked detailed late toxicity data, this study
554
was the only prospective study which have enabled
prospective data collection and therefore, better doc-
umentation of the events, especially important for late
toxicity. Toxicity data also reconfirmed that occa-
sional fatal (grade 5) event may occur. Although in
the study of Gressen et al. (10) a single patient died
due to possible radiation therapy pneumonitis author
did not exclude a possibility of the disease progres-
sion after receiving 30 Gy of reirradiation together
with concurrent and post-radiochemotherapy.
Of all potential prognostic factors investigated, age
was not shown to influence survival (Gressen et al.
2000; Ebara et al. 2007; Cetingoz et al. 2009).
Additionally, no difference in the treatment outcome
between patients \70 years and those C70 years was
observed (Gressen et al. 2000; Ebara et al. 2007). This
may indicate greater applicability of external beam
radiation therapy in this disease in elderly, in partic-
ular, irrespective of treatment intention and also when
severe late effects may become less important. Also,
neither tumor size nor its location was shown to
influence outcome (Cetingoz et al. 2009). Treatment
response may have positively influenced treatment
outcome (Green and Melbye 1982) as well as good
performance status (Green and Melbye 1982; Tada
et al. 2005), but not unequivocally (Ebara et al. 2007).
In the study of Tada et al. (2005), performance status
influenced survival being 12.6, 7.1, and 1.1 months
for patients with performance status 0–1, performance
status 2, and performance status 3, respectively. The
variable that was shown that may influence treatment
outcome was time interval between the end of first
radiation therapy and reirradiation. Interestingly,
studies of Tada et al. (2005) and Cetingoz et al.
(2009) showed that longer intervals may be advanta-
geous for better survival. In addition to it, Kramer
et al. (2004) observed that none of the patients with an
interval \10 months survived [5 months, while all
patients surviving [1 year had a tumor-free interval
of [1 year. Contrary to that, in the study of Gressen
et al. (2000) the time interval (C10 months ver-
sus \10 months), did not influence outcome, simi-
larly to the study of Ebara et al. (2007) who could not
document it when cut-off value was 13 months. Dose-
response was evaluated in the study of Jackson and
Ball (1987) and was found similar between 20 and
30 Gy (median doses). No influence of pre-radiation
therapy and reirradiation dose was found in the study
of Ebara et al. (2007). Stage was also found in one
B. Jeremić et al.
study to influence survival (9), with patients with
stage I and II having better survival then those with
IIIA or IIIB, with the latter two groups of patients
having similar survival. Also, an improvement in
symptom (dyspnea) control did not lead to improved
survival in the study of Gressen et al. (2000).
General observation coming from the literature is
that external beam radiation therapy is safe and
effective way of retreating recurrent non-small-cell
lung cancer after initial radiation therapy. It achieved
symptom control in substantial proportion of cases
(overall, approximately 80%). In many studies
asymptomatic patients were also included, indicating
therefore, intention of more ‘‘radical’’ approach of
investigators. This had led to longer survivals, espe-
cially when high-doses were successfully delivered,
leading to the median survival time of 15 months and
2-year survival of 51%, not different from those
achieved with contemporary radiochemotherapy
studies in treatment-naive locally advanced non-
small-cell lung cancer. They were also accompanied
with very low high grade toxicity (3–5%), especially
when modern radiation therapy technologies were
used. It seems that a course of both palliative radia-
tion therapy (e.g., 30 Gy in 10 daily fractions) or
more radical radiation therapy (e.g., 50 Gy in 25 daily
fractions) can be either repeated after initial radiation
therapy leading to total cumulative doses of
85–100 Gy without increased toxicity after a time
interval of 10–12 months. While no formal radiobi-
ological modeling was ever attempted to bring more
insight into ‘‘recommended’’ dose(s), these ‘‘obser-
vations’’ from the data from the literature should be
used cautiously.
Although there is great variety of radiation therapy
characteristics, especially total dose, dose per fraction
and dose prescriptions used, likely as the cause of
different techniques used, additional observations and
conclusions would include the following:
(1) there is tendency toward the use of smaller mar-
gins during treatment planning, especially in
more recent studies, using sophisticated tech-
niques of treatment planning; they allow high-
precision of dose delivery to as conformal vol-
umes as possible as necessary mode of achieving
total cumulative doses that surpass known total
tolerance doses in cases of primary, treatment-
naive non-small-cell lung cancer (Emami et al.
1991),
Radiation Therapy for Recurrent Disease
(2) there is tendency for better reporting of toxicity
occurring during and after reirradiation using
toxicity scoring systems; this is especially
important due to a need for better reporting of late
toxicity, an additional advantage for clinicians
and radiobiologists when large total cumulative
doses are concerned,
(3) there is a general lack of radiobiological impact
in this field, a disappointing fact due to some-
times surprisingly high total cumulative doses
which exceeded general belief of normal tissue
tolerance (Emami et al. 1991), especially when
this was coupled with low toxicity,
(4) Even in cases when chemotherapy had been
administered initially, concurrent chemotherapy
seems feasible to be safely administered during
reirradiation course due to low toxicity in studies
reporting its use, and
(5) time intervals between the initial radiation ther-
apy and reirradiation were specified more fre-
quently in more recent studies (Okamoto et al.
2002; Wu et al. 2003; Tada et al. 2005; Ebara
et al. 2007; Cetingoz et al. 2009; Poltninikov
et al. 2005), but not always (Coon et al. 2008;
Chang et al. 2008). In particular, the issue of time
interval between first and second radiation ther-
apy may be an important issue for better under-
standing natural history of the disease, its
potential influence on decision-making process,
and discussing the issue of potential prognostic
factors as well as toxicity expected to occur to a
lesser degree after prolonged time periods
between first and second radiation therapy. Reir-
radiation started as early as 1–6 months after the
first radiation therapy course and was as late as
39–87 months after it, with the similar median
values of 13–16 months (Wu et al. 2003; Tada
et al. 2005; Ebara et al. 2007; Poltninikov et al.
2005) and only exception were studies of
Cetingoz et al. (2009) where it was 8.5 months
and the study of Okamoto et al. (2002) where it
was 23 months. Importance of understanding the
influence of time interval between the first radi-
ation therapy and reirradiation comes from the
study of Tada et al. (2005) who showed that
besides performance status, time interval was
another important factor influencing treatment
outcome. Interval between first and second radi-
ation therapy also influenced treatment outcome:
555
the median survival time associated with time
intervals of less than 12 months, 12–18 months
and more than 18 months were 2.1, 7.1, and
11.5 months, respectively. Although Gressen
et al. (2000) did not observe this influence, this
was recently reconfirmed by Cetingoz et al.
(2009) who performed a multivariate analysis to
show that time interval between the first radiation
therapy and reirradiation was the only indepen-
dent prognosticator influencing overall survival.
These findings may imply less aggressive
behavior of tumors being both diagnosed and
reirradiated later, or simply better local control
achieved in cases of reirradiation occurring later,
but also preference of involved radiation oncol-
ogists to use higher doses with prolonged time
intervals between first radiation therapy and re-
irradiation. Although not specified in any study,
the latter item need to be put into the context of
speculation whether likelihood of reirradiation
(and if so, its characteristics) was affected by
initial radiation therapy characteristics. Interest-
ingly, in a large systematic review of palliative
thoracic radiation therapy there was more reirra-
diation to the thorax after low-dose palliative
radiation therapy compared to high-dose, but this
was insignificant (Fairchild et al. 2008).
Also, novel technologies, diagnostic and thera-
peutic, such as stereotactic radiation therapy, intensity
modulated radiation therapy, protons, or carbon ions
could enable earlier diagnosis as well as successful
dose escalation with low toxicity and provide neces-
sary tool for reirradiating local recurrence which need
radiation therapy with or without concurrent chemo-
therapy. Taking into account previous radiation ther-
apy characteristics, performance status and time
interval between initial radiation therapy and irradi-
ation could be seen as a starting point for discrimi-
nating curative from palliative intent in these patients
with former case advocating for higher doses, smaller
fields, and possible administration of concurrent
chemotherapy. Local recurrences not suitable for
radical treatment may require palliative radiation
therapy with fewer fractions given in shorter time.
While no clearly established guidelines can be
expected to appear soon helping clinicians in this
early task, due to great variety in basic tumor, patient
and radiation therapy characteristics of the accumu-
lated data from the literature, current wisdom calls for
556
prudent use of available technology in external beam
radiation therapy for reirradiation of locally recurrent
lung cancer, with clear objectives set up front.
5 Radiation Therapy in Reirradiation
of Small-Cell Lung Cancer
Radiation therapy was infrequently used to treat
locoregional recurrence of small-cell lung cancer.
Because of the fear that it may add only toxicity
without clear benefit for patients, this was especially
in cases of limited disease previously treated with a
combined radiochemotherapy approach. In cases of
extensive disease, radiation therapy at the time of
recurrence after initial chemotherapy also can be
considered, but this was mostly related to a symp-
tomatic patient. Investigators (Ihde et al. 1979; Ochs
et al. 1983; Salazar et al. 1991) used the doses as low
as 21 Gy but also as high as 60 Gy in patients har-
boring recurrences from both limited and extensive
disease small-cell lung cancer. Observed responses
within the radiation therapy field ranged 52–77%
patients, with the median survival times ranging only
3–4 months. Likely cause of such dismal figures
seems to be early systemic progression. Nevertheless,
the wide range of doses used gave an opportunity to
the authors to speculate about higher doses (C40 Gy)
producing better palliation, an important matter in
patients with limited remaining lifetime.
6 Endobronchial Brachytherapy
in Reirradiation of Locally
Recurrent Lung Cancer
In addition to external beam radiation therapy,
endobronchial brachytherapy was occasionally used
alone to treat recurrent bronchogenic carcinoma. This
was especially so in cases when previous external
beam radiation therapy has been given. Similarly to
the literature on the use of external beam radiation
therapy, the vast majority of reports included various
histologies combined with only a minority of patients
having small-cell histology. Unfortunately, some
reports included even patients with primary lung
carcinomas, additionally obscuring the picture. More
than 25 years ago early reports provided different
aspects of endobronchial radiation therapy with
B. Jeremić et al.
different sources such as 137-CS, 198-Au, or 192-Ir,
sometimes combined with low-dose external beam
radiation therapy (Mendiondo et al. 1983) with sat-
isfactory palliative results. Subsequent studies pro-
vided evidence on the effectiveness of endobronchial
brachytherapy using different dose rate in this disease.
The vast majority of these used high-dose rate
(Seagren et al. 1985; Mehta et al. 1989; Bedwinek
et al. 1991; Sutedja et al. 1992; Gauwitz et al. 1992;
Gustafson et al. 1995; Micke et al. 1995; Delclos et al.
1996; Ornadel et al. 1997; Hatlevoll et al. 1999; Kelly
et al. 2000; Zorlu et al 2008; Hauswald et al. 2010).
Importantly, in majority of reports previous external
beam radiation therapy was used with median doses
mostly ranging 54–58 Gy (Bedwinek et al. 1991;
Sutedja et al. 1992; Gauwitz et al. 1992; Gustafson
et al. 1995; Micke et al. 1995; Hauswald et al. 2010),
although in the study of Zorlu et al. (2008) the median
total conventional equivalent dose was 30 Gy (range,
30–70 Gy). Only rarely studies reported on the use of
a single fraction of endobronchial irradiation of either
10 Gy (Seagren et al. 1985; Hatlevoll et al. 1999;
Zorlu et al. 2008), or 15 Gy (Zorlu et al. 2008), or
20–30 Gy (Mehta et al. 1989). The dose per fraction
ranged 6–15 Gy, while in two German studies (Micke
et al. 1995; Hauswald et al. 2010) it was 5 Gy,
delivered in 2–4 fractions. Subjective response to
treatment was observed in 66–94%. In the study of
Ornadel et al. (1997), the percentage of patients with
scores 0 or 1 (none or mild) for each symptom pre-
treatment and at 3 months were as follows: cough
62–77% (43% improving by at least one grade),
dyspnea 32–56% (50% improvements by at least one
grade), hemoptysis 78–97%, and performance status
65–84% (54% by at least one grade). In the study of
Zorlu et al. (2008) performance status was improved
and symptomatology reduced in 81% of patients. Ten
out of 14 (71%) dyspneic patients recovered clini-
cally, while hemoptysis in 5 (36%) patients recov-
ered. However, the mean period of palliation was
disappointingly low, being only 45 days (range,
0–9 months). The period of palliation was signifi-
cantly longer in patients with high Karnofsky Per-
formance Status score (C80) at the initial evaluation.
The most recent study of Hauswald et al. (2010)
showed that relief of symptoms was documented as
excellent in 12% of patients and good in 46% of
patients. Complete remission was observed in 15% of
patients, and partial response in 58% of patients,
Radiation Therapy for Recurrent Disease
while 10% of patients showed no response to treat-
ment and 15% had progressive disease. In other
studies, objective response measured during bron-
choscopy was observed in 72–100% patients, while
radiologic documentation of re-aeration was observed
in 64–88% patients. Duration of response ranged
4.5–6.5 months. Actuarial local control rates were
rarely reported, being in the most recent study
of Hauswald et al. (2010) 17% at 1-year and 3% at
2-years, respectively. In that study, the median local
progression-free survival time was 4 months (range,
1–23 months). Reported survivals were as high as
25% at 1 year (Bedwinek et al. 1991), while Kelly
et al. (2000) and Hauswald et al. (2010) achieved
identical survival of 18% and 7% at 1- and 2-year,
respectively). The median survival time ranged
5–9 months (Bedwinek et al. 1991; Gauwitz et al.
1992; Delclos et al. 1996; Micke et al. 1995; Kelly
et al. 2000; Zorlu et al. 2008; Hauswald et al. 2010)
and two studies reported identical median survival
time of 7 months for responders (Sutedja et al. 1992;
Kelly et al. 2000). Various treatment-related compli-
cations have been observed; the most feared being
fatal bleeding. Incidence of severe pulmonary bleed-
ing in initial reports (Seagren et al. 1985; Bedwinek
et al. 1991; Sutedja et al. 1992) ranged 25–32%, while
most recent studies (Gauwitz et al. 1992; Gustafson
et al. 1995; Delclos et al. 1996; Kelly et al. 2000;
Zorlu et al. 2008; Hauswald et al. 2010) reported on
significantly lower incidence of this complication
ranging from 0 to 7%. Although a number of factors
were investigated upon their influence of the inci-
dence of fatal bleeding, no firm conclusion could be
drawn due to different nature of reporting (crude
versus actuarial), and due to frequently lacking pre-
treatment patient and tumor characteristics. However
in one such attempt, Ornadel et al. (1997) identified
prior laser resection as major factor contributing to a
risk (20% at 2 years in their study) of fatal hemopt-
ysis. While majority of studies concentrated on the
incidence of fatal hemoptysis, Hauswald et al. (2010)
also provided detailed analysis of other side-effects of
this treatment modality, such as tissue necrosis, pen-
umothoraces causing dyspnoea, bronchomediastinal
fistulas or mild hemoptysis not requiring transfusion.
It became obvious that detailed documentation of all
side-effects occurring during and after the treatment is
necessary as to enable one to put overall results of
endobronchial brachytherapy in this setting also into a
557
perspective of cost-benefit analysis, especially when
single-fraction HDR is considered. Regardless of
these shortcomings, endobronchial brachytherapy
remains to be one of the cornerstones of successful
palliative approaches in patients with symptomatic
endobronchial recurrences of lung cancer. This
treatment modality will be dealt upon in more detail
in another chapter.
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 Radiation Therapy for Metastatic Disease
Dirk Rades
Contents
1 Bone Metastases .......................................................
1.1 Background ................................................................
1.2 Radiation Therapy of Bone Metastases....................
1.3 Radiation Therapy of Bone Metastases: Meta-
Analyses.....................................................................
1.4 Re-irradiation (Re-RT) for Recurrent Bone Pain.....
1.5 Complicated Bone Metastases ..................................
2 Metastatic Spinal Cord Compression ...................
2.1 Background ................................................................
2.2 Radiation Therapy of Metastatic Spinal Cord
Compression ..............................................................
2.3 Radiation Therapy Preceded by Decompressive
Surgery .......................................................................
2.4 Re-irradiation for a Local Recurrence of Metastatic
Spinal Cord Compression..........................................
3 Brain Metastases......................................................
3.1 Background ................................................................
3.2 Radiation Therapy of Multiple Brain Metastases ....
3.3 Radiation Therapy of 1–3 Brain Metastases ............
4 Liver and Lung Metastases ....................................
4.1 Background ................................................................
4.2 Stereotactic Body Radiation Therapy of Liver
Metastases ..................................................................
4.3 Stereotactic Body Radiation Therapy of Lung
Metastases ..................................................................
References.......................................................................... 570
D. Rades (&)
Department of Radiation Oncology,
University of Lübeck, Lübeck, Germany
e-mail: Rades.Dirk@gmx.net
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_275, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
Bone metastases occur in up to 40% of NSCLC
562 patients. If associated with pathological fractures or
562 metastatic spinal cord compression (MSCC), they are
562
considered ‘‘complicated’’ lesions. Otherwise, they
563 are considered ‘‘uncomplicated’’. 1x8 Gy of radiation
564 therapy (RT) can be considered the standard treat-
564 ment of most uncomplicated painful bone metastases.
564 Single-fraction RT requires re-RT more often than
564 multi-fraction RT regimens. However, re-RT after
1x8 Gy is safe and effective. If re-RT is required after
565
longer-course RT with 10x3 Gy or 20x2 Gy, the
565 second RT course should be delivered using high-
precision techniques. For a pathological fracture,
566
surgical stabilisation followed by RT should be
566 performed. Remineralization of the osteolytic bone is
566 better after multi-fraction RT. For MSCC, short-
566
568 course RT is as effective as longer RT programs
regarding motor function. Local control of MSCC is
568
better after longer-course RT. Patients with MSCC
568
from NSCLC and a favorable survival prognosis
569 may be considered candidates for decompressive
surgery followed by longer-course RT. Decompres-
570
sive surgery would also be the first choice for a
local recurrence of MSCC after longercourse RT.
A recurrence after short-course RT can be safely
treated with another short-course of RT. Brain
metastases occur in 20–40% of cancer patients.
NSCLC is the most common primary tumor and
which accounts for at least 40% or more of these
patients. Most patients have multiple (4) lesions and
usually receive whole-brain radiotherapy (WBRT)
alone. Patients with a poor survival prognosis should
receive 5x4 Gy in one week, whereas patients with a
561
562
more favourable prognosis are candidates for longer-
course WBRT. Patients with 1–3 brain metastases
have a considerably better survival prognosis
and may benefit from more intensive treatments
including radiosurgery or surgery. WBRT in addition
to radiosurgery or surgery leads to improved local
control. The non-invasive regimen radiosurgery +
WBRT is at least as effective as surgery + WBRT,
and, therefore, preferable. Most data of SBRT of liver
metastases have been obtained from colorectal cancer
patients bur can be ‘‘extrapolated’’ to liver metastases
from NSCLC. SBRT if used for a limited number of
liver metastases can lead to high local control rates
and considered a reasonable alternative to other local
treatments. If SBRT is used for the treatment of lung
metastases, lung tissue density correction during
treatment planning is very important. In the treatment
of a limited number of lung metastases, SBRT can
result in excellent local control rates and median
survival times of more than three years. In summery,
radiation therapy if appropriately tailored to the
individual patient with metastasis from NSCLC can
provide valuable results in terms of relief of symp-
toms and improvement of the patient’s prognosis.
1 Bone Metastases
1.1 Background
Bone metastases occur in up to 40% of lung cancer
patients during the course of their disease (Coleman
2006). If bone metastases lead to pathological frac-
tures or metastatic spinal cord compression, they are
considered ‘‘complicated’’ lesions. Otherwise, they
are considered ‘‘uncomplicated’’. The survival prog-
nosis depends on the type of primary tumor. Patients
with bone metastases from lung cancer have an
unfavorable prognosis of a few months (Coleman
2006). However, there are long-term survivors as well
(Coleman and Rubens 1987).
1.2 Radiation Therapy of Bone
Metastases
Radiation therapy (RT) alone is the standard treat-
ment for uncomplicated painful bone metastases.
The treatment volume generally encompasses the
D. Rades
metastases plus a margin of 2–3 cm. Overall response
rates of 50–90% were reported, and complete
response rates ranged from 10 to 50% (Amouzegar-
Hashemi et al. 2008; Bone Pain Trial Working Party
1999; Foro Arnalot et al. 2008; Gaze et al. 1997;
Hartsell et al. 2005; Hoskin et al. 1992; Jeremic et al.
1998; Koswig and Budach 1999; Nielsen et al. 1998;
Niewald et al. 1996; Okawa et al. 1988; Rasmusson
et al. 1995; Roos et al. 2005; Steenland et al. 1999;
Tong et al. 1982). During RT, the phenomenon of
pain flare, a transient increase of bone pain, may
occur. The pain flare rate reported to be 14–44%
can be reduced by prophylactic administration of
dexamethasone (Chow et al. 2007a). Several ran-
domized trials compared different fractionation
regimens with respect to response, need for re-RT
because of recurrent pain, and pathological fractures
following RT. Two randomized trials compared
different single-fraction regimens. In 1992, Hoskin
et al. showed in 270 patients that 1 9 8 Gy was
superior to 1 9 4 Gy for overall pain response
(69 vs. 44%, P \ 0.001) and need for re-RT (9 vs.
20%, P \ 0.05) (Hoskin et al. 1992). Complete pain
relief was similar in both groups (39 vs. 36%,
P [ 0.05). In 1998, Jeremic et al. compared 1 9 4,
1 9 6 and 1 9 8 Gy in 327 patients (Jeremic et al.
1998). The rates of overall response were 59% after
1 9 4 Gy, 73% after 1 9 6 Gy and 78% after
1 9 8 Gy. Complete pain relief was achieved in 21,
27 and 32% of patients, respectively. Results after
1 9 6 and 1 9 8 Gy were not significantly dif-
ferent. 8 Gy may be considered as probably ‘‘low-
est’’ optimal single-fraction RT.
Also, several randomized trials compared single-
fraction RT of 1 9 8 Gy to a multi-fraction short-
course regimen such as 5 9 4 or 6 9 4 Gy given in
five or six working days. Two large trials are men-
tioned in detail. A randomized trial from the United
Kingdom compared 1 9 8 to 5 9 4 Gy in a series of
761 patients (Bone Pain Trial Working Party 1999).
No significant difference was observed between 1 9 8
and 5 9 4 Gy with respect to overall pain response
(72 vs. 68%, P [ 0.05), complete pain relief (52 vs.
51%, P [ 0.05) and post-RT pathological fractures
(2 vs. \1%, P = 0.2). Re-irradiation for another
episode of pain in the same area was required more
often after 1 9 8 than 5 9 4 Gy (23 vs. 10%,
P \ 0.001). A randomized trial of 1,171 patients from
The Netherlands compared 1 9 8 to 6 9 4 Gy
Radiation Therapy for Metastatic Disease
Fig. 1 Example of stereotactic body radiation therapy (SBRT) of a bone metastasis in the vertebral column. SBRT provides
excellent sparing of spinal cord and kidney
(Steenland et al. 1999). No significant difference was
observed between 1 9 8 and 6 9 4 Gy with respect to
overall pain response (72 vs. 69%, P = 0.24) and
complete pain relief (37 vs. 33%, P [ 0.05). The rate
of post-RT pathological fractures was significantly
higher in the 1 9 8 Gy group although being consid-
erably low (4 vs. 2%, P \ 0.05). Re-irradiation was
required more often after 1 9 8 Gy (25 vs. 7%,
P \ 0.001). Several other randomized trials compared
single-fraction RT of 1 9 8 Gy to multi-fraction
longer-course RT of 10 9 3 Gy in two weeks. In the
largest trial (N = 888), no significant difference was
observed between 1 9 8 and 10 9 3 Gy with respect
to overall pain response (65 vs. 66%, P = 0.6), com-
plete pain relief (15 vs. 18%, P [ 0.05) and post-RT
pathological fractures (5 vs. 4%, P [ 0.05) (Hartsell
et al. 2005). The need for re-irradiation for another
episode of pain in the same area was greater after 1 9 8
than 10 9 3 Gy (18 vs. 9%, P \ 0.001). Randomized
trials that compared different multi-fraction regimens
such as 5 9 4, 5 9 5, 10 9 3, or 15 9 2 Gy showed
that no particular regimen was superior to another
regimen (Niewald et al. 1996; Okawa et al. 1988;
Rasmusson et al. 1995; Tong et al. 1982).
563
1.3 Radiation Therapy of Bone
Metastases: Meta-Analyses
In 2003, Wu et al. presented a meta-analysis of eight
randomized trials with 3,260 patients that compared
1 9 8 Gy to multi-fraction regimens ranging from
5 9 4 to 10 9 3 Gy (Wu et al. 2003). In the treatment
per-protocol analysis (N = 2,683), 39% of patients after
1 9 8 Gy and 50% of patients after multi-fraction RT,
respectively, achieved complete pain relief (relative risk
[RR] 0.98; 95%-confidence interval [CI] 0.89-1.07;
P = 0.6). The overall response rates were 73 and 73%,
respectively (RR 1.00; 95%-CI 0.95-1.04; P = 0.9).
Wu et al. did not report the need for re-irradiation and
post-RT pathological fracture rates. Similar results
were reported by Sze et al. for 3,621 patients from 12
randomized trials (Sze et al. 2003). The rates of complete
pain relief were 34% after single-fraction RT and 32%
after multi-fraction RT (odds ratio [OR] 1.10; 95%-CI
0.94-1.30, P [ 0.05). The overall pain response rates
were 60 and 59%, respectively (OR 1.03; 95%-CI
0.90-1.19; P [ 0.05). The re-irradiation rates were
22% after single-fraction and 7% after multi-fraction RT
(OR 3.44; 95%-CI 2.67-4.43; P \ 0.05). The post-RT
564
pathological fracture rates were 3.0 and 1.6%, respec-
tively (OR 1.82; 95%-CI 1.06-3.11; P \ 0.05). This
may be explained by the fact that 10 9 3 Gy can lead to
a significantly higher increase in bone density than
1 9 8 Gy (Koswig and Budach 1999). In 2007, Chow
et al. presented a meta-analysis of 5,000 patients from 16
randomized trials (Chow et al. 2007b). The overall
pain response rates were 58% after single-fraction RT
(mostly 1 9 8 Gy) and 59% after multi-fraction RT
(mostly 5 9 4 or 10 9 3 Gy) (OR 0.99; 95%-CI
0.95-1.03; P = 0.60). Complete pain relief was
achieved in 23 and 24% (558/2,351) of patients,
respectively (OR 0.97; 95%-CI 0.88-1.06; P = 0.51).
The re-irradiation rates were 20% after single-fraction
and 8% (158/2,032) after multi-fraction RT, respectively
(OR 2.50; 95%-CI 1.76-3.56; P \ 0.001). The rates of
pathological fractures following RT were not signifi-
cantly different, 3.2 and 2.8%, respectively (OR 1.10;
95%-CI 0.61-1.99; P = 0.75). This result is in contrast
to the data of the meta-analysis of Sze et al. (2003). Thus,
it remains unclear whether single-fraction RT is really
associated with a higher rate of pathological fractures.
1.4 Re-irradiation (Re-RT) for Recurrent
Bone Pain
Re-RT after single-fraction RT is safe and effective
(Jeremic et al. 1999; Mithal et al. 1994). Acute toxicity
of re-RT has been reported to not exceed grade 2. In a
retrospective study of 105 patients, the overall pain
response rate after re-RT was 87% (Jeremic et al. 1999).
Eight patients received a third course of RT to the same
region. Response was observed in seven patients.
In another study of 109 patients, the overall response
rate to re-RT was 74% (Mithal et al. 1994). If re-RT
is required after longer-course RT with 10 9 3 or
20 9 2 Gy, the second course of RT should be delivered
using high-precision techniques (stereotactic body RT,
radiosurgery, intensity-modulated RT, proton beams) to
better spare healthy tissues and reduce the risk of late
toxicity. An example of stereotactic body RT from the
University of Lubeck, Germany, is given in Fig. 1.
1.5 Complicated Bone Metastases
In case of a pathological fracture, surgical stabilisa-
tion should be performed whenever possible. Because
surgery usually does not result in complete removal of
D. Rades
the tumour tissue, post-operative RT is required to
avoid a recurrence and slackening or dislocation of
the osteosynthetic material. Another important goal of
radiation therapy is the remineralization of the oste-
olytic bone, which appears better after multi-fraction
than after single-fraction radiation therapy (Koswig
and Budach 1999). Because significant remineraliza-
tion can only be expected several months after RT,
patients with a favorable survival prognosis may not
be treated with single-course RT. However, many
patients with bone metastases from non-small cell
lung cancer have a poor survival prognosis and,
therefore, are candidates for single-fraction RT. The
survival prognosis of patients with bone metastases
can be estimated with scoring systems (Katagiri et al.
2005; Van der Linden et al. 2005). Another possible
complication is metastatic spinal cord compression,
which is covered below.
2 Metastatic Spinal Cord
Compression
2.1 Background
Metastatic Spinal Cord Compression (MSCC) occurs
in 5–10% of all patients with cancer during the course
of their disease (Loblaw et al. 2003; Bach et al. 1990).
Lung cancer is one of the most common primary
tumors in patients with MSCC accounting for about
20% of these patients. Despite improved treatment
approaches, the treatment of MSCC still is a chal-
lenge, in particular when one intends to tailor the
treatment to each patient. The most common symp-
tom of MSCC is back pain (70–96%) followed by
motor deficits (61–91%), sensory deficits (46–90%),
and dysfunction of bladder or bowel control
(40–57%) (Bach et al. 1990; Gilbert et al. 1978).
If pain is the only symptom without neurologic defi-
cits, the situation can be described as impending
MSCC. Dysfunction of bladder or bowel control
occurs late and requires surgical intervention when-
ever possible. However, radiation RT alone is the
most common treatment for MSCC. It should be
supplemented by administration of dexamethasone
whenever possible. To avoid severe side affects such
as gastrointestinal bleeding and psychosis, an inter-
mediate dose of 12–40 mg/day with a taper during or
immediately after RT is recommended.
Radiation Therapy for Metastatic Disease
2.2 Radiation Therapy of Metastatic
Spinal Cord Compression
The treatment volumes of RT for MSCC usually
encompass one to two normal vertebral bodies above
and below the metastatic lesions. If only a limited
number of vertebrae are involved and the survival
prognosis is favorable, RT can be administered to the
involved vertebrae plus a safety margin of 1–2 cm
based on computed tomography-based treatment
planning. The most appropriate RT regimen depends
on the patient’s survival prognosis and the endpoints.
Improvement of motor function is generally consid-
ered the most relevant endpoint. Four published pro-
spective studies compared different RT regimens with
respect to functional outcome (Rades et al. 2004,
2011; Maranzano et al. 2005, 2009). In 2004, a non-
randomized prospective study of 214 patients from
Germany compared 10 9 3 Gy in two weeks and
20 9 2 Gy in four weeks (Rades et al. 2004). The
rates of improvement of motor function (43 vs. 41%,
P = 0.80) and post-RT ambulatory status (60 vs.
64%, P = 0.71) were similar in both groups. In 2005,
a randomized trial of 276 patients from Italy
compared 2 9 8 Gy and a split-course regimen
(3 9 5 Gy in three days followed by four-day-rest
and 5 9 3 Gy in one week) and found both schedules
similarly effective (Maranzano et al. 2005). In 2009,
another randomized study from Italy demonstrated
that 1 9 8 and 2 9 8 Gy in eight days resulted in
similar functional outcome (Maranzano et al. 2009).
Recently, a prospective study of 265 patients from
Germany and The Netherlands comparing short-
course (1 9 8 or 5 9 4 Gy) to longer-course RT
(10 9 3, 15 9 2.5 or 20 9 2 Gy) suggested both
regimens to be similarly effective with respect to
functional outcome (Rades et al. 2011b). Motor
function improved in 37% after short-course and 39%
after longer-course RT (P = 0.95).
One retrospective study that focused particularly
on patients with MSCC from NSCLC was reported
in 2006 (Rades et al. 2006). That study compared
short-course and longer-course RT with respect to
functional outcome. Improvement of motor function
was observed in 15% of patients after short-course
and 13% after longer-course RT (P = 0.87).
Furthermore, these results showed that patients with
MSCC from NSCLC have a worse functional out-
come after RT than patients with other primary
565
tumors. Besides functional outcome, local control
of MSCC is another important endpoint, in partic-
ular for long-term survivors. These patients may
live long enough to experience such a recurrence.
In a prospective study, longer-course RT resulted in
significantly better 1-year local control than short-
course RT (81 vs. 61%, P = 0.005) (Rades et al.
2011b). Thus, short-course RT appears preferable
for patients with a poor expected survival including
most NSCLC patients. Patients with a better
survival prognosis may benefit from longer-course
RT in terms of better remineralization of the oste-
olytic bone and better local control of MSCC. The
survival prognosis of MSCC patients can be esti-
mated with a validated scoring system (Rades et al.
2008a; 2010a). Patients with a very favorable
prognosis may be candidates for high-precision RT,
which allows better sparing of the surrounding
normal tissues and/or a dose escalation to the
metastatic site.
2.3 Radiation Therapy Preceded
by Decompressive Surgery
The major advantages of spinal surgery when com-
pared with RT are immediate decompression of the
spinal cord and direct mechanical stabilization of the
spine. Indications for spinal surgery include intras-
pinal bony fragments, spinal instability, impending or
present sphincter dysfunction, no response to previous
radiotherapy treatment, and a recurrence of MSCC
after longer-course RT. The benefit of surgery plus
RT compared to RT alone is still controversial.
A small randomized study of 101 patients found a
benefit for surgery followed by 10 9 3 Gy compared
to 10 9 3 Gy alone (Patchell et al. 2005). Signifi-
cantly more patients in the surgery group were able to
walk after treatment (84 vs. 57%, P = 0.001).
Patients who received surgery maintained the ability
to walk for a longer period (122 vs. 13 days,
P = 0.003). However, several researchers suggested
that the results may have been confounded due to
methodological problems (Kunkler 2006; Knisely and
Strugar 2006). Furthermore, the study appeared sta-
tistically underpowered, and only very selected
patients with an expected survival of C3 months,
a good performance status, and involvement of
only one spinal area were included. In a recent
566
multi-national matched-pair analysis of 324 MSCC
patients, improvement of motor function occurred in
27% after surgery plus RT and 26% after RT alone
(P = 0.92) (Rades et al. 2010b). Post-treatment
ambulatory rates were 69 and 68%, respectively
(P = 0.99). An additional matched-pair analysis
performed by the same group for tumors considered
unfavorable with respect to response to RT alone
(including NSCLC) suggested that these patients do
benefit from decompressive surgery in addition to RT
(Rades et al. 2011c). Motor function improved in 28
and 19% of patients, respectively (P = 0.024).
NSCLC patients with a relatively favorable survival
prognosis may be considered candidates or decom-
pressive surgery followed by longer-course RT.
2.4 Re-irradiation for a Local Recurrence
of Metastatic Spinal Cord
Compression
A local recurrence of MSCC in the previously irra-
diated area of the spinal cord may occur. 1-year
local failure rates of 19% after longer-course and
39% after short-course RT have been reported
(Rades et al. 2011b). Decompressive surgery would
be the first choice in patients who develop a recur-
rence of MSCC in the previously irradiated region.
However, the indication for surgery is limited to
10–15% of these patients and re-irradiation may be
the only alternative option (Patchell et al. 2005;
Prasad and Schiff 2005). However, a second series
may result in a relatively high cumulative biologi-
cally effective dose (BED) and an increased risk of
radiation myelopathy. Re-irradiation seems well
tolerated if the cumulative BED is B120 Gy2, which
is the case if two series of short-course RT are
administered (Rades et al. 2008b). Re-irradiation
with 1 9 8, 5 9 3 or 5 9 4 Gy proved to be effec-
tive (Rades et al. 2008b, 2005). Improvement of
motor function occurred in 40% of the re-irradiated
patients, and progression of motor deficits was
stopped in another 45% (Rades et al. 2005). After
longer-course RT with a higher BED (75 Gy2 for
10 9 3 Gy and 80 Gy2 for 20 9 2 Gy), the cumu-
lative BED is likely to exceed 120 Gy2 (Rades et al.
2008b). In such a situation, high-precision RT
should be used. Improvement of neurological deficits
was reported in 42 and 84% of patients after high-
D. Rades
precision RT (Milker-Zabel et al. 2003; Gerszten
et al. 2007).
3 Brain Metastases
3.1 Background
Brain metastases occur in 20–40% of all cancer
patients during the course of their disease (Khuntia
et al. 2006). NSCLC is the most common primary
tumor, which accounts for 40% or more of all patients
with brain metastases. The number of brain metastases
is an important prognostic factor. About 60% of
patients have multiple (C4) lesions, and about 40%
have a limited number of 1–3 lesions or a single lesion.
A solitary lesion is defined as a single lesion without
additional extracerebral metastases. Headache is
the most common clinical symptom. Depending on
the metastatic site, symptoms may vary including
seizures, vision disturbances, hearing problems, nau-
sea, motor deficits, and others.
3.2 Radiation Therapy of Multiple Brain
Metastases
Patients with multiple brain metastases usually receive
whole-brain radiotherapy (WBRT) plus dexametha-
sone (12–40 mg/day with a taper during or immedi-
ately after WBRT) (Khuntia et al. 2006). Most patients
with brain multiple metastases have a poor survival
prognosis. This accounts particularly for patients with
brain metastases from NSCLC. The median survival
of untreated patients with multiple lesions is about one
month (Zimm et al. 1981). Even with WBRT, these
patients have a median life expectancy of only a few
months (Sundstrom et al. 1998). Thus, short-course
WBRT such as 5 9 4 Gy in 1 week would be pref-
erable, if it provided similar outcomes as longer
WBRT programs such as 10 9 3 Gy in 2 weeks and
20 9 2 Gy in 4 weeks. A few studies compared short-
course to longer-course WBRT for multiple brain
metastases (Harwood and Simson 1977; Priestman
et al. 1996; Borgelt et al. 1980; Borgelt et al. 1981;
Chatani et al. 1994). Whereas most studies found no
significant differences in survival, one prospective
study suggested a marginally better median survival
after long-course WBRT with 10 9 3 Gy than after
Radiation Therapy for Metastatic Disease
Fig. 2 Example of linear accelerator based stereotactic radiosurgery of a single brain metastasis
short-course WBRT with 2 9 6 Gy (2.8 vs.
2.5 months, P = 0.04) (Priestman et al. 1996). Only
one study focused on NSCLC patients and compared
5 9 4 Gy (n = 140) to 10 9 3 or 20 9 2 Gy
(n = 262) with respect to survival (Rades et al.
2007a). Of the 404 patients, 16% had a single lesion.
The survival rates at 6, 12, and 24 months were 40, 16,
and 6%, respectively, after 5 9 4 Gy, and 30, 17, and
10%, respectively, after longer-course WBRT
(P = 0.55). Thus, most patients with multiple brain
metastases from NSCLC appear not to benefit from
longer-course WBRT. Patients with a favorable sur-
vival prognosis may be candidates for longer-course
567
WBRT with lower doses per fraction, as it has been
suggested that the risk of radiation induced neuro-
cognitive deficits is lower with doses per fraction of
\3Gy (De Angelis et al. 1989). The survival prog-
nosis of patients with brain metastases can be
estimated with the help of prognostic scores (Gaspar
et al. 1997; Rades et al. 2011a). The attempt to
improve the survival after WBRT with the addition of
chemotherapy has failed (Antonadou et al. 2002;
Postmus et al. 2000; Mornex et al. 2003). However,
data from a very limited number of patients suggested
median survival times of more than a year with the use
of tyrosine-kinase inhibitors (Ma et al. 2009).
568
3.3 Radiation Therapy of 1–3 Brain
Metastases
Patients with 1–3 brain metastases have a consider-
ably better survival prognosis than patients with C4
lesions and may benefit from a more intensive treat-
ment including radiosurgery or surgery. An example
of stereotactic radiosurgery from the University of
Lubeck, Germany, is given in Fig. 2.
For patients with a single lesion, three small
randomized trials compared WBRT alone to
WBRT ? surgery (Patchell et al. 1990; Vecht et al.
1993; Mintz et al. 1996). Patchell et al. reported a
longer median survival time (9.2 vs. 3.5 months,
P \ 0.01) and fewer local recurrences (20 vs. 52%,
P \ 0.02) after combined treatment than WBRT
alone in 48 patients (Patchell et al. 1990). Median
survival times in the study of Vecht et al. (N = 63)
were 10 months after WBRT ? surgery and
6 months after WBRT alone (P = 0.04) (Vecht et al.
1993). Mintz et al. (N = 84) did not find a significant
difference in median survival (5.6 vs. 6.3 months,
P = 0.24) (Mintz et al. 1996). In a more recent ret-
rospective study of 195 patients, WBRT ? surgery
resulted in better 1-year survival (48 vs. 26%,
P \ 0.001) and 1-year intracerebral control (57 vs.
24%, P \ 0.001) than WBRT alone (Rades et al.
2008c). Considering the available data, WBRT ?
surgery is superior to WBRT alone. In a randomized
trial of 95 patients that compared surgery alone to
surgery ? WBRT, surgery ? WBRT resulted in
better 1-year intracerebral control (82 vs. 30%,
P \ 0.001), whereas median survival was similar in
both groups (Patchell et al. 1998).
In patients with 1–3 lesions, radiosurgery alone
was reported to be superior to WBRT alone
with respect to 1-year local control (64 vs. 26%,
P \ 0.001) and 1-year survival (52 vs. 33%,
P = 0.045) in a retrospective series of 186 patients
(Rades et al. 2007b). Another retrospective study of
144 patients compared radiosurgery alone to WBRT
plus radiosurgery (Rades et al. 2008d). 1-year survival
rates were 53% after radiosurgery alone and 56%
after WBRT ? radiosurgery (P = 0.24); 1-year local
control rates were 66 and 87% (P = 0.003), respec-
tively. In a randomized trial of 132 patients with 1–4
brain metastases from Japan, the 1-year survival rates
were 39% in the WBRT ? radiosurgery group and
28% in the radiosurgery alone group (P = 0.42)
D. Rades
(Aoyama et al. 2006); 1-year local control rates were
53 and 24%, respectively (P \ 0.001). A more recent
randomized trial of 359 patients compared radiosur-
gery or surgery alone to radiosurgery or surgery plus
WBRT (Kocher et al. 2011). Survival was similar in
both groups (P = 0.89). The addition of WBRT
improved local control after surgery (P \ 0.001) and
radiosurgery (P = 0.40). Local control is an impor-
tant endpoint, because an intracerebral recurrence
(and not the addition of WBRT) is considered the
most relevant factor for a post-treatment decline in
neurocognitive function (Meyers et al. 2004; Aoyama
et al. 2007). Aoyama et al. (2007) showed in a sub-
group analysis of their randomized trial that the
neurocognitive function at one and two years was
significantly better in those patients receiving WBRT
in addition to radiosurgery.
In two retrospective studies that compared radio-
surgery ? WBRT to surgery ? WBRT, all patients
had received WBRT (Schöggl et al. 2000; Rades
et al. 2009). Schöggl et al. (2000) who compared
both treatment regimens in 133 patients with a single
brain metastasis, reported median survival times of
12 months in the radiosurgery and 9 months in the
surgery group (P = 0.19). Local control was sig-
nificantly (P \ 0.05) better in the radiosurgery
group. Rades et al. (2009) reported a matched-pair
analysis of 104 patients with 1–3 brain metastases.
The 1-year local control rates were 87% after radi-
osurgery ? WBRT and 66% after surgery ? WBRT
(P = 0.021). 1-year survival rates were 56 and 41%,
respectively (P = 0.08). The non-invasive regimen
radiosurgery ? WBRT appears at least as effective
as surgery ? WBRT, and, therefore, appears pref-
erable to surgery ? WBRT for both patients with a
single lesion and patients with 1–3 lesions. WBRT
should be performed as longer-course WBRT, pref-
erably with doses per fraction of \3 Gy, in order to
further reduce the risk of post-treatment neurocog-
nitive deficits.
4 Liver and Lung Metastases
4.1 Background
Because systemic therapies have considerably
improved in the treatment of metastatic NSCLC, in
particular in the case of liver and lung metastases, the
Radiation Therapy for Metastatic Disease
Fig. 3 Example of stereotactic body radiation therapy (SBRT) of a single pulmonary lesion providing excellent sparing of heart
and lungs
role of conventional RT has become less important.
This accounts in particular for whole-liver irradiation
(Timmerman et al. 2009). However, if only a limited
number of liver or lung metastases require treatment,
stereotactic body radiation therapy (SBRT) may be an
option, particularly if a resection of the metastases is
not possible or refused by the patient.
4.2 Stereotactic Body Radiation Therapy
of Liver Metastases
Most data regarding SBRT of liver metastases have
been obtained from colorectal cancer patients and not
from NSCLC patients. However, ‘‘extrapolation’’ of
the data from liver metastases from colorectal cancer
to metastases from NSCLC appears possible. Gener-
ally, the size of liver metastases treated with SBRT
should be \5 cm, although fractionated SBRT has
been used for lesions of up to 10 cm (Timmerman
et al. 2009). Radiation-induced liver disease (RILD)
including symptoms such as hepatomegaly, ascites
and elevated liver transaminases is a serious toxicity
following liver irradiation and may also occur
following SBRT (Hoyer et al. 2006; Blomgren et al.
1995). If the treatment is given in three fractions, no
569
more than 50% of the liver should receive 15 Gy, and
no more than 30% should receive 21 Gy. In case of a
single-fraction treatment, the doses are 12 and 7 Gy,
respectively. A few small studies are available that
investigated local control and survival after SBRT for
liver metastases (Wulf et al. 2001; Mendez Romero
et al. 2006; Herfarth et al. 2001; Katz et al. 2007;
Kavanagh et al. 2006). Two studies administered three
fractions of 10 (Wulf et al. 2001) and 12.5 Gy
(Mendez Romero et al. 2006), respectively. The 2-year
local control rates were 61 and 82%, respectively, and
the 2-year survival rates were 41 and 50%, respec-
tively. Herfarth et al. presented a dose-escalation
study of single-fraction SBRT (15–26 Gy) and
achieved a 67% local control rate at 18 months
(Herfarth et al. 2001). Katz et al. (2007) used dif-
ferent fractionation regimens (30–55 Gy given in
5–15 fractions); at 20 months, local control and
survival rates were 57 and 37%, respectively.
Kavanagh et al. reported an actuarial local control
rate of 93% after SBRT with 3 9 20 Gy for 1–3
liver metastases, which they considered safe (Kava-
nagh et al. 2006). Thus, SBRT if used for a limited
number of liver metastases can lead to high local
control rates and can be considered a reasonable
alternative to other local treatments.
570
4.3 Stereotactic Body Radiation Therapy
of Lung Metastases
An example of SBRT for a pulmonary lesion from the
University of Lubeck, Germany, is given in Fig. 3.
If SBRT is used for the treatment of lung metastases,
lung tissue density correction during treatment plan-
ning is very important (Timmerman et al. 2009).
Toxicities which may occur after RT of lung tumors
and metastases include pneumonitis, decline in
pulmonary function, hemoptysis, and atelectasis. The
risk of such toxicities is higher for central lesions.
Because most lung metastases are located peripher-
ally, the risk of RT- related toxicity is lower than for
primary lung tumors. Furthermore, the irradiated lung
volume is smaller with SBRT than with conventional
RT. Between 1995 and 2003, several small studies
with less than 25 patients were reported using a great
variety of different fractionation regimens (Blomgren
et al. 1995; Wulf et al. 2001; Uematsu et al. 1998;
Nakagawa et al. 2000; Nagata et al. 2002; Hara et al.
2002; Lee et al. 2003). The local control rates ranged
between 67 and 98%. In 2006, Okunieff et al. reported
on 50 patients who received 10 9 5 Gy of SBRT for
1–5 pulmonary lesions (Okunieff et al. 2006). Of the
total of 125 lesions, eight progressed (local control
rate 94%). The median overall survival time was
23.4 Gy. In 2008, Norihisa et al. presented 34 patients
who received 4–5 9 12 Gy of SBRT for 1–2 lesions
(Norihisa et al. 2008). The 2-year local control rate
was 90%, the 2-year overall survival rate was 84%,
and the median survival time was [36 months. In a
most recent study presented by Rusthoven et al.
(2009) the 2-year actuarial local control rate was
96%, and the median survival time was 19 months.
For a limited number of lung metastases, SBRT can
result in excellent local control rates and median
survival times of more than three years.
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 Advances in Supportive and Palliative Care
for Lung Cancer Patients
Michael J. Simoff

Contents
1 Introduction.............................................................. 575
2 Dyspnea ..................................................................... 576
2.1 Hypoxia...................................................................... 576
2.2 Chronic Obstructive Pulmonary Disease .................. 576
2.3 Endobronchial Disease .............................................. 577
3 Pleural Disease ......................................................... 584
4 Tracheoesophageal Fistula...................................... 587
5 Cough ........................................................................ 587
6 Hemoptysis................................................................ 588
7 Conclusion ................................................................ 589
References.......................................................................... 589
1 Introduction
Abstract
As advancements are continuing to be made in the
diagnosis and treatment of lung cancer, the number
of symptoms that patients present to their managing
physicians with, also increases. The most significant
of these; dyspnea, cough, and hemoptysis can be
very difficult to treat. The goal of this chapter is to
offer clinicians a greater awareness to the variety of
possible etiologies and the possible therapeutic
interventions available to them and their patients

The majority of patients with lung cancer will expe-

rience some symptoms (dyspnea, cough, and/or
hemoptysis) during the course of their disease. These
symptoms can greatly affect, not only the quality of
life of these patients, but may also influence the
therapeutic modalities that their physician may want
to employ to deliver further therapy.
Most physicians would define palliation as the
relief or soothing of symptoms of a disease, but not
affecting cure. The term palliation has often been
associated with end of life care of patients with can-
cer. In this chapter a broader view of palliation will be
used. As an example of this, relief of an airway
M. J. Simoff (&)
obstruction in a patient with end-stage lung cancer
Bronchoscopy and Interventional Pulmonology, may allow them not to suffocate as their cause of
Pulmonary and Critical Care Medicine, death, versus a patient diagnosed with an airway
Henry Ford Medical Center, obstruction, subsequently proven to be cancer. This
Wayne State University School of Medicine,
Detroit, MI 48202, USA
patient’s airway obstruction is relieved and the patient
e-mail: msimoff1@hfhs.org can breathe better and thereby undergo more

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 575
DOI: 10.1007/174_2011_313, Ó Springer-Verlag Berlin Heidelberg 2011
576
aggressive therapy as well as have a diminished risk
of a post obstructive pneumonia. Although ‘‘cure’’
may not be effected by the direct intervention, many
palliative techniques can increase survival of patients
in addition to improving their quality of life. In the
study by Brutinel et al. (1987) in a patient population
affected by airway obstruction, 84–92% of their
patients had symptomatic palliation of symptoms
solely with laser resection of the endobronchial tumor.
Survival at 7 months was better in the laser bronchos-
copy group (60%, n = 71) than in the control group
(0%, n = 25) (Brutinel et al. 1987). This idea is an
expansion on the traditional view of palliation; with
more modern tools and techniques, this broader view
should be a part of all treating physicians’ thinking.
Symptoms that patients with lung cancer may
experience include: dyspnea, cough, and hemoptysis.
Many different manifestations of lung cancer (local
invasion, metastasis, or paraneoplastic syndromes)
may be responsible for any or all of these. The goal of
this chapter will be to expand the treating physician’s
awareness of a variety of these etiologies and a
variety of possible therapeutic interventions.
2 Dyspnea
Dyspnea will affect 65% of all patients with lung
cancer during some time in their disease course
(Jacox et al. 1994; World Health Organization 1990).
The etiologies of dyspnea can vary including:
hypoxia, progression of underlying diseases [i.e.
chronic obstructive pulmonary disease (COPD),
asthma, congestive heart failure (CHF), etc.], airway
obstruction, pleural disease, deconditioning from
inactivity brought on from therapy or from extended
stays in the hospital; depression and malnutrition can
also be a cause as these also occur in many patients
(Hoegler 1997).
Dyspnea is a very complex problem as the myriad
of etiologies or combinations of conditions can lead to
a difficult time for patients and physicians. If the
etiology for the dyspnea can be identified correctly it
can be managed successfully. With some type of
palliative treatment, the patient may have a much
greater tolerance for further interventions (whether it
be radiation therapy, chemotherapy, or surgery),
which might have been impossible except for this
intervention.
M. J. Simoff
2.1 Hypoxia
When a patient is short of breath, it is often an
automatic response by patients, nurses and physi-
cians that the patient needs oxygen. Hypoxia is a
common complication in patients with lung cancer.
Hypoxia is defined as an oxygen saturation of \88%.
Some patients will have hypoxia at rest. Other
patients will maintain adequate oxygenation while
resting but quickly desaturate with activity devel-
oping dyspnea. Supplemental oxygen is a very
common intervention to help relieve dyspnea do to
desaturations in patients with hypoxia both at rest
and with exertion (Escalante et al. 1996). When
patients are hypoxic with rest or with activity, the
use of oxygen with sleep can often help improve
rest. The prescription of oxygen particularly with
activity should be titrated to ensure that patients are
receiving the appropriate doses.
Hypoxia is an objective diagnosis, but dyspnea is
not. The simple technique of directing a hand-held fan
toward your face can help diminish the sense of
shortness of breath. Galbraith et al. (2010) have
demonstrated this in their study published in 2010,
which supports the hypothesis that a hand-held fan
directed to the face reduces the sensation of breath-
lessness. It must be remembered by practitioners that
oxygen should be prescribed for patients with
hypoxia, but if a patient is not hypoxic other etiolo-
gies of dyspnea should be looked for.
2.2 Chronic Obstructive Pulmonary
Disease
It is not uncommon for patients with lung cancer to
have other underlying diseases of their lungs, partic-
ularly chronic obstructive pulmonary disease
(COPD). During therapy for lung cancer, the treat-
ments themselves and/or infections brought on by
immunosuppression of the treatments can lead to
exacerbations of a patient’s chronic underlying dis-
order. Beta-2 agonists, antibiotics, and sometimes
steroid use can often improve the tracheobronchitis
and/or bronchospasm associated with the flare-ups.
The use of aggressive treatment regimens can assist in
controlling some of the underlying lung disease,
which can manifest as worsening shortness of breath.
Checking airway mechanics with objective testing
Advances in Supportive and Palliative Care for Lung Cancer Patients
Fig. 1 Endobronchial obstruction from a lung cancer
such as spirometry can assist in the assessment of
patients with increasing shortness of breath and
underlying disease. Tell-tale reductions in dynamic
airway volumes (FEV1 and FVC) can help guide
therapeutic approaches and measure response of those
therapies with return to baseline values.
2.3 Endobronchial Disease
Most new cases of lung cancer in the United States
will be in an advanced stage (Cancer Facts and
Figures 2001). More than 50% of these patients will
have some involvement of the central airways (Fig. 1)
(Luomanen and Watson 1968). This can be in the
form of bulky endobronchial disease, endobronchial
extension, or extrinsic compression of the airways by
the tumor or by lymphadenopathy. These patients
may have respiratory symptoms: shortness of breath,
hemoptysis, and/or cough. Many of these patients
may benefit from endobronchial intervention as part
of the management of their disease (Cancer Facts and
Figures 2001).
We as humans have a great capacity of reserve in
our ability to breath. It is very uncommon to have
dyspnea until the airways are greater than 50%
obstructed. Not all endobronchial disease causes
complete obstruction of the airways. Patients who
have partial airway obstruction (less than 50%), will
577
often develop worsening shortness of breath as their
therapy progresses, particularly during radiation
treatments. When radiation treatments involve the
areas of obstruction mucosal inflammation occurs
causing worsening airway obstruction. When this
becomes greater than 50%, symptoms will begin.
Therefore, endobronchial techniques should not only
be considered as the end-stage of lung cancer man-
agement but also both at the beginning and throughout
the management of patients with lung cancer (Cortese
and Edell 1993).
Lastly, when all management options have been
used, end-stage patients can develop compromise of
their airways as the cancer continues to progress. In
these situations, endobronchial techniques may ben-
efit the patient in its more traditionally accepted role
of palliation. Endobronchial management options
may help to relieve some of their symptoms,
allowing the patient freedom from shortness of
breath in conjunction with hospice or other end-
of-life therapies. (Cortese and Edell 1993; Sutedja
et al. 1995).
Most patients with dyspnea due to airways
obstruction are at home and limited but ambulatory, a
smaller number of patients are inpatient due to the
degree of their dyspnea and others are receiving
mechanical ventilatory support due to the severity of
their disease. The majority of procedures performed
in the United States for airway obstructions are
therefore performed on an outpatient basis. Those
patients hospitalized due to dyspnea, post-obstructive
pneumonia, or respiratory failure, very commonly
improve quickly, often being extubated or discharged
home postoperatively. This rapid symptomatic
improvement allows patients to remain ambulatory
with an improved quality of life. It may also allow
them to continue with or begin additional anti-cancer
treatment. Although interventional procedures are not
definitive therapies, they often provide partial to total
relief of the severe dyspnea produced by nearly
complete airway occlusion.
Interventional pulmonary programs that include
endobronchial procedures should include an arma-
mentarium of therapeutic modalities rather than a
single-invasive approach to manage patients with
complicated lung cancer. As each patient’s anatomy
differs, the manner in which the patient’s cancer leads
to symptoms varies. Several procedures used in
conjunction (i.e. laser and stenting) may be necessary to
578
Fig. 2 Flexible bronchoscope
provide the most effective treatment. The necessity of
multiple modalities can also be affected by the patient’s
medical condition, for instance, patients with high-
oxygen requirements cannot be treated with traditional
thermal energy modalities. Regarding endobronchial
prosthesis, the use of both metallic and silastic stents is
very important as each stent type has great advantages
over the other. A program offering a wide variety of
modalities allows the best selection of approaches for
any given patient (Cortese and Edell 1993).
The following sections discuss a variety of tech-
niques and tools available to the interventionalist. In
many cases, no one technique is better than the other,
and some combination of these techniques often
offers the greatest benefit to the patient.
2.3.1 Bronchoscopy
Since the inception of flexible fiberoptic bronchos-
copy in the late 1960s in Japan and in 1970 in
the United States, the flexible bronchoscope has
M. J. Simoff
Fig. 3 Rigid bronchoscope
become the most wide-spread tool for evaluating
and diagnosing diseases of the airways and lungs
(Fig. 2) (Ikeda 1970, 1995). The rigid broncho-
scope, the flexible bronchoscope’s predecessor, was
in many regards forgotten as a tool until interven-
tional pulmonology evolved in the 1980s. Inter-
ventional pulmonologists reevaluated this tool and
found its properties advantageous for the procedures
that are currently performed. A survey in 1991 by
the American College of Chest Physicians reported
that only 8% of responding pulmonologists used a
rigid bronchoscope (Prakash and Stubbs 1991).
Despite the expansion of interventional pulmonolo-
gy, the number of pulmonologists who use a
rigid bronchoscope as part of their practice remains
very low.
Overall, both the flexible bronchoscope and the
rigid bronchoscope are necessary for the practice of
interventional pulmonology. The rigid bronchoscope
offers many advantages to the interventional pulmo-
nologist, one of which is superior control of the air-
way. Ventilation is performed through the rigid
bronchoscope itself rather than around the flexible
bronchoscope. The larger-bore rigid bronchoscopes
allow optical systems, large caliber suction catheters,
and ablative instruments to pass through the scope
simultaneously. Large biopsy forceps are used
through the rigid bronchoscope, which can provide
Advances in Supportive and Palliative Care for Lung Cancer Patients
more significant tissue biopsies as well as assist in
mechanical debulking of lesions.
The rigid bronchoscope itself (Fig. 3) can be used to
debulk tumor from the airway lumen. The distal end of
the bronchoscope has a beveled end. This edge can be
used to shear large sections of endobronchial tumor
away from the airway wall in a technique often referred
to as applecoring. In a report on 56 patients with
endobronchial obstruction from the trachea to the distal
mainstem bronchi, Mathisen and Grillo (1989) descri-
bed improvement in 90% of their patients. Only 3 of the
56 patients had more than minor bleeding with this
procedure. Applecoring combined with the use of lar-
ger biopsy forceps allows tumor to be quickly resected
from the obstructed airway.
There is debate in terms of the use of only a
flexible bronchoscope versus a flexible bronchoscope
in conjunction with a rigid bronchoscope. It is true
that more tools and techniques have been developed
for the flexible bronchoscope; it is an excellent tool
for many airways procedures. The rigid broncho-
scope is a more difficult instrument to use than a
flexible bronchoscope, and the rigid bronchoscope
requires additional training beyond the typical fel-
lowship. Rigid bronchoscopy is also most commonly
performed in the operating room with general
anesthesia, limiting its availability to some pul-
monary physicians. Despite this, to provide the best
therapeutic options for patients with airways disease,
the use of both tools is necessary.
2.3.2 Laser Therapy
Lasers have many medical uses, including the
endobronchial ablation of lung cancer. Several types of
lasers are currently used within the bronchi: neodymium:
yttrium-aluminum-garnet (Nd:YAG), potassium-
titanyl-phosphate (KTP), and carbon dioxide (CO2).
Newer diode as well as the yttrium–aluminum–
perovskite (YAP) lasers have also entered the mar-
ketplace. Still, the most commonly used endoscopic
laser is the Nd:YAG, which delivers energy at
a wavelength of 1,064 nm. The laser energy is
conducted via a quartz monofilament and thus can be
easily used with either the rigid or flexible broncho-
scopes. Normally, Nd:YAG is used at 30–60 W, but it
has a wide range of power outputs, up to 100 W.
Depending on the energy level used, the laser can
treat superficially, penetrate tissue several millimeter
in depth, or provide complete tissue destruction.
579
Fig. 4 Main carina after laser resection of endobronchial
tumor
The KTP laser has many of the same properties as
the Nd:YAG with a delivered wavelength of 532 nm.
The CO2 laser is more difficult to apply to endo-
bronchial tumors as it requires a direct line of fire and
is therefore only used with suspension laryngoscopy.
A new fiberoptic adaptor and fiber has become
available from Omniguide (Omniguide Inc., Cam-
bridge, MA). Although an excellent cutting tool, the
CO2 laser is not a good photocoagulation device, in
contrast to Nd:YAG and YAP wavelengths and
despite the newer fiberoptic option, the CO2 laser
remains less commonly used.
The predominant tissue effects of lasers are ther-
mal necrosis (photodessication) and photocoagulation
(Fig. 4). Thermal necrosis uses higher energy levels
to destroy tissue, causing the formation of eschar or
actual photodessication of tissue. This technique must
be used cautiously as most lung cancers have signif-
icant vascularity. When destroying tissue with laser
energy, large blood vessels can be perforated with the
tissue destruction, leading to significant hemorrhage.
The technique of photodessication is an excellent tool
for managing airways disease, but does require a
skillful operator. Photocoagulation uses lower energy
levels with longer exposure intervals, causing tumors
to ‘‘shrink’’ and diminishing blood flow to that region.
By devascularizing the tumor, more rapid mechanical
debulking can be performed with improved control of
bleeding.
580
Table 1 Advantages/disadvantages of silastic stents
Advantages
Removable and replaceable
No growth through stent
Low cost
Low likelihood of granulation tissue formation
Disadvantages
Potential for migration/dislodgment
Rigid bronchoscopy needed for placement
Possible secretion adherence
Table 2 Advantages/Disadvantages of Metal Stents
Advantages
Easy to place
Good wall/internal diameter relationship
Powerful radial force
Excellent conformity for irregular tracheal or bronchial
walls
Good epithelialization
Disadvantages
Permanent
Tumor regrowth (non-covered)
Possible migration of covered stents
Significant granulation tissue stimulation
Epithelialization adversely affecting wall mechanics and
secretion clearance
Radial force causing necrosis of bronchial wall, erosion,
fistulas, perforation
Laser therapy can be performed via either flexible
or rigid bronchoscopy. Many interventionalists prefer
rigid bronchoscopy for laser procedures when possi-
ble. Nd:YAG laser fibers can be passed through the
working channel of most flexible bronchoscopes. An
advantage of using the flexible bronchoscope is that
laser energy can be delivered to areas that cannot be
reached with a rigid bronchoscope (Brutinel et al.
1987; Mathisen and Grillo 1989; Hetzel et al. 1983;
Mehta et al. 1985; McDougall and Corese 1983; Toty
et al. 1981; Dumon et al. 1982; Arabian and Spagnolo
1984; Beamis et al. 1991; Sonett et al. 1995; Macha
et al. 1994; Desai et al. 1988; Stanopoulos et al. 1993;
Cavaliere et al. 1994; Ross et al. 1990). For this
reason, a fiberoptic bronchoscope can be inserted
through the rigid bronchoscope whenever necessary
M. J. Simoff
Fig. 5 Montgomery T-tube
to improve angulations or exposure of parts of an
airway obstruction.
The reported success rate of symptom palliation
using laser energy in the endobronchial management
of lung cancer is high. Reports of clinical improve-
ment rates range from 84 to 92% following laser
bronchoscopy (Dumon et al. 1982; Beamis et al.
1991; Cavaliere et al. 1988; Kvale et al. 1985;
Eichenhorn et al. 1986). Other studies demonstrate
improved survival in patients treated with laser
bronchoscopy (Brutinel et al. 1987; Desai et al. 1988;
Stanopoulos et al. 1993; Petrovich et al. 1981).
2.3.3 Endobronchial Prosthesis
Endobronchial prosthesis are airway stents, which can
be placed in response to several clinical situations:
intrinsic, extrinsic, or mixed endobronchial obstruc-
tion. Stents are composed of silastic rubber, metal
alloys, or hybrids (mixed materials). Stents work well
in conjunction with other modalities such as laser and
mechanical debulking of tumors. Advantages and
disadvantages of each stent type are noted in Tables 1
and 2.
2.3.3.1 Silastic Stents
Many of the silastic stents now in use evolved from
the Montgomery T-tube, which was first used in the
early 1960s. This T-shaped stent supports the entire
trachea with an arm that extends through a tracheot-
omy. In patients with a patent tracheostomy, the
Montgomery T-tube remains an excellent tool for the
management of endotracheal, particularly sub-glottic
disease (Fig. 5) (Colt and Dumon 1993; Cooper et al.
1989; Montgomery 1965).
Advances in Supportive and Palliative Care for Lung Cancer Patients 581

Fig. 6 a The Dumon silastic

stent. b The Dumon-Y stent

In 1990, Dumon (1990) reported the use of what is

now referred to as the Dumon stent (Novatech, Plan
de Grasse, France). Developed in 1987, it is a silastic
stent with evenly spaced studs along its outside walls.
(Fig. 6a, b) The studs are intended to minimize
migration of the stent in the airway. The studs also
allow the clearance of secretions around the walls of
the stent.
Dumon stents are effective in maintaining their
structural integrity when placed endobronchially. The
solid walls of the stent prevent tumor growth from
re-obstructing airways. In the situation of a newly
diagnosed lung cancer with airways obstruction, the
endobronchial tumor can be debulked and then a stent is Fig. 7 The Hood bronchial stent
placed prior to the initiation of radiotherapy, chemo-
therapy, or both. Both external beam radiotherapy and
brachytherapy can be used with a Dumon stent in place. Another silastic stent is the hood stent (Hood
Another advantage of the Dumon stent is the ease of Laboratories, Decatur, Georgia). The Hood stent is
its removal. This can be important when endobronchial similar to the Dumon stent in design and use. The
procedures are used early in the management of cancer Hood stent is placed in the same manner as the
patients. After definitive therapies have been used Dumon stent, using a rigid bronchoscope (Fig. 7)
(radiation, chemotherapy), re-evaluation of the airway (Gaer et al. 1992).
can be performed, at which time the stent can be left in
place, removed (if deemed of no further clinical 2.3.3.2 Metallic Stents
advantage), or replaced with a larger stent that would Metallic stents, such as the ultraflex (Boston Scien-
further improve the caliber and stability of the airway. tific, Boston, MA) and AERO stent (Merit Medical
The disadvantages of the Dumon stent are the potential Systems, Inc., South Jordan, Utah) have been used in
for migration and the need for a rigid bronchoscope the endobronchial management of lung cancer. The
for placement. Migration occurs less often when an advantage of metal stents is the relative ease for
experienced interventional endoscopist places the stent placement via a flexible bronchoscope with fluoro-
(Petrovich et al. 1981; Dumon 1990; Mehta 2008; scopic assistance. This ease of placement has led
Diaz-Jimenez et al. 1994; Freitag et al. 1995; Clarke some bronchoscopists to use these stents as their only
et al. 1994). method to manage endobronchial disease. Such a
582
Fig. 8 The Ultraflex stent-covered and uncovered
practice limits the options to patients who may
otherwise be available if all interventional modalities
were offered. The wire mesh design of many of the
original metal stents did not prevent the tumor from
growing through the stent. The ultraflex stent is also
available in covered versions and the AERO stent is
covered. A wrap is applied to the outside of the wire
mesh to prevent tumor invasion through the stent.
There is good data for the use of these stents in the
endobronchial management of lung cancer (Colt and
Dumon 1991, 1993; Mehta 2008; Bolliger et al. 1993;
Gelb et al. 1992).
Ultraflex stents are made of nitinol, a titanium and
nickel alloy, which has little bioreactivity. This stent
has excellent inner to outer diameter ratio and con-
forms well to various airway shapes, maintaining an
equal pressure along the entire length of the stent
despite expansion size. Ultraflex stents are available
in a variety of lengths and diameters. Overall the
covered version of this stent is excellent for use in
palliation of airway obstruction (Fig. 8).
AERO stents (previously alveolus stents) are
another metallic stent, which is available for clinical
use (Fig. 9). This stent has similar advantages as the
Ultraflex stents, but are completely covered form end-
to-end. This added covering can assist intervention-
alists in limiting tumor from reinvading airways after
resection. It has also been demonstrated that the
AERO stents complete coverage allows less compli-
cated removal, much like the Dumon stent (Dumon
1990).
The uncovered portions of metal stents epithelial-
ize as they remain in the airways, thereby becoming
incorporated into the wall of the bronchus. This
M. J. Simoff
Fig. 9 The AERO stent
Fig. 10 The Dynamic-Y hybrid stent
epithelization changes the mechanics of the airways
with time by making them stiffer, which may lead to
further airway complications (Freitag et al. 1995;
Gelb et al. 1992). This may not be a concern in situ-
ations of palliation of late-stage disease, but must be
considered if long-term survival is expected. Another
consideration with metal stents is that once they are
inserted, their removal can be difficult and often
impossible. Although uncommon, another risk with
the use of metal stents is the erosion that can occur
through bronchial/tracheal walls. This was more of a
concern with the older Gianturco stents, which are no
longer used, than with newer metallic stents.
2.3.3.3 Hybrid Stents
The Dynamic-Y stent (Boston Scientific, Boston,
MA) is a hybrid stent with silastic walls and stainless
steel c-rings that artificially represent the cartilage
(Fig. 10). The posterior wall of the stent is made of a
thinner silastic rubber to make it more dynamic,
similar to the membranous trachea. The three avail-
able sizes of this stent are designed to traverse the
entire length of the trachea with branches into the
right and left mainstem bronchi. The Dynamic-Y stent
requires rigid bronchoscopy and is difficult to place,
Advances in Supportive and Palliative Care for Lung Cancer Patients
Fig. 11 The Polyflex stent
remaining uncommon in clinical practice. Despite
this, the Dynamic-Y stent offers excellent results
when placed in the appropriate.
The Polyflex stent (Boston Scientific, Boston, MA)
is another hybrid stent made of woven polyester
monofilament network with a complete coating of
silicone. The Polyflex stents solid wall design pre-
vents tumor growth but this stent does have a very
high expansion pressure to the airway wall (Fig. 11).
Stents are effective tools for the endobronchial
management of lung cancer. Stents should be chosen
carefully, weighing advantages and disadvantages of
each.
2.3.4 Photodynamic Therapy
Photodynamic therapy (PDT) is an adjunctive
modality to the management of endobronchial dis-
ease. It has been reported in use with bulky
obstructing airways disease, but it has a limited role
and does not replace Nd:YAG lasers, stents, and rigid
bronchoscopy (Lam 1994; Sutedja et al. 1994). The
most suitable lesions for PDT are in situ carcinomas
or those limited to 2–4mm of microinvasion (not
through the cartilaginous layer of the airway) (Furuse
et al. 1993).
A photosensitizing drug is intravenously adminis-
tered to the patient 48–72 h prior to the procedure.
Porfimer sodium (Photofrin, Axcan Pharma Inc.,–
United States, Birmingham, Alabama) is the most
common agent used. This photosensitizer penetrates
all cells systemically. It is not cleared as quickly from
cancer cells as in most other cells of the body and is
therefore found in higher concentrations in cancer
cells as opposed to the endothelium surrounding the
tumor at the time of treatment (Furuse et al. 1993;
Hayata et al. 1993). An argon dye or diode laser is
then used to provide the 632 nm wavelength light
energy required to activate the intracellular porfimer
583
sodium. The laser energy is transmitted via a flexible
quartz fiber, which can be used through either a
flexible or rigid bronchoscope. The fiber tip can be
placed in close proximity to the tumor mass or it can
be imbedded into the tumor to provide the energy
needed to start the intracellular activation of the
porfimer sodium. This reaction leads to an intracel-
lular photooxidative reaction and subsequent cellular
destruction. Tissue necrosis ensues as the cancer cells
die (Furuse et al. 1993; Hayata et al. 1993; Moghissi
et al. 1999).
As the neoplastic tissue becomes necrotic, it must
be removed. This requires repeated bronchoscopies,
the first within 36 h of the treatment. Bronchoscopy
can then be repeated as it is deemed necessary by the
degree of necrosis and tissue sloughing identified.
One of the reasons PDT is a poor selection for
obstructing airways disease is that the necrosis of
bulky tumor can be dangerous to the patient if the
necrotic tissue separates from the bronchial wall and
occludes the airway. In programs that use only PDT
for obstructing airway tumors, patients remain intu-
bated following the procedure for 1–2 days because
of this concern. If necrotic tissue is removed over the
first 24–48 h, a second laser application to the cancer
can be performed, thus improving the cancer tissue
destruction.
PDT is an excellent therapeutic modality for
patients with early-stage cancers. It destroys neo-
plastic tissue effectively and is an outstanding thera-
peutic modality in the management of carcinoma in
situ and microinvasive cancers. Further discussion of
this is beyond the scope of this chapter. PDT is a
necessary tool in the armamentarium of endobron-
chial treatments, but the time delays and multiple
steps of management make it a more cumbersome
therapy for the management of late-stage endobron-
chial lung cancer (Moghissi et al. 1999).
2.3.5 Cryotherapy
Cryotherapy is another method to destroy malignant
tissue that obstructs the tracheobronchial tree. Tissue
is frozen and then thawed to destroy it, instead of the
heat used in laser-based technologies. A probe is
placed onto or into an obstructing tumor mass. Liquid
nitrogen (–196°C) or nitrous oxide (–80°C) cools
the probe tip when performing cryotherapy. The
tissue freezing and thawing cycle used in cryotherapy
leads to the destruction of all cells in an area of
584
approximately 1 cm in diameter of the probe tip.
The vascular thrombosis that occurs with the super-
cooling of tissue minimizes the bleeding during the
eventual resection of the tumor.
The limiting factor to using cryotherapy is that
the tissues destroyed with the freezing procedure take
time to die and necrose. This requires another
procedure to remove the necrosed tissue and, in some
cases, repeating treatments. Although cryotherapy is
effective at tumor destruction and management, the
necessity of repeated procedures makes this a more
time-consuming technique to perform, limiting its
usefulness in the management of bulky endobronchial
disease causing severe dyspnea (Maiwand and
Homasson 1995). An advantage of cryotherapy is that
it can be used at any level of oxygen (FiO2) a patient
may require to correct hypoxia. Laser, electrocautery,
and argon plasma coagulation all must be used in an
environment with an FiO2 \40%. If the FiO2 is
greater than 40%, the risk of an airway fire becomes
very high and places the patient at significant risk.
2.3.6 Electrocautery/Argon Plasma
Coagulation
Electrocautery devices or the argon plasma coagula-
tion (APC) catheters can be introduced through a
flexible bronchoscope (one that is grounded and
designed for this therapy) and can then be used to
debulk endobronchial disease. With both devices
electrical energy is used to cauterize tissue, thus
minimizing the bleeding that occurs with tumor
resection. Endobronchial electrocautery treatment can
be used similar to laser therapy and/or cryotherapy for
managing advanced endobronchial lung cancer
(Gerasin and Shafirovsky 1988).
Electrocautery uses unipolar electrodes to deliver
electric current to the tissue. The delivered energy
affects the tissue in three ways: an electrolytic effect
(altering chemical bonding), a capacitance effect
(affecting the electrical potential of local structures),
and a thermal effect (due to the resistance of the tissue
to he flow of electrical current). Of these, the thermal
effect is clinically that, which is most desired.
Argon plasma coagulation, instead of using a uni-
polar contact delivery mechanism for electrical
energy, uses ionized argon gas as the conductance
medium between the electrode and tissue. This non-
contact tool allows a ‘‘painting’’ of the desired area
with, in essence, a gaseous form of electrical energy
M. J. Simoff
causing a similar thermal effect as electrocautery. This
delivery of energy allows large areas to be treated
relatively quickly and can be an ideal tool when
significant bleeding is encountered. On the other hand,
the more defined area of contact with the electrocau-
tery delivery devices allows a higher energy to be
delivered point specific to the tissue, creating an
excellent tool for cutting as well as coagulating.
2.3.7 Balloon Dilatation
Balloons used for intravascular procedures can be
used to manage endobronchial stenosis secondary to
both malignant and benign disease. Most balloons
come in a variety of diameters and lengths to help
dilate areas of bronchial compromise. Some currently
available balloons will dilate to three different
diameters depending on the pressure applied to the
balloon. Malignant strictures are sometimes dilated
prior to the placement of a stent or even used inside of
a stent to fully expand it once it has been placed.
The balloon is passed endobronchially via either a
rigid or flexible bronchoscope. The appropriate
diameter and length of the balloon are chosen for the
particular lesion. Ideally, 5–10 mm of balloon should
extend beyond the lesion both proximally and distally.
The treatment should be performed as a series of
dilatations with gradual increase in the balloon
diameter to minimize the risk of tracheobronchial
rupture. The balloon is inflated with a fluid, usually
saline. The use of fluid provides a even more distri-
bution of pressure across the entire balloon rather than
the unequal pressures seen when air is used to inflate
the balloon. Once inflated to the prescribed pressure,
the dilatation pressure should be maintained for
1–2 min. Two minutes is preferable if the patient can
tolerate this without discomfort or hypoxia.
Balloon dilatation is an adjunctive therapy to
bronchoscopy, laser, and/or stenting. When used
alone, its effects are most often temporary and
symptom recurrence sill often occurs.
3 Pleural Disease
Malignant pleural effusions occur in 7 to 15% of lung
cancer patients (Cohen and Hossain 1966; Emerson
et al. 1959; Johnston 1985; Le Roux 1968), greater than
half of whom develop dyspnea (Chernow and Sahn
1977). The mechanism of dyspnea with pleural
Advances in Supportive and Palliative Care for Lung Cancer Patients
effusions is unclear. Mechanical factors influencing the
chest wall, mediastinum, pleural space, and lung itself
may all contribute to the sensation of dyspnea in the
patient with a pleural effusion.
Pleural effusions in the setting of lung cancer may
be malignant or benign. The primary techniques used
to diagnose malignant pleural effusions are: thora-
centesis, closed needle pleural biopsy, and pleuros-
copy or medical thoracoscopy.
Thoracentesis is the most common technique used
in the initial evaluation of pleural effusion. Pleural
fluid obtained by thoracentesis yields cytology posi-
tive for malignant cells in 62–90% of true malignant
pleural effusions (Hsu 1987; van de Molengraft and
Vooijs 1988; Starr and Sherman 1991; Loddenkemper
et al. 1983). Closed-needle pleural biopsies remain an
option for the evaluation of a malignant pleural
effusion. Pleural biopsy historically has a lower
diagnostic yield than cytology from thoracentesis,
40–75% (Starr and Sherman 1991; Loddenkemper
et al. 1983; Prakash and Reiman 1985; Poe et al.
1984; Escudero Bueno et al. 1990). There is a 7–12%
additive yield from closed needle biopsy over cytol-
ogy alone (Starr and Sherman 1991; Loddenkemper
et al. 1983; Prakash and Reiman 1985). Perhaps
because of this small, added benefit, the practice of
closed-needle pleural biopsies has diminished in most
clinical practises.
Medical thoracoscopy is a procedure more com-
monly being used by non-surgeons for the diagnosis
and treatment of pleural effusions. This technique has
excellent results in the diagnosis and treatment of
malignant pleural effusions in appropriate popula-
tions. In a study of patients being evaluated for
malignant effusion, all enrolled patients had cytologic
assessment by thoracentesis, closed-needle pleural
biopsies, followed by thoracoscopy. This representa-
tive study demonstrated diagnostic yields of 62% for
thoracentesis, 44% for closed-needle pleural biopsy,
with a combined sensitivity of 74%, and a diagnostic
yield for medical thoracoscopy of 95% (Loddenkemper
1998). Other studies have demonstrated similar
results (Boutin et al. 1981; Oldenburg and Newhouse
1979; Menzies and Charbonneau 1991; Canto et al.
1977). After medical thoracoscopy had been per-
formed less than 10% of effusions remain undiag-
nosed (Boutin et al. 1981; Canto et al. 1977;
Loddenkemper 1981; Martensson et al. 1985), while
after thoracentesis for cytology and closed-needle
585
pleural biopsy are performed greater than 20% of
effusions remain undiagnosed (Storey et al. 1976;
Hirsch et al. 1979; Lamy et al. 1980).
In institutions where medical thoracoscopy is not
performed, most thoracic surgeons can perform
video-assisted thoracoscopic surgery (VATS). VATS
differs from medical thoracoscopy in that patients
undergoing VATS will have general rather than
moderate anesthesia, they will be intubated, usually
with a double lumen tube, rather than be spontane-
ously breathing, and three incisions will be made
rather than the typical one (two for certain proce-
dures). VATS is an excellent procedure, but is very
aggressive for a diagnostic procedure in an otherwise
uncomplicated pleural effusion.
The major indication for treating a pleural effusion
is for the relief of dyspnea. Once the diagnosis has
been made, a therapeutic plan needs to be established;
remembering that the etiology of the dyspnea is more
complex than the amount of fluid identified in the
pleural space (Estenne et al. 1983; Light et al. 1986;
Agusti et al. 1997; Karetzky et al. 1978; Brown et al.
1978; Krell and Rodarte 1985), and may be related to
problems with the lung itself (lymphangitic spread of
tumor, atelectasis, direct tumor invasion, etc.). The
limitation of diaphragmatic movement caused by fluid
accumulation is a major mechanism of dyspnea in
patients with untreated pleural effusions. Trapped
lung due to parenchymal or pleural disease will
minimize the relief of dyspnea by the evacuation of
pleural fluid and/or pleurodesis. Therefore initially, a
therapeutic thoracentesis should be performed to
assess the effects upon breathlessness by fluid
removal and the ability of the lung to re-expand, as
well as the rate and degree of reaccumulation. Chest
X-ray should be performed pre- and post-therapeutic
thoracentesis to evaluate for lung re-expansion.
Chest radiographs should be used to assess as to
whether or not the pleural fluid is free flowing or loc-
ulated, as well as the mediastinal position in respect to
the volume of the pleural effusion. Contralateral shift of
the mediastinum with large effusions suggests that
evacuation of the effusion should provide relief of
dyspnea to the patient. Expert opinion would suggest
that no greater than one to one and a half liters of
effusion be removed at each thoracentesis, stopping
earlier should the patient experience dyspnea, chest
pain, or coughing. The coughing and/or pain experi-
enced by a patient is considered to be due to the
586
expansion of the lung. It is suggested that this
subpopulation of patients (those that have pain, etc.)
may benefit from immediate chest tube placement with
pleural evacuation or medical thoracoscopy with
pleurodesis due to the common belief that the patient’s
lung is re-expanding (ATS Guidelines 2000).
Ipsilateral or at least no contralateral mediastinal
shift identified on chest radiographs suggests trapped
lung or endobronchial obstruction, potentially limiting
the relief of dyspnea a patient may experience with
evacuation of pleural fluid. Limited removal of fluid
(\300 ml) by thoracentesis is suggested in this sub-
population to minimize reducing the pleural pressure
rapidly and increasing the risk of re-expansion pul-
monary edema in these patients (ATS Guidelines 2000).
Pleural pressure monitoring can be performed
before, during, and after thoracentesis to determine
the amount of fluid that can be removed in a physi-
ologic manner. The use of this technique may mini-
mize the risk of re-expansion pulmonary edema and
help assess for the presence of a trapped lung at the
time of the diagnostic/therapeutic thoracentesis
(Rodriguez-Panadero and Lopez-Mejias 1989; Light
et al. 1980; Lan et al. 1997). Pleural pressure moni-
toring may be a more objective assessment for trap-
ped lung than chest radiograph assessment but is
complex and not regularly practiced.
Therapeutic modalities for managing malignant
pleural effusions include repeated therapeutic thora-
centesis, chemical pleurodesis via chest tube or medical
thoracoscopy, pleuroperitoneal shunting, pleural
drainage catheters, and systemic therapy. Repeated
therapeutic thoracentesises are a viable option for those
patients with poor performance status or with advanced
disease. There are no studies upon which to base
repeated thoracentesis. If the malignant pleural effusion
continues to accumulate, a more definitive procedure
can be considered. A variety of new and old agents can
and are being used for pleurodesis.
Chemical pleurodesis has reported a complete
response rate of 64%. A comprehensive review of
pleurodesis further discussed response; fibrosing
agents as a group had a 75% complete response, with
talc specifically, 93%. Antineoplastic agents had a
reported complete response at initial pleurodesis of
44% (Walker-Renard et al. 1994).
Talc is currently the sclerotic agent of choice for
pleurodesis and can be used either via chest tube
placement with pleural evacuation and talc slurry
M. J. Simoff
instillation, or during medical thoracoscopy or video-
assisted thoracic surgery, with talc poudrage.
Poudrage and slurry pleurodesis methods demon-
strated clinical success rates of 91% with no signifi-
cant difference in recurrence rates of effusions
(Hartman et al. 1993; Hamed et al. 1989; Fentiman
et al. 1986; Kennedy et al. 1994; Todd et al. 1980;
Fentiman et al. 1983; Yin et al. 1996). The greatest
concern with the use of talc is the 1% risk of devel-
oping fatal acute respiratory distress syndrome
(ARDS) and the 4% risk of non-fatal ARDS reported
in the literature. Most of the ARDS complications
have been reported in the United States. It has been
suggested that this may be due to the size of the talc
particles used here versus those used in Europe
(Milanez Campos et al. 1997; Rehse et al. 1996).
Despite these reported risks, talc is the most com-
monly used pleurodesis agent.
Other pleurodesis agents used include doxycycline,
which when compared to historical controls had a
similar clinical success rate as previous studies with
tetracycline, 80–85% (Patz et al. 1998; Heffner et al.
1994; Pulsiripunya et al. 1996). Bleomycin has been
used and compared in randomized testing to tetracy-
cline, and found to have similar complete response
rates (Hartman et al. 1993; Moffett and Ruckdeschel
1992; Martinez-Moragon et al. 1997). Doxycycline
when compared directly with bleomycin had a 79%
complete response to bleomycin’s 72% (Hayata et al.
1993). When bleomycin was compared to talc, talc
demonstrated superior complete response rates in all
studies (Walker-Renard et al. 1994; Hamed et al.
1989; Zimmer et al. 1997).
The use of pleuroperitoneal shunting has been
reported for the management of malignant and other
intractable pleural effusions. All of these studies are
case series rather than randomized in any fashion.
Initial data looks promising, but it has not been eval-
uated in head-to-head studies with more conventional
treatment methods (i.e. chest tube drainage with
chemical pleurodesis) (Ponn et al. 1991; Pope and
Joseph 1989; Schulze et al. 2001; Reich et al. 1993;
Petrou et al. 1995).
Another technique, tunneled long-term catheter
drainage of the pleural space is also found in several
studies in case series formats. These studies suggest
good results for the relief of dyspnea over extended
time in patients with malignant effusions. Although
encouraging, many of these studies are retrospective
Advances in Supportive and Palliative Care for Lung Cancer Patients
in assessment with no comparison to other treatment
modalities (Chen et al. 2000; Pien et al. 2001; Pollak
et al. 2001). One device, the PleurX catheter (Denver
Biomedical, Golden, CO) is an important addition to
the management of malignant pleural effusions. This
device when placed into the pleural space, allows the
patient to drain a portion of their pleural effusion on a
daily basis, thereby controlling the build-up of fluid
and in doing so, limiting the dyspnea patients expe-
rience due to this complication. When used daily, one
study (Putnam et al. 1999) suggests that approxi-
mately 50% of these patients will experience pleu-
rodesis without the use of sclerotic agents in a median
of 25 days. Such techniques should be explored
further to fully understand their possible palliative
implications.
For malignant effusions due to small-cell lung
cancer the lung cancer therapy of choice is systemic
chemotherapy. Often these patients will respond
with resolution of pleural effusions and dyspnea
(Livingston et al. 1982).
4 Tracheoesophageal Fistula
Tracheo-esophageal fistulas are serious complications
of lung and esophageal cancer. The life expectancy
after the development of a tracheoesophageal fistula
with no therapy is estimated as 1–7 weeks. Patients
have repeated aspiration of food, gastric contents, and
saliva. This persistent aspiration leads to patient
distress due to coughing and shortness of breath.
Patients can develop recurrent pneumonia with per-
sistent inflammation of the airways. Patients frequently
lose weight and become dehydrated secondary to their
intolerance of taking anything by mouth. Even with
abstinence from eating and drinking most patients
continue to have symptoms due to lack of control of
their own secretions and reflux of gastric contents.
Curative resection of the involved tracheal–bronchial
and/or esophageal segments in face of a malignancy
should not be considered, as most of these patients are at
the end-stage of their lung cancer and palliative man-
agement should be emphasized. Esophageal bypass
procedures should also not be considered, as they have
very high morbidity.
The goals of therapy for tracheoesophageal fistula are
to restore patency of the trachea, bronchi, and/or
esophagus, to prevent spillage and further contamination
587
of the lung, and ensure the patient receives nutrition and
fluid. By addressing all of these issues, the most debili-
tating symptoms of this condition, the dyspnea and
coughing, are also corrected.
Double stenting of the tracheo-bronchial tree and
the esophagus appears to be the procedure that yields
the best overall results for symptomatic relief in
patients with this condition. Clinical series have
attempted either esophageal or tracheo-bronchial
stenting individually with mixed results. Most series
with higher success rates use a double-stenting tech-
nique. With limited published information, our clini-
cal experience has been most successful with initial
bronchial stenting followed in close succession with
esophageal stenting (Freitag et al. 1996; Colt et al.
1992; Alexiou et al. 1998; Koeda et al. 1997; Spivak
et al. 1996; Cook and Dehn 1996).
Placement of a percutaneous entero-gastric (PEG)
or percutaneous entero-jejunal (PEJ) tubes can ensure
proper nutrition and fluid management in patients
with tracheoesophageal fistulas. Patients may be able
to eat once the double stenting is performed, but
maintaining adequacy of fluid status and nutrition is
often difficult.
5 Cough
Cough can be a debilitating symptom for some
patients with lung cancer. As with dyspnea, the eti-
ology of the cough should be identified to best treat a
patient. Cough can be a manifestation of endobron-
chial disease, pleural disease, or tracheoesophageal
fistula as discussed above. Cough can also originate
from something as uncommon as endobronchial irri-
tation status-post resection, when the staples migrate
endobronchially and become foreign bodies in the
airways. Or cough may be a manifestation of some-
thing more common, such as the patients underlying
COPD with or without a tracheobronchitis. Again, the
most useful management remains that specifically
suited to the patient’s individual problem.
Sometimes though, the etiology of cough is never
identified. It is in these situations where cough
suppressants like benzonate (Doona and Walsh 1998)
or opiates (particularly codeine) can be used.
Occasionally beta-2 agonists are prescribed with
identified underlying COPD but are only occasionally
of significant benefit (Kvale et al. 2003).
588
6 Hemoptysis
Hemoptysis will be the presenting symptom in 7–10%
of lung cancer patients. About 20% of lung cancer
patients will have hemoptysis some time during their
clinical course, with 3% having terminal massive
hemoptysis (Miller and McGregor 1980; Chute et al.
1985; Hyde and Hyde 1974; Grippi 1990; Frost et al.
1984). Massive hemoptysis, that which most com-
monly requires intervention, has a broad definition as
expectoration of from 100 to 600 ml of blood in 24 h.
Blood clot formation obstructing airways is suggested
as the most common cause of respiratory insufficiency
from massive hemoptysis.
Initial evaluation of patients with known lung
cancer in a specific location is somewhat different
from that of those patients without a known diagnosis.
Massive hemoptysis due to lung cancer has a much
poorer prognosis than hemoptysis of other etiologies.
One retrospective review defined the mortality of
massive hemoptysis as 59% in patients with bron-
chogenic carcinoma (Corey and Hla 1987). In many
of these patients surgery, a more definitive therapeutic
modality is not on the algorithm for intervention in
that many of these patients are already non-surgical
candidates from their primary disease.
The initial priority in managing a patient with
massive hemoptysis should be, maintaining adequate
airway protection (Cahill and Ingbar 1994;
Jean-Baptiste 2000). This may require endotracheal
intubation to maintain good control. It is suggested
that use of a single lumen endotracheal tube is of
greater benefit than double-lumen endotracheal tubes
(Strange 1991).
Standard endotracheal intubation should use the
largest tube possible. Occasionally selective right or
left mainstem intubations are performed to protect the
non-bleeding lung. This technique can be beneficial in
protecting the good lung, but the fact that when a right
sided intubation is performed, it often occludes the
right upper lobe and the difficulty of selective left
sided intubations need to be considered prior to
attempting this.
Optimization of oxygenation needs to then be
undertaken to clinically stabilize the patient with
massive hemoptysis. Next, assessment and manage-
ment of cardiovascular/hemodynamic status has to
take place for proper management of the patient with
M. J. Simoff
hemoptysis (Cahill and Ingbar 1994; Jean-Baptiste
2000). Reversal of any coagulation disorders should
to be considered at the time of hemodynamic man-
agement. If the bleeding site is known, the bleeding
lung should be placed in the dependent position to
help protect the non-bleeding lung. Cough suppres-
sion with a narcotic (particularly codeine) can be used
to help minimize further endobronchial bleeding in
non-intubated patients.
Bronchoscopy is often used to identify the source of
bleeding. Early bronchoscopy to assess the site of
bleeding is recommended. Studies have demonstrated
identification of the bleeding site 91% of the time when
performed early versus 50% when delayed (Credle
et al. 1974). A more recent retrospective study had
much less supportive results, with the limitation of
early being defined as less than 48 h. Despite this, these
results suggest early bronchoscopy which is indicated
(Gong et al. 1981). The goal of early bronchoscopy
should first be to lateralize the bleeding side, secondly
localization of the specific site to a lesion, lobe, or
segment, and lastly identify the lesion that is bleeding
whenever possible.
In the patient with hemoptysis, several studies have
looked at the use of early high-resolution computed
tomography (HRCT). In those patients without a
diagnosis, this technique appears to have benefits. The
use of HRCT may help diagnose: bronchiectasis, an
aspergilloma, and possibly identify a previously undi-
agnosed lung cancer (Set et al. 1993; McGuiness et al.
1994; Muller 1994; Hirschberg et al. 1997). In the
patient with the known diagnosis of lung cancer, this
technique will be of limited value, particularly in those
patients who have had previous radiation therapy.
A very important therapeutic tool in the manage-
ment of hemoptysis due to malignancy is external
beam radiation (Hoegter 1997). Prior to initiation of
this therapy, other procedures are often necessary to
temporize the patient and localize the area that needs
to be treated.
Endobronchial management of hemoptysis should
be subdivided into identification of the location of the
bleed (i.e. bleeding from the anterior segment of the
left upper lobe) versus bleeding from an identified
source (i.e. bleeding from an endobronchial tumor).
When the location of the bleed is identified, but no
direct source is found, endobronchial management
includes: bronchoscopic tamponade of the segment,
usually recommended with continuous suctioning
Advances in Supportive and Palliative Care for Lung Cancer Patients
collapsing the segment (Zavala 1976). The use of
vasoactive drugs (i.e. 1:10,000 epinephrine solution)
is suggested, although this is most useful on visual-
ized lesions (Magee and Williams 1982; Worth et al.
1987). Ice saline lavage is discussed as a temporizing
technique for control of hemoptysis (Sahebjami 1976;
Conlan and Hurwitz 1983). Balloon tamponade
techniques, using a variety of different balloons, can
control hemoptysis and minimize risk of further
aspiration of blood. It is suggested that balloons
remain in place for 24–48 h to allow tamponade of
hemoptysis (Schlehe et al. 1984; Tsukamoto et al.
1989; Bense 1990).
When an endobronchial source of bleeding is iden-
tified, attempts with vasoactive drugs can be used, but
often this type of bleeding requires a more aggressive
mode of management. Use of Nd:YAG photocoagula-
tion is an efficient tool for the management of bleeding
endobronchial lesions with a reported response rate of
60% (Hetzel and Smith 1991; Jain et al. 1985; Clarke
et al. 1994). Use of electrocautery is also suggested in
the literature but support other than anecdotal reporting
is limited for the management of hemoptysis. Use of
argon plasma coagulation in one study demonstrated
resolution of hemoptysis in 100% of patients with a
3 month follow-up (Morice et al. 2001).
Bronchial artery embolization appears to be a
semi-definitive therapy for hemoptysis. Embolization
stops bleeding in greater than 85% of all patients for
whom it is used. This excellent success rate should be
tempered with the fact that 10–20% of these patients
have rebleeding in the next 6–12 months (Mal et al.
1999; White 1999; Osaki et al. 2000; Eurvilaichit
et al. 2000). The management and long-term follow-
up of bronchial artery embolization is limited by the
few cases of lung cancer managed in almost all
studies. Much of the information used must be
extrapolated to the lung cancer population.
Surgery would appear to be the most definitive
therapeutic modality available. Retrospective studies
demonstrate good long-term results with surgical
resection of the source of bleeding (Knott-Craig et al.
1993; Bobrowitz et al. 1983). This route should be
cautioned in that limited information regarding sur-
gical resection of a bleeding source as lung cancer is
available. If a lung cancer was previously diagnosed,
surgical resection should have been considered had
the patient been a surgical candidate and the tumor
amenable to surgical resection. If a tumor was
589
previously not amenable to surgical treatment, the
addition of hemoptysis to this scenario should not
give cause to surgical intervention at the time of this
complication. In the case where a cancer is newly
diagnosed at the time of management of hemoptysis,
controlling the hemoptysis with other techniques to
allow full assessment/staging prior to acute surgical
management should be performed. Rarely, in a life-
threatening situation, surgical intervention for both
the hemoptysis and the lung cancer may be effective.
Extreme measures are sometimes required in cases
of massive hemoptysis. Our case report was due to the
erosion of the pulmonary artery into the right main-
stem bronchus with massive persistent bleeding. After
stabilizing the patient, we had the entire right pul-
monary artery embolized, through a complex proce-
dure. This completely removed blood flow and
perfusion to the right lung. As this would put a huge
physiologic burden on the patient, we next filled the
airways of the right lung with fibrin glue and placed a
stent over the airway, eliminating all ventilation.
After this was accomplished, the patient was then
extubated and was soon ambulatory on two liters
nasal cannula oxygen. He was home until his death
9 months later of different complications of his lung
cancer (Chawla et al. 2009).
7 Conclusion
There are many symptoms associated with lung can-
cer that can be palliated to allow patients the oppor-
tunity to maximize other more definitive treatments of
their lung cancer. With newer tools and techniques we
can provide much more advanced care to patients
today than ever before. Understanding what can be
done is the responsibility of treating physicians.
Consultation with a team of experts at your facility or
a regional referral center will allow the quickest
assessment of a patient’s complaints and the most
rapid institution of therapeutic measures.
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 Hematological Toxicity in Lung Cancer
Francesc Casas, Ferran Ferrer, and Núria Viñolas

Contents Abstract
The toxicity of tumor cells after chemo and
1 Introduction.............................................................. 598 radiotherapy, administered either alone or in
2 Toxicity in Chemotherapy ...................................... 598 combination is dose-dependent. Aggression to the
bone marrow, which is expressed by a reduction in
3 Toxicity in Radiotherapy ........................................ 600
circulating blood cells, is often the main dose-
4 Hematologic Toxicity After Combined Chemo limiting toxicity because of the risks of anemia,
and Radiotherapy .................................................... 600
bleeding, and infection. Prophylactic treatment
5 Preventive or Support Treatment of Hematologic with granulocyte-colony stimulating factors
Toxicity in Lung Cancer......................................... 603 (G-CSFs) is available to reduce the risk of
References.......................................................................... 606 chemotherapy-induced neutropenia. In 2005, a
European Guidelines Working Party was set up
by the European Organization for Research and
Treatment of Cancer (EORTC) to systematically
review the data published on the appropriate use of
G-CSF in adult patients receiving chemotherapy.
An update of this review was published in 2010.
The ASCO has made evidence level II recommen-
dations concerning the treatment of anemia with
r-Hu-EPO. For patients with chemotherapy-
associated anemia the Committee continues to
recommend the implementation of an erythropoi-
esis-stimulating agent (ESA) when hemoglobin
F. Casas (&) (Hb) values approach or fall below 10 g/dL, to
Radiation Oncology Department,
Hospital Clínic i Universitari, increase Hb values and decrease transfusions. An
Villarroel 170, 08036 Barcelona, Spain individual patient data-analysis has shown that
e-mail: fcasas@clinic.ub.es ESA increase the mortality in all patients with
F. Ferrer cancer, and a similar increase might exist in
Radiation Oncology Department, patients on chemotherapy. Finally, only a few trials
Institut Català d’Oncologia, have examined indications for ESA similar to the
Gran Via de les Corts Catalanes,
Bellvitge, Spain indications approved by the Food and Drug
Administration.
N. Viñolas
Medical Oncology Department,
Hospital Clínic i Universitari,
Villarroel 170, 08036 Barcelona, Spain

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 597
DOI: 10.1007/174_2011_271, Ó Springer-Verlag Berlin Heidelberg 2011
598
1 Introduction
This chapter will describe the normal physiology of
bone marrow followed by a synthesis of the current
knowledge of the toxicity of these two treatments
either alone or in combination. Lastly, support treat-
ments and the management of these secondary effects
are proposed.
The toxicity of tumor cells after chemo and
radiotherapy, administered either alone or in combi-
nation is dose-dependent. Aggression to the bone
marrow, which is expressed by a reduction in circu-
lating blood cells, is often the main dose-limiting
toxicity because of the risks of anemia, bleeding, and
infection. Strategies aimed at protecting the hemato-
poietic cells or the stroma of the bone marrow from
death induced by the treatment, and the acceleration
of hematopoiesis after treatment, may theoretically
allow more intensive treatments in lung cancer (LC)
without the above-mentioned associated risks. It is
necessary to know the structure and function of the
bone marrow as an organ to know the true impact of
individual or combined, sequential or concurrent
treatment and thereby act accordingly. Thus, the
pluripotent stem cells replicate and differentiate in
lymphoid or myeloid lines through a complex process
regulated by a network of hematopoietic growth
factors as well as by cellular interactions. The cascade
through myeloid differentiation leads to the erythro-
cytes, platelets, granulocytes, and macrophages, while
lymphoid differentiation leads to T and B cells.
Families of growth factors (or cytokines) which
control these processes of replication and differenti-
ation have been identified. The hematopoietic pro-
genitor cells and their daughter cells are enveloped in
a stroma of endothelial cells, adventitial cells, fibro-
blasts, macrophages, and fat cells in the sinus of the
bone marrow. This microscopic medium physically
supports and directs the development of the replica-
tion process. In addition, the geographic distribution
of the bone marrow is particularly relevant to know
the possible local effects of radiotherapy in the
treatment of LC. The most functional and important
localizations are the pelvis, the vertebrae (these two
represent 60% of the total bone marrow), as well as
the ribs, the sternum, the cranium, the scapula, and the
proximal portions of the femur and humeral bones.
It should be remembered that hematopoietic stem
F. Casas et al.
cells are also found in the spleen and circulate in the
blood.
Bone marrow dysfunction in neoplastic processes
may be due to different etiologies:
1. Depletion or direct lesions of the hematopoietic
stem cells.
2. Functional or structural damage of the stroma or
the microcirculation.
3. Lesion of other collaborator cells which have a
regulator function or hemostasis.
The consequences of the aggression of cytotoxic
and radiotherapeutic treatment to the bone marrow
should, therefore, be understood within the context of
the previously described mechanisms. Nonetheless, it
may be difficult to elucidate the most important
variables due to limitations in the evaluation of both
the structure and the bone marrow function. Periph-
eral determination of the blood cells fails to demon-
strate the true extension of bone marrow suppression
or its capacity to tolerate additional cytotoxic therapy
mainly because of the capacity of the bone marrow to
transitorily compensate the aggression. To evaluate
several quantitative and functional aspects of the bone
marrow cultures of progenitor cells, histopathologic
studies (bone marrow aspirate and biopsy), and
determined radioisotopes or stromal cell cultures may
be used, albeit to a limited extent.
2 Toxicity in Chemotherapy
The myelosuppression directly caused by chemo-
therapy (CH) not only depends on the agent used but
also on patient-dependent factors, such as age and
general status. Important factors in relation to the type
of CH administered are the dosis, the interval of the
dosis, the route of administration, or the use of a
single or several antitumoral agents. On the other
hand, the site of action of the antineoplastic drug
within the cellular cycle also appears to influence
myelosuppression.
Damage results from a depletion in the total
number of stem cells (the stem cell pool) with a late
myelosuppression pattern which takes place when the
peripheral blood cells die and cannot be replaced.
That is to say that myelotoxicity by CH agents pro-
duces a decrease in the production of blood cells more
than an immediate elimination of the peripheral cells
(Ratain et al. 1990).
Hematological Toxicity in Lung Cancer
Because of differences in the peripheral blood half
life, drugs that induce myelosuppression first result in
leukopenia followed by thrombocytopenia with the
first former generally being more severe than the
latter. Thus, the nadir for neutrophils and platelets is
normally between 7 and 15 days after drug adminis-
tration. For most of the compounds, neutropenia and
thrombocytopenia are reversible and not accumula-
tive. In addition to the direct cytotoxicity at the level
of the progenitor cells, at an erythrocytic level
implicating blood cells with a more prolonged half
life, the mechanism involved may be direct hemolysis
of the red blood cells after the administration or a
decrease in the production of endogenous erythro-
poietin due to chronic renal insufficiency by cisplatin
(Pivot et al. 2000). The pluripotent stem cells are
protected from the toxic effects of CH because of their
slow proliferation.
CH-induced febrile neutropenia (FN) is a poten-
tially fatal complication of cancer treatment when it
heralds infection and sepsis and is most often seen
during the initial cycles of myelosuppressive therapy
(Timmer-Bonte et al. 2005). FN is defined as an
absolute neutrophil count (ANC) of \0.5 9 109/L or
\1.0 9 109/L predicted to fall below 0.5 9 109/L
within 48 h, with fever or clinical signs of sepsis
(Crawford et al. 2010). The European Society for
Medical Oncology (ESMO) defines fever in this set-
ting as a rise in axillary temperature to [38.5°C
sustained for at least 1 h. It is suggested that therapy
be initiated if a temperature of[38°C is presented for
at least 1 h or a reading of [38.5°C is obtained on a
single occasion.
Some of the adverse consequences of CH-induced
FN may lead to treatment delay and dose reductions
which may potentially adversely affect tumor control
(Khan et al. 2008). For instance, poor outcome in
cancer patients has been attributed to failure to deliver
planned CH regimens for LC (Radosavljevic et al.
2009).
Recognizing patients at risk for complications of
FN can be achieved using risk indices such as those
developed by the Multinational Association for Sup-
portive Care in Cancer (MASCC) (De Souza et al.
2008). Using the MASCC score, patients with a score
of 21 or more points are considered at high risk of
infectious complications. Identifying patients at risk
of bacteremia facilitates appropriate initiation of
antibiotics (Klastersky et al. 2010).
599
Patient-related risk factors should be evaluated in
the overall assessment of FN risk before administer-
ing each cycle of CH. Particular consideration should
be given to the elevated risk of FN for elderly patients
(aged 65 and over). Other adverse risk factors that
may influence FN risk include advanced stage of
disease, experience of previous episode(s) of FN, lack
of G-CSF use, and absence of antibiotic prophylaxis.
The risk of FN associated with CH regimens must be
taken into account when evaluating the need for
prophylactic intervention. The new CH regimens with
the addition of targeted agents have been shown to
improve survival. This is the case of the addition of
cetuximab or bevacizumab to chemotherapy in
NSCLC patients (Pirker et al. 2009; Reck et al. 2009).
An increased incidence of FN has been reported in
patients receiving bevacizumab and chemotherapy
compared with CH alone (Sandler et al. 2006). Con-
sideration should be given to the elevated risk of FN
when using certain CH regimens such as docetaxel/
carboplatin (Milward et al. 2003).
One of the main factors of toxicity for a given
CH agent is the pharmacodynamic interaction
between the drug and the combination of other an-
ticancerous drugs. Thus, one of the general princi-
ples for combining different drugs is that they should
have a different limiting toxicity, although a sum of
these effects is normally produced in relation to
myelotoxicity. There is, however, an exception to
this rule in the case of the combination of paclit-
axel–carboplatin: paclitaxel decreases the platelet
toxicity of carboplatin in relation to a non pharma-
cokinetic mechanism (Calvert et al. 1999).
The most frequent schedules of CH currently used
in NSCLC include combinations of cisplatin or car-
boplatin with some of the new drugs (gemcitabine,
vinorelbine, paclitaxel, docetaxel). All have shown to
be similar in regard to efficacy in stage IV, although
the toxicities observed, including hematologic toxic-
ity, differ (Schiller et al. 2002). These combinations
of CH cause grades 3 and 4 neutropenia which varies
from 40 to 70% with febrile neutropenia in less than
10%. Grades 3 and 4 platelet toxicity was observed in
1 to 55% of the patients, with a schedule combining
cisplatin and gemcitabine showing a greater percent-
age of thrombocytopenia (Cardenal et al. 1999).
Patients with carboplatin-based chemotherapy are
more likely to experience thrombocytopenia
(Luo et al. 2010).
600
In regard to anemia, the percentages vary from 10
to 30%, with the schedules based on cisplatin and
gemcitabin or vinorelbin being those producing the
greatest percentage of patients with anemia (Kelly
et al. 2001).
The sequence of administration is also very
important since an increase in myelotoxicity has been
observed when cisplatin is administered before pac-
litaxel. Platelet toxicity is not of note in schemes
including paclitaxel combined with carboplatin sug-
gesting that paclitaxel is protective. The combination
of cisplatin and etoposide produces less neutropenia
than the CAV and CAE schemes, albeit with more
anemia (Fukuoka et al. 1991). The profile of hema-
tologic toxicity with the combination of etoposide and
carboplatin is similar to that found with the schedule
of cisplatin except with a higher percentage of
thrombocytopenia.
3 Toxicity in Radiotherapy
In the case of irradiation in LC, acute toxicity of the
bone marrow depends on the volume irradiated, the
dose of radiation, and its rate. Although the com-
pensatory mechanisms are mainly relevant for the
knowledge of long-term effects, some effects are
acute. Thus, when volumes limited to the bone mar-
row are irradiated, such as, for example, 10 to 15%,
the remaining bone marrow responds by increasing
the population of progenitor cells. This is why the
bone marrow, as an organ as a whole, is able to
regenerate the previously irradiated zone in a com-
pensatory way. This compensatory phenomenon may
be observed by factors (CSFs) from the cell stroma
suggesting the implication of a humoral mechanism.
It has been shown that there is an extensive com-
munication and compensation network in the bone
marrow after aggression with radiation and this may
be summarized as follows:
1. Regeneration within the field of irradiation.
2. Hyperactivity in non irradiated regions.
3. Extension of the function of bone marrow pro-
duction in previously dormant zones (Tubiana
et al. 1979).
This reparation or compensatory capacity of the
bone marrow makes it difficult to clinically observe
bone marrow toxicity secondary to exclusive radio-
therapy treatment in lung cancer. Nonetheless, this
F. Casas et al.
exclusive irradiation using standard fractionation
leads to subclinical, albeit quantifiable, hematologic
toxicity which will be described in greater depth later
when we discuss combined treatment (chemo- and
radiotherapy) and compare the resulting myelotoxic-
ity using references from randomized studies related
to radiotherapy alone.
4 Hematologic Toxicity After
Combined Chemo
and Radiotherapy
The selective action of CH agents for different pop-
ulations of hematopoietic cells determines the tem-
porary consequences of the tolerance of the bone
marrow to radiation after CH. In addition, when wide
fields are used before CH, the tolerance expected is
poor. This may be due not only to the suppression or
ablation of determined segments or portions of the
bone marrow, but also to the increase in the sensi-
tivity of non exposed zones of the bone marrow
which, at that time, are in a period of hyperactivity.
This is produced in the case of sequential treatments
further complicating the question when referring to
combined treatments of radio and CH. In the case of
SCLC, the study by Abrams et al. (1985) is of note.
These authors randomized 42 patients to receive
either CH alone or in combination with thoracic
irradiation. In the group receiving combined treat-
ment an increase was observed in both hematopoietic
toxicity and in the circulating number of progenitor
cells suggesting that the toxicity of concurrent treat-
ment is additive. It was found that:
a. The combination of CH and thoracic radiotherapy
produces more hematologic toxicity during the
period of irradiation than when CH is administered
alone.
b. This increase may be explained by a generally
subclinical, although measurable, toxicity of the
thoracic radiotherapy when administered alone.
c. The potential of hematopoietic toxicity by irradi-
ation itself may vary in relation to the timing, the
volume of treatment, to the region irradiated, and
the treatment fields used. That is, the greater the
volume treated and the greater the quantity of
the cardiac circuit and bone marrow involved in
the irradiated fields, the greater the toxicity.
Hematological Toxicity in Lung Cancer
Table 1 Hematologic toxicity in randomised concurrent hyperfractionated arms on SCLC
Leukopenia
Grade % Grade
Jeremic et al. (1995, 1997) 3 21
4 11
Turrisi et al. (1999) 3 38
4 44
Takada et al. (2002) 3 51
4 38
In recent years, the contribution of not only the
importance of the timing of the administration (early
or late) in concurrent combined treatment, but also the
alterations of the fractionation (accelerated hyper-
fractionation vs. standard fractionation) in patients
with SCLC condition changes in hematological tox-
icity. Thus, Murray et al. (1993) randomized a group
of patients into two arms of early (in the third week)
versus late (in the 15th week) concurrent irradiation
and found that although the differences between
neutropenia and thrombocytopenia greater than or
equal to grade 3 were not statistically significant for
either of the treatment arms, they were so in relation
to grade 3 anemia, which was greater in the late
administration (P \ 0.03).
In a study by Jeremic et al. (1997), 107 patients
were randomized to receive either CH plus early hy-
perfractionated radiotherapy (weeks 1 to 4) with
concurrent CH versus late administration (weeks 6 to
9) and did not find statistically significant differences
in hematologic toxicity. In the same year the group of
the EORTC (Gregor et al. 1997) published another
randomized study in patients with limited stage SCLC
comparing sequential radioCH versus alternating
treatment and reported that the latter schedule was as
effective as the sequential administration but caused
greater grades 3 and 4 hematologic toxicity.
Turrisi et al. (1999) carried out a randomized study
comparing concurrent CH with hyperfractionated
radiotherapy versus the same CH with standard frac-
tionated radiotherapy and found greater toxicity in the
treatment with hyperfractionated radiotherapy. Lastly,
Takada et al. (2002) randomized concurrent versus
sequential chemoradiotherapy and observed greater
hematological toxicity in the first treatment arm
(Table 1). Finally, in SCLC ongoing clinical trials
addressing radiotherapy-related questions include the
601
Trombocytopenia Anemia
% Grade %
3 25 3 11
4 13 4 2
3 13 3 23
4 8 4 5
3 23 3 54
4 5 4 –
Concurrent ONce daily vErsus twice daily Radio-
Therapy (CONVERT) study, the Intergroup study
(CALGB 30610/RTOG 0538), and the Randomized
trial of chest irradiation in extensive disease small cell
lung cancer (REST) study (Favre-Finn et al. 2010)
which will provide new information related to
hematologic toxicities secondary to more limited
radiotherapy fields, current technology, and different
dose fractionation.
At the beginning of the 1990s a series of ran-
domized studies in NSCLC were performed evaluat-
ing both the effectiveness and the toxicity of
concurrent or sequential radioCH versus irradiation
alone (Table 2). Firstly, the study by Le Chevalier
et al. (1991) was of note. In this study 353 patients
were randomized to receive 65 Gy of irradiation
alone versus the same irradiation preceded by three
cycles of vindesine, lomustine, cisplatin, and cyclo-
phosphamide. The group receiving irradiation alone
showed threefold less hematologic toxicity than the
group administered combined therapy. Dillman et al.
(1990) randomized 155 patients to receive two cycles
of cisplatin and vinblastine followed by 60 Gy of
irradiation versus radiotherapy alone at the same
doses. Although the hematologic toxicity in this study
was not correctly explained, it was of note that neu-
tropenic infection was more prevalent in the patients
receiving CH with double the number of admissions
due to severe infections versus the patients adminis-
tered irradiation alone.
In a study by Trovo et al. (1992) 173 stage III
patients were randomized to receive 45 Gy versus the
same irradiation administered concurrently with a
daily dose of 6 mg/m2 of cisplatin. The hematologic
toxicity of the combined treatment was only slightly
superior to that of radiotherapy alone. In 1993,
Schaake-Koning et al. (1992) randomized 331 patients
602
Table 2 Hematologic toxicity in randomised trials on NSCLC
Hematologic toxic RT group
effect (%)
Le Chevalier et al. (1991) Grade 2–5 1.4
(sequential)
Trovo et al. (1992) (concurrent) Hemoglobin 1.7
(grade 1–2)
Leukopenia 1.1
Schaake-Konig et al. (1992) Leukopenia (grade 3.3
(concurrent) 3–4)
Trombopenia 0.6
(grade 3–4)
Dillman et al. (1990) Neutropenia 3 7
(sequential)
to receive 56 Gy administered by split-course or the
same radiotherapy plus 30 mg/m2 of cisplatin admin-
istered each week of irradiation versus the same total
dosis of irradiation administered continuously with a
daily dosis of 6 mg/m2 of cisplatin during irradiation. It
was found that grades 3–4 hematologic toxicity was
fourfold greater in the group with concurrent admin-
istration with weekly cisplatin compared to radio-
therapy alone and was double in the concurrent
treatment with daily versus weekly CH.
Sause et al. (1995) published a randomized study
on whether patients receiving CH followed by irra-
diation showed longer survival than hyperfractionated
radiotherapy or irradiation with standard fractionation
in patients with stage III NSCLC. Neutropenic
toxicity greater than grade 3 was presented in 50% of
the patients with combined treatment and was null in
the other two treatment arms. Jeremic et al. (1995)
randomized 169 patients to receive hyperfractionated
radiotherapy at 1.2 Gy/twice a day up to a total dosis
of 64.8 Gy versus the same dosis of irradiation plus
100 mg of carboplatin on days 1 and 2 and 100 mg of
etoposide on days 1 and 3 of each week of irradiation
versus a third group in which the same radiotherapy
was administered plus 200 mg of carboplatin admin-
istered on days 1 and 2 and 100 mg of VP-16 on days
1 and 5 of the first, third, and fifth week of irradiation.
Likewise, the toxicity was greater in the combined
treatment, especially in the second group.
On demonstration of the greater effectiveness, albeit
with greater hematological toxicity, of sequential
treatment versus exclusive irradiation, the next step
was to demonstrate that concurrent administration was
F. Casas et al.
CH ? RT group (monthly CH ? RT group (daily
CH) (%) CH) (%)
4.2 –
– 2.3
– 1.7
6.6 (weekly CH) 14.5
0.9 (weekly CH) 1.8
–
greater than sequential. This was corroborated by Fu-
ruse et al. (1999) in a study in which 320 stage III
SCLC patients were randomized to receive concurrent
treatment with cisplatin, vindesine, and mitomycin and
56 Gy administered by split-course versus the same
CH and one continuous dosis of 56 Gy. Greater
immunosuppression was also observed in the concur-
rent treatment arm.
A second similar trial published involved concur-
rent versus sequential radioCH with cisplatin and
vinorelbine in locally advanced NSCLC (Zatloukal
et al. 2004). Grade 3 or 4 toxicity was more frequent
in arm A than in arm B, with a significantly greater
incidence of leukopenia (53 vs. 19%, P = 0.009).
A new combination of treatment has also been
investigated with a simultaneous radioCH (paclitaxel
60 mg/m2, weekly) compared with radiotherapy alone
after induction CH in inoperable stage IIIA or IIIB
NSCLC: the CTRT99/97 study by the Bronchial
Carcinoma Therapy Group (Huber et al. 2006).
Induction CH was well tolerated with 3.8% patients
with grade 3 or 4 leukopenia (grade 4, 2.1%).
Hematologic toxicities during radiotherapy alone or
radioCH were both equivalent and without grade
3 or 4.
In a randomized phase II, the Cancer and Leuke-
mia Group B (CALGB) studied the effectiveness and
tolerance of two cycles of induction CH followed by
two additional cycles of the same CH plus concurrent
radiotherapy. The CH used was doublets of cisplatin
with gemcitabine, vinorelbine, and paclitaxel (Vokes
et al. 2002) and in this study hematologic toxicity was
presented separately in the induction and also in the
Hematological Toxicity in Lung Cancer 603

Table 3 Hematologic toxicity in randomised trials studying the role of induction CH in concurrent CH-RT on NSCLC
Hematologic toxic Induction RT group CH ? RT
effect group (%) (%) group (%)
Huber et al. (2006) (weekly CH-RT vs. RT alone Leukopenia (grade 3.8 0 0
after induction CH) 3–4)
Anemia (grade – 0 0
3–4)
Vokes et al. (2007) (inmediate CH-RT vs. induction Granulocytopenia Inmediate After
CH-RT) CH-RT induction
Grade 3 18 11 24
Grade 4 20 4 7
Anemia
Grade 3 1 5 12
Grade 4 0 0 0

concurrent treatment. In the first part grade 3–4
granulocytopenia was of note in 50% of the patients
in the three treatment arms presented, and in the arm
with gemcitabine 25% of the patients also presented
grades 3 and 4 thrombocytopenia. In regard to the
toxicity observed with concurrent treatment it was of
note that notable differences were found in the three
treatment arms of the study. Thus, while in the groups
treated with gemcitabine and paclitaxel grades 3 and
4 granulocytopenia were observed in 51 and 53%
respectively, in the group receiving vinorelbine this
hematologic toxicity was seen in 27% of the patients.
Platelet toxicity was also found to be greater (50%) in
the group with concurrent treatment with gemcita-
bine. With this background the CALGB made a phase
III trial on immediate concurrent radioCH with car-
boplatin area under the concentration–time curve
(AUC) of 2 and paclitaxel 50 mg/m2 given weekly
during 66 Gy of chest radiotherapy, or arm B, which
involved two cycles of carboplatin AUC 6 and plac-
litaxel 200 mg/m2 administered every 21 days fol-
lowed by identical radioCH. The accrual was 360
patients (Vokes et al. 2007). There was no difference
in survival between the two arms. Adverse events to
treatment during induction CH on arm B included
grade 3 or 4 granulocytopenia in 18 and 20% of
patients, respectively. Neutropenia was significantly
increased in arm B reflecting the accumulative effect
of induction CH (Table 3).
Finally, a phase III trial by the Hoosier Oncology
Group showed that consolidation docetaxel after
cisplatin/etoposide and concurrent radiotherapy (PE/
XRT) results in increased toxicities but does not
further improve survival compared with PE/XRT
alone in patients with stage III inoperable NSCLC. In
patients receiving docetaxel, 10.9% experienced feb-
rile neutropenia (Hanna et al. 2008). A total of 28.8%
of patients were hospitalized during docetaxel
(vs. 8.1% in the observation arm) and 5.5% died as a
result of docetaxel. To date, there is insufficient evi-
dence indicating that treatment extending beyond
concurrent CH alone further improves survival rates.
Many questions remain unanswered in the treatment
of stage III stage disease including defining the
optimal CH regimen and the utility of lower dose
radiosensitizing CH, individualization of the radio-
therapy dose and fractionation, specifically after sur-
vival improving metaanalysis with accelerated
radiotherapy (Saunders et al. 2010) based on pul-
monary function, tumor volumes, and newer radio-
therapy technologies.
5 Preventive or Support Treatment
of Hematologic Toxicity in Lung
Cancer
Prophylactic treatment with G-CSF is available to
reduce the risk of CH-induced neutropenia. However,
the use of G-CSF prophylactic treatment varies widely
in clinical practice, both in the timing of the therapy
and in the patients to whom it is offered. In 2005, a
European Guidelines Working Party was set up by the
European Organization for Research and Treatment of
Cancer (EORTC) to systematically review the pub-
lished data available and derive evidence-based
604
recommendations on the appropriate use of G-CSF in
adult patients receiving CH (Aapro et al. 2006).
Nonetheless, with regard to the use of daily G-CSF
versus once-per cycle pegylated G-CSF, additional
evidence has emerged since the publication of the last
EORTC guidelines. In addition, further filgastrim
biosimilar molecules have been approved. These
developments highlight the need to reassess the current
evidence and to update the existing guidelines
regarding the prophylactic use of G-CSF. This update
was published in 2010 (Aapro et al. 2011).
The strongest evidence supporting the use of
G-CSF to prevent FN comes from three level I
metaanalyses (Lyman et al. 2002; Bohlius et al. 2008;
Kuderer et al. 2007). This last trial described the
information about 13 randomised trials and with 3122
patients with lymphoma and solid tumor and reported
that the addition of G-CSF to standard CH resulted in
a significant reduction in early mortality. A small
level II study has suggested a trend to improved long-
term survival in patients with favorable-prognosis
SCLC receiving VICE CH (vincristine–ifosfamide–
carboplatin–etoposide) plus G-CSF compared with
CH alone (Woll et al. 1995).
Moreover, a harmful effect has been observed with
the use of this cytokine in patients with an intratho-
racic stage who had been concomitantly treated with
CH and radiotherapy as well as in extrathoracic stages
treated with high-dose CH (Adams et al. 2002). In
1996, the American Society of Clinical Oncology
(ASCO) recommended that the use of CSF be avoided
in patients who had received concomitant radioCH,
and 4 years later specified that its use should be
avoided in patients with radioCH if the mediastinum
had been irradiated (Ozer et al. 2000) as in the case of
LC. Nevertheless, an ongoing trial in SCL, the
CONVERT trial, is currently studying the possibility
of CSF administration in a few cases of LC receiving
irradiation.
The use of antibiotic prophylaxis to prevent
infection and infection-related complications in can-
cer patients at risk of neutropenia is still contentious
(Cullen et al. 2005). Two metaanalysis (Gafter-Gvili
et al. 2005; Herbst et al. 2009) and a systematic
review (van de Wetering et al. 2005) have indicated
that evidence is too limited to allow conclusions to be
drawn regarding the relative merits of antibiotic ver-
sus CSF primary prophylaxis.
F. Casas et al.
Nonetheless, in certain high risk patients with clear
predictive factors of worse outcome (for example in
sepsis, pneumonia, fungal infections, etc.) the use of
CSF together with antibiotics may be justified
(Bennett et al. 1999). In 2002, a systematic review
was published on the randomized trials conducted
on the role of CSFs in the treatment of SCLC
(Berghmans et al. 2002). Twelve randomized trials
including a total number of 2,107 patients divided into
three groups were considered: maintenance of dose-
intensity with standard doses and time intervals of CH;
accelerated CH with increase dose-intensity; and
concentration of CH on an overall shorter duration time
with a lower number of cycles. The results of this
systematic review were negative for all the strategies:
in the maintenance group, CSF administration was
associated with a detrimental effect on overall survival;
in the accelerated group, no significant impact was
found in the response rate or survival, and concentrated
CH was associated with no difference in response rate
and a reduced survival.
Only a few randomized trials have been reported
on CH with or without granulocyte growth factors as
primary prophylaxis in NSCLC. On the other hand, in
patients receiving first-line CH for advanced NSCLC,
the occurrence of CH-induced neutropenia has been
associated with a significantly longer survival
(Di Maio et al. 2005).
In the recent years, adjuvant CH after radical sur-
gery has become the standard for early stage NSCLC.
Cisplatin-based chemotherapy was used in all the
recent trials showing a significant advantage for
treatment compared to observation (Douillard et al.
2006). Nonetheless, despite the significant hemato-
logical toxicity of these regimens, the incidence of FN
is reportedly much lower than 20%, therefore primary
prophylaxis with CSFs according to guidelines is not
advised (Winton et al. 2005).
In relation to anemia, another known effect of bone
marrow toxicity, it should be remembered that its
etiology is multifactorial and includes an inappropri-
ate production of erythropoietin in response to the
alteration of the normal hemoglobin (Hb) levels. This
abnormality in the production of erythropoietin is also
exacerbated by CH. On the other hand, recombinant
human erythropoietin (r-HuEPO epoietin-alfa) has
been used to improve the anemia observed in patients
with cancer, with an increase being observed in the
Hematological Toxicity in Lung Cancer
number of erythroid progenitors in both the bone
marrow and peripheral blood.
Several large, community-based studies have
demonstrated that epoetin-alfa effectively corrects
anemia and improves the quality of life of anemic
cancer patients receiving CH (Kosmidis and
Krzakowski 2005). However, the contribution of
erythropoietin to curative cancer treatment outcome is
controversial (Machtay et al. 2007). A safety analysis
in a randomized trail suggested decreased survival in
patients with advanced NSCLC treated with epoeitin-
alfa (Wright et al. 2007). The ASCO has made an
evidence level II recommendations concerning the
treatment of this anemia with r-Hu-EPO (Rizzo et al.
2008). For patients with CH-associated anemia, the
Committee continues to recommend initiating an
erythropoiesis-stimulating agent (ESA) as Hb values
approach or fall below 10 g/dL to increase Hb and
decrease transfusions.
An individual patient data-analysis shows that
ESA increase the mortality in all patients with cancer,
and a similar increase might exist in patients on CH
(Bohlius et al. 2009). CH was given to patients in
38% (72%) of 53 studies included in the metaanalysis,
with radiotherapy in three (6%) and radioCH in five
(9%). In the further five (9%) studies, no CH or
radiotherapy was given to patients. The most frequent
tumors were breast cancer [4302 (31%) of 13933] and
LC [3076 (22%)]. The increase in mortality seemed to
be more pronounced in patients treated with ESA
once a week than in those who were treated with these
drugs more or less often. Finally, only a few trials
have examined the indications for ESA that were
similar to the indications approved by the Food and
Drug Administration. A study by Casas et al. (2003)
on the approved indication also studied the impact of
the use of erythropoietin in the maintenance of Kar-
nofsky and Hb levels in patients with LC receiving
con current treatment of radioCH after induction CH
(11 SCLC and 40 NSCLC). In addition to finding a
beneficial and significant impact of the administration
of erythropoietin at the level of general status and Hb
levels, it was also found to be a significant prognostic
factor of survival on multivariate analysis, together
with classical factors such as weight loss and final
improvement in Hb, the histology of SCLC and
finally, Hb levels greater than 10 g/dL prior to con-
current radioCH.
605
In relation to thrombopenia, thrombopoietin, the
synthetized factor for the stimulation of this series
based on preventing hemorrhagic problems after
myelosuppressive CH is still under evaluation and
clinical implementation. Thrombopoietin (TPO), a
key physiologic regulator of platelet production, has
been found to be the most potent thrombopoietic
cytokine studied so far. Unfortunately, the clinical
development of recombinant human thrombopoietin
has met challenges related to the biology of TPO with
a delayed peak platelet response and the findings of
neutralizing antibodies to the pegylated molecule
(Vadhan-Raj 2005).
In addition to the development of specific cytokines
for the production and secretion of different hemato-
logic cells, trials with medications such as glutation are
currently ongoing on different methods of prevention
of bone marrow toxicity. Glutation has shown to be an
effective chemoprotector against toxicity induced by
cisplatin. Although the main experience is in ovarian
cancer, randomized studies in other types of tumors
such as LC and the head and neck have demonstrated
lower hematologic toxicity in patients receiving glu-
tation compared with the control group (Schmidinger
et al. 2000). Other drugs such as amiphostin have also
shown a significant reduction in hematologic toxicity
in randomized studies including patients with LC
undergoing concurrent radioCH (Antonadou et al.
2003 and Komaki et al. 2002). Nonetheless in two
more recent phase III (Movsas et al. 2005) and ran-
domized phase II studies (Han et al. 2008), both in LC,
amiphostine was associated with higher FN.
There is a new pathway to reduce bone marrow
toxicity secondary to radiotherapy alone or associated
with CH. Radiotherapy modulated by dose-intensity
(IMRT) in different locations has demonstrated to be
useful in significantly reducing the doses of radio-
therapy in critical tissues (Lujan et al. 2003).
With IMRT planning it may be possible to reduce
both bone marrow volume at a thoracic level and
cardiac circulation, thereby allowing blood cells to be
irradiated with radiotherapy alone or in combination.
Prospective studies aimed at achieving a reduction in
hematologic toxicity should be undertaken.
Finally, it is currently possible to prospectively
monitor or even predict bone marrow toxicity after
radiotherapy. One article has demonstrated that the
variations in the cytokine called Glt-3 ligand in
606
plasma directly reflect the damage induced by radio-
therapy in the bone marrow during fractionated
radiotherapy, even when this damage is maintained at
subclinical levels (Huchet et al. 2003). This may be
very useful for preventive monitoring of hematologic
toxicity in determined groups of patients with LC
receiving CH or radiotherapy treatment.
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 Radiation-Induced Lung and Heart Toxicity
Liyi Xie, Xiaoli Yu, Zeljko Vujaskovic, Mitchell S. Anscher,
Timothy D. Shafman, Keith Miller, Robert Prosnitz,
and Lawrence Marks

Contents 4 Modifiers of RT-Induced Lung Injury ................. 616

5 Cardiotoxic Effects of Thoracic Radiation
1 Pulmonary Effects of Thoracic Radiation Therapy..................................................................... 617
Therapy..................................................................... 609 References.......................................................................... 620
1.1 Clinical RT-Induced Lung Toxicity ......................... 609
2 Biology of Radiation-Induced Lung Injury.......... 612
Abstract
3 Predictors of RT-Induced Lung Injury ................ 614
For many patients with lung cancer, thoracic
radiation therapy (TRT) is an integral part of their
treatment. The effect of TRT on normal structures
L. Xie
L. Marks (&)
Department of Radiation Oncology, is an important consideration when optimizing
University of North Carolina, Campus Box 7512, treatment plans for patients. This chapter will
101 Manning Drive, Chapel Hill, NC 27514, USA review radiation therapy (RT)-induced lung and
e-mail: marks@med.unc.edu
heart injury including both the clinical and
L. Xie
X. Yu biological mechanisms for these toxicities. It
Department of Radiation Oncology,
will also analyze the variety of predictors of
Fudan University Shanghai Cancer Center,
200032 Shanghai, China RT-induced lung and heart damage as well as
methods to prevent and treat these toxicities.
Z. Vujaskovic
Radiation Oncology and Pathology,
Department of Radiation Oncology,
Duke University Medical Center, Box 3455,
Durham, NC 27710, USA
M. S. Anscher
1 Pulmonary Effects of Thoracic
Department of Radiation Oncology, Radiation Therapy
Virginia Commonwealth University School of Medicine,
401 College Street, PO Box 980058, 1.1 Clinical RT-Induced Lung Toxicity
Richmond, VA 23298-0058, USA
T. D. Shafman 1.1.1 Introduction
Landmark Medical Centre, 115 Cass Ave,
Radiation-induced lung toxicity is a common occur-
Woonsocket, RI 02895, USA
rence in patients treated with curative intent for
K. Miller
lung cancer. Approximately 5–20% of patients
21st Century Oncology, Fort Myers, FL, USA
treated with RT for lung cancer have been reported to
R. Prosnitz
develop RT-induced lung injury (Favaretto et al.
Department of Radiation Oncology,
University of Pennsylvania School of Medicine, 1996; Segawa et al. 1997; Fu et al. 1997; Monson et al.
2 Donner Building, 3400 Spruce Street, 1998; Yamada et al. 1998; Nyman et al. 1998;
Philadelphia, PA 19104, USA

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 609
DOI: 10.1007/174_2011_273, Ó Springer-Verlag Berlin Heidelberg 2011
610 L. Xie et al.

Table 1 Incidence of RT-induced clinical and radiologic lung injury

Reference (No) Number of Symptom rate (%) Incidence of radiologic Follow-up duration
patients Grade Grade Grade Grade changes (%) (months)
1 2 3 4
Favaretto et al. 39 13 64–90
(1996)
Segawa et al. 89 38a 5.6 8.9 5.6 58 –
(1997)
Fu et al. (1997) 60 – 17a 8 – 23
Monson et al. 83 8 2 7 34 C4
(1998)
Yamada et al. 60 – 13.3a 11.6 3.4 85 C6
(1998)
Nyman et al. 90 – – 8a – 22 (minimum)
(1998)
Van den Brande 23 – – 11a – [24
et al. (1998)
Makimoto et al. 111 15 \6
(1999)
Graham et al. 99 – 14–20a 24 (median)
(1999)
Robnett et al. 144 – – 8.3a 11.5 (median)
(2000)
Sunyach et al. 54 – 29 (Lent-Soma scale) 37 C6
(2000)
Inoue et al. (2001) 191 36a 13 C12
Hernando et al. 201 – 13 4 – C6
(2001)
Oetzel et al. (1995) 46 20 [3
Perry et al. (1987) 391 7 17.3 (median)
Gross (1977) _ 5–15 65 _
Simpson et al. 316 3 36
(1985)
Kwon et al. (2000) 47 – 8.5a – – 2–33
Perez et al. (1980) 365 4 60
Martel et al. (1994) 42 21.4 [7
Tucker et al. (2010) 442 14.9a 4.5 22.2 2.5 C6
– 22.6b 21 0.5
a
RTOG criteria
b
CTCAE 3.0

Van den Brande et al. 1998; Makimoto et al. 1999;
Graham et al. 1999; Robnett et al. 2000; Sunyach et al.
2000; Inoue et al. 2001; Hernando et al. 2001; Oetzel
et al. 1995; Perry et al. 1987; Gross 1977; Simpson
et al. 1985; Kwon et al. 2000; Perez et al. 1980; Martel
et al. 1994; Tucker et al. 2010) (Table 1). Clinical
symptoms range from mild shortness of breath to
chronic pulmonary dysfunction requiring oxygen
therapy and potentially leading to death. The wide
range in incidence of reported toxicity is secondary to
the different methods used to measure pulmonary
dysfunction. While most patients have radiographic
changes, few have changes in functional endpoints and
even less have severe clinical symptoms (Table 1).
Radiation-Induced Lung and Heart Toxicity
Clinical endpoints for RT-induced lung injury have
traditionally been divided into acute (early) and
chronic (late) toxicity. Acute pneumonitis typically
occurs 1–6 months after TRT, with a peak incidence
of around three months (Van Dyk et al. 1981).
Chronic lung fibrosis usually evolves six months to
several years after treatment.
1.1.2 Early Toxicity
Patients with RT-induced pneumonitis often present
shortness of breath, cough, congestion, and some may
have a low-grade fever. For patients with chronic
obstructive pulmonary disease (COPD), it may be
difficult to distinguish a flare COPD from acute
pneumonitis. In general, the severity of the symptoms
is related to the amount of normal lung irradiated.
Pneumonitis usually responds well to steroids and
40–60 mg of prednisone each day for several weeks,
followed by a slow taper. This provides relief for most
patients. It is important to consider the possibility of
infection since this might become worse due to the
steroids. In situations where either infection or
pneumonitis appear likely, an initial trial of empiric
antibiotics, followed by steroids if there is no
response to antibiotics, may be indicated. In patients
with an unsatisfactory response to either treatment,
tumor progression and/or lymphangitic tumor should
be considered. Severe RT-induced pneumonitis can
result in severe respiratory distress requiring hospi-
talization, intubation and possibly death.
Thoracic radiation therapy can also cause acute
irritation of the pleura, with secondary pleuritic pain
and this can be treated with anti-inflammatory and/or
narcotic pain relief medicines. Irritation of the trachea
and bronchial airways, which can lead to a cough,
may also occur and is treated with cough suppression
medicines.
1.1.3 Late Toxicity
The most prominent late consequence of TRT is pul-
monary fibrosis. Radiological changes consistent with
fibrosis are seen in most patients. Symptomatic
patients show progressive chronic dyspnea and this
can occur months to years after TRT (Gross 1977;
Perez et al. 1980; Martel et al. 1994; McDonald et al.
1995; Morgan and Breit 1995; Abid et al. 2001).
Relief from symptoms is the goal of treatment as
the reversal of the fibrosis is highly unlikely. Treat-
ment includes anti-inflammatory agents such as
611
corticosteroids, and in some cases, supplemental
oxygen is needed. Similar to acute pneummonitis,
tumor progression, infection and COPD flare must be
ruled out as exacerbating factors for symptomatic
fibrosis and treated appropriately. As noted earlier,
radiographic evidence of regional lung scarring is seen
in almost all patients, including those without clinical
symptoms. There does not appear to be an association
between the presence of an abnormality on CT scan
and the development of symptoms, though this has not
been extensively studied. (Garipagaoglu et al. 1999).
After high doses of TRT there have been rare reports
of pulmonary complications, such as bronchial
stenosis, bronchomalacia, and mediastinal fibrosis
with secondary recurrent laryngeal nerve injury
(Maguire et al. 2001; Dechambre et al. 1998).
1.1.4 Radiographic Changes
Radiographic findings are common in patients fol-
lowing TRT, and also among patients who do not
have symptoms of RT-induced lung injury. The fre-
quency of finding these changes depends on the type
of radiographic assessment performed. A chest x-ray
(CXR) performed after TRT can reveal a diffuse
infiltrate corresponding to the radiation field. There
can also be an associated volume loss of the affected
portion of the lung and in late toxicity, there can be
extension of the findings outside the treated area and
deviation of the trachea towards the irradiated area.
Computed tomography (CT) scans are more sen-
sitive than CXR and can detect abnormalities in
more than 50% of patients (Mah et al. 1987). CT
scans are very sensitive to slight changes in lung
densities and therefore are the favored diagnostic
procedure for the detection of RT-induced lung
injury (Mah et al. 1987; Libshitz and Shuman 1984).
There is a well-defined dose–response relationship
for the patterns seen on CT scans after TRT and
these include: homogeneous, slight increase in lung
density; patchy consolidation; discrete consolidation;
solid consolidation (Libshitz and Shuman 1984;
Mah et al. 1986). Chronic changes in the thorax that
can be seen on the CT scan following TRT include
lung contraction, pleural thickening, tenting of the
diaphragm, and deviation of the mediastinal struc-
tures toward the treated area. These can appear
months to years after radiotherapy.
Lung perfusion and ventilation can be abnormal
following TRT (Gross 1977; Prato et al. 1977).
612
Single-photon-emission computed tomography
(SPECT) perfusion and ventilation scans are more
frequently abnormal than planar images, similar to
CT’s advantage over chest X-rays (CXR) (Gross
1977; Prato et al. 1977). Perfusion appears to be more
sensitive than ventilation in the evaluation of RT-
induced lung injury, and both are more sensitive than
CXR or CT (Bell et al. 1988; Shapiro et al. 1990).
This is most apparent at modest doses, 15–40 Gy,
where often there is no change seen in tissue density,
yet clear reductions in both ventilation and perfusion.
Perfusion and ventilation abnormalities have been
seen in 53–95 and 35–45% of irradiated patients,
respectively. The inconsistencies between changes in
ventilation and perfusion support the idea that
following TRT, some areas remain ventilated, but are
not adequately perfused (Bell et al. 1988; Marks et al.
1993).
Several studies that have reported rates of both
clinical pneumonitis and radiographic abnormalities
following TRT are summarized in Table 1. As shown,
radiographic changes occur far more frequently than
clinical symptoms.
1.1.5 Functional Endpoints
In general, abnormalities in pulmonary function tests
(PFTs) do not occur during the first weeks following
TRT. Following this, changes in PFTs can occur
along with the signs and symptoms of pneummonitis
and/or fibrosis. Pulmonary function tests measure the
transfer of large volumes of air through the conduct-
ing airways, and transfer of gases through the alveolar
surfaces. Spirometry assesses the rate of gas move-
ment and the most commonly measured parameter is
the forced expiratory volume in one second (FEV1).
FEV1 is a measurement of air movement and can be
normalized to the forced vital capacity (FVC), a
measurement of ‘‘useful’’ lung volume, which is the
FEV1% (FEV1/FVC). While the response of the
tumor to TRT may lead to an increase in FEV1, FVC
may decrease secondary to restrictive disease (fibro-
sis) and thus FEV1% (FEV1/FVC) may increase.
Reductions in FEV1 following TRT range from 0 to
30%, but there are a wide variety of confounding
variables that limit the meaningful interpretation of
this data.
A variety of PFTs measure lung volume including
the total lung capacity (TLC), vital capacity (VC),
forced vital capacity (FVC), and residual volume
L. Xie et al.
(RV). The volume of air in the lung can increase
following TRT if there is an expansion of lung
volume or could decrease secondary to fibrosis.
Reports in the literature describe both and the range
varies from -20% to +9.5% (Van den Brande et al.
1998; Sunyach et al. 2000; Mattson et al. 1987;
Choi and Kanarek 1994; Rubenstein et al. 1988;
Brady et al. 1965; Bonnet et al. 2001) (Table 2).
Gas exchange in the lungs is measured via the
carbon monoxide (CO) diffusion capacity (DLCO)
quantifying the transfer of CO from inspired gas into
pulmonary capillary blood. Many complex factors,
besides gas diffusion, contribute to DLCO, including
ventilation/perfusion characteristics of alveolar units,
capillary blood volume, hemoglobin concentration,
and the reaction rates between CO and hemoglobin.
In addition, other clinical factors such as diurnal
variation, menstrual cycle, ethanol ingestion, and
cigarette smoking can effect DLCO (Garipagaoglu
et al. 1999). The DLCO is frequently corrected for
anemia but the other factors known to affect the
DLCO are difficult to control during its calculation.
(Garipagaoglu et al. 1999). The DLCO tends to be
affected by TRT to a greater degree than the other
parameters and has been shown to be reduced from 5
to 35% following TRT (Table 2). It is difficult to
generalize changes in PFTs, given the wide variety of
pre-treatment values and the diverse amounts of lung
irradiated in each patient. Other standard measure-
ments of pulmonary function, such as the 6 min walk
test or exercise stress tests, have not been routinely
used to measure RT-induced lung injury.
2 Biology of Radiation-Induced Lung
Injury
Radiation-induced lung injury is characterized by
progressive histological changes which are linked
with the clinical symptoms and radiological findings
of pulmonary dysfunction. Current thinking suggests
that the underlying molecular processes of RT-
induced lung injury is a dynamic interplay of several
molecular factors. These processes can be loosely
separated into three major phases.
The early responses to pulmonary radiation include
an increased production of reactive oxygen/nitrogen
(ROS/RNS) species and proinflammatory/profibrotic
cytokine expression resulting in tissue inflammation.
Radiation-Induced Lung and Heart Toxicity
Table 2 Percent reduction in pulmonary function parameters after thoracic radiation therapy
Reference (No) FEV1
Sunyach et al. (2000) +0.1
Marks et al. (1993)
Van den Brande et al. (1998) 10
Mattson et al. (1987) 18
Choi and Kanarek (1994) 11
Rubenstein et al. (1988)
Brady et al. (1965) 8 11.5
Simultaneously, DNA damage in various cell types,
including type I and II pneumocytes and endothelial
cells, results in apoptosis, which further triggers the
secretion of growth factors and proteases, and deg-
radation of the extracellular matrix. This process also
leads to increased permeability and loss of integrity of
vessels, leading to edema, impaired tissue perfusion,
and hypoxia. The initial latent period following TRT
until the manifestation of detectable injury may reflect
the inherent turnover time of these cells (Gross 1977;
Travis et al. 1977; Travis 1980).
Histologically, RT-induced pneumonitis is typified
by an exudate of proteinaceous material into the
alveoli, desquamation of epithelial cells from the
alveolar lining, alveolar edema, and an infiltration of
inflammatory cells. This leads to thickening of the
alveolar septa, reduced lung compliance, and even-
tually impairment of gas exchange. Radiation causes
the early release of surfactant by type II pneumocytes
and this results in alterations in alveolar surface ten-
sion and low lung compliance (Rubin et al. 1980,
1983).
As noted above, damage to vascular endothelial
cells results in increased permeability of capillaries
(Gross 1977). The endothelial cells become pleo-
morphic, vacuolated, producing areas of denuded
basement membrane and occlusion of the capillary
lumen by debris and thrombi (Gross 1980). Many of
these findings are apparent well before RT-induced
pneumonitis develops and they persist throughout the
course of the illness and beyond.
A delayed response, consisting of a second wave
of cytokine induction and hypoxia along with mac-
rophage infiltration in the lung, occurs at 6–8 weeks.
Chronic inflammation, as a result of the recruitment
of leukocytes and cascade of chemokines, cytokines,
and growth factors at the injury site, can further
613
DLCO FVC TLC VC
4.3 6.5
27 16
25 15
28 22 10 20
14
5.5 +6
provoke the cell loss and aggravate hypoxia
throughout the transition to late toxicities. There is
progressive fibrosis of alveolar septae, which become
thickened with bundles of elastic fibers while small
vessel walls become obliterated by collagen deposits
(Gross 1977; Katzenstein and Askin 2006; Roswit and
White 1977). The alveoli eventually collapse and
become obliterated by connective tissue. This usually
occurs beyond 4–6 months following TRT. This is an
active process and there is evidence that it may be
genetically determined (Haston et al. 2002).
Many of the molecular events described above
occur as a result of increased expression and activa-
tion of transcription factors that regulate oxidative
stress response and cytokine function (Brach et al.
1991; Hallahan et al. 1991, 1994). After exposure to
ionizing radiation these events proceed rapidly and
involve multiple cells within the lungs (Hong et al.
1995, 1997; Rubin et al. 1995). These events occur
during a period of clinically normal lung function,
and result in elevated tissue levels of ROS/RNS,
proinflammatory/profibrotic cytokines, such as IL-1,
TNF-a PDGF, and TGF-b (Rubin et al. 1995;
Finkelstein et al. 1994; Franko et al. 1997; Epperly
et al. 1999; Hallahan et al. 1989). If sustained, this
chronic inflammation and overexpression of cytokines
lead to overt lung injury.
Late injury is often observed in the form of fibro-
sis. Histologically, lung fibrosis and pulmonary
hypoxia can be seen by about six months post-RT,
and are characterized by increased collagen and
expression of the hypoxia marker carbonic anhydrase-
9. The chronic overexpression of ROS/RNS and
cytokines maintains the chronic inflammatory state
and contributes to the progression of RT-induced lung
fibrosis (Johnston et al. 2002) [for details see the
recent review by Graves et al. (2010)].
614
3 Predictors of RT-Induced Lung
Injury
Given the pitfalls of diagnosing and describing the
continuum of clinical and radiological RT-induced
lung damage, predicting its occurrence is complicated
and fraught with deficiencies. The quality of the
predictions is related to the endpoint chosen and the
method used to calculate the risk.
Several studies tried to relate changes in PFTs
based on the percent of functional lung irradiated
(Choi and Kanarek 1994; Rubenstein et al. 1988;
Abratt et al. 1990; Curran et al. 1992). In these
investigations, the percent of lung at risk was
approximated from planar ventilation and perfusion
scans. The observed decline in PFTs was typically
less than the models predicted (Choi and Kanarek
1994; Rubenstein et al. 1988; Abratt et al. 1990;
Curran et al. 1992). Consequently, investigators have
used newer three-dimensional (3D) planning software
and related local RT doses to lung SPECT perfusion/
ventilation-defined regional lung injury (Woel et al.
2002; Seppenwoolde et al. 2000; Mah et al. 1994).
Clear dose–response relationships for radiographic
lung injury have been found. However, predictions of
PFT changes and clinical symptoms based on regional
dose–response data have been inconsistent (Fan et al.
2001; Theuws et al. 1998).
Patients with lung cancer are typically treated with
multiple beams that enter the lungs from different
directions resulting in a complicated 3D dose distri-
bution. Attempts to predict RT-induced lung injury
from field size and dose are made difficult by an
incomplete understanding of complex dose and volume
parameters. While both higher dose per fraction and
total dose were found to be correlated with symptom-
atic lung injury, less consistent results have been found
with two-dimensional (2D) field size (Robnett et al.
2000; Byhardt et al. 1993; Roach et al. 1995). The use
of 3D treatment planning has provided investigators
with the tools to better evaluate the risk of RT-induced
lung injury. Traditionally, the 3D dose distributions are
recalculated into a 2D dose-volume histogram (DVH)
which is easier to interpret. The percent of lung volume
receiving equal to or greater than a specific dose can be
found from a DVH and typically a ‘‘single value of
merit’’ is derived from the DVH, such as the percent of
lung receiving at least 20 (V20) or 30 (V20) Gy. Many
L. Xie et al.
studies demonstrate that these ‘‘threshold’’ dosimetric
parameters are useful in predicting the likelihood of
RT-induced lung injury. Similarly, the mean lung dose
has also been associated with RT-induced lung injury.
The recent QUANTEC review provides a good
summary of the available data relating the risk of
symptomatic pneumonitis to either threshold doses, or
mean lung dose in Figure 2 of that paper. Note the
gradual increase in pneumonitis risk with mean dose
(Marks et al. 2010). While these parameters have been
individually correlated with clinically significant lung
injury, they are highly related to each other and none
has been shown to be superior. The greatest benefit of
these data may not be for absolute risk assessment, but
to provide a means to compare treatment plans for their
relative risks.
It is clear from the wide variety of results that the
volume of irradiated lung may not be sufficient to
accurately predict RT-induced lung toxicity. The data
derived from DVHs disregard all spatial information
and it is known that some regions of the lung have
greater functional importance. In patients with heal-
thy lungs, the ventilation perfusion ratio reveals that
gas exchange is better at the lung bases than at the
apices. For lung cancer patients with COPD,
emphysema preferentially affects the apical lung and
therefore the lung bases may be more important for
respiration in these patients. Finally, tumor-related
lung dysfunction is also related to lung anatomy and
is not accounted for in DVHs. Taken together, these
data suggest that the utility of traditional DVHs to
predict RT-induced lung injury may be suboptimal.
Some recent studies of RT-induced lung injury uti-
lized anatomic information and report that treatment
to the lower portion of the lung may be more toxic
than treatment of the upper lung, however, this has
not been confirmed (Graham et al. 1999; Yorke et al.
2002a; Tsujino et al. 2003). A SPECT perfusion scan
is able to define functional areas of the lung and
therefore dose-function (i.e. perfusion) data extracted
from this test may be more predictive for RT-induced
lung injury than the traditional DVH (Woel et al.
2002; Seppenwoolde et al. 2000; Lind et al. 2002).
Many studies have addressed the role of potential
biologic predictors of RT-induced lung injury. These
are markers found in the blood prior to or during TRT
that reflect a predisposition for RT-induced lung
injury. TGF-b is a multifunctional regulator of cell
growth and differentiation that stimulates connective
Radiation-Induced Lung and Heart Toxicity
tissue formation and decreases collagen degradation
which can result in fibrosis. In a series of patients
receiving TRT it was found that elevated TGF-b
levels at the completion of TRT was associated with a
significantly higher incidence of clinical pneumonitis
(Anscher et al. 1994). The dosimetric predictor V30
combined with the TGF-b plasma concentration has
been shown to improve the accuracy of predicting
pneumonitis (Fu et al. 2001). In patients with a
V30 \ 30% and stable TGF-b during RT, the inci-
dence of symptomatic RT-induced lung injury was
6.9%. Patients with a V30 C 30% or a TGF-b
increasing during RT (but not both), had an incidence
of RT-induced lung injury that was 22.8%. With a
rising TGF-b and V30 C 30%, the incidence was
42.9% (P = 0.02). A more recent study from the
same group (Evans et al. 2006) still showed some
predictive ability with TGF-b in patients with high
V30. Other cytokines have also been implicated in
RT-induced lung injury. Elevated plasma levels of the
pro-inflammatory cytokines IL-1a and IL-6 are asso-
ciated with the development of pneumonitis (Chen
et al. 2002). These studies suggest that biologic
markers may be useful in identifying patients at risk
for RT-induced lung injury (Zhao et al. 2009).
Many commonly used chemotherapeutic drugs
have lung toxicity when used alone (Abid et al. 2001).
The use of combinations of chemotherapy with RT,
either concurrently or sequentially, raises the concern
for added toxicity. While there is evidence for an
increased risk of pulmonary toxicity with concurrent
RT and doxorubicin, mitomycin-C, cyclophospha-
mide, and bleomycin, these drugs are not commonly
used in lung cancer patients (McDonald et al. 1995).
Recent trials using platinum-based regimens have not
shown increased RT-induced lung toxicity. In a study
comparing induction chemotherapy with cisplatin,
vinblastine, and followed by thoracic RT to the same
dose of RT alone, the frequency of severe lung toxicity
was reported to be only one percent in each treatment
group (Dillman et al. 1990). In comparison of
sequential cisplatin, vindesine, and mitomycin with RT
versus concurrent treatment with the same agents, the
rate of grade two or higher pulmonary toxicity was
reported to be 2.6 and 1.9% in the concurrent and
sequential treatment arms, respectively (P = 0.86)
(Furuse et al. 1999). It does not appear that the current
standard of platinum-based concurrent chemotherapy
increases the risk for RT-induced lung injury while
615
with more modern agents (e.g. docetaxel and gemcit-
abine) used in concurrent/consolidate chemoradiation
modalities, higher rates of pulmonary toxicity may be
observed (Marks et al. 2010; Barriger et al. 2010).
Tumor location may be a valuable component for
assessing the probability of RT-induced lung injury.
Reduction in the size of an obstructing tumor may
improve respiratory status, even if some lung is
injured, so the prediction of post-RT lung function
can be complicated by anatomy. It has been shown
that patients with central obstructing tumors which
result in a shift of ventilation or perfusion away from
the area to be treated are more likely to have an
improvement of lung function following TRT (Choi
and Kanarek 1994; Marks et al. 2000). Among
patients with a V/Q shift of [10% to the uninvolved
side of the lung by a central cancer, pulmonary
function improved in 60% of patients after RT, 20%
remained essentially stable, and only 20% had the
reduction in PFTs that was predicted by the volume of
lung irradiated (Choi and Kanarek 1994). A separate
study demonstrated that, in patients with central lung
tumors, 8/20 (40%) with adjacent SPECT hypoper-
fusion had improvements in DLCO following radia-
tion, while only 3/17 (18%) of patients without
hypoperfusion had improvement (P = 0.10) (Marks
et al. 2000). Patients with central tumors are likely at
greater risk of bronchial injury following high-dose
RT (e.g. [73 Gy) than are patients with more
peripherally placed lesions (Miller et al. 2005).
While it is reasonable to associate cigarette smok-
ing with an increased risk of RT-induced lung toxicity,
the data are somewhat confounding. Chronic lung
disease caused by a long history of smoking makes
patients more susceptible to lung injury, however,
some data suggest that active smoking may have a
protective effect (Hernando et al. 2001; Garipagaoglu
et al. 1999; Johansson et al. 1998). A retrospective
review of patients with RT-induced symptomatic
pneumonitis following treatment of esophageal and
breast cancer found a lower incidence of lung injury in
smokers (Johansson et al. 1998). A large study of
patients irradiated for lung cancer noted a similar
finding (Jin et al. 2009). A study of CT density after
RT to the thorax for lymphoma and breast cancer
found that smokers had significantly smaller changes
(P = 0.002); however, there was no significant ven-
tilation or perfusion differences (Theuws et al. 1998).
A multivariate analysis evaluated SPECT-generated
616
dose response curves and found an increase in
radiation sensitivity in the dose range [40 Gy for
non-smokers versus smokers (Garipagaoglu et al.
1999). There has been some speculation that this
protective effect may be due to a cytokine effect.
These observations are not a reason for patients to
continue smoking while undergoing TRT, however,
one day they could help lead to related pharmaco-
logical interventions.
While many of the methods presented have some
utility in predicting RT-induced lung injury, it is
likely that a combination of data from several dif-
ferent clinical, biological, and dosimetric functions
will ultimately provide the most valuable risk
assessment. For example, as the cytokine cascade in
the pathogenesis of RT-induced lung injury becomes
better understood, biologic data will be combined
with dosimetric information and patient-specific lung
function, which hopefully will lead to improved
prognostication of RT-induced lung injury.
4 Modifiers of RT-Induced Lung
Injury
A variety of strategies have been attempted to
decrease RT-induced lung toxicity, including dosi-
metric variations, pharmacologic agents, and altering
dose using patient-specific biological information.
There have been several randomized trials of the cy-
toprotector amifostine (WR-2721) in patients receiv-
ing TRT. Amifostine (WR-2721) is a phosphorylated
aminothiol that demonstrates cytoprotection of normal
tissues when combined with RT (Wasserman 1999).
Cytoprotection is believed to result from elimination
of free radicals produced by the interaction of ionizing
RT and water molecules (Capizzi 1999). There is
conflicting evidence that amifostine can offer a pneu-
moprotective benefit in patients receiving TRT. A
randomized trial was performed in Greece using
patients with advanced stage lung cancer and who
received TRT with or without amifostine (Antonadou
et al. 2001). During the first month after TRT, dyspnea
with minimal exertion was observed in 27% of control
and only 12% of the patients treated with amifostine
(P = 0.058). After three months, the incidence
of [ grade 2 pneumonitis was 52% in the control arm
compared to 12% in the amifostine arm (P \ 0.001).
At six months, significantly more patients in the
L. Xie et al.
control arm were found to have fibrosis on a chest CT
scan (53 vs. 28%, P \ 0.005). Equally by important,
there was no difference noted in tumor response
(Antonadou et al. 2001).
A separate trial at M.D. Anderson Cancer Center
randomized patients receiving concurrent chemo-
therapy and hyperfractionated TRT to amifostine or
no amifostine (Komaki et al. 2002). In this trial, acute
pneumonitis was significantly reduced in patients
treated with amifostine (31 vs. 7.4%, P = 0.03).
There was no difference in the median survival times
(Komaki et al. 2002).
The radiation therapy oncology group (RTOG
98-01) has recently completed a randomized trial
looking at the addition of amifostine to induction
carboplatin and paclitaxel (C/P) followed by concur-
rent hyperfractionated TRT and C/P with or without
amifostine. In contrast to earlier studies, this trial
demonstrated no difference in pneumonitis rates with
or without amifostine Werner-Wasik et al. (2003).
However, in this trial, patients received twice-a-day
TRT, but amifostine only once-a-day, resulting in
potential protection for just half of the treatments.
There was also a high drop-out rate of patients in the
treatment arm and when the results were analyzed by
intent to treat, a large portion did not receive ami-
fostine. Because of these caveats, a new trial with
once-a-day radiation and subcutaneous amifostine, to
hopefully decrease toxicity, is being initiated. At
present, it is unclear if the use of amifostine in
patients treated with TRT will be of significant benefit
in reducing RT-induced lung injury.
Assessing changes in biological markers during the
course of TRT and changing treatment plans
according to risk categories could potentially lead to a
decrease in RT-induced lung toxicity. This has been
undertaken and a series of patients were treated with
twice-daily TRT and based on TGF-b levels during
the course of therapy, RT dose was escalation
(Anscher et al. 2001). Fourteen patients whose TGF-b
levels were normal after 73.6 Gy were escalated to
80 Gy (n = 8) and 86.4 Gy (n = 6). Overall, the rate
of significant lung toxicity was low in patients with
stable or declining TGF-b levels, indicating that there
is the potential to individualize TRT according to
patient-specific biological factors.
In general, patients with lung cancer are simulated
for treatment using chest CT scans and standard 3D
planning systems. Fields are arranged to treat the
Radiation-Induced Lung and Heart Toxicity
tumor, involving lymph nodes, elective mediastinal,
and sometimes supraclavicular lymph nodes.
Variations of these methods could lead to a decrease in
RT-induced lung injury. For example, limiting
radiation to only areas with known tumor would
exclude elective nodal treatment and potentially spare
normal lung tissue (Rosenzweig et al. 2001). Treating
only positron emission tomography (PET), positive
nodal disease has been attempted with no apparent
change in tumor control and low pneumonitis rates
(Belderbos et al. 2003). Limiting elective nodal
irradiation is a simple method to decrease the potential
for RT-induced lung injury and should become a more
widespread technique for patients receiving TRT
(De Ruysscher et al. 2005; van Loon et al. 2010).
A method to use the information from ventilation/
perfusion scans to decrease dose to the most func-
tional portion of the lung has the potential to reduce
RT-induced lung injury. While most treatment plans
are developed with this intention, it is difficult to
accomplish with the present day technology. Perfu-
sion-weighted optimization using perfusion dose-
functional histograms (DFHs) has been attempted and
the results appear promising (Seppenwoolde et al.
2002). Thus, as more sophisticated treatment planning
systems are developed, better tailoring of dose using
radiological/physiologic data may reduce RT-induce
lung injury. Intensity modulated radiation therapy
(IMRT) has been suggested as a means to steer inci-
dental dose away from better-functioning regions of
the lung (Yin et al. 2010; Das et al. 2004).
Several methods have been attempted to eliminate
the need for larger treatment volumes to compensate
for respiratory motion. Respiratory gating is the tim-
ing of TRT with the respiratory cycle and the deep
inspiration breath-hold technique maintains the GTV
in the same position during treatment (Ford et al.
2002; Yorke et al. 2002). Gating, possibly together
with IMRT, may allow for a more conformal treat-
ment plan and, thus, reduce the potential risks of
treatment. Further evaluations of these techniques are
necessary before they become widely accepted.
The use of IMRT is becoming more widespread
and it has been used in TRT. However, the long-
standing question of whether a little dose to a large
volume of normal lung is better than a high dose to a
smaller volume of lung has not been answered.
An analysis of this issue was recently performed by
comparing varying doses to the normal lung during
617
TRT with the incidence of pneumonitis (Willner et al.
2003). When each lung was analyzed separately, the
incidence of pneumonitis was highly correlated to the
volume of ipsilateral lung receiving [40 Gy. In
contrast, the incidence of pneumonitis decreased as
the volume of lung receiving less than 10 Gy
increased. These results indicate that it is reasonable
to spread low doses of RT outside the target area and
in this study, it appeared that reducing the volume of
lung receiving [40 Gy and increasing the volume
receiving \10 Gy will lead to less RT-induced lung
injury (Willner et al. 2003). These data could be the
basis for DVH constraints in IMRT (Willner et al.
2003). A separate study compared dose escalation
strategies using either 3D treatment planning or
IMRT using the same dose constraint of
MLD \24 Gy (Marnitz et al. 2002). It was possible to
give higher doses to the target volume while keeping
within the MLD restriction using IMRT (Marnitz
et al. 2002). A similar study compared IMRT to 3D
treatment planning as well as to traditional treatment
planning with elective nodal irradiation (Grills et al.
2003). When meeting all of the standard normal-tis-
sue constraints, IMRT delivered 25–35% higher dose
to the target compared to 3D and [100% higher than
standard treatment planning including elective nodal
irradiation (Grills et al. 2003). In the near future it is
likely that a significant amount of prospective data
will be available regarding the benefit (or lack of)
IMRT planning to reduce RT-induced lung injury.
Two relatively recent non-randomized studies have
suggested lower rates of Radiation Pneumonitis with
IMRT versus conventional 3D conformal approaches
(Yom et al. 2007; Liao et al. 2010).
5 Cardiotoxic Effects of Thoracic
Radiation Therapy
Heart injury is an inherent risk in the treatment of
lung cancer arising from the use of TRT, either alone
or in combination with cardiotoxic chemotherapeutic
agents. At least a portion of the heart is typically
exposed to a relatively high dose of radiation when
the mediastinum and/or primary lung tumors are tar-
geted. However, cardiac injury is not commonly
reported in patients who receive TRT for lung cancer.
There are two primary reasons for this. First, most
patients treated with TRT for unresectable lung
618
cancer have a short life expectancy. Second, patients
treated for lung cancer typically have pre-existing
cardiopulmonary disease, and subsequent functional
deterioration is typically ascribed to pre-existing
disease, RT-induced lung dysfunction, and/or tumor
progression, rather than to cardiotoxicity. As our
ability to successfully treat lung cancer and concur-
rent pulmonary disease/injury improves, minimizing
cardiotoxicity will become an important goal of the
thoracic radiation oncologist.
Cardiac injury in irradiated lung cancer patients
has not been well studied for the reasons described
above. However, the late effects of radiotherapy on
the heart have been extensively studied in survivors of
Hodgkin’s disease and breast cancer. While the
radiotherapy fields and doses used in the treatment of
Hodgkin’s disease and breast cancer differ markedly
from those used to treat lung cancer, these studies
illustrate the fundamental principles of radiation-
induced cardiotoxicity which may be applicable to
patients with lung cancer.
Incidental cardiac irradiation has been strongly
associated with the development of pericarditis and
premature coronary artery disease, and weak associ-
ations also exist for a wide range of clinical syn-
dromes including cardiomyopathy, valvular disease,
conduction system abnormalities, and autonomic
dysfunction. When they occur following the treatment
of children or adolescents, these syndromes are often
distinguished by their early age of onset. When older
patients are irradiated, the resultant cardiac syn-
dromes are generally indistinguishable on clinical
grounds from the more usual forms of the disease.
Although changes in the structure and function of the
intrathoracic viscera after TRT should be considered,
the manifestations of TRT-induced heart disease are
essentially treated the same as the more usual forms
of heart disease (Adams et al. 2003a, 2003b).
An increased risk of death from acute myocardial
infarction (AMI) has been observed in long-term
survivors of Hodgkin’s disease treated with radio-
therapy fields that encompassed at least part of the
heart. Mediastinal radiation fields typically used for
Hodgkin’s disease deliver 20–40 Gy to the medial
aspect of the heart, and thus include the ostium of the
coronary arteries. Occasionally, the remainder of the
heart may receive a lesser dose. In patients treated as
adults, the relative risk for death from AMI ranged
2.6–14.9 compared with age and gender-matched
L. Xie et al.
controls (Boivin and Hutchison 1982; Boivin et al.
1992; Brierley et al. 1998; Gustavsson et al. 1990;
Hancock et al. 1993a, 1993b; Hancock and Hoppe
1996; Henry-Amar et al. 1990; Ng et al. 2002; Po-
hjola-Sintonen et al. 1987). The relative risk of death
from AMI for patients treated as children was even
higher (41.5), reflecting the increased sensitivity of
children to the cardiotoxic effects of radiation and/or
the low baseline risk of AMI in the general population
below age 50 (Hancock et al. 1993) (Aleman et al.
2007; Swerdlow et al. 2007). Pericarditis has also
been reported following mediastinal irradiation for
Hodgkin’s disease, and its incidence is strongly
related to the volume of heart irradiated (Carmel and
Kaplan 1976). The results of these studies have had a
significant impact on the management of Hodgkin’s
disease today. Many of the patients in these studies
were treated with radiotherapy alone to doses in
excess of 40 Gy. The current treatment approaches
emphasize combination chemotherapy followed by
low-dose consolidative RT, in part to reduce the
expected long-term cardiac toxicity of treatment.
An increased risk of cardiac death, in particular
AMI, has also been seen in older trials of post-mas-
tectomy RT, particularly for left-sided breast cancer
(Gyenes 1998; Cuzick et al. 1987, 1994; Rutqvist and
Johansson 1990; Rutqvist et al. 1992; Early Breast
Cancer Trialists’ Collaborative Group 1990, 1995,
2000; Host et al. 1986; Jones and Ribeiro 1989;
Paszat et al. 1998). These older trials used RT tech-
niques that resulted in a larger volume of heart in the
RT field than is typically seen with modern treatment
approaches. As a result, reductions in breast cancer
deaths in these trials were offset by increases in car-
diac deaths, such that post-mastectomy RT had a
detrimental effect on the overall survival. With more
modern RT techniques, cardiac toxicity appears to
have been reduced, resulting in a net mortality benefit
following post-mastectomy RT (Overgaard et al.
1997, 1999; Ragaz et al. 1997; Whelan et al. 2000).
With modern RT approaches, however, cardiac tox-
icity may result. Modern techniques typically incor-
porate tangential fields that incidentally include the
anterior myocardium. Furthermore, some patients are
treated with beams that are directed from the anterior
direction towards the medial breast/chest-wall and
internal mammary lymph nodes. Typical doses are
45–50 Gy. The incidence of cardiac dysfunction fol-
lowing radiation for breast cancer is related to the
Radiation-Induced Lung and Heart Toxicity
volume of heart irradiated (Rutqvist et al. 1992; Gyenes
et al. 1998). Pericarditis has also been reported in
these patients.
Subclinical cardiac injury is very common. Non-
lethal symptomatic cardiac injury is reported to occur
in 0–50% of patients receiving incidental cardiac
irradiation during treatment for Hodgkin’s disease,
carcinoma of the breast, lung, esophagus, or medul-
loblastoma (Pohjola-Sintonen et al. 1987; Carmel and
Kaplan 1976; Cosset et al. 1988, 1991; Applefeld and
Wiernik 1983; Jakacki et al. 1993; Yu et al. 2003).
Among asymptomatic patients, subclinical damage
can be detected by electrocardiogram (EKG), echo-
cardiogram (ECHO), or other radiological studies in
approximately 0–67% (Carmel and Kaplan 1976;
Strender et al. 1986; Constine et al. 1997; Gomez
et al. 1983; Gottdiener et al. 1983; Lagrange et al.
1992; van Rijswijk et al. 1987; Hardenbergh et al.
2001; Makinen et al. 1990; Watchie et al. 1987).
We and others have used SPECT cardiac perfusion
imaging as a means to detect microvascular injury in
the myocardium. In patients irradiated for left-sided
breast cancer, approximately 50–75% of patients will
develop new perfusion defects if C5% of the left
ventricle is included within the radiation field (Marks
et al. 2003). These defects appear to be associated
with the corresponding abnormalities in wall motion
and the possibly subtle reductions in ejection fraction.
With longer follow-up, most of these perfusion
defects persist (Prosnitz et al. 2007).
The reported incidence of RT-induced cardiac
toxicity varies widely depending on the endpoint
used. The reported frequency of cardiac morbidity
also depends on the population of patients considered.
Studies that report on a group of patients seen by
cardiologists tend to overestimate the incidence, since
asymptomatic patients are often not included. Con-
versely, retrospective studies of patients evaluated
some years following RT tend to underestimate the
incidence since only the evaluable survivors are
included. Nevertheless, the preponderance of the data
suggests that RT-induced cardiac damage, either
clinical or subclinical, is common.
The experience with Hodgkin’s disease and breast
cancer demonstrates the potential impact of TRT on
cardiac function in patients irradiated for lung cancer.
As outlined above, the generally poor survival rates
and concurrent illnesses in patients irradiated for lung
cancer probably account for the low reported incidence
619
of radiation-associated cardiac events in these patients.
Nevertheless, there are some data that demonstrate that
this may be an important clinical problem. In a meta-
analysis, post-operative RT was associated with a 6%
increased rate of mortality, cause not specified (PORT
Meta-analysis Trialists Group 1998). In a randomized
clinical trial assessing the utility of post-operative
TRT, the addition of RT increased the rate of cardiac
mortality three fold compared to non-irradiated con-
trols. Five percent of the irradiated patients died of
cardiac disease; non-lethal morbidity was not addres-
sed (Dautzenberg et al. 1999). Cardiac toxicity has not
been reported in patients treated definitively for lung
cancer, but has been reported in the post-operative
setting where survival rates are higher (Dautzenberg
et al. 1999). This observation supports the concept that
such cardiac events may be under-reported in long-
term survivors of lung cancer.
The concern for RT-induced cardiotoxicity is
heightened by the widespread use of potentially car-
diotoxic systemic therapy and the high prevalence of
cardiac risk factors in the lung cancer patient popu-
lation. Paclitaxel, a widely used agent in the treatment
of lung cancer, is potentially cardiotoxic (Vogt et al.
1996; Kelly et al. 1997). A variety of clinical factors
(age, male gender, tobacco use, obesity, diabetes
mellitus, family history, hypercholesterolemia, and
hypertension) have been associated with an increased
incidence of ischemic cardiac disease. Many of these
factors such as, hypertension (Lauk and Trott 1988),
lack of exercise (Geist et al. 1990), and high choles-
terol/fat diet (Artom et al. 1965; Amromin et al.
1964), may increase the risk of RT-induced cardiac
injury (Hull et al. 2003).
A clinical study from Memorial Sloan Kettering
Cancer Center suggests that the dose to the inferior
lung is more predictive for radiation pneumonitis than
is dose delivered to the superior aspect of the lung
(Yorke et al. 2002). A similar finding has been
reported in mice (Tucker et al. 1997; Travis et al.
1997). It is possible that irradiation of the inferior-
lung may be a barometer for incidental cardiac irra-
diation, as the heart is located in the inferior chest in
both mice and humans. Interestingly, in rats (where
the heart is located in the superior left hemi-thorax),
irradiation of the superior or left lung resulted in more
‘‘lung’’ toxicity than did similar treatment to the right
or inferior lung (Jiresova et al. 2002). In concert,
these data suggest that incidental cardiac irradiation
620
Fig. 1 Non-axial beams to limit cardiac dose
may result in subclinical injury that masquerades as,
or interacts with, ‘‘lung’’ toxicity.
In light of these issues, we recommend that care be
taken to minimize incidental cardiac irradiation dur-
ing TRT for lung cancer. Towards this goal, we often
use non-axial beams to minimize incidental cardiac
irradiation. This is most useful in patients with lower
lobe tumors with hilar/mediastinal nodes. In this set-
ting, one is often able to shadow the primary tumor
with the nodal disease and therefore the beam aper-
ture can actually be smaller with non-axial beams
than with axial beams. For example, a primary tumor
in the left lower lobe with metastases to the left hilum
and pre-carinal area, can often be treated with oblique
fields oriented from right-anterior–superior and
opposed left-posterior-inferior directions, resulting in
irradiation of a smaller cardiac volume (Fig. 1).
It is important to remember that incidental cardiac
irradiation is a concern for tumors in both the left and
right thorax. Off-cord oblique axial boost fields for
right lung tumors usually include the anterior heart.
Given the degree of cardiac injury observed in
patients irradiated for breast cancer, Hodgkin’s disease
and other mediastinal neoplasms, it is extremely likely
that similar events are occurring in patients irradiated
for lung cancer. To date, this has not been recognized
as an important clinical problem, due primarily to
L. Xie et al.
competing morbidity/mortality. The possibility of
RT-associated cardiac dysfunction should be consid-
ered in patients who have been irradiated for lung
cancer. Additional study is needed to better understand
the clinical importance of such injury.
Acknowledgment This work was supported by NIH Grant
2R201 CA69579-09.
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 Spinal Cord Toxicity
Timothy E. Schultheiss
Contents
1 Introduction.............................................................. 627
2 Signs and Symptoms ............................................... 628
3 Diagnosis ................................................................... 628
4 Pathology .................................................................. 629
5 Radiation Protection of the Spinal Cord.............. 630
6 Dose Limits ............................................................... 630
6.1 Differential Sensitivity—Cervical
Versus Thoracic......................................................... 630
6.2 Fractionation .............................................................. 631
6.3 Experimental Studies................................................. 631
6.4 Dose Gradients .......................................................... 632
7 Retreatment .............................................................. 632
8 Chemotherapy .......................................................... 632
9 Other Factors Affecting Response......................... 633
10 Treatment of Radiation Myelopathy..................... 633
References.......................................................................... 633
T. E. Schultheiss (&)
City of Hope National Medical Center,
1500 Duarte Road, Duarte, CA 91010, USA
e-mail: schultheiss@coh.org
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_274, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
Radiation myelopathy is a feared and generally
avoidable complication of thoracic irradiation.
A better understanding of the radiation response
of the spinal cord and advances in radiation
therapy delivery techniques mean that this com-
plication should be preventable in nearly all
treatment situations. A better understanding of
the pathogenesis of the injury has lead to the
protection of the spinal cord from radiation in
experimental studies and to the possible treatment
of radiation myelopathy.
1 Introduction
Thoracic radiation myelopathy does not appear to be
pathologically different from cervical radiation mye-
lopathy. Fortunately, the morbidity of thoracic radi-
ation myelopathy is less than that of cervical radiation
myelopathy simply because the injury occurs at a
lower level of the spinal cord. However, radiation
myelopathy is still the most feared radiation compli-
cation of lung cancer treatment.
Radiation myelopathy may have been studied more
than any other normal tissue injury with the possible
exception of skin. It has been studied in mice, rats,
cats, guinea pigs, rabbits, pigs, dogs, and monkeys.
These experimental studies have focused primarily on
the pathogenesis, dose response, and fractionation
effects. In the early years of radiation oncology new
technologies (e.g., introduction of Co-60 and linear
accelerators) and new treatment techniques (e.g.,
hypofractionation, split course treatment, multiple
627
628
fractions per day) sometimes resulted in an unex-
pectedly high incidence of radiation myelopathy
because of unexpected changes in the dose distribu-
tion or in the biological dose. Although the field and
our understanding of radiation myelopathy have
advanced to the point where a new technique rarely
has an unanticipated risk of radiation myelopathy, the
complication continues to occur. It is now almost
completely confined to mistakes or to the most idio-
syncratic cases, which are by definition difficult to
predict. In the following section, we will try to
address the known parameters that influence the
incidence of thoracic radiation myelopathy as well as
the putative factors that could be considered when one
may be required to push the spinal cord dose in favor
of tumor control.
2 Signs and Symptoms
The initial symptoms of radiation myelopathy are
subtle and nonspecific. Lhermitte sign may precede
the development of permanent radiation myelopathy
by several months. This sign is more frequently seen
in a large field or cervical irradiation, but can also
occur in thoracic irradiation. However, its occurrence
is probably independent of the development of radi-
ation myelopathy since it occurs with radiation
doses well below those that would cause radiation
myelopathy. It does not predict permanent injury.
Symptoms associated with permanent radiation
myelopathy progress at various rates. The first signs
generally include unilateral paresthesias, numbness,
clumsiness, lower extremity weakness, and decrease
in proprioception. By the time the patient complains
of symptoms, the symptoms will have intensified in
severity and could also include signs and symptoms
such as changes in gait, weakness, hemiparesis,
Brown–Sequard syndrome, spasticity, pain, hyperre-
flexia. Babinski signs are common. The signs usually
start in the lower extremities and progress rostrally.
The degree of morbidity can stabilize at almost any
level, and the ultimate severity has not been shown to
be related to the radiation dose. These symptoms are
generally characteristic of most demyelinating dis-
eases except that they are irreversible and do not wax
and wane. It is not unusual that a traumatic event,
such as a fall, precedes or initiates neurological
symptoms.
T. E. Schultheiss
The prognosis with radiation myelopathy is
determined by the level of the lesion (Schultheiss
et al. 1986) and the degree to which the cord is
transected (Holdorff 1980). As with any myelopathy,
total cord transection is a poor prognostic sign, and
more inferior lesions have a better prognosis.
3 Diagnosis
In an adult, the latency period for radiation myelop-
athy is rarely less than 6 months from the completion
of radiation, with no apparent difference between the
cervical and thoracic myelopathies (Chouchair 1991;
Feldmann and Posner 1986; Schultheiss et al. 1984a).
If a patient’s symptoms date from less than 6 months
post radiation, then one should seek alternative
diagnoses (including unknown causes), determine
whether there were excessive doses or mistakes in
dosimetry, or investigate factors that could have
combined with the radiation to alter the normal spinal
cord tolerance. Paraneoplastic syndromes sometimes
involve the CNS and may have similarities with
radiation myelopathy. Furthermore, these syndromes
are more common in patients with lymphomas and
lung cancer than most other tumors (Chouchair 1991;
Feldmann and Posner 1986; Schultheiss et al. 1984a).
A definitive diagnosis of radiation myelopathy
may be difficult to make because of the lack of
pathognomonic lesions or findings. Further work up
will generally include CT scans, MRI scans, and
plane films all of which must be negative for tumor or
other etiology. Myelograms are rarely performed
now, but information from cerebrospinal fluid can be
useful, especially when neoplastic cells are found in
the fluid. Unless an overdosage or predisposing con-
dition is clearly indicated, there is no logical reason to
eliminate other causes from the diagnosis of a former
radiation patient with myelopathic symptoms. Any
disease affecting the CNS can potentiate a radiation
injury. Chemotherapy, surgery, and congenital con-
ditions may also reduce the spinal cord’s radiation
tolerance (Abadir 1980; Zulch and Oeser 1974).
When performed, myelograms are rarely positive
in radiation myelopathy, although complete blocks
are sometimes seen. Swelling is often noted. Total
protein, myelin basic protein, and lymphocytes in
the CNS may be elevated (Kitamura et al. 1979;
Lechevalier et al. 1973; Marty and Minckler 1973;
Spinal Cord Toxicity
Worthington 1979). This could be true of other
demyelinating conditions as well. Measurements of
nerve conduction velocities show slowed spinal con-
duction or complete blocks (Dorfman et al. 1982;
Snooks and Swash 1985).
Wang et al. (1992) reported ten cases of radiation
myelopathy imaged with magnetic resonance.
Of eight cases examined 2–8 months after onset of
symptoms, they noted spinal cord swelling in six
cases and low intensity on T1 weighted images and
high signal intensity on T2 weighted images in eight
cases. Diffuse atrophy was found in two cases
examined 36 and 53 months after onset of symptoms.
Enhancement with Gd-DTPA contrast is also seen
(Alfonso et al. 1997; Koehler et al. 1996; Wang et al.
1992).
4 Pathology
Because the spinal cord has relatively few mechanisms
it can deploy in response to injury, there are no patho-
gnomonic features of radiation injury to the spinal cord.
Demyelination, white matter necrosis, and malacia are
characteristic of radiation injury to the spinal cord.
Histopathologic studies of radiation myelopathy in
humans are obviously limited to the autopsy material
(Schultheiss et al. 1988). This results in descriptions of
lesions that are relatively more severe or advanced.
Experimental studies provide a more comprehensive
view of these lesions, both in terms of severity and age
of the lesion (Black and Kagan 1980; Ruifrok et al.
1994; van der Kogel 1974, 1979).
Traditionally, it is common to divide the radiation
injury to the spinal cord into two categories, the white
matter response and the vascular response. The white
matter response includes demyelination of isolated
nerve fibers and progressing to groups of fibers.
Demyelination can progress to active malacia where
the breakdown of the neuropil is ongoing. Active
malacia will have areas with increased numbers of
astrocytes and microglia. These cells perform repair
and phagocytosis, but they may also play a role in the
pathogenesis of the lesion through an increase in the
production or the release of cytokines such as IL-1
and TNFa (Nordal and Wong 2005; Schultheiss and
Stephens 1992). Blood may fill a necrotic area
(hemorrhagic necrosis). Inactive malacia may be
629
characterized by collapse of the normal architecture
and vacuolation (status spongiosis), spheroids, and
glial scars. Mineral deposits may be seen. These
lesions can occur without any clearly associated
changes to the vasculature, with the exception that
vascular lesions occur in close association with
hemorrhagic necrosis.
Vasculopathies after spinal cord radiation include
the more subtle changes of increased vascularity,
telangiectasia, and thickening or degeneration of the
hyaline. Edema and fibrin exudation are commonly
seen. Perivascular fibrosis, fibrinoid necrosis, throm-
bosis, and hemorrhage are more severe manifestations
of vascular injury. These changes are found in other
conditions as well.
The inflammatory response is quite variable and
obviously depends on the age of the lesions. Microglia
and astrocytes show the most dramatic changes.
Occasionally there are regions with the normal white
matter completely replaced with microglial macro-
phages and astrocytes. A brisk astrocytic response
is a common feature of the irradiated spinal cord and
has led to much speculation regarding the role of
astrocytes in the repair process and as a mediator of
injury.
The pathogenesis of white matter necrosis has been
controversial. Oligodendrocytes and their precursors
have been viewed as the target cells whose radiation
death leads ultimately to demyelination and malacia.
Extensive studies have been performed on the iden-
tification and radiation response of glial progenitor
cells (Hornsey et al. 1981; Hubbard and Hopewell
1979; Myers et al. 1986; Otsuka et al. 2006; Philippo
et al. 2000, 2005; Ruifrok et al. 1994; van der Maazen
et al. 1990, 1991, 1992, 1993). On the other hand,
endothelial cells have long been suggested as the
alternative to glial cells as the primary target cells for
radiation injury.
Nordal et al. (2004) studied the up-regulation of
vascular endothelial growth factor (VEGF) in irradi-
ated rat and mouse spinal cords. They found rapidly
increasing cellular expression of VEGF starting
4 weeks before white matter necrosis and a steep
dose–response curve for the expression of VEGF.
The VEGF expressing cells were identified as astro-
cytes. Up-regulation of VEGF is associated with
increased vascular permeability, edema, and hypoxia
in the CNS.
630
Using boron neutron capture therapy (BNCT) as a
probe for studying CNS radiation injury, Coderre
et al. 2006 have shown that the incidence of radiation
myelopathy does not track the survival of glial pro-
genitor cells (Morris et al. 1994, 1996, 1997, 1998).
In these studies, surviving fractions of O2A glial
progenitor cells were determined at various times
after irradiation under conditions where the vascular
endothelium could be preferentially irradiated or the
entire white matter uniformly irradiated. Very differ-
ent surviving fractions of glial progenitor cells were
seen under irradiation techniques that yielded
approximately equal incidences of myelopathy and
conversely similar surviving fractions were seen
under conditions yielding very different myelopathy
rates. Moreover, the endothelial doses tracked well
with the myelopathy rates.
Thus is it currently believed that the primary target
cell giving rise to radiation myelopathy is located in
the vasculature, presumably the vascular endothelium
(Hopewell and van der Kogel 1999). White matter
necrosis resulting from oligodendroglial cell death
(with or without the death of its progenitor cell) is no
longer considered to be a viable hypothesis. Blood–
brain barrier breakdown, edema, hypoxia, astrocytic
responses, and alterations of cytokine expression are
all potentially involved in the pathogenesis (Blake-
more and Palmer 1982; Hornsey et al. 1990; Myers
et al. 1986; Nordal and Wong 2005; Schultheiss and
Stephens 1992). The pathways to injury are not
completely understood, but strategies for treatment of
this injury continue to be developed.
5 Radiation Protection of the Spinal
Cord
Hornsey et al. (1990) found that certain vasoactive
drugs delayed the expression of ataxia and reduced its
incidence. Their conclusion was that white matter
necrosis was secondary to vessel leakage, edema,
infarction, and transient ischemia and the adminis-
tration of these drugs prevented some of the vascular
injury thereby reducing the consequential white
matter injury.
In a study by Lyubimova and Hopewell (2004),
rats were given Gammaphos, a radioprotector also
known as WR-2721 or Amifostine, prior to under-
going brain irradiation. These were compared to rats
T. E. Schultheiss
irradiated without the drug. After 65 weeks, in
Gammaphos rats the endothelial cell number was
significantly higher and vasculature abnormalities and
necrosis were dramatically lower. This study provides
increased evidence that injury to the vascular endo-
thelium and not glial cells injury leads to white matter
necrosis in the CNS.
Following this study, Nieder et al. (2005) treated
rats with a combination of WR-2721 and insulin-like
growth factor (IGF) at the time of re-irradiation with
17–21 Gy. This was given 21 weeks after an initial
dose of 16 Gy. The rats receiving IGF showed a
significantly lower myelopathy incidence.
6 Dose Limits
The published ‘‘safe’’ limits of spinal cord dose have
varied over the years. Doses as high as 60 Gy in
conventional fraction sizes have been suggested
(Baekmark 1975; Kim and Fayos 1981; Verity 1968).
Certainly, 45 Gy is currently the most widely accep-
ted dose limit on the spinal cord. However, in practice
one sees that 45 Gy is often treated as an absolute
dose limit, with lower doses being commonly used.
Clearly, one should not irradiate the spinal cord to
doses higher than are necessary to achieve the thera-
peutic goal. However, the converse is also true.
Tumor control should not be sacrificed solely to
respect a spinal cord tolerance that is unrealistically
low.
6.1 Differential Sensitivity—Cervical
Versus Thoracic
Kramer (1968) was the first to publish different dose
limits for the cervical and thoracic spinal cord. They
were 50 Gy in 5 weeks and 45 Gy in 4 1/2 weeks,
respectively. At this time, it was common to treat with
one field per day with two opposing fields. Generally
the cervical cord was included in lateral head and
neck fields, and was therefore a midline structure and
received the same dose each day from the left and
right lateral fields. However, the thoracic cord is
generally only about 5 cm from the posterior skin and
would have received a high dose on days when the
posterior field was treated and a low dose on the days
of anterior field treatment. (Co-60 would have been
Spinal Cord Toxicity
the most common teletherapy machine in this time
period.) Because the spinal cord is more sensitive to
fraction size than most tissues, the effect of the
alternating high and low daily doses was to increase
the myelopathy risk above that which would have
been seen if the same total dose had been delivered in
constant daily fractions. The result was that the tho-
racic cord was erroneously believed to have a lower
tolerance than the cervical cord. The importance of
the individual fraction size was first noted by Marks
et al. in 1973 (Marks et al. 1973).
Forty-five Gy at 1.8–2.0 Gy per day is the most
commonly held dose limit. No well documented
myelopathies have been published at this dose level in
the absence of extenuating circumstances. These cir-
cumstances are factors in the medical history that
could predispose the patient to radiation injury, one
field per day treatment, neurotoxic chemotherapy, or
dosimetry errors. Because 45 Gy is on a relatively flat
portion of the dose–response curve and because the
great majority of cases at this dose will have other
significant contributory factors, it is highly likely that
cases of myelopathy occurring at 45 Gy would
also occur at 40 Gy. Thus a miniscule reduction in
the myelopathy is achieved by routinely using a
lower dose.
6.2 Fractionation
Fractionation schedules and incidences of myelopa-
thy have been collected and published elsewhere
(Schultheiss et al. 1995). Generally, the dose sched-
ules in which more than one occurrence of radia-
tion myelopathy has been seen have employed
doses per fraction larger than 2 Gy. This is espe-
cially true for schedules involving thoracic radiation
myelopathy.
The dose response of the cervical cord has been
shown to fit a logistic function (Schultheiss 2008).
The value of a/b of the LQ model was 0.87 Gy. This
is in reasonable agreement with the available animal
data. The slope of the dose-response function was also
not significantly different from that reported for non-
human primates (Schultheiss et al. 1990). However,
no satisfactory fit was obtained for the thoracic cord.
Nearly all of the dose-incidence points for thoracic
myelopathy lie to the right of the cervical cord’s
dose-response function. This would indicate that the
631
thoracic cord’s tolerance is greater than the cervical
cord. However, this primarily pertains to the high
dose experience. In the lower dose region, the inci-
dence is so low that the responses are statistically
indistinguishable at this time. Generally a lower tol-
erance is respected for pediatric patients (Knowles
1983; Schultheiss et al. 1984b), especially when
radiation is combined with chemotherapy.
The spinal cord was unexpectedly sensitive to
dose schedules involving multiple fractions per day
(Dische and Saunders 1989; Wong et al. 1991). This
observation resulted in the addition of incomplete
repair to the LQ model to address the time depen-
dence of interfraction repair of radiation damage
(Thames 1989; Thames et al. 1988). Marcus and
Million (1990) reported no cervical myelopathies in
a BID regimen of 1.2 or 1.0 Gy per fraction to total
cord doses of 40–45 Gy in 107 patients or 45–50 Gy
in 90 patients using an interfraction interval of 4–6 h.
It appears that in BID treatments, a fraction size of
1.2 Gy to a dose of 45–50 Gy is safe. The interval
between fractions should be at least 6 h. Because the
half time of repair and even the validity of first order
repair kinetics are uncertain, it would be risky to use
the LQ model with incomplete repair to extrapolate
from a single daily fraction regimen to determine
an equivalent multiple-fractions-per-day regimen.
This risk applies to the clinical use of such a calcu-
lated dose. Dose escalation with hyperfractionation
should be undertaken with caution.
6.3 Experimental Studies
It is well known that the total doses used in animal
experiments cannot be directly applied to humans. It
is not known whether this is also true of fraction size,
interfraction interval, relative volume, number of
fractions, and overall time. This could cast doubts on
the validity of some experimental work that cannot be
validated at least in part in humans.
Much of the early isoeffect studies in rats seemed
to have been in response to clinical observations that
the human spinal cord was more sensitive to increases
in dose per fraction than was anticipated (Ang et al.
1983; Hornsey and White 1980; Masuda et al. 1977;
van der Kogel 1977). This clinical observation was
partially a result of the experimentation with split
course radiation schedules, large doses per fraction
632
used in hyperbaric oxygen treatments, and hypofrac-
tionation with insufficient spinal cord shielding.
The initial experimental work on radiation mye-
lopathy concentrated on fractionation effects. In most
studies involving the cervical and upper thoracic
levels, the a/b ratio was about 2 Gy (van der Kogel
1991). This is not significantly different from the
finding in the human cervical cord of 0.87 Gy
(Schultheiss 2008). Careful work by Wong et al.
(1992) found an a/b ratio of 3.4 Gy for rat cord
treated in up to ten fractions, whereas with more than
ten fractions they found a/b =0.5 Gy.
Investigators at M. D. Anderson Cancer Center
performed extensive fractionated studies in rhesus
monkeys using 2.2 Gy fractions (Ang et al. 1993,
2001; Schultheiss et al. 1990, 1992, 1994; Stephens
et al. 1983). The treatments were primarily directed at
the cervical cord. They found that the ED50 ± 1 SE
(median tolerance ± standard error) was 76.1 ±
1.9 Gy, and the volume effect was consistent with the
probability model (Schultheiss et al. 1983). In
humans, no field size effect has been observed with
respect to incidence, latency, or severity of symptoms.
However, this is probably a result of too few data
rather than no actual effect.
6.4 Dose Gradients
An important volume effect for modern treatment
technique is the effect of dose fall off across the spinal
cord. In proton treatments of chordomas and chon-
drosarcomas at Massachusetts General Hospital, the
spinal cord was allowed to receive 53 Gy (equivalent)
to the center of the cord and 64 Gy maximum to the
surface (Austin et al. 1993). No myelopathies have
been observed. It is difficult to quantify the effect of
dose fall off, but it is clear that the reported spinal
cord limits should refer to a dose given uniformly
across the spinal cord and along a length of several
centimeters. The spinal cord can tolerate very small
volumes taken to doses that would be unacceptably
high for the entire field length.
There have been few cases of radiation myelop-
athy reported following stereotactic radiosurgery
(Gibbs et al. 2009; Ryu et al. 2007; Sahgal et al.
2010). These cases are characterized by high doses
per fraction, very few fractions (1–3), and small
T. E. Schultheiss
volumes of spinal cord, inhomogeneously irradiated.
The latency for these cases is consistent with con-
ventional cases. Because of the few cases, analysis
of incidence is not practicable. One aspect of these
cases is that they may progress to complete paralysis
with less certainty than in cases found following
conventional treatments. However, any conclusions
are preliminary.
7 Retreatment
It is clear that the spinal cord has a significant capacity
for recovery from occult damage (Ang et al. 1993,
2001). van der Kogel (1991) has shown that retreatment
tolerance doses increase approximately linearly with
time after the initial dose, for at least 200 days fol-
lowing treatment. Moreover his data show that the
occult damage remaining 200 days after retreatment
increases with the magnitude of the initial dose. The
greater the initial dose, the less recovery there is. How
these data may be used to inform clinicians regarding
retreatment in humans is uncertain. The initial dose
received by a patient in whom retreatment is being
considered is likely to be very far from tolerance. From
the animal data, this would imply increased recovery.
In general, higher retreatment doses may be given with
lower initial doses and longer intervals between treat-
ments. From the sparse clinical and primate data, it
appears that at least 50% recovery of 45 Gy would be
obtained 2 years after treatment.
8 Chemotherapy
Most patients receiving thoracic irradiation will have
chemotherapy as part of their treatment regimen.
Many cytotoxic and cytostatic agents are known to be
neurotoxic, but the effect of chemotherapy on the
tolerance of the spinal cord is unknown. It is likely
that there is relatively little effect unless the treat-
ments are nearly concurrent or the chemotherapy
neurotoxic on its own. Although recommended dose
limits apply in the absence of chemotherapy treat-
ments and chemotherapy may reduce the radiation
tolerance, 45 Gy in conventional fraction sizes should
still be well tolerated.
Spinal Cord Toxicity
9 Other Factors Affecting Response
Treatment in hyperbaric oxygen (HBO) has been
observed to reduce the tolerance of the thoracic spinal
cord to radiation (Coy and Dolman, 1971). In HBO
treatments for head and neck cancers, van den Brenk
et al. (1968) did not find an increase in radiation
myelopathy. In a somewhat related finding, Dische
et al. (1986) demonstrated a significant positive effect
of pretreatment hemoglobin level on the incidence
of radiation myelopathy. Although hypertension is
known to reduce radiation tolerance in some organs,
this cannot be confirmed in the spinal cord. There are
some experimental data that suggest that this is the
case (Asscher and Anson 1962; Hopewell and Wright
1970).
Disease processes and congenital or acquired
spinal abnormalities, may also effect the radiation
tolerance of the spinal cord to an unknown degree.
These effects are anecdotal and their discovery is
made only after a myelopathy has occurred. If a
patient presents severe spinal abnormalities, one
should attempt to spare the cord as much as possible.
10 Treatment of Radiation
Myelopathy
Treatment of radiation myelopathy with hyperbaric
oxygen or steroids has generally not been successful.
Bevacizumab is a humanized murine monoclonal
antibody against VEGF. It is used in the treatment of
malignant glioma in combination with radiation ther-
apy. Reasoning that upregulation of VEGF may con-
tribute to radiation necrosis in the CNS through
breakdown of the blood brain barrier and edema,
Gonzalez et al. (2007) suggested that bevacizumab may
have a beneficial effect against radiation brain necrosis .
Upon retrospective review of patients treated with
bevacizumab and radiation, they identified 8 patients
with radiation brain necrosis diagnosed by MRI and
biopsy confirmed. All 8 patients showed a reduction in
the volume of the imaging abnormalities after bev-
acizumab treatment for their malignancy. To reiterate,
these cases were found on retrospective review.
Following this report, two additional studies were
published with patients who had known cerebral
radiation necrosis and were treated with bevacizumab.
633
Wong et al. (2008) reported success treatment of
neurological symptoms of a woman with temporal
lobe necrosis following treatment for nasopharyngeal
cancer extending into the sphenoid sinus. Liu et al.
(2009) reported four cases of children treated for
pontine glioma who were suspected to have radiation
necrosis. Three showed improvement clinically and in
imaging studies; the fourth was determined to have
progressive disease rather than necrosis. Two of the
three cases subsequently had clinical progression, but
whether this was tumor related or due to the necrosis
was unclear.
Finally, Levin et al. (2010) reported a randomized,
double-blind placebo-controlled trial of bevacizumab
for patients with radiation necrosis. All seven patients
treated with bevacizumab showed MRI responses and
improvement in neurological symptoms. Five of the
seven placebo patients showed worsening of symp-
toms and two showed only MRI progression. Five of
the placebo patients crossed over to receive bev-
acizumab after progression. All of these patients
improved with the treatment.
There has been one reported case of spinal cord
infarction after bevacizumab for non-small cell lung
cancer (Masselos et al. 2009). This patient did not
receive any radiation. However, her medical history
included epilepsy and hypertension, and she was
being treated with an extensive array of drugs at the
time of presentation. The authors concluded that
bevacizumab was not necessarily the sole causative
agent.
It is unclear whether radiation myelopathy can be
successfully treated with bevacizumab and such
treatment does have side effects. However, no con-
sistently successful treatment currently exists. If one
were to treat radiation myelopathy, early treatment
would be important since lesions can progress to
complete cord transection. As the pathophysiology of
radiation myelopathy becomes increasingly eluci-
dated, we may reasonably expect progress in the
treatment and prevention of radiation myelopathy.
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 Radiation Therapy-Related Toxicity:
Esophagus
Voichita Bar Ad and Maria Werner-Wasik

Contents
1 Pathophysiology and Clinical Picture
of Esophagitis ........................................................... 638
2 Evaluation of Esophagitis ....................................... 639
3 Incidence of Esophagitis and Predisposing
Factors....................................................................... 639
4 Dosimetric Factors Associated
with Esophagitis ....................................................... 641
5 Strategies Used to Prevent or Treat
Esophagitis................................................................ 643
References.......................................................................... 644
Abstract
Radiation-induced esophagitis is a dose-limiting
toxicity of lung cancer treatment. The majority of
patients receiving concurrent chemotherapy and
thoracic irradiation experience acute esophagitis.
Acute esophagitis may be disabling and necessitate
hospitalization, placement of a feeding tube in the
stomach, or initiation of parenteral nutrition.
Moreover, interruption of the course of radiation
therapy may be required in order to permit healing
of the esophageal injury. Such treatment breaks
have been demonstrated to decrease survival of
patients with unresectable lung cancer. Proper
prevention, diagnosis, and treatment of esophagitis
are therefore essential, as it may have a direct
influence on tumor control and survival.

Abbreviations

LD Lethal dose
NCI CTCAE National Cancer Institute’s Common
Terminology Criteria for Adverse
Events
RTOG Radiation Therapy Oncology Group
CHART Continuous hyperfractionated accel-
erated radiation therapy
EORTC European Organization for Research
and Treatment of Cancer
V. Bar Ad (&)
M. Werner-Wasik 3DCRT Three-dimensional conformal radia-
Department of Radiation Oncology, tion therapy
Kimmel Cancer Center of Jefferson Medical College, DVHs Dose–volume histograms
Thomas Jefferson University Hospital,
QUANTEC Quantitative analysis of normal tissue
111 South 11th Street, Philadelphia,
PA 19107, USA effects in the clinic
e-mail: Voichita.Bar-Ad@Jeffersonhospital.org CT Computed tomography

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 637
DOI: 10.1007/174_2011_204, Ó Springer-Verlag Berlin Heidelberg 2011
638
MTD Maximal tolerated dose
Vx Volume receiving more than x Gy
SBRT Stereotactic body radiation therapy
TITE-CRM Time-to-event continual reassessment
method
DLTs Dose-limiting toxicities
TD Tolerance dose
IMRT Intensity modulated radiation therapy
NTCP Normal tissue complication
probability
CGE Cobalt-gray equivalent
CCT Concurrent chemotherapy
1 Pathophysiology and Clinical
Picture of Esophagitis
The esophagus is lined with a convoluted squamous
epithelium, with a basal cell layer, submucosa and a
layer of striated muscle fibers underneath and without
surrounding serosa. In mice treated with a single fraction
of radiation therapy to the thorax, evidence of damage to
the esophagus was observed at a dose of 20.0 Gy,
starting 3 days after radiotherapy (Phillips and Ross
1974). This included vacuolization of the basal cell
layer, absence of mitosis, and submucosal edema. Some
regeneration was evident by 1–2 weeks from radio-
therapy, including proliferating basal cells, regenerating
epithelium, and scattered areas of complete esophageal
denudation. At 3 weeks, the regeneration of the esoph-
ageal lining was complete, and after 4 weeks the
appearance of the irradiated esophagus was normal. For
fractionated radiotherapy doses, the LD50/28 (or radio-
therapy dose causing death of 50% of the animals over
28 days) was estimated as 57.45 Gy (in ten fractions).
Radiological findings of esophageal injury were
described in 30 symptomatic patients who received
thoracic radiotherapy to 45–60 Gy. The most common
finding was esophageal dysmotility, such as failure to
complete primary peristaltic waves, non-peristaltic or
tertiary contractions, or failure of distal esophageal
sphincter relaxation. Smooth esophageal strictures
were demonstrated in some patients, and one frank
ulceration of the irradiated site was observed (Goldstein
et al. 1975). Abnormal esophageal motility was noted to
occur within 4–12 weeks from radiotherapy alone and
as early as after 1 week of concurrent chemotherapy
and radiotherapy (Lepke and Libshitz 1983).
V. Bar Ad and M. Werner-Wasik
The first symptoms of acute esophagitis usually
start in the second or third week of thoracic radiation
therapy, corresponding to a dose of 18.0–21.0 Gy of
standard fractionated radiotherapy, and include a
sensation of difficult swallowing (dysphagia). This
may progress to painful swallowing of food and saliva
(odynophagia) and later to constant pain not neces-
sarily related to the swallowing act. In severe cases,
patients may not be able to swallow at all. In patients
receiving concurrent chemotherapy and thoracic
radiotherapy, maximal symptoms of acute esophagitis
developed within 1, 2, and 3 months from the start of
radiotherapy in 19, 32, and 33% of the patients,
respectively (Werner-Wasik et al. in press).
Patients with esophagitis require steady supportive
care, starting with a low-acid and bland diet when the
first sensation of difficulty swallowing is reported.
Patients should be instructed to avoid coffee, hot bev-
erages, spicy foods, citrus fruit and juices, tomato
products, alcohol, and tobacco. In addition, a mixture
of a local anesthetic (2% viscous lidocaine), coating
substance (benadryl elixir), and saline/baking soda
(‘‘Magic Mouthwash’’) is frequently prescribed to be
taken liberally before meals to facilitate swallowing.
Once symptoms progress (e.g., pain is more severe and
only a soft diet is feasible), stronger oral analgesic
agents should be instituted (hydrocodone with acet-
aminophen; liquid morphine; prolonged action opiate
preparations, etc.) to control pain and allow adequate
oral nutrition. High-calorie liquid oral nutritional sup-
plements are helpful in maintaining satisfactory caloric
intake and minimizing weight loss and anemia. Once
adequate oral intake of fluids is impaired (as deter-
mined by dietary interview, positional changes in
blood pressure and low urinary output), intravenous
fluids should be instituted promptly in order to break
the vicious cycle of dehydration-poor oral intake-more
dehydration. A simple initial step is to give fluids
intravenously on an outpatient basis for a day or two
while continuing thoracic radiotherapy. When the
patient is unable to swallow despite optimal oral
analgesics, hospitalization is indicated for intravenous
hydration and intravenous pain control. In extreme
cases, placement of a gastric tube, parenteral nutrition,
or urgent operative intervention may be necessary. The
speed of recovery from acute esophagitis seems related
to the recovery from neutropenia induced by concur-
rent delivery of chemotherapy. Prolonged neutropenia
prevents sufficient healing of the esophageal mucosa.
Radiation Therapy-Related Toxicity: Esophagus
Table 1 Version 4.0 of National Cancer Institute’s Common Terminology Criteria for Adverse Events
Grade 1 Grade 2
Dysphagia Symptomatic, able to eat Symptomatic and
a regular diet altered eating/
swallowing
Esophagitis Asymptomatic; clinical Symptomatic;
or diagnostic altered eating/
observations only; swallowing; oral
intervention not supplements
indicated indicated
TPN total parenteral nutrition
This is a classic indication for a temporary suspension
of radiotherapy and administration of a granulocyte-
stimulating factor preparation in order to shorten the
neutropenic period. Short of this, thoracic radiotherapy
should be continued as long as clinical judgment
allows, since radiotherapy breaks are strongly associ-
ated with decreased chances of tumor control (Cox
et al. 1993).
Symptoms of acute esophagitis commonly persist
for 1–3 weeks after the completion of radiotherapy.
Late esophageal damage may subsequently develop at
3–8 months from completion of radiotherapy. It most
often manifests as dysphagia to solids, caused by a
permanent narrowing of the esophagus (stricture).
The presence of stricture requires periodic surgical
dilation of the esophagus, usually with excellent
results (Choi et al. 2005).
Acute esophagitis may be disabling, resulting in
hospitalization, placement of a feeding tube in the
stomach, or parenteral nutrition for a period of time.
Additionally, the course of radiotherapy may need to be
halted temporarily in order to allow for healing of the
esophageal lining. Treatment breaks in turn have been
unequivocally demonstrated to decrease survival of
patients with unresectable lung cancer (Cox et al. 1993).
Steps toward prevention, prompt diagnosis, and effective
treatment of radiation esophagitis may therefore have a
direct impact on tumor control and overall survival.
2 Evaluation of Esophagitis
Various criteria have been used to grade acute
esophagitis. ‘‘Esophagitis’’ is defined in Version 4.0
of National Cancer Institute’s Common Terminology
639
Grade 3 Grade 4 Grade
5
Severely altered eating/ Life-threatening Death
swallowing; tube consequences;
feedings or TPN or urgent intervention
hospitalization indicated indicated
Same as above Life-threatening Death
consequences;
urgent operative
intervention
indicated
Criteria for Adverse Events (v4.0, CTCAE scale)
as a disorder characterized by inflammation of the
esophageal wall, and its grading is predominantly
based on symptoms, altered diet, and need for inter-
vention (Table 1).
Grading systems such as the NCI CTCAE describe
toxicity at one point in time, but they do not provide
information about the length of time over which the
patient experiences the symptoms of esophagitis.
Esophagitis index (Werner-Wasik et al. 2002) is another
measure of toxicity that is obtained by plotting the
esophagitis grade over time. It may be a more compre-
hensive measure of normal tissue toxicity than maxi-
mum grade alone. Its calculation requires prospective
accumulation of data points of toxicity over time, how-
ever, and its applicability may therefore be limited to
investigational pursuits. The Radiation Therapy Oncol-
ogy Group (RTOG) 98-01 study (Movsas et al. 2005)
implemented other measures of esophagitis, based on
physician assessment (weekly physician dysphagia log)
as well as daily patient assessment of their difficulty in
swallowing (patient swallowing diary). These measures
allow a direct comparison of health care worker- vs.
patient-reported outcome endpoints.
3 Incidence of Esophagitis
and Predisposing Factors
The reported incidence of severe acute esophagitis
(Grade [3) in patients treated with standard thoracic
radiotherapy alone is 1.3% (Werner-Wasik et al. in
press). Induction chemotherapy increases this risk
slightly (Byhardt et al. 1998). Only 6% of patients
receiving induction chemotherapy followed by
640 V. Bar Ad and M. Werner-Wasik

Table 2 RTOG/EORTC late esophagitis criteria

Grade 0 Grade 1 Grade 2 Grade 3 Grade 4
Esophagus No Mild fibrosis; slight Unable to take solid food Severe fibrosis; able to Necrosis/
symptoms difficulty in normally; swallowing swallow only liquids; may perforation
swallowing solids; no semi-solid food; dilation have pain on swallowing; fistula
pain on swallowing may be indicated dilation required
RTOG/EORTC Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer

standard radiotherapy developed severe acute
esophagitis. When chemotherapy is given concur-
rently with thoracic radiotherapy, however, a strong
radiosensitizing effect is evident. In the RTOG
experience, 95% of patients receiving concurrent
chemotherapy and thoracic radiotherapy experienced
some degree of acute esophagitis. The highest grade
of esophagitis reported was Grade 1 in 20% of
patients, Grade 2 in 41%, Grade 3 in 31%, and
Grade 4 in 2%. The incidence of severe esophagitis
was higher (70 vs. 22%; p \ 0.0001) in patients
receiving hyperfractionated radiotherapy than in
patients treated with conventional fractionation
(Werner-Wasik et al. in press). In other series,
altered fractionation has been found to worsen the
severity and duration of esophagitis. Ball et al.
(1995) demonstrated that the duration of symptom-
atic esophagitis was 1.4 months in the conventional
radiotherapy arm, 1.6 months in the arm given
conventional radiotherapy with concurrent carbo-
platin, 3.2 months in the accelerated radiotherapy
arm, and 2.4 months in the arm where accelerated
radiotherapy was combined with concurrent carbo-
platin. With the continuous hyperfractionated accel-
erated radiation therapy (CHART) regimen, used
without chemotherapy for locally advanced non-
small-cell lung cancer, 19% of patients experienced
severe esophagitis (Saunders et al. 1997). Another
altered fractionation scheme, the concomitant boost
technique, resulted in a dose-limiting incidence of
severe esophagitis of 33% of patients when delivered
concurrently with chemotherapy (Dubray et al.
1995).
It had been reported that particular agents, such as
doxorubicin, cause severe primary or recall esopha-
gitis at radiotherapy doses as low as 20.0 Gy (Boal
et al. 1979). Gandara et al. (2003) reported a
20% incidence of severe acute esophagitis with
radiotherapy using the cisplatin/etoposide regimen
concurrently. Vokes et al. (2002) described an inci-
dence of 52% of severe acute esophagitis (35% Grade
3 and 17% Grade 4 esophagitis) with concurrent
gemcitabine and thoracic radiotherapy. Pulsed low-
dose paclitaxel (at escalating doses of 15, 20, and
25 mg/m2 infused on Monday, Wednesday, and Fri-
day, respectively) delivered concurrently with daily
chest irradiation for radiosensitization was associated
with 17% risk of Grade 3 esophagitis; no Grade 4 or 5
esophagitis was reported in this study (Chen et al.
2008). Other study used weekly paclitaxel 60 mg/m2
concurrently with standard fractionated radiotherapy;
the major toxicity was esophagitis, with 20% of the
patients developing Grade 4 esophagitis (Choy and
Safran 1995). These experiences indicate that it is
difficult to predict the severity of esophageal toxicity
a novel chemoradiation regimen will cause. Whether
the degree of esophagitis is related to scheduling of
chemotherapy used (daily vs. weekly vs. every three
weeks) is uncertain.
Other factors associated with a higher risk of
esophagitis include age [70 years (Langer et al.
2001), presence of dysphagia before radiotherapy
initiation (Ahn et al. 2005), low pre-treatment body
mass index (Patel et al. 2004), and nodal stage of N2
or worse (Ahn et al. 2005). The extent of nodal
involvement probably serves as a surrogate for the
volume of esophagus irradiated.
Despite high rates of acute esophagitis, late
esophageal damage was infrequent (2% incidence) in
the RTOG experience. Death due to esophagitis was
practically non-existent (Werner-Wasik et al. in
press). Ahn et al. (2005) showed that the presence of
acute esophageal injury was the most predictive factor
for the development of late esophageal toxicity
(stricture or fistula). The RTOG/EORTC (Radiation
Therapy Oncology Group/European Organization for
Research and Treatment of Cancer) criteria for late
esophagitis are presented in Table 2.
Radiation Therapy-Related Toxicity: Esophagus
4 Dosimetric Factors Associated
with Esophagitis
Preclinical data suggest that doubling the length of
irradiated portion of the esophagus leads to a decrease
of the LD50 (dose causing the death of 50% of irra-
diated animals) (Michalowski and Hornsey 1986).
However, the clinical evidence that esophageal tox-
icity is correlated to esophageal length irradiated
remains controversial. Ball et al. (1995) analyzed the
outcomes of 100 patients divided into three groups
based on length of treatment field (\14.0, 14.0–15.9,
and [16.0 cm) presumed to correlate with the length
of esophagus irradiated. No relationship between
treatment field length and the severity of esophagitis
was observed. In Choy’s analysis of 120 patients
(Choy et al. 1999), there was no correlation between
esophagitis grade and length of esophagus in either
the primary (p = 0.4) or boost (p = 0.1) radiation
fields. We studied 105 lung cancer patients treated
with concurrent chemoradiotherapy or radiotherapy
alone. Acute esophagitis was scored prospectively in
a uniform fashion, and precise measurements of the
esophageal length within each radiation field were
available (Werner-Wasik et al. 2000). Again,
increasing length of esophagus in the radiation field
did not predict for the severity of acute esophagitis.
Recent advances in three-dimensional conformal
radiation therapy (3DCRT) allows us to correlate vol-
umetric data to organ damage rather than rely on the
older estimates based on organ length (esophagus). The
dosimetric study by Maguire et al. (1999) established a
relationship between high dose irradiation of the entire
esophageal circumference and esophagitis risk. They
reported a detailed dosimetric analysis of 91 patients
treated to a median corrected dose of 78.8 Gy. The
percent of esophageal volume treated to[50.0 Gy and
the maximum percent of esophageal circumference
treated to[80.0 Gy were significant predictors of late
(but interestingly not acute) esophagitis. The concept
emerging from this data was the importance of sparing
portions of the esophageal circumference to limit
esophageal toxicity.
The association between esophageal dose–volume
histograms (DVHs) and the risk of radiation-induced
esophagitis was further evaluated by several authors.
These data were recently reviewed by the organ
specific quantitative analysis of normal tissue effects
641
Fig. 1 Incidence of acute esophagitis according to Vx (volume
receiving more than x Gy). X-axis values estimated according to
range of doses reported. Each curve annotated as follows: Vdose
(investigator, number of patients, percentage with concurrent
chemotherapy [CCT]. Percentage of patients who received
sequential chemotherapy in in studies by Ahn et al. (2005),
Belderbos et al. (2005), and Kim et al. (2005) was 44, 38, and
15%, respectively. Data for V50 (Ahn et al. 2005) at 15, 45, and
75 Gy represent reported rates of Grade 2 or greater acute
esophagitis plotted in dose bins at \30, 30–60, and [60%,
respectively. Similarly, for V70 (Ahn et al. 2005), V50
(Rodriguez et al. 2005), and V60 (Kim et al. 2005), each
symbol represents rates of acute esophagitis at \10% versus
11–30% versus 31–64%, and\30 versus[30%, and\30 versus
[30%, respectively. Dashed horizontal lines reflect dose ranges
ascribed to each data point. Upper x-axis range of greatest data
point for V50 (Rodriguez et al. 2005), V50 (Ahn et al. 2005),
and V60 (Kim et al. 2005), are indefinite according to data
(light-gray dotted bars). Solid and open symbols represent
reported rates of Grade 2 or greater acute esophagitis and Grade
3 or greater acute esophagitis, respectively. Thicker and thinner
solid lines represent higher and lower doses of Vx, respectively
(i.e., thicker line for V70 and thinner line for V20). Reprinted
from Werner-Wasik et al. (2010). Copyright (2010), with
permission from Elsevier
in the clinic (QUANTEC) group (Werner-Wasik et al.
2010). In general, the data are consistent with some
risk of acute esophagitis at intermediate doses of 30–
50 Gy and an increasing effect for greater doses.
Volumes of esophagus receiving doses higher than
50 Gy have been identified as highly statistically
significantly correlated with acute esophagitis in
several studies. Rates of acute Grade [2 esophagitis
appear to increase to over 30% as V70 exceeds 20%,
V50 exceeds 40%, and V35 exceeds 50% (Fig. 1).
However, due to diverse methods of reporting volu-
metric data (absolute volume or area, relative volume
or area, and circumferential measures), no consensus
for definitive dosimetric recommendations has been
642
reached. Another confounding factor is the fact that in
some studies the entire esophagus was not delineated,
making volumetric measurements difficult to inter-
pret (Werner-Wasik et al. 2010). The entire length
has to be identified (from the crycoid cartilage to
the gastro-esophageal junction). Moreover, on axial
computed-tomography (CT) imaging, the esophageal
circumference varies significantly. This is a reflection
of the swallowing act, and it does not reflect the ana-
tomic reality of a relatively uniform circumference
(Kahn et al. 2005). Therefore, conventional DVHs
might not correctly reflect the partial volume dose and
may be misleading. Likewise, the esophagus is
slightly mobile; the cephalad, middle, and caudal
esophagus can move \ 5, 7, and 9 mm, respectively
during normal respiration (Dieleman et al. 2007). This
may introduce additional uncertainties into volumetric
analyses based on planning CT scans. No specific
margin recommendations can be given at the present
time (Werner-Wasik et al. 2010).
Recent studies evaluating escalating radiotherapy
dose (standard fractionation) or hypofractionated
schedules for lung cancer have been published or
designed. In each situation, novel restraints had to be
placed on the doses to be delivered to the normal organs
in the chest such as lung, esophagus, and spinal cord.
RTOG 93-11 study evaluated the feasibility of
dose escalation for patients with locally advanced
non-small-cell lung cancer treated with 3DCRT to the
gross tumor only, without elective nodal irradiation.
Maximum doses of 77.4–90.3 Gy were prescribed,
depending on the percentage of the total lung
receiving more than 20.0 Gy. This trial of thoracic
radiotherapy alone escalated the dose to the tumor up
to 90.3 Gy in group 1 (\25% of both lungs receiving
[20 Gy), up to 83.8 Gy in group 2 (25–37% of lungs
receiving [20 Gy) and up to 77.4 Gy in group 3
([37% of lung receiving [20 Gy). The maximum
dose allowed to 1/3 of esophageal volume was 65 Gy;
to 2/3 of the volume, 58 Gy; and to the whole
esophagus, 55 Gy, respectively. The clinical endpoint
was esophageal stricture or perforation. No severe
acute esophagitis was observed even in the highest
radiotherapy dose level. However, the estimated rate
of late Grade [3 esophageal toxicity at 18 months
was 8, 0, 4, and 6% for group 1 patients receiving
70.9, 77.4, 83.8, and 90.3 Gy,respectively and 0 and
5%, respectively for group 2 patients receiving 70.9
and 77.4 Gy (Bradley et al. 2005), suggesting a dose–
V. Bar Ad and M. Werner-Wasik
response relationship. In the currently ongoing RTOG
0617 Phase III comparison of 60 vs. 74 Gy thoracic
radiotherapy with concurrent and consolidation pac-
litaxel, carboplatin chemotherapy ± cetuximab in
patients with stage IIIA/IIIB non-small-cell lung
cancer, a mean esophageal dose of\ 34 Gy is strongly
recommended, but not absolutely required. The
esophageal V60 (volume of the esophagus exceeding
60 Gy) should be calculated for each patient.
Hypofractionated radiotherapy for centrally loca-
ted lesions may expose parts of the esophagus to large
doses per fraction. The clinical experience using this
treatment approach for non-small-cell lung cancer is
very limited. The ongoing RTOG 0813 Phase I/II
study is a radiotherapy dose escalation trial using
stereotactic lung radiotherapy for early stage, cen-
trally located, non-small-cell lung cancer in medically
inoperable patients. The primary end point of the trial
is to determine the maximal tolerated dose (MTD) of
stereotactic body radiation therapy (SBRT) delivered
in five fractions over 1.5–2 weeks of treatment. The
maximum dose aimed to be reached in this trial is
60 Gy using 12 Gy per fraction over 1.5–2 weeks.
Doses will be allocated to the enrolled patients by
using the time-to-event continual reassessment
method (TITE-CRM) rather than the conventional
Phase I design of 3 patients for each dose level. The
first patients are treated with 50 Gy delivered using
10 Gy per fraction over 1.5–2 weeks. Dose levels for
subsequent patients enrolled in this study will be
determined based on the dose limiting toxicities
(DLTs) to the critical organs experienced in previous
patients. Moreover, a patient may not be assigned to a
next higher dose level until there is at least 1 year of
cumulative observation at the ‘‘in progress’’ dose
level. As a result, more patients will be spared DLTs
and more patients will be treated at a dose level that
ultimately will be selected as the most appropriate
one. The maximum point dose to the esophagus
accepted is 105% of the target prescription; it is
recommended that less than 5 cc of the esophagus
(non-adjacent wall) will receive a maximum dose of
less than 27.5 Gy (5.5 Gy per fraction).
The existing models and dose–volume parameters
should be applied only to regimens using conven-
tional fractionated radiotherapy regimens using
between 30 and 35 fractions. A prospective assess-
ment of the dose–volume parameters related to
esophageal toxicity associated with hypofractionated
Radiation Therapy-Related Toxicity: Esophagus
schedules of radiotherapy is required, given the
growing interest in this radiation therapy treatment
approach.
Compared to acute esophagitis, late esophageal
toxicity is far less common. The TD5/5 (tolerance
doses for the esophagus causing clinical stricture or
perforation in 5% of irradiated patients at 5 years) are
quoted as 60 Gy for the entire esophagus, 58 Gy for
two-thirds of the organ and 55 Gy for one-third of the
esophagus (Emami 1996).
5 Strategies Used to Prevent or Treat
Esophagitis
Up to now, standard radiotherapy techniques have not
been able to lower the maximum radiotherapy doses to
the esophagus significantly. Intensity modulated
radiation therapy (IMRT) seems well suited for such a
purpose, with its ability to deliver concave-shaped
radiotherapy dose distributions around organs at risk,
such as esophagus. Grills et al. (2003) compared four
different radiotherapy techniques for 18 patients with
stage I–IIIB inoperable non-small-cell lung cancer:
IMRT, optimized 3DCRT using multiple beam angles,
limited 3DCRT using 2–3 beams, and traditional
radiotherapy using elective nodal irradiation to treat
the mediastinum. The techniques were compared by
giving each plan a tumor control probability equiva-
lent to that of the optimized 3DCRT plan delivering
70 Gy. Using this method, IMRT and 3DCRT offered
similar results with regard to the mean lung dose and
the esophageal normal-tissue complication probability
(NTCP) in lymph node negative patients. However,
IMRT reduced the lung V20 and the mean lung dose
by approximately 15% and the lung NTCP by 30%
when compared with 3DCRT in lymph node positive
cases. The authors concluded that IMRT is beneficial
in selected patients, particularly those with positive
lymph nodes or those with target volumes in close
proximity to the esophagus. Moreover, in lymph node
positive patients, IMRT allowed delivery of radiation
doses 25–30% greater than 3DCRT while maintaining
an equal probability of pulmonary and esophageal
toxicity.
Proton beam radiotherapy allows a rapidly
increasing dose at the end of the beam range (Bragg
peak). Therefore, with proper distribution of proton
energies the dose can be uniform across the target
643
volume and essentially zero deep to it. As a result,
dose to the tumor can be increased, while the fre-
quency and severity of the treatment-related toxicity
could theoretically be decreased. This suggests a
significant potential for therapeutic gains (Suit et al.
2003).
Chang et al. (2009) analyzed data on 42 patients
diagnosed with stage III non-small-cell lung cancer
treated with thoracic radiotherapy using proton beam
therapy to a total dose of 74 CGE (Cobalt-Gray
Equivalent) with concurrent carboplatin and paclit-
axel. Esophagitis was reported in only 6.7% of the
cases. However, clinical experience with proton
radiation therapy for non-small-cell lung cancer has
been rather limited to date.
Complete exclusion of the esophagus from the
standard radiotherapy field designed to treat a locally
advanced lung cancer is most often not feasible due to
the organ’s central position in the mediastinum.
Therefore, strategies to limit esophagitis using a
radioprotective agent have been explored.
A number of clinical trials have investigated the
use of amifostine as a radioprotective agent with
thoracic irradiation for lung cancer. Encouraging
results reported in Phase II (Komaki et al. 2004) as
well as Phase III randomized trials (Antonadou et al.
2001) led to the development of RTOG 98-01, a large
cooperative group Phase III randomized study that
tested the efficacy of amifostine in preventing
esophagitis in non-small-cell lung cancer patients
receiving thoracic radiotherapy with concur-
rent carboplatin, paclitaxel chemotherapy (Movsas
et al. 2005). Patients were randomized to receive
amifostine (500 mg intravenously four times weekly,
preceding the afternoon dose of radiotherapy) versus
no amifostine. RTOG 98-01 showed that amifostine
did not reduce severe esophagitis (30% rate with
amifostine vs. 34% without), as assessed by the NCI
CTCAE criteria and weekly physician dysphagia logs.
Evaluation of patient diaries, however, indicated that
amifostine conferred a significant reduction in swal-
lowing dysfunction measured over time (equivalent of
esophagitis index), a decrease in pain after chemora-
diotherapy, and diminished weight loss in patients
receiving chemoradiation (Sarna et al. 2008). Of note,
only 40% of all radiotherapy fractions were ‘‘pro-
tected’’ by amifostine infusion in that study, and only
29% of patients received the medication according
to the protocol. Further investigation of this agent
644
is therefore justified, possibly with subcutaneous
administration in order to increase the compliance and
to allow higher dose intensity of amifostine.
Another agent utilized to limit esophagitis is oral
sucralfate. Although applied commonly in the clinic,
this agent was shown not to have value in decreasing
acute esophagitis in a double-blind Phase III ran-
domized trial of 97 patients receiving thoracic
radiotherapy (McGinnis et al. 1997).
An interesting approach of plasmid/liposome
delivery by the human manganese superoxide dis-
mutase transgene has been reported to be successful
in prevention of radiation esophagitis in mice
receiving carboplatin, paclitaxel, and thoracic radio-
therapy (Stickle et al. 1999).
Palifermin is a human recombinant keratinocyte
growth factor shown to significantly reduce severe
oral mucositis in patients with hematological malig-
nancies treated with bone marrow transplantation
(including total body irradiation) (Spielberger et al.
2004). However, the clinical data including patients
with non-hematological tumors treated with radio-
therapy are limited.
In summary, significant progress has been
accomplished in our understanding of the basis of
radiation-induced esophageal injury. Addressing this
dose-limiting toxicity is imperative for the intensifi-
cation of radiotherapy and chemotherapy protocols.
Future effort is necessary in order to find effective
measures to minimize or eliminate esophagitis.
Disclosure No conflict of interest to declare.
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 Brain Toxicity
C. Nieder
Contents
1 Introduction.............................................................. 647
2 Pathogenesis of Radiotherapy-Induced
Brain Toxicity .......................................................... 648
3 Acute and Subacute Radiotherapy-Induced
Brain Toxicity .......................................................... 650
4 Delayed or Chronic Radiotherapy-Induced
Brain Toxicity .......................................................... 650
5 Toxicity Prevention Strategies ............................... 653
6 Treatment of Radiotherapy-Induced Brain
Toxicity...................................................................... 655
7 Aspects of Chemotherapy-Induced Brain
Toxicity...................................................................... 655
References.......................................................................... 655
C. Nieder (&)
Department of Oncology and Palliative Medicine,
Nordland Hospital, P.O. Box 1480, 8092 Bodø, Norway
e-mail: carsten.nieder@nordlandssykehuset.no
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_221, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
Since lung cancer generally has a high, stage- and
histology-dependent propensity for brain metasta-
ses, many patients receive prophylactic or thera-
peutic radiotherapy to the brain and are therefore at
risk for developing acute, subacute or chronic side
effects. Certain types of systemic treatment might
also cause brain toxicity. In this chapter the
different types of toxicity, the pathogenesis and
emerging prevention and treatment strategies are
reviewed.
1 Introduction
Prevention and treatment of brain metastases contin-
ues to be an important issue despite considerable
improvements in local and systemic therapy for lung
cancer. As long as many patients are diagnosed in
advanced stages of the disease, their risk for devel-
oping brain metastases is high. Up to 60% of patients
with small-cell lung cancer (SCLC) will be diagnosed
with brain metastases at some time during the natural
course of the disease. Therefore, prophylactic cranial
irradiation (PCI) is now recommended in the majority
of patients with SCLC. The second indication for
brain irradiation in lung cancer is palliation of
symptoms from brain metastases. Depending on the
number of lesions, their size and location and well
established prognostic factors (Nieder et al. 2009),
whole-brain radiotherapy (WBRT), open surgical
resection or stereotactic radiosurgery (SRS) may be
the preferred option. Another indication is adjuvant
radiotherapy after resection of brain metastases,
which is usually administered by means of WBRT.
647
648
However, adjuvant tumor bed SRS or brachtherapy is
also under investigation. This chapter will therefore
cover the normal tissue effects of both partial brain
radiotherapy and WBRT to the normal adult brain.
The issue of reduced tolerance in the immature brain
will not be discussed, due to the fact that it is less
relevant in the context of lung cancer.
The physical and technical developments and
refinements over the last decades in radiation oncol-
ogy have been impressive. But still, the easiest and
most effective way of avoiding side effects to the
normal brain is by minimizing its exposure to ionizing
radiation. While individually-shaped, highly confor-
mal dose distributions can be created, this does not
solve the problem of the presence of normal tissue
within the irradiated target volume (the result of dif-
fuse microscopic spread, which escapes current
imaging technology). Therefore, many patients con-
tinue to receive WBRT. Where a reduction of the
irradiated volume is not feasible, further progress can
only be expected from efforts directed at optimizing
fractionation or widening the therapeutic window
between tumor and normal tissue through modulation
of the patient’s responses to radiotherapy.
We will discuss the pathogenesis of radiation-
induced brain toxicity, the incidence of typical side
effects, risk factors, diagnostic aspects and the role of
multimodal treatment concepts in the development of
side effects. Increasing evidence can be found in the
literature about the influence of cytotoxic drugs and
the general side effects of cancer treatment, such as
anemia, on the normal brain. Finally, pre-clinical and
clinical data on the prevention and treatment of side
effects will be reviewed.
2 Pathogenesis of Radiotherapy-
Induced Brain Toxicity
Early evaluations of radiotherapy-induced central
nervous system (CNS) toxicity date back to over
70 years ago. It is not the aim of this chapter to dis-
cuss these historical data, which have been summa-
rized in previous reviews, for example, by van der
Kogel (1986). When appropriate, data from spinal
cord radiotherapy will be included in the current
chapter because of the similarity of radiation-induced
changes in the brain and the spinal cord. In brief,
previous experimental studies have indicated that
C. Nieder
signs of diffuse demyelination develop in animals
2 weeks after CNS radiotherapy. After approximately
2 months, remyelination processes have been
observed. These early changes correspond to clinical
symptoms such as Lhermitte’s sign and somnolence
in humans. After a variable latency period, and
dependent on total dose, white matter necrosis may
develop. The gray matter is less sensitive. Latency
time decreases with increasing radiation dose. The
most important determinants of CNS tolerance are the
volume of normal tissue exposed, dose per fraction
and total dose. Overall treatment time is less impor-
tant. With multiple fractions per day, incomplete
repair needs to be taken into account, especially when
the interfraction interval is less than 6 h.
When WBRT is being administered, the complete
intracranial vascular system is exposed to ionizing
radiation, although at relatively modest doses, in
contrast to focal treatment where only limited parts of
the blood vessels might receive a significantly higher
dose. When high focal doses are combined with lower
doses to a large surrounding volume, tolerance
decreases, compared with the same focal treatment
alone.
Significant long-term recovery has been observed
after spinal cord radiotherapy. Although not experi-
mentally tested in the same fashion, it can be assumed
that the brain recovers, too. Especially with larger
intervals of at least 1–2 years and when the first
treatment course was not too close to tolerance, re-
irradiation is now considered as a realistic option.
Experimental data from fractionated radiotherapy of
rhesus monkeys suggest a recovery of up to 75% of
the initial damage within 2–3 years (Ang et al. 2001).
The past few years have witnessed a significant
improvement as far as techniques are concerned in
cellular and molecular biology, resulting, for exam-
ple, in a description of more and more radiobiologi-
cally-relevant cellular pathways. Better methods for
the identification of stem and progenitor cells have
been developed. This progress has led to a better
understanding of tissue responses to ionizing radia-
tion. Obviously, radiation-induced reactions of the
CNS are not limited to reproductive or mitotic cell
death in mature parenchymal and vascular cell pop-
ulations. Apoptosis, induced by sphingomyelinase-
mediated release of ceramide, has been described as
an early reaction in endothelial cells within the
irradiated CNS (Pena et al. 2000), as well as in
Brain Toxicity
oligodendrocytes (Larocca et al. 1997). Besides cell
death, a large number of alterations in gene expres-
sion, transcription factor activation and functional
changes in basically every cell type examined may
develop (Raju et al. 2000). Current models of radio-
therapy-induced brain alterations include a cascade of
complex and dynamic interactions between paren-
chymal cells (oligodendrocytes, astrocytes, microg-
lia), stem and progenitor cells and vascular
endothelial cells (Tofilon and Fike 2000; Fike et al.
2009). The latent time preceding the clinical mani-
festation of damage is viewed as an active phase,
where cytokines and growth factors play important
roles in intra- and intercellular communication
(Nieder et al. 2007). Clinically recognized phenom-
ena, such as intellectual decline, memory loss, leth-
argy, dysphoria, dementia and ataxia, also suggest the
possible involvement of neurons in radiotherapy-
induced CNS reactions. In vitro studies have dem-
onstrated that neurons may undergo apoptosis after
radiotherapy (Gobbel et al. 1998). Fractionated brain
irradiation inhibited the formation of new neurons in
the dentate gyrus of the hippocampus in rats (Madsen
et al. 2003). Animals with blocked neurogenesis
performed poorer in short-term memory tests that are
related to hippocampal function. The deficit in neu-
rogenesis is based on both the reduced proliferative
capacity of progenitor cells and alterations in the
microenvironment that regulates progenitor cell fate
(disruption of the microvascular angiogenesis, acti-
vation of microglia) (Monje et al. 2002, 2007).
CNS radiotherapy induces production of inflam-
matory cytokines, such as tumor necrosis factor a
(TNF-a) and interleukin-1 (IL-1), by microglia and
astrocytes (Chiang and McBride 1991; Hayakawa
et al. 1997). IL-1 release leads, via autocrine mech-
anisms, to further activation and proliferation of these
glia cells. As shown in vivo, this cascade results in the
development of astrogliosis (Chiang et al. 1993).
Already 2 h after single-fraction radiotherapy to the
midbrain of mice (25 Gy), TNF-a and IL-1 mRNA
levels have been shown to increase (Hong et al.
1995). After 24 h, the levels start returning to normal.
Experimental rat brain irradiation has also been
shown to induce apoptosis, which, in turn, appears to
result in an increase in the number of microglial cells
participating in phagocytotic reactions. Besides the
cytotoxic effects of TNF-a on oligodendrocytes, for
example, through induction of caspase-mediated
649
apoptosis (Hisahara et al. 1997; Akassoglou et al.
1998; Gu et al. 1999), the cytokine in vitro prevents
the differentiation of O-2A progenitor cells into oli-
godendrocytes. Thus, compensation for radiation-
induced cell loss can be impaired. TNF-a is also
known to damage endothelial cells, leading to
increased vascular permeability. TNF-a and IL-1
induce the expression of intercellular adhesion mol-
ecule-1 (ICAM-1) in oligodendrocytes and micro-
vascular endothelial cells (Satoh et al. 1991; Wong
and Dorovini 1992). Increased levels of ICAM-1
mRNA were detectable after midbrain irradiation
with 2 Gy (Hong et al. 1995). Results of localized
single-fraction treatment with 20 Gy confirm the
presence of an early inflammatory response, an
increased numbers of leukocytes, increased vascular
permeability, altered integrity of endothelial tight
junctions and increased cell adhesion (Yuan et al.
2003). The exact role of such cytokines and mediators
after radiotherapy with conventional fraction sizes is
not well understood yet; clearly, the cellular and
molecular events during the latent phase require fur-
ther research.
Studies of boron neutron capture therapy (BNCT)
support the view that vascular damage is one of the
crucial components of radiotherapy-induced CNS
toxicity. The choice of boron compounds that are
unable to cross the blood–brain barrier allows a lar-
gely-selective irradiation of the vessel walls with
BNCT. Nevertheless as with conventional non-
selective radiotherapy methods, spinal cord lesions
(with a similar histological appearance) have been
induced. Latency time also is comparable between
damage induced by BNCT and conventional radio-
therapy (Morris et al. 1996). Additional evidence has
been provided by histological examinations of rat
brains after radiotherapy with 22.5 or 25 Gy, resulting
in reduced numbers of blood vessels and endothelial
cells before manifestation of necrosis (Calvo et al.
1988). These changes are accompanied by hyperper-
meability, resulting in perivascular edema and con-
secutive ischemic damage (Hopewell and van der
Kogel 1999). Microvascular networks, consisting of
arterioles, capillaries and venoles, which impact the
delivery of oxygen and nutrients to tissues and organs,
are the most radiosensitive parts of the vascular sys-
tem (Roth et al. 1999). Common therapeutic doses
of ionizing radiation lead to functional and, later,
to structural vascular damage, such as increased
650
permeability and changes in shape and diameter, as
well as in fibrous proliferation, ultimately resulting in
reduced perfusion. These changes develop earlier in
small versus large vessels. After lower doses, struc-
tural changes are hardly ever seen. After WBRT in
rats (five fractions of 4 Gy) alterations in vessel
configuration, either density or diameter, were not
detected (Mildenberger et al. 1990). Interestingly, a
localized significant increase of microglia was found
after 6 months, possibly as a result of the loss of
axons in the striatal white matter. The pattern was
suggestive of vascular insufficiency in this region,
which was being perfused by only few small vessels.
Electron microscopy in rats 15 days after the end of
conventional fractionated WBRT (40 Gy) showed
increased vascular permeability without structural
changes of the blood–brain barrier or astrocytes
(Cicciarello et al. 1996). A follow-up examination
after 90 days revealed ultrastructural changes of the
microvasculature and the neuropil, as well as astro-
cytes with perivascular edema.
Another study (partial brain irradiation with 40 or
60 Gy, or WBRT with 25 Gy in rats) showed a 15%
reduction in the number of endothelial cells 24 h to
4 weeks after radiotherapy. A further reduction was
seen with even longer intervals (Ljubimova et al.
1991). Kamiryo et al. showed how the latency to
development of vascular damage after SRS to the
parietal cortex of rat brain with a 4 mm collimator
decreases from 12 months to 3 weeks with an
increase in radiation dose from 50 to 75 Gy or
120 Gy (Kamiryo et al. 1996). The amount of vessel
dilation, increased permeability, thickening of the
vessel wall, vessel occlusion and necrosis also
increased with dose. In a different model of rat brain
irradiation, time and dose-dependent vascular altera-
tions were also seen (dilation, wall thickening, reac-
tive hypertrophy of neighboring astrocytes) before the
development of white matter necrosis (Hopewell et al.
1989). Rubin et al. performed comprehensive mag-
netic resonance imaging (MRI) and histological
examinations of rat brains after 2–24 weeks following
high dose, single-fraction irradiation with 60 Gy
(Rubin et al. 1994). After 2 weeks, a significant
increase in blood–brain permeability was observed.
Partial recovery occurred after 8–12 weeks, followed
by pronounced deterioration after 24 weeks, when the
first sites of necrosis developed. Spinal cord data
suggest an increase in the release of vascular
C. Nieder
endothelial growth factor (VEGF) as a result of
impaired perfusion and hypoxia signaling. Obviously,
the clinically observed latent phase is characterized
by persistent and increasing oxidative stress and
active responses to this factor. The extreme sensitivity
of the myelin membrane to oxidative damage explains
the preference of radiotherapy-induced lesions for
white matter.
3 Acute and Subacute Radiotherapy-
Induced Brain Toxicity
As stated in the previous paragraph, acute and suba-
cute radiotherapy-induced brain toxicity can develop
within hours from the start of treatment even if low
doses are given. It is usually characterized by
increased vascular permeability, edema and demye-
lination manifesting as headache, nausea, somnolence
or lethargy. However, it has been characterized as a
temporary, self-limiting reaction, which responds to
corticosteroid treatment (Schultheiss et al. 1995).
Subacute reactions may develop 2–6 months after
WBRT, resulting, for example, in lethargy, reduced
vigilance and impaired cognitive performance. Most
likely, such symptoms are related to a second phase of
transient demyelination and blood–brain barrier dis-
turbance. Treatment with corticosteroids again is
likely to improve the patient’s condition. With SRS,
acute reactions are rare. They include symptomatic
edema, seizures and nausea and vomiting, especially
when doses [3.75 Gy are given to the area postrema.
Antiemetics, corticosteroids and anticonvulsant drugs
may be used to treat these symptoms. Temporary
blood–brain disturbance may result in increased
contrast enhancement in computed tomography (CT)
or MRI during the first few months after SRS. These
changes should not be misinterpreted as tumor pro-
gression. Usually they resolve with longer follow-up.
4 Delayed or Chronic Radiotherapy-
Induced Brain Toxicity
Sustaining toxicity that may impair the patient’s
lifestyle significantly can be observed even several
years after radiotherapy in the form of radionecrosis
and cognitive dysfunction associated with leukoen-
cephalopathy. Necrosis develops for the most part
Brain Toxicity 651

after 1–3 years (Keime-Guibert et al. 1998). Symp-

toms of radionecrosis depend on localization and are
comparable to tumor-related symptoms before treat-
ment (focal neurologic deficits and seizures, speech
disturbance, signs of increased intracranial pressure).
CT and T1- and T2-weighted anatomic MRI are
unable to firmly discriminate between hypometabolic
necrosis and tumor relapse. Dynamic susceptibility
contrast-enhanced MRI, magnetic resonance spec-
troscopy (MRS) and functional imaging by means of
positron emission tomography (PET) and 201Tl-single
photon emission computed tomography (SPECT) can
provide useful additional information (Munley et al.
2001; Nakajima et al. 2009). Eventually, in some
cases, only histopathological examination of resection
specimens can establish the diagnosis. The typical
finding is coagulation necrosis in the white matter,
with a largely normal appearance of the cortex.
Fibrinoid necrosis and hyalinous wall thickening of
blood vessels are commonly observed. The risk of
radionecrosis amounts to approximately 5% within
5 years (ED5/5) after conventional fractionated partial
brain radiotherapy (one third of the brain) with 60 Gy
or WBRT with 45 Gy. The dose–response curves are
quite steep. Thus the risk increases to 10% within
5 years when a partial brain dose of 65 Gy is applied
(according to data from the randomized U.S. inter-
group low-grade glioma trial) and 50% when 75 Gy is
given. Irradiated volume, dose per fraction and total
dose are the most important risk factors (Lawrence
et al. 2010). Recent series reported radionecrosis after
SRS of brain metastases in 1–6% of cases, probably
dependent on brain region and vascular supply. Fig. 1 Initial CT scans (top) before whole-brain radiotherapy
Commonly prescribed doses are in the range of 15– (30 Gy in 10 fractions of 3 Gy) in a 66 year old man with
20 Gy, depending on volume, technique of SRS and multiple brain metastases from small cell lung cancer (no
previous prophylactic brain irradiation). The lower CT scan
use of additional WBRT. The risk increases when was taken 2 years later and shows moderate brain atrophy and
more than 10 cm3 of the normal brain receives more white matter changes. In addition periventricular calcifications
than 10 Gy. The optic apparatus should not receive (white arrow) can be seen. The patient had developed overt
more than 8 Gy (Mayo et al. 2010). Varlotto et al. neurocognitive decline interfering with activities of daily living
reported the results of SRS in 137 patients with brain
metastases who had a minimum follow-up of 1 year B2 cm3 and 16% for those with larger lesions. Age
after SRS (Varlotto et al. 2003). The median marginal and additional use of WBRT did not influence the
tumor dose was 16 Gy. NSCLC was the underlying complication rate. Therapeutic intervention with
primary tumor in 77 patients. Eleven patients devel- corticosteroids or anticoagulants is sometimes suc-
oped serious side effects, such as visual loss, hemor- cessful (Glantz et al. 1994). Often, surgical resection
rhage and persistent steroid-dependent edema or is the only way to effectively improve the symptoms.
necrosis necessitating surgical intervention. The Diffuse white matter changes are frequently observed
actuarial incidence of such adverse events was 4% in imaging studies (Figs. 1 and 2). Fluid-attenuated
after 5 years for patients with brain metastases inversion recovery (FLAIR) and diffusion-weighted
652
Fig. 2 Initial T2-weighted MRI scan before stereotactic radi-
osurgery (gamma knife, peripheral dose 20 Gy) in a 67 years
old woman with solitary brain metastasis from non-small-cell
lung cancer. The lower MRI scan was taken 2.8 years later and
shows focal white matter changes (white arrow). No clinical
late toxicity was apparent
MRI may improve visualization of white matter
abnormalities. These abnormalities are not necessarily
associated with clinical symptoms but often present
after fractionated doses of C30 Gy. Neuropsycho-
logical sequelae typically manifest within 4 years of
radiotherapy. Psychometric findings suggest greater
vulnerability of white matter and subcortical struc-
tures, resulting in reduced processing speed, height-
ened distractibility and memory impairment. Within
C. Nieder
the temporal lobe, the hippocampal formation plays a
central role in short-term memory and learning. These
functions are related to the activity of neural stem
cells. The hippocampal granule cell layer undergoes
continuous renewal and restructuring. Radiotherapy
can affect this sensitive cell layer leading to impaired
function without overt pathological changes. Our own
retrospective data from 49 patients who had received
WBRT with a median dose of 30 Gy showed that
33% of patients developed mild to moderate clinical
symptoms of brain toxicity (in one case, RTOG/EO-
RTC grade III, median follow-up 10 months, median
dose per fraction 3 Gy) (Nieder et al. 1999). This
resulted in a Karnofsky-performance status decline in
10 patients (20%). None of the PCI patients belonged
to this subgroup. CT showed increasing brain atrophy
and bilateral periventricular hypodensity in most
patients (Fig. 1). The actuarial risk of brain atrophy
was 84% after 2 years. Median time to development
of this side effect was 11 months. Patients with pre-
existing brain atrophy had a higher risk of further
shrinkage of the brain parenchyma than those with
normal baseline status. White matter changes were
observed in 85% of surviving patients. Radiologic
abnormalities did not correlate with the rate of clin-
ical symptoms. Previous studies described such cor-
relations for patients treated with PCI and
chemotherapy for SCLC (Laukkanen et al. 1988;
Johnson et al. 1990). Whether or not clinical symp-
toms, quality of life and radiologic abnormalities
correlate, might depend on variables such as length of
follow-up, methods of assessment and severity of
clinical symptoms.
When evaluating radiotherapy-induced cognitive
impairment, it is important to consider reference
values from the normal population. A Canadian Study
of Health and Aging with 9,008 randomly selected
men and women 65 years or older showed cognitive
impairment 5 years after baseline examination in 9%
and dementia in an additional 6% (Laurin et al. 2001).
Decline was significantly associated with reduced
physical activity. There is increasing evidence that
partial brain radiotherapy alone rarely causes signifi-
cant neurocognitive decline (Torres et al. 2003;
Duchstein et al. 2003). After WBRT, neuropsycho-
logical tests in 29 patients showed no significant
decrease (Penitzka et al. 2002). In this study, patients
with SCLC were significantly below average before
PCI, but did not deteriorate further. Patients with
Brain Toxicity
fewer cycles of preceding chemotherapy performed
better before PCI. These results are in accordance
with earlier prospective findings where 97% of
patients with SCLC had cognitive dysfunction prior to
PCI (Komaki et al. 1995). Six to twenty months later,
no further deterioration was identified. Some authors
found indications for increased toxicity when fraction
size exceeded 2 Gy (Herskovic and Orton 1986;
Twijnstra et al. 1987; De Angelis et al. 1989). Also
the large intergroup study that used PCI with 10
fractions of 2.5 Gy in patients with SCLC reported
mild deterioration of intellectual and memory func-
tion (Le Pechoux et al. 2011). The largest study in
patients with NSCLC was reported by Sun et al.
(2011). Randomization between PCI (30 Gy in 15
fractions of 2 Gy) and observation was done in a
group of 356 patients. PCI was associated with a
significant decline in memory at 1 year (Hopkins
Verbal Learning Test; recall deterioration in 26 vs.
7% and delayed recall deterioration in 32 vs. 5%).
Three months after PCI, but not at later time points,
there was also a significant deterioration in Mini-
Mental-Status examination (36 vs. 21%). In patients
who developed brain metastases, WBRT has also
been shown to interfere with recall functions as
measured by the Hopkins Verbal Learning Test (64%
in patients treated with WBRT plus SRS as compared
to 20% in those with SRS alone after 4 months, i.e. in
the subacute phase) (Chang et al. 2009). However,
such decline might also precede progression of brain
metastases. In patients with impaired neurocognition
before WBRT who respond to this treatment
improvements might be observed. Ongoing trials
examine WBRT with hippocampal avoidance in order
to better preserve neurocognitive functions.
Neurocognitive dysfunction was reported to sta-
bilize spontaneously (van de Pol et al. 1997; Arm-
strong et al. 2002) or to progress over time (Johnson
et al. 1990, Regine et al. 2001). In extreme cases,
subcortical dementia may result which often is asso-
ciated with gait disturbance and incontinence. Due to
the lack of effective treatment, most patients with this
severe complication die after several months or a few
years. Histopathologic findings include diffuse spon-
giosis and demyelination, as well as disseminated
miliary necrosis.
Further late complications in terms of stenosis of
blood vessels and moyamoya syndrome (multiple,
diffuse, progressive infarctions due to occlusion of the
653
anterior and medial cerebral arteries) have occasion-
ally been described, mostly in patients irradiated at a
younger age. Endocrine dysfunction resulting from
damage to the pituitary gland or the hypothalamic
region can result in hypothyroidism, amenorrhea, etc.
Hearing loss is very uncommon after doses typically
prescribed for lung cancer metastases.
Importantly, all types of iatrogenic neurotoxicity
can only be diagnosed after comprehensive evaluation
excluding other causes, for example brain metastases,
leptomeningeal spread, infections, cerebral infarction
and hemorrhage. In addition, systemic metabolic
disorders (hypercalcaemia, hepatic failure, diabetes,
changes in osmolality etc.), alcoholic cerebellar
degeneration, Wernicke-Korsakoff syndrome and
paraneoplastic disorders (for example, limbic
encephalitis, chorea, cerebellar degeneration and
Lambert-Eaton myasthenic syndrome in SCLC) must
be considered. Besides physical and neurologic
examination, blood tests, EEG and cerebrospinal fluid
diagnostic are indicated. In addition to imaging
studies—for example, myelography, CT, MRI and
functional imaging—factors such as time interval
between radiotherapy and diagnosis, dose per frac-
tion, number of fractions per day, total dose and
location of the treatment fields need to be considered.
In the era of multimodal treatment regimens, injury
should not be attributed solely to one modality.
Therefore, interdisciplinary evaluation integrating the
radiobiological knowledge of radiation oncologists is
mandatory when radiotherapy-induced neurotoxicity
is being considered.
5 Toxicity Prevention Strategies
At present, pharmacologic or biologic prevention is
not clinically established despite intriguing pre-
liminary data, e.g. from a non-randomized trial of
SRS of arteriovenous malformations, where patients
treated with gamma linolenic [omega-6] acid had less
permanent complications than those who did not
receive this medication (Sims and Plowman 2001).
Therefore, the most effective way of toxicity pre-
vention is a reduction of fraction size and normal
tissue volume, the latter, for example, by means of
several high-precision techniques. However, rational
experimental interventions based on the pathogenetic
models reviewed in this chapter have been studied or
654
are currently under investigation. The clinical effec-
tiveness of these putative prevention strategies has yet
to be established. The prophylactic use of dexa-
methasone 24 and 1 h before radiation exposure
reduced the expression of TNF-a, IL-1 and ICAM-1
(Hong et al. 1995). In vitro, corticosteroids influence
the function of microglial cells and inhibit their pro-
liferation (Tanaka et al. 1997). The hyperpermeability
of blood vessels could be reduced at all time points
after irradiation by application of rh-MnSOD (man-
ganese superoxide dismutase), suggesting that free
oxygen radicals could be involved in the dysfunction
of microvessels. Fike et al. reported that i.v. injection
of a-difluoromethylornithine (DMFO), a polyamine
synthesis inhibitor, starting 2 days before and
continuing for 14 days after 125I brachytherapy
reduced the volume of radionecrosis in irradiated dog
brain (Fike et al. 1994). Kondziolka et al. irradiated
rats with implanted cerebral C6 glioma by SRS, either
with or without i.v. administration of U-74389G, a
21-aminosteroid which is largely selective for endo-
thelium (Kondziolka et al. 1999). The compound
reduced the development of peritumoral edema and
radiation-induced vascular changes in the parts of the
brain that were within the region of the steep dose
gradient outside the target volume. No tumor pro-
tection was observed. In general, normal tissue
selectivity of prevention approaches is an important
issue. Protecting tumor cells against the effects of
radiation can counteract the effort of improving the
therapeutic ratio.
More recent data suggest the possible role of cer-
tain growth factors with antiapoptotic effects that also
influence the proliferation of stem cells, neurogenesis
and angiogenesis. Pena et al. showed that i.v. injec-
tions of basic fibroblast growth factor (FGF-2) 5 min
before, immediately after and 1 h after total body
irradiation in mice (1–20 or 50 Gy) significantly
reduced the number of apoptotic vascular and glial
cells in the CNS (Pena et al. 2000). Spinal cord
experiments suggest that other growth factors, such as
platelet-derived growth factor (PDGF) and insulin-
like growth factor-1 (IGF-1) can increase the long-
term radiation tolerance by approximately 5–10%
(Andratschke et al. 2005). Whether these effects result
primarily from protection of the vascular system or
from more widespread action is presently not known.
The experiments, however, demonstrate that delayed
toxicity can be prevented by early intervention at the
C. Nieder
time of radiation treatment, and they offer new strat-
egies of toxicity prevention.
The growing body of evidence linking radiation-
induced brain injury with oxidative stress and/or
inflammation has provided the rationale for applying
proven anti-inflammatory-based interventions to pre-
vent radiation-induced cognitive impairment. Recent
studies have tested drugs that can either attenuate
inflammation or reduce chronic oxidative stress,
namely peroxisome proliferator-activated (PPAR)
agonists and renin angiotensin system (RAS) block-
ers. Given the putative role of oxidative stress/
inflammation in radiation-induced brain injury, Zhao
et al. (2007) tested the hypothesis that administration
of the PPARc agonist, pioglitazone (Pio), would
mitigate the severity of radiation-induced cognitive
impairment. Indeed, administering Pio to young adult
rats starting prior to, during, and for 4 or 54 weeks
after the completion of fractionated WBRT, prevented
cognitive impairment measured 52 weeks post-irra-
diation. Robbins et al. (2009) hypothesized that
blocking the brain RAS with the AT1RA, L-158,809,
would prevent or ameliorate radiation-induced cog-
nitive impairment. As hypothesized, administering
L-158,809 before, during, and for 28 or 54 weeks
after fractionated WBRT prevented or ameliorated
cognitive impairment observed 26 and 52 weeks
postirradiation. Moreover, giving L-158,809 before,
during, and for only 5 weeks postirradiation amelio-
rated the significant cognitive impairment seen
26 weeks postirradiation.
Transplantation of stem cells or stimulation of the
endogenous stem cell compartment by growth factor
application might also offer exciting prospects. In
principle, mature functional cells can be generated by
proliferation and differentiation from stem and pro-
genitor cells or by recovery and repair of damage in
already existing cells, which then continue to survive.
IGF-1 has been found to influence the restoration of
neurogenesis in the adult and aging hippocampus
(Lichtenwalner et al. 2001) and might thus offer inter-
esting prospects. In another recently published exper-
iment, athymic nude rats subjected to head irradiation
were transplanted 2 days afterward with human
embryonic stem cells (hESC) into the hippocampal
formation and analyzed for stem cell survival, differ-
entiation, and cognitive function (Acharya et al. 2009).
Animals receiving hESC transplantation exhibited
superior performance on a hippocampal-dependent
Brain Toxicity
cognitive task 4 months post-irradiation, compared to
their irradiated counterparts that did not receive hESCs.
Significant stem cell survival was found at 1 and
4 months postirradiation.
6 Treatment of Radiotherapy-
Induced Brain Toxicity
Despite improvements in biologic understanding of
CNS reactions, treatment options unfortunately are
still limited. It is of course important to exclude other
causes of CNS dysfunction, to correct any metabolic
abnormality and to optimize the treatment of
endocrinological dysfunction, depression and other
comorbid conditions. A few case reports have
described successful treatment of late CNS toxicity by
hyperbaric oxygen treatment (HBO). For example,
one out of seven patients with cognitive impairment at
least 1.5 years after radiotherapy improved after
30 sessions of HBO (Hulshof et al. 2002). In contrast,
HBO during radiotherapy can cause radiosensitiza-
tion. Patients with leukencephalopathy and moderate
hydrocephalus (diagnosed by intracranial pressure
monitoring) may profit from ventriculoperitoneal
shunt insertion (Perrini et al. 2002). Quality of life can
be improved by supportive measures (cognitive
training, rehabilitation, special education etc.) and
possibly by methylphenidate medication (Meyers
et al. 1998). Memantine and donepezil are also under
investigation. For radionecrosis, therapeutic inter-
vention with bevacizumab might offer new prospects
(Levin et al. 2011). Previously, surgical resection
often was the only way to effectively improve the
symptoms. As suggested from a recent double-blind
placebo controlled trial intravenous bevacizumab
given every 3 weeks might improve both clinical and
radiological symptoms.
7 Aspects of Chemotherapy-Induced
Brain Toxicity
Chemotherapy can cause a variety of brain injuries. Most
of these changes are temporary and reversible. Some-
times the symptoms are secondary to hyponatremia or
hypomagnesemia. Posterior reversible encephalopathy
syndrome can develop after systemic administration
of cytotoxic drugs, including gemcitabine, cisplatin,
655
5-fluorouracil (5-FU), methotrexate and paclitaxel.
White matter hyperintensity from vasogenic edema can
clinically result in headache, somnolence and seizures.
Symptoms can be reversed when the drugs are dis-
continued. Cerebellar toxicity of 5-FU is rare and
mostly found in patients with a deficiency of dihydro-
pyrimidine dehydrogenase. Cisplatin is able to induce
cerebral edema and cortical blindness, as reviewed by
(Sloan et al. 2003; Rajeswaran et al. 2008). Mild to
moderate, typically transient neurocognitive impair-
ment can develop after systemic chemotherapy, for
example with paclitaxel (Ahles and Saykin 2001;
Herbst et al. 2002) and cisplatin/etoposide (Whitney
et al. 2008). Chronic encephalopathy also can result
from chemo- or radiochemotherapy (Keime-Guibert
et al. 1998).
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 Quality of Life Outcomes in Radiotherapy
of Lung Cancer
M. Salim Siddiqui, Farzan Siddiqui, and Benjamin Movsas

Contents
1 Introduction..............................................................
1.1 What is Quality of Life.............................................
1.2 How is QOL Measured .............................................
1.3 How is QOL Analyzed..............................................
1.4 QOL Studies in Lung Cancer ...................................
2 Conclusions and Future Directions ....................... 670
References.......................................................................... 671
Abstract
Lung cancer is one of the most common cancers in
661 the world. There has been an increased interest in
662 quality of life (QOL) as a clinically meaningful
662
666
endpoint in clinical trials for lung cancer. Patient-
668 reported outcome (PRO) measurements have
allowed oncologists to better understand the
impact of cancer therapies on the physical, emo-
tional and social well-being of their patients. This
chapter provides a review of the clinical relevance,
measurement, analysis and challenges of quality of
life in lung cancer trials. A summary of salient
quality-of-life studies, particularly involving radi-
ation treatment for lung cancer, is included.

1 Introduction

Over the past two decades, quality of life (QOL) has

not only grown in interest, as evidenced by the
increasing QOL literature, but also has become a
well-accepted endpoint in clinical trials for cancer, in
general, and lung cancer, specifically. As focus on
improving physical, emotional, and social well-being
has increased, QOL outcome measurements have
allowed oncologists to better understand the impact of
various cancer therapies on QOL and to make
M. Salim Siddiqui
B. Movsas (&) recommendations to improve the overall QOL of the
Department of Radiation Oncology, patient. Such improvements are even more important
Henry Ford Hospital, 2799 W Grand Boulevard, when one considers the poor prognosis in the majority
Detroit, MI 48202, USA
e-mail: bmovsas1@hfhs.org of lung cancer patients. In many cases, treatments for
lung cancer may be associated with toxicities which
F. Siddiqui
Department of Radiation Oncology, Ohio State University, could adversely impact QOL. In such settings,
300 W. 10th Avenue, Columbus, OH 43210, USA assessment of QOL endpoints may help to identify

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 661
DOI: 10.1007/174_2011_259, Ó Springer-Verlag Berlin Heidelberg 2011
662
significant differences in such treatment-related tox-
icities, while the traditional endpoints may be equiv-
ocal. QOL studies afford knowledge to accurately
communicate potential treatment-related changes in
functional and emotional well-being to future
patients. As a result, efforts can be directed to prevent
or mitigate such toxicities or changes in well-being.
Since 1985, the United States Food and Drug
Administration (FDA) recognized the importance of
QOL by including the requirement for a favorable
effect on survival and/or QOL in the approval of new
anti-cancer drugs (Johnson and Temple 1985). Drugs
such as gemcitabine, irinotecan, vinorelbine, oxyco-
done, mitoxantrone, and erythropoietin have been
approved, at least in part, based on QOL endpoints
(Leitgeb et al. 1994; Burris et al. 1997). Similarly, the
National Cancer Institute (NCI) has also emphasized
the importance of improving QOL in cancer patients
as exemplified in the mission statement of the Divi-
sion of Cancer Treatment of the NCI which states that
‘‘research aimed at improving survival and QOL for
persons with cancer is of the highest priority to the
Cancer Therapy Evaluation Program’’ (NCI, C. T. C.
G. P 1988). The NCI convenes QOL conferences to
develop recommendations for including QOL
assessments in clinical trials (Cella and Tulsky 1990;
Strain 1990).
Given the continued growth of QOL outcomes in
cancer, and particularly in lung cancer, this chapter
will provide an overview of the significance, meth-
odology, analysis, limitations and challenges of QOL
studies. The chapter will include relevant examples of
QOL studies in lung cancer.
1.1 What is Quality of Life
The inherent subjective and abstract nature of the
term ‘‘Quality of Life’’ provides a considerable
challenge to define this construct. In addition, the
notion of QOL spans a broad range of an individual’s
feelings, beliefs and perceptions of life. As a result,
QOL remains a fluid concept, influenced by various
social, physical, financial, cultural and emotional
factors. The challenges to objectively quantify this
construct are further compounded by the inter- and
intra- patient cross-cultural and temporal variability
of QOL (Leplege and Hunt 1997). However, appli-
cation of this construct in the clinic necessitates not
M. Salim Siddiqui et al.
only its definition and quantification, but also its
scientific study in the realm of clinical trials. Broadly,
according to the World Health Organization (WHO),
‘‘Quality of life is defined as individuals’ perceptions
of their position in life in the context of the culture
and value system where they live, and in relation to
their goals, expectations, standards and concerns. It is
a broad ranging concept incorporating in a complex
way a person’s physical health, psychological state,
level of independence, social relationships, personal
beliefs and relationship to salient features of the
environment’’ (WHO 1996). The WHO defined health
as ‘‘a state of complete physical, mental and social
well-being and not merely the absence of disease’’.
1.2 How is QOL Measured
There are several major considerations to address
regarding the measurement of QOL in clinical studies.
First, self-reporting by the patient remains the gold
standard for measuring an individual’s QOL.
Attempts to rate QOL by physicians, other medical
personnel, or even family members, have been found
to be significantly different from patient reports
(Slevin et al. 1988; Watkins-Bruner et al. 1995). The
importance of such patient-reported outcomes (PROs)
has been recognized by both the NCI and the FDA.
A PRO is defined as any report of the status of a
patient’s health condition provided directly by the
patient, without interpretation of the patient’s
response by anyone else. Examples of PROs include
QOL, treatment preferences, symptoms, and satis-
faction with care. However, PROs are not yet
standardized in adverse event reporting. Currently,
physicians tend to underestimate the frequency and
severity of patients’ symptoms when reporting
adverse events utilizing health-care provider instru-
ments (e.g. NCI Common Terminology Criteria for
Adverse Events, or CTCAE). As a result, the current
reporting structure likely under-represents the true
treatment-related toxicity burden in clinical trials. To
address this discrepancy between physician-reported
outcomes and PROs, particularly for adverse events,
the NCI has initiated the PRO-CTCAE project to
create patient-reported versions of those symptom
criteria.
The next major consideration centers on whether
QOL should be measured in all clinical trials.
Quality of Life Outcomes in Radiotherapy of Lung Cancer
Finite financial, data management, and human
resources, limit the measurement of QOL outcomes in
clinical trials. Moreover, QOL outcomes may serve
limited function in certain settings, such as phase I
and II trials, which usually aim to answer questions
about maximally tolerated doses and preliminary
efficacy data for new treatments. Inclusion of QOL
measures in such trials would not only create undue
patient burden, but also afford limited return. Rather,
Phase III randomized trials, which allow for the
careful design and implementation of a well-formu-
lated QOL hypothesis, provide a more meaningful
clinical arena to measure such outcomes. Gotay
(2004) suggested the following guidelines for inclu-
sion of QOL endpoints in a Phase III trial: (1) If QOL
is considered to be the primary endpoint, such as a
study comparing two palliative regimens. (2) If the
treatments are expected to be equivalent in terms of
efficacy (e.g. survival), such that one treatment would
be considered preferable if it is associated with a
relative QOL advantage. (3) If the advantage of one
arm in terms of outcome may be real, but nevertheless
offset by increased toxicity and deterioration in QOL.
(4) If the treatments differ in short-term efficacy, but
the overall failure rate is high (Gotay 2004). Simi-
larly, Moinpour et al. (1989) proposed the following
guidelines: (1) the disease site is associated with a
poor prognosis, (2) different treatment modalities are
being compared, (3) different treatment intensities
and/or duration are being compared, and (4) expected
survival is assumed equivalent, but the QOL is
expected to be different between the two regimens.
The third critical consideration is the selection of
the most appropriate QOL instrument. In reviewing,
testing and validating any QOL instrument, particular
attention must be placed on the reliability, validity,
sensitivity, and responsiveness to change over time of
the instrument (Testa and Simonson 1996). The FDA
issued a guidance document on PROs which encodes
these standards and specifies that PRO measures
should demonstrate reliability, validity,and sensitivity
to score changes, and have appropriate recall periods
(FDA 2009). The reliability quantifies the freedom
from random error of the instrument. In other words, a
reliable instrument reports values that remain con-
sistent with repeated measurement under constant
conditions. Generally, an instrument reliability of
0.70 or higher is considered acceptable for clinical
trials (Nunnaly and Bernstein 1994). The validity of
663
an instrument can be assessed in terms of content
(i.e. does it address the relevant issues), construct (i.e.
does it indeed measure what it claims to measure),
and clinical focus (i.e. does it differentiate patient
groups with differing clinical and/or sociodemo-
graphic features). Simply put, a valid test must
appropriately focus on the intended target and then
measure the outcome that it claims to measure.
Responsiveness refers to the ability of an instrument
to detect changes in an outcome over time within a
particular individual or group (Husted et al. 2000).
Similar to responsiveness, sensitivity is the ability of
the instrument to measure true changes or differences
in outcome. Both the responsiveness and sensitivity of
an instrument may be affected by ‘‘ceiling’’ or ‘‘floor’’
effects when outcome scores from patient response
rest at the limits of the possible score range. In such
circumstances, the instrument would not allow for
measurement of any positive or negative movement
beyond the ‘‘ceiling’’ or ‘‘floor’’, respectively.
Regardless of such effects, a sensitive and responsive
instrument should measure stable outcomes when
there is no change in outcome. After reviewing the
reliability, validity, sensitivity, and responsiveness of
an instrument, the actual task of selecting the
‘‘optimal’’ QOL instrument remains. Primarily, this
selection should focus on the QOL instrument that the
investigator(s) believe is most suited to answer the
hypothesis of the study and that is most relevant for
the population studied in the clinical trial. Four con-
siderations have been suggested when selecting the
‘‘best’’ QOL instrument: (1) the underlying hypothe-
sis or purpose of the trial, (2) the patient population,
(3) the treatments and their toxicity profiles, and (4)
the degree of resources available (Gelber and Gelber
1995).
1.2.1 QOL Instruments
QOL instruments can be categorized by their focus
and/or by their targeted clinical population. Generic
QOL instruments have the broadest focus and are
designed to assess the general health status of
individuals with a broad range of diagnoses. How-
ever, the inherent breath of these questionnaires may
result in their inability to account for clinical issues in
site-, condition, or treatment-specific measures.
Examples of such instruments include the Sickness
Impact Profile (SIP) (Bergner et al. 1976, 1981),
the Medical Outcomes Study (MOS) (Stewart and
664
Ware 1992), and the Medical Outcomes Study 36
item Short Form Health Survey (MOS SF-36) (Ware
and Sherbourne 1992; McHorney et al. 1993, 1994).
The Sickness Impact Profile (SIP) is a self-adminis-
tered 136 item questionnaire that assesses physical
and psycho-social domains and 12 categories (sleep
and rest, eating, work, home management, recreation
and pastimes, ambulation, mobility, body care and
movement, social interaction, alertness behavior,
emotional behavior and communication) (Bergner
et al. 1976, 1981). The Medical Outcomes Study is a
116 item questionnaire that assesses physical health
(i.e. physical functioning, satisfaction with physical
ability, mobility, pain effects, pain severity, role
limitations due to physical health), mental health
(i.e. psycho-social distress, anxiety and depression,
psychological well-being, cognitive functioning,and
role limitations due to emotional problems), and
general health (i.e. energy/fatigue, sleep problems,
psycho-physiologic symptoms, social functioning,
role functioning) (Stewart and Ware 1992). A trun-
cated version of the MOS, the MOS 36-item Short
Form survey (MOS SF-36) is widely used for routine
outcome studies in adult patients (Ware and Sher-
bourne 1992; McHorney et al. 1993, 1994). Higher
scores on this form correlate with a better QOL.
Other QOL instruments have been developed that
combine generic and specific measurements into one
instrument. Such instruments assess patients with a
specific clinical condition through a set of common
core questions plus a set of clinical condition-specific
questions. Examples of this type of instrument in
oncology are the European Organization for Research
and Treatment of Cancer (EORTC), Quality of Life
Questionnaire Core 30 (QLQ-C30) (Aaronson et al.
1993) and the Functional Assessment of Cancer
Therapy-General (FACT-G) (Cella et al. 1993). For
lung cancer patients, in addition to generic and
condition-specific QOL instruments, site-specific
instruments are sometimes used, such as the Lung
Cancer Symptom Scale (LCSS) (Hollen et al. 1993,
1994a, 1994b).
The EORTC QLQ-C30 is an oncology instrument
containing 30 items with scores from 0 (not at all) to 4
(very much) for items 1–28 and from 1 (very poor) to
7 (excellent) for items 29 and 30. The instrument has
been validated (Aaronson et al. 1993) and has been
translated in over 50 languages. The EORTC QLQ-
C30 assesses various elements of QOL through nine
M. Salim Siddiqui et al.
multi-item scales: five functional scales (physical,
role, cognitive, emotional, and social); three symp-
tom scales (fatigue, pain, and nausea and vomiting);
and additional global health and quality-of-life
scales. In addition to the EORTC QLQ-C30, the
QLQ-LC13 has been developed and validated for
lung cancer (Bergman et al. 1994). The QLQ-LC13
is a 13 item lung cancer specific questionnaire that
consists of one three-question subscale (dyspnea)
and 10 symptom items (cough, hemoptysis, sore
mouth, dysphagia, peripheral neuropathy, alopecia,
pain in chest, pain in shoulder, pain and pain med-
ication). The score of each item ranges from 0 to
100 with better functioning indicated by a higher
value on the functional scales and increased symp-
toms indicated by a higher score on the symptom
items. The QLQ-LC13 questionnaire has also been
validated for lung cancer patients (Nicklasson and
Bergman 2007).
The FACT-G instrument consists of a 27-item
questionnaire measuring physical well-being (7-items),
social/family well-being (7-items), emotional well-
being (6-items) and functional well-being (7-items).
Each item can be scored from 0 to 4 with a range of 0–28
for physical, social/family and functional well-being
and 0–24 for emotional well-being and a total score
range of 0–108. This oncology questionnaire has been
validated and is also available in over 50 languages
(Cella et al. 1993). In addition to the FACT-G, the
FACT-L has been developed and validated for lung
cancer (Cella et al. 1995). The FACT-L is a 9 item lung
cancer specific questionnaire that assesses dyspnea,
cough, weight loss, chest pain, alopecia, appetite loss,
and smoking. In contrast to the EORTC QLQ-LC13,
the FACT-L does not assess hemoptysis, sore mouth,
dysphagia, or peripheral neuropathy. Of note, the
FACT-TOI (trial outcome index) combines the physical
well-being and functional well-being domains of the
FACT-G with the FACT-L subscale. The FACT-TOI
has also been validated in lung cancer patients (Cella
et al. 2002).
The Lung Cancer Symptom Scale (LCSS) consists
of a 9 item patient-reported questionnaire and an
optional 6 item observer questionnaire (Hollen et al.
1993, 1994a, 1994b). The patient-reported question-
naire consists of six lung cancer symptoms
(i.e. appetite loss, fatigue, cough, dyspnea, hemopty-
sis, and pain) and three general items (i.e. symptom-
atic distress, activity status, and overall QOL).
Quality of Life Outcomes in Radiotherapy of Lung Cancer
The optional observer portion consists of a question-
naire assessing the same six lung cancer symptoms as
in the patient-reported portion. The score for each
item is summed into a total score between 0 and 100.
A higher score correlates with a better QOL (Hollen
et al. 1994a).
1.2.2 Frequency and Timing of QOL
Measurements
After selection of the most appropriate QOL instru-
ment, attention must be turned to establishing the
optimal timing and frequency of administration of the
instrument. Such administration will vary between
clinical trials and will be influenced by the hypothesis
and the treatment protocol of the clinical trial, the
natural course of the disease, and the anticipated side-
effects of treatment (Osoba 1996). Regardless of these
factors, every clinical trial with QOL endpoints
should perform a pre-treatment QOL assessment.
Such an assessment not only establishes a baseline
QOL, which is essential for QOL analysis, but also
has prognostic significance for lung and other cancers
(Coates et al. 1997; Dancey et al. 1997; Langendijk
et al. 2000a; Blazeby et al. 2001; de Graeff et al.
2001; Montazeri et al. 2001; Fang et al. 2004; Efficace
and Bottomley 2005; Movsas et al. 2009). The base-
line assessment also determines differences in pre-
treatment QOL in treatment groups and individuals
and allows comparison to post-treatment QOL. Dur-
ing the course of the clinical trial, the frequency of
QOL data collection must balance the cost of data
collection/management and patient burden with the
benefit of the additional QOL data. The frequency of
collection can be directed by a time-based (e.g. at a
set time after randomization) or an event-based (e.g.
after a specific treatment cycle) approach. Typically,
QOL assessments at the completion of treatment and
post-completion (i.e. a few months later) are helpful.
Such measures afford not only the study of treatment
side-effects, but also knowledge regarding the course
and nature of recovery from those side-effects. Such
knowledge can be particularly useful in making
clinical decisions and recommendations.
1.2.3 Compliance
Low compliance, or missing data, remains the most
important challenge in QOL trials. Loss of such data
may affect the integrity of the QOL study, by
increasing the tendency toward bias and decreasing
665
statistical power, thus affecting the generalizability of
the results to the larger population. Low compliance
may result in either ‘‘missing items’’ or ‘‘missing
forms’’ (Fayers et al. 1998), also known as ‘‘item non-
response’’ and ‘‘unit non-response’’, respectively
(Troxel et al. 1998).
In the case of ‘‘missing items’’, the patient does not
respond to some questions on the QOL questionnaire.
This lack of response may be due to a number of
causes, including, but not limited to, the patient was
too ill or distressed, or forgot, or was unable to
understand the questions (Ganz et al. 1989; Curran
et al. 1998; Langendijk et al. 2000b; Aaronson and
Fayers 2002). Such missing data results in informa-
tive censoring, which may underestimate or overes-
timate the QOL of patients. For example, consider the
‘‘healthy survivor’’ effect, which results when patients
who are sicker or not doing well on treatment do not
provide complete responses on QOL questionnaires.
An association between such ‘‘nonignorable’’ missing
data and patients’ status has been suggested
(Moinpour et al. 2000). While most patients, who
agree to enroll on QOL studies, understand the benefit
their contribution makes for medical research and
future patients, they may not appreciate that such
benefit can only be fully realized if complete
responses are provided. Of course, patients should be
informed of their choice not to answer any question(s)
that make them feel uncomfortable.
The case of ‘‘missing forms’’, which is more
serious than ‘‘missing items’’, can be further catego-
rized as: (1) intermittent missing forms, (2) dropouts
from the study, or (3) patients entering the study late
(Curran et al. 1998). Possible explanations for such
missing forms may be: (1) administrative failure to
distribute the questionnaire, (2) patient considered the
questionnaire a violation of privacy, (3) patient
thought the questionnaire time consuming, (4) patient
refusal or withdrawal, (5) patient felt too ill, and/or
(6) disease progression (Curran et al. 1998). Cer-
tainly, clinical investigators can anticipate and
address some of these explanations through adequate
infrastructure and logistical support for data collec-
tion and careful and thoughtful reassurance and
encouragement of patients.
For QOL to be a key component of a clinical trial,
high-patient compliance and minimal data loss need
to be a goal. In addition, quality control measures
should ensure standard procedures for administering
666
and reviewing the QOL questionnaires. Often such
responsibilities are performed by data managers or
trained research nurses. Centralizing such responsi-
bilities and establishing quality control measures may
result in high-compliance rates (Sadura et al. 1992;
Langendijk et al. 2000a).
Beyond traditional centralized QOL data collec-
tion by mail or telephone, real-time tracking soft-
ware may also be utilized to maintain records and
alert personnel regarding missing data. Recently,
such QOL data tracking has been piloted by the
Radiation Therapy Oncology Group (RTOG) in a
study (RTOG 0828) attempting to reduce missing
QOL data. The Health Insurance Portability and
Accountability Act (HIPPA)-complaint software for
internet-based reporting can track particular ques-
tions not routinely being answered, alert medical
research personnel about missing items and ask
patients if they would like to answer the missing
questions or not. This allows for automatic e-mail
reminders for patients to complete QOL question-
naires. Moreover, this may allow patients to log-in
from outside the clinic (i.e. home, office, etc.) to
complete questionnaires, not only minimizing time
spent in the clinic, but also allowing less disruption
of their daily lives. Ideally, assuming broad-scale
internet access, such real-time data tracking affords a
feedback loop to assess the level of completion rates
between questionnaires, determines questions con-
sistently not answered, and thus, may help minimize
missing data.
Regardless of the various strategies employed to
maximize patient compliance and minimize data
loss, missing data are common in QOL studies. As a
result, any QOL study should document the number
of missing questionnaires throughout the course of
the study and provide an explanation for missing
data. Advanced statistical methods have been pro-
posed in literature to deal with missing data,
including index function models, propensity scores,
instrumental variables, and simple and multiple
imputation methods (Rubin 1997; Curran et al. 1998;
Fairclough et al. 1998; Fayers et al. 1998; Hahn
et al. 1998; Troxel et al. 1998; Zee 1998; Qian et al.
2000; Little and Rubin 2002; Ribaudo and
Thompson 2002; Sales et al. 2004). Comprehensive
discussion of these statistical methods is beyond the
scope of this chapter.
M. Salim Siddiqui et al.
1.3 How is QOL Analyzed
The challenge in the statistical analysis of QOL data
arises from the inherent complexity of the data and
the desire to present the results in a simple and
comprehensible manner. Ideally, the results are not
only statistically significant, but also clinically rele-
vant. The concern of ‘‘overanalysis’’ plagues such
large and complex databases with fears of spurious
statistically significant relationships. As a result,
various statistical methods have been proposed to
understand and interpret QOL data. A review article
by Wyrwich et al. (2005) and the Clinical Signifi-
cance Consensus Meeting Group discusses these
issues more comprehensively. For the purpose of this
chapter, some of these methods and relevant literature
are briefly reviewed.
1.3.1 Anchor-Based and Distribution-Based
Analysis
The anchor-based method of analysis correlates the
scores on the HRQOL instrument used in a study (i.e.
the target instrument) with another independent
measure (i.e. the anchor). This method can be further
categorized by the nature of the anchor as individual-
focused (i.e. single-anchor) or population-focused
(i.e. multiple-anchor) (Guyatt et al. 2002). The indi-
vidual-focused method attempts to address the ques-
tion of whether small changes in QOL are clinically
relevant. By defining a threshold between important
and trivial change, this method introduces the concept
of minimum important difference (MID), which is
‘‘the smallest difference in the score in the domain of
interest that patients perceive as important, either
beneficial or harmful, and which would lead the cli-
nician to consider a change in the patient’s manage-
ment’’(Guyatt et al. 2002). Osoba et al. (1998) used a
series of EORTC QLQ-C30 questionnaires to inves-
tigate QOL and a subjective significance question-
naire (SSQ) to investigate the MID. The SSQ allowed
assessment of ‘‘subjectively significant’’ perception of
change since the last time the patient completed the
QLQ C30. In the SSQ, the patient scored their per-
ception of change with a seven-category scale ranging
from ‘‘much worse’’ to ‘‘no change’’ to ‘‘much
better’’. They found that if the mean change in scale
scores on the QLQ C30 was zero, the patients per-
ceived ‘‘no change’’ in their condition. However, if
Quality of Life Outcomes in Radiotherapy of Lung Cancer
the mean change in scale scores was from 5 to 10
points, patients indicated their condition was ‘‘a little’’
better/worse. Similarly, for mean change in scale
scores of 10–20 and [20, patients perceived that
change in their condition was ‘‘moderate’’ and ‘‘very
much’’ better/worse, respectively. In a similar man-
ner, Cella and colleagues used the FACT-L ques-
tionnaire to investigate QOL and clinically
meaningful change (CMC) to determine the MID
(Cella et al. 2002). They found that a 2–3 point
change in the Lung Cancer Subscale and a 5–7 point
change in the Trial Outcome Index were clinically
meaningful (Cella et al. 2002). These examples
highlight how the use of the MID approach affords the
determination of clinically meaningful changes in the
scores of QOL instruments for patients. As the name
implies, the population-focused, or the multiple-
anchor, method correlates target measure with mul-
tiple anchors, instead of defining thresholds, such as
the MID. Please refer to Ware and Keller for an
example of the population-focused method (Ware
et al. 1996).
In the distribution-based method, interpretation of
the data centers on the relationship between the
magnitude of change and some measure of variability
in results (Guyatt et al. 2002) or the underlying dis-
tribution of the results (Movsas 2003). The magnitude
of change analyzed may occur in the score of an
individual patient or patient group (i.e. treatment and
control groups). Because, some degree of variability,
either between-patient or within-patient, exists in
QOL data sets and, for that matter, most large data
sets, this approach may appear advantageous over the
anchor-based methods. Cohen has proposed a criteria
that a change of 0.2 SD correlates with a ‘‘small’’
change in a measure, while changes of 0.5 and 0.8 SD
correlate with ‘‘moderate’’ and ‘‘large’’ changes in the
measure, respectively (Cohen 1988; Guyatt et al.
2002). While some have found this approach arbitrary
(Guyatt et al. 2002) and others have found the MID
from their studies to rest in the 0.2–0.5 SD range
(Osoba et al. 1998; Norman et al. 2003) have found
that the threshold for perception of change in QOL
measure is 0.5 SD. They performed a review 38
studies that determined MID. In all but six studies, the
MID values were approximately 0.5 SD. They sug-
gested that this may result from the limit of humans to
discriminate on a scale, which is approximately one
part in seven (Miller 1956), or approximately 0.5 SD.
667
An inherent limitation of the distribution-based
method arises from the difference in the measure of
variability between studies as a result of patient group
and population heterogeneity. Wyrwich and
colleagues have suggested that the standard error of
measurement may afford a solution to this inherent
limitation and may correlate with the MID (Wyrwich
et al. 1999a, 1999b, 2002; Wyrwich 2004).
1.3.2 Clinical Relevance
Regardless of the method of analysis, the most
important result of any QOL study, for both the
physician and the patient, is the clinical relevance of
the QOL outcome. Effectively, does the result con-
tribute in a clinically meaningful manner to treatment
benefit and/or risk? In the case of baseline QOL,
multiple studies have shown the independent
prognostic significance of this outcome for survival
and/or loco-regional control (Coates et al. 1997;
Dancey et al. 1997; Langendijk et al. 2000b; Blazeby
et al. 2001; de Graeff et al. 2001; Montazeri et al.
2001; Fang et al. 2004; Efficace and Bottomley 2005;
Movsas et al. 2009). Indeed, Movsas et al. (2009)
reported that the baseline QOL score was indepen-
dently predicted for 5-year overall survival in patients
with Stage III NSCLC treated with chemoradiation.
Given this relationship, the question still remains,
how mitigating patients’ symptoms, and thus
improving patients’ QOL would affect this prognostic
significance.
As for other QOL outcomes, the clinical impact
must be understood in the context of the overall
treatment regimen. For example, in the case of
palliative regimens, while traditional endpoints may
be equivocal, QOL endpoints may demonstrate clin-
ically meaningful differences. For example, in a
double-blinded, palliative study of advanced endo-
crine-insensitive tumors, Beller et al. (1997) ran-
domized 240 patients to either 12 weeks of high- or
low-dose megesteral acetate (MA) versus a placebo.
Nutritional status (weight, skinfold thickness and
midarm circumference) and QOL (using six linear
analogue self-assessment [LASA] scales) were
assessed at randomization and after 4, 8 and
12 weeks. While the traditional ‘‘objective’’ nutri-
tional status endpoints did not demonstrate a statisti-
cally significant difference, the QOL endpoints
demonstrated significant improvement in appetite,
mood, and overall QOL in patients receiving MA.
668
Even in studies with an expected difference in sur-
vival between two study arms, QOL outcome can help
weigh the risk/benefits of the various treatments. The
challenge remains when QOL outcomes from a nec-
essary treatment indicate an unavoidable detriment to
the QOL of the patient. In such a setting, beyond
providing a needed awareness of the treatment chal-
lenges for the patient, such QOL results necessitate
the development of interventions aimed at mitigating
treatment-induced QOL detriment.
1.4 QOL Studies in Lung Cancer
The number of studies investigating QOL outcomes
in patients with small-cell lung cancer (SCLC) and
non-small-cell lung cancer (NSCLC) has continued to
grow. Much of this interest stemmed from the poor
prognosis and palliative intent of many treatment
regimens for patients with advanced lung cancer.
However, beyond palliative regimens, as definitive
treatment regimens continue to increase, QOL studies
may help clinically weigh the risks and benefits of
treatment regimens with similar traditional outcomes.
A comprehensive summary of lung cancer studies that
have assessed QOL endpoints is beyond the scope of
this chapter. However, a review of some salient QOL
studies, particularly involving radiation treatment for
lung cancer is included.
Multiple randomized trials have been guided by
QOL assessments in investigating palliative irradia-
tion regimens for patients with inoperable NSCLC.
Bleehen et al. (1991) compared 30 Gy in ten fractions
or 27 Gy in six fractions versus 17 Gy in two frac-
tions for 369 patients with inoperable NSCLC. QOL
assessment was not significantly different between
treatment arms. As the traditional endpoint of survival
was also not significantly different between these
treatment arms, the two fraction regimen (i.e. F2
regimen) was recommended. Similarly, Sundstrom
et al. (2004) studied three palliative irradiation regi-
mens (i.e. 17 Gy/2 fractions versus 42 Gy/15 frac-
tions versus 50 Gy/25 fractions) for 421 patients with
Stage III or IV NSCLC. Using the EORTC QLQ-C30
and QLQ-LC13 instruments, they assessed QOL at
baseline and at 2, 6, 14, 22, 30, 38, 46, and 54 weeks
from the start of radiation therapy. No significant
differences were observed in median survival, symp-
tom relief, or QOL. As a result, short-term hypo
M. Salim Siddiqui et al.
fractionated palliative treatment was recommended.
Surprisingly, in contrast to these results, in another
randomized trial (Macbeth et al. 1996) by the Medical
Research Council Lung Cancer Working Party,
Macbeth and co-workers compared the F2 regimen
versus 39 Gy in 13 fractions (i.e. F13 regimen) in 509
patients with inoperable NSCLC and found that while
the F2 regimen had more rapid palliation and less
dysphagia, the F13 regimen had longer survival.
Similarly, Erridge et al. (2005) randomized 149
advanced lung cancer patients to palliative radiation
with either 10 Gy in one fraction or 30 Gy in 10
fractions. Although both treatment regimens met the
pre-determined 20% difference in the number of
patients achieving improvement in the total symptom
score and had equivalent treatment toxicity, signifi-
cantly more patients experienced complete resolution
and palliation of chest pain and dyspnea with the
fractionated regimen. In another randomized trial,
Bezjak et al. (2002) compared 10 Gy in 1 fraction
versus 20 Gy in 5 fractions for palliation of thoracic
symptoms in 230 patients with inoperable lung can-
cer. Interestingly, as judged by patient daily diary
scores, no significant difference was found between
the two treatment arms at 1-month post RT; however,
QOL scores measured using the Lung Cancer
Symptom Scale indicated that the fractionated RT
group (i.e. five fractions group) had significant
improvement in symptoms related to lung cancer,
pain, ability to conduct normal activities, and better
global quality of life. Moreover, patients in this
treatment group survived on average 2 months longer
with no significant difference in treatment-related
toxicity. Recently, Temel et al. (2010) assessed the
impact of early palliative care on PROs and end-
of-life care among ambulatory patients with newly
diagnosed metastatic NSCLC. Using the FACT-L
scale and the Hospital Anxiety and Depression scale,
they evaluated QOL and mood, respectively, in 151
patients with metastatic NSCLC at baseline and at
12 weeks. Patients were randomized to early pallia-
tive care or standard care. They found that patients in
the early palliative care arm not only had significant
improvement in both QOL and mood, but also had
longer median survival (11.6 months vs. 8.9 months,
p = 0.02) despite receiving less therapy (Temel et al.
2010).
Beyond QOL studies for palliative radiation
treatments in lung cancer patients, prospective
Quality of Life Outcomes in Radiotherapy of Lung Cancer
longitudinal studies in such patients undergoing rad-
ical or curative radiation treatments have also been
completed. Langendijk et al. (2001) assessed QOL
measures in 164 patients with NSCLC who received
radical radiotherapy (i.e. 60 Gy in 24 fractions). In
addition, the study also investigated the association
between level of symptom relief and objective tumor
response and radiation-induced pulmonary changes.
This study was one of the first to follow the dynamics
of QOL changes during and after radiation treatment
using the EORTC QLQ-30 and QLQ-LC13. Radical
radiotherapy offered not only good palliation of
respiratory symptoms, but also improved QOL in a
good proportion of patients. Specifically, the QOL
response rates were excellent for hemoptysis (83%);
good for arm/shoulder pain (63%), chest wall pain
(68%), and appetite loss (60%); and minimal for
dyspnea (37%), cough (31%), and fatigue (28%)
(Langendijk et al. 2001). The global QOL response
rate improved overall in 36%. While radiographic
tumor response was associated with palliation of
symptoms, no significant overall association between
such response and either palliation of symptoms or
QOL was demonstrated.
Similar QOL outcomes were found in an earlier
study of palliative radiation for inoperable lung can-
cer patients by Langendijk et al. (2000a). After
curative radiotherapy (i.e. 70 Gy in 35 fractions) in 46
patients with medically inoperable Stage I NSCLC,
Langendijk et al. (2002) found a significant gradual
increase in dyspnea, fatigue, appetite loss ,and a
gradual decline for role functioning. As other symp-
toms and functioning scales of the EORTC QLQ-C30
and QLQ-LC30 did not significantly change, they
suggested the observed QOL outcomes may have
been a function of pre-existing, slowly progressive
chronic obstructive pulmonary disease and radiation-
induced pulmonary changes. Balancing the QOL
outcomes with the low incidence of regional recur-
rence and a median survival of 19 months, they
concluded that local curative radiation treatment of
the primary tumor without elective nodal irradiation
may be the most appropriate treatment for medically
inoperable patients with small, peripherally located
tumors. More recently, van der Voort et al. (2010)
reported QOL outcomes on 39 patients with medi-
cally inoperable Stage I peripherally located NSCLC
tumors treated with stereotactic radiotherapy (i.e.
60 Gy in 3 fractions). They evaluated the dynamics of
669
QOL changes during and after radiation treatment
using the EORTC QLQ-30 and QLQ-LC13. In con-
trast to conventional study above (Langendijk et al.
2000a), in the stereotactic study (van der Voort et al.
2010), QOL scores were maintained and emotional
functioning significantly improved, while local
recurrence and toxicity were low and survival was
acceptable. As more evidence continues to suggest
that stereotactic radiotherapy should play an increas-
ing role for managing medically inoperable Stage I
NSCLC patients, Louie et al. (2010) developed a
Markov model to compare the quality-adjusted life
expectancy and overall survival in medically operable
Stage I NSCLC undergoing conventional standard of
care surgery versus stereotactic radiotherapy. Their
model revealed that stereotactic radiotherapy may
offer comparable overall survival and quality-adjusted
life expectancy as surgery. They concluded by stating
the need for prospective studies comparing not only
survival and cost, but also the QOL characteristics of
these treatment modalities (Louie et al. 2010).
A comparative study of radiotherapy versus che-
motherapy and its impact on QOL was reported by
kaasa et al. (1989). They reported a QOL study
comparing radiation (i.e. 42 Gy in 15 fractions)
versus chemotherapy (combination of cisplatin and
etoposide) in 102 patients with inoperable NSCLC.
Psychosocial well-being, disease-related symptoms,
physical function and everyday activity were assessed
with a validated patient-reported self-administered
questionnaire. They found significant differences in
psycho-social well-being and global QOL that
favored radiotherapy with no significant differences in
physical functioning or daily activities. The impact of
the addition of chemotherapy to radiation therapy
versus aggressive radiotherapy alone was recently
assessed in a study of 75 lung cancer patients
(Pijls-Johannesma et al. 2009). They evaluated the
evolution of QOL changes using the EORTC QLQ-30
and QLQ-LC13. While overall QOL scores initially
decreased after the end of RT, the scores returned to
baseline within 3 months (Pijls-Johannesma et al.
2009). Significant predictors of QOL were maximal
esophageal toxicity ([ or = grade 2), Stage IIIA/B,
gender and fatigue.
RTOG 9801 was a study designed to test whether a
radioprotector (i.e. amifostine) would reduce the rate
of chemoradiation-associated esophagitis, and thus
improve QOL in patients with locally-advanced
670
NSCLC (Movsas et al. 2005). In this study, 243
patients with Stage II or IIIA/B NSCLC received
treatment consisting of induction paclitaxel, followed
by concurrent weekly paclitaxel and carboplatin with
hyperfractionated RT (69.6 Gy in fractions of 1.2 Gy
given twice per day), starting day 43. Patients were
randomized at registration to either receive amifostine
(500 mg IV) four times per week or not receive it
during chemoradiotherapy. Toxicity was assessed
using NCI-Common toxicity criteria (NCI-CTC),
physician dysphagia logs (PDLs), and daily patient
swallowing diaries. The EORTC-QLQ C30 and QLQ-
LC13 were utilized to collect prospective QOL
information. Each arm had comparable baseline
demographics. The median survival rates were com-
parable between both treatment arms (17.3 months
with amifostine vs. 17.9 months without amifostine,
p = 0.87). Interestingly, Movsas et al. (2009) recently
reported that patient-reported baseline QOL in this
study was an independent prognostic factor for
overall survival, replacing traditional prognostic fac-
tors, such as KPS and stage. While others [e.g.
(Langendijk et al. 2000b)] have demonstrated this
prognostic value in patients receiving palliative
radiotherapy, this study (Movsas et al. 2009) was the
first to report this prognostic significance in patients
treated with chemoradiotherapy. Interestingly, RTOG
9801 demonstrated no significant difference Grade C3
esophagitis rates (i.e. 30% with amifostine vs. 34%
without amifostine, p = 0.9). However, based on
patient swallowing diaries, amifostine significantly
lowered swallowing dysfunction during chemoradia-
tion (Z-test, p = 0.03), especially among females
(p = 0.006) and patients [65 years (p = 0.003). In
addition, based on QOL forms, patients receiving
amifostine demonstrated less deterioration in patient-
reported pain at 6 weeks of follow-up (versus pre-
treatment) (p = 0.003). Thus, while there was no
significant difference between NCI-CTC physician-
reported esohpagitis, PRO suggested that amifostine
had some benefit. This result highlights ‘‘disconnect’’
between the PRO (e.g. the swallowing diaries/QOL
forms in RTOG 9801) and the physician-reported
information (e.g. CTCAE toxicity measures) (Sarna
et al. 2008). This not only suggests that current clin-
ical toxicity endpoints may not be sensitive enough,
but also may primarily reflect the physician rather
than the patient perspective. Such ‘‘disconnect’’ has
been observed in other studies, where again
M. Salim Siddiqui et al.
physician-reported assessments underestimated
patient distress, particularly in the case of pain (Basch
et al. 2006, 2009; Jensen et al. 2006). This ‘‘discon-
nect’’ may provide an opportunity for a new approach
in adverse symptom reporting. Basch et al. (2009)
studied 163 patients with lung cancer receiving che-
motherapy and used a time-dependent Cox regression
model to compare PROs and physician-reported out-
comes relating to sentinel clinical events. They found
that physician-reported CTCAE assessments were
better predictors of unfavorable clinical events;
however, PROs were better predictors of daily health
status. Effectively, they concluded that the PRO and
physician-reported outcomes were complementary
clinically meaningful data sets. The implication of
this result would be that both data sets should be
collected in clinical trials, or that these approaches
should be combined.
2 Conclusions and Future
Directions
Lung cancer remains a leading cause of cancer death
for both men and women. Even with advances in
diagnostics and treatments, clinical trials in lung
cancer should not only evaluate traditional outcome
parameters, such as survival and local control, but
also investigate QOL measures. As the number of
QOL studies in lung cancer continue to grow, certain
challenges will need to be addressed. Particularly in
an era of increasing electronic medical records, new
electronic, privacy-secure, and internet-based pro-
grams should allow more efficient and real-time QOL
data collection and tracking. Hopefully, such pro-
grams will improve compliance and minimize data
management and resource burdens. Secondly, given
the clinical relevance of PROs, the NIH has devel-
oped an initiative, Patient-Reported Outcomes Mea-
surement Information System (PROMIS) to develop
brief QOL instruments to capture patient-reported
symptoms and PROs in clinical practice (Garcia et al.
2007). Such initiatives should afford a dynamic series
of instruments to measure PROs. Thirdly, while much
work has been done testing the validity and reliability
of current QOL instruments, evolution in treatment
techniques will require continued refinement for more
focused and validated QOL instruments. Another
challenge centers on understanding the clinical
Quality of Life Outcomes in Radiotherapy of Lung Cancer
relevance of QOL outcomes as treatments continue to
evolve. Future studies are beginning to elucidate the
biologic underpinnings supporting the relationship
between QOL and survival (Sprangers et al. 2009).
Regardless of these challenges, the most compelling
reason to assess QOL and the impetus to address these
challenges will still center on patient themselves, and
their clear desire to discuss QOL issues (Detmar et al.
2002; Velikova et al. 2004). Ultimately, QOL will
become a routine clinical tool in the art of caring for
our patients.
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 Prognostic Factors in Lung Cancer
Frank B. Zimmermann
Contents
1 Introduction.............................................................. 676
2 Non-Small-Cell Lung Cancer.................................
2.1 Tumor-Related Factors ..............................................
2.2 Patient-Related Factors..............................................
2.3 Treatment-Related Factors ........................................
3 Small-Cell Lung Cancer ......................................... 682
3.1 Tumor-Related Factors .............................................. 682
4 Patient-Related Factors...........................................
4.1 Performance Status (Karnofsky Index
and Weight-Loss) ......................................................
4.2 Gender and Age.........................................................
4.3 Laboratory, Hematological and Immunological
Factors........................................................................
5 Treatment-Related Factors..................................... 684
References.......................................................................... 685
F. B. Zimmermann (&)
University Hospital Basel, Basel, Switzerland
e-mail: FZimmermann@uhbs.ch
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_308,  Springer-Verlag Berlin Heidelberg 2011
Abstract
Lung cancer is a heterogeneous clinical entity of
non-small-cell and small-cell lung cancer types as
676 well as mixed types, with even different clinical
676 behaviors and prognoses within particular patho-
679 logical subgroups. Current guidelines for treatment
681
decisions in NSCLC and SCLC are based on tumor
extension and certain additional clinico-histopha-
tological parameters only. Besides this, numerous
683 clinical laboratory tests and investigations of the
cellular, molecular and genetic biology of lung
683
cancer and the environment have been introduced
684
into routine in pathology, clinical chemistry and
684 even nuclear medicine, describing the tumor better
than ever before. This knowledge might support
the treatment decision, research design and anal-
ysis, and may support the development of complex
risk models for prediction of lung cancer mortality,
and for the selection of an appropriate treatment
for each individual case. Unfortunately, countless
articles describing more than 150 different prog-
nostic factors but with enormous heterogeneity by
interstudy variations, patient selection bias, low
number of patients in most trials, retrospective
nature of the trials, and poor statistical power may
cause confusion. The main purpose of this article
with special focus on cancer related, patient
related, and environmental aspects is to allow an
impression on most important and significant
prognostic factors, and to offer a basis for
treatment decision in clinical practice concerning
patients with small-cell and non-small-cell lung
cancer. Most of those factors should not be taken
into account for treatment selection, but to
675
676
carefully use them for stratification in prospective
clinical trials. It should always be kept in mind,
that the development of new substances in medical
oncology, and the improvements in both surgical
and radiation oncology increase the therapeutic
window, and will change the value of some of the
mentioned prognostic factors in near future.
1 Introduction
Lung cancer is a heterogeneous clinical entity, con-
taining the broad spectrum of non-small cell lung
cancer including not otherwise specified cancer, and
the group of small-cell-cancer, as well as mixed types.
All groups share molecular and cellular origins, but
have distinct clinical behaviors and prognoses, even
within their particular pathological subgroups.
The afflicted patients present a diverse constella-
tion of clinical symptoms and biochemical values, in
part caused by different manifestations of the primary
tumor, distinct distribution of involved metastatic
sites, and a varied extent of paraneoplastic syn-
dromes, and even comorbidities. Inspite of the
remarkable predictability of population survival
outcomes this knowledge is of limited value for
treatment decisions in a single patient, due to the
marked heterogeneity of the clinical course in the
individual patient (Brundage et al. 2002). Current
guidelines for treatment decisions in NSCLC and
SCLC are based on tumor extension (mainly TNM
staging system) and certain additional clinico-
histopathological parameters only.
Besides this, there is a need for an explanation and
a new classification of the heterogeneous nature of the
disease and, thereby, select the best individual treat-
ment by the prognosis for each patient. In the previ-
ous years, numerous clinical laboratory tests, and,
most recently, investigations of the cellular, molecu-
lar and genetic biology of lung cancer and the
environment have been introduced into routine in
pathology, clinical chemistry, and even nuclear
medicine, describing the tumor better than ever before
(Buccheri and Ferrigno 2004; Feld et al. 1994;
Brundage et al. 2002; Goldstraw et al. 2011; Filosso
et al. 2011; Paesmans et al. 2010). This knowledge
may play an essential role in explaining the different
outcomes of the patients, and might support the
F. B. Zimmermann
treatment decision, research design and analysis, and
health policy development (Brundage et al. 2001;
MacKillop 2001; Goldstraw et al. 2011). There is
increasing interest to develop complex risk models
for prediction of lung cancer mortality, and for
the selection of an appropriate treatment for each
individual case.
Countless articles have been published, including a
lot of reviews, describing more than 150 different
prognostic factors, and with increasing focus on
molecular and biological markers. Nevertheless, it
must be considered that the literature is markedly
heterogeneous with inter-study variations, patient
selection bias, low number of patients in most trials,
retrospective nature of the trials, and poor statistical
power (Brundage et al. 2002; Ou et al. 2007;
Mandrekar et al. 2006; Goldstraw et al. 2011).
Therefore, the main purpose of the following
overview is to allow an impression on most important
and significant prognostic factors, and to offer a basis
for treatment decision in clinical practice concerning
patients with small-cell and non-small-cell lung
cancer.
In principle, prognostic factors can be divided into
three subgroups (Goldstraw et al. 2011):
• Cancer related as tumor type, size, site, and dif-
ferentiation, and extent of disease.
• Patient-related as comorbidities, gender, perfor-
mance status, individual habits as smoking.
• Environmental factors as treatment options, social
support, available treatment.
These factors can be used individually, and may
create a formula of a composite prognostic factor,
influenzing the treatment decision among other
things.
2 Non-Small-Cell Lung Cancer
2.1 Tumor-Related Factors
2.1.1 Tumor Stage
The definition of major clinical subgroups on the
basis of tumor stage (TNM staging system) has been
consistently shown to be the strongest determinate of
the outcome of NSCLC patients overall. Within
this system each single parameter describing the
anatomic burden of disease (T = local extent of
tumor; N = site of nodal metastases; M = number
Prognostic Factors in Lung Cancer
and location of distant metastases) reflects prognosis
(Buccheri and Ferrigno 2004; Ou et al. 2007). Revi-
sions to the TNM-system were made in 1997 and in
2010, to provide greater specificity for patient sub-
groups, recognizing the prognostic relevant difference
even between subgroups of T1 (pT1a: \2 cm; pT1b:
[2–3 cm) and T2 (pT2a: [3–5 cm; pT2b:[5–7 cm),
the importance of tumor-related factors (e.g., cN2 or
cT4 disease) that estimate the likelihood of definitive
resectability within stage III, and of the presence of
intrapulmonary satellite tumor metastases in a dif-
ferent ipsilateral lobe from that of the primary (T4)
(Goldstraw et al. 2011; Sobin et al. 2010). Besides
T-category, it is known that tumor size is the powerful
predictor of survival in patients who have disease that
is amenable to resection but who are inoperable due to
medical reasons and will undergo definite radiother-
apy (Wigren et al. 1997; Ou et al. 2007; Sobin et al.
2010; Olson et al. 2011).
In summary, the anatomical extent of the tumor,
defined by the TNM-system, is one of the most
important prognostic factors, the most accurate and
reliable way to estimate the patients perspective (Li
et al. 2011a). Therefore, accurate clinical assessment
of the TNM stage is of utmost importance (Birim
et al. 2006). However, it cannot predict precisely the
5-year survival rate even in fictitious homogeneous
early stage tumors (mean value 67%) (Mountain
1997; Kwiatkowski et al. 1998). This indicates that
the TNM-system based on clinical, radiological,
invasive and even histopathological investigations is
far from sufficient. It might be explained by problems
in staging procedures, but will also be influenced by
other prognostic factors, tumor or patient related,
having been studied in addition to anatomical extent
by the IASLC staging project (Sculier et al. 2008).
2.1.2 Tumor Histology
The prognostic significance of histopathological cell
type of NSCLC (e.g., large-cell, adenocarcinoma,
squamous cell, undifferentiated cancer) has been
studied extensively. Some authors did not find a prog-
nostic implication of cell subtype, but the majority of
retrospective trials have shown an independent supe-
rior outcome in squamous cell carcinoma (Komaki
et al. 1996; Birim et al. 2006), with an advantage of
about 10% in 5-year survival rate. Unfortunately, the
results are conflicting, with Sculier et al. (2008)
reporting a significant prognostic value of histology
677
cell type only in stage III A disease, whereas the Lung
Cancer Study Group reported superior postoperative
outcome for patients with squamous cell carcinoma in
all but stage III disease (Mountain et al. 1987). From the
preponderant studies, it can be concluded that squa-
mous cell type has a small but independent positive
impact on survival prognosis, and adenosquamous
carcinomas have a comparably poor prognosis (Filosso
et al. 2011). In summary, the histological subtype of
NSCLC has lower prognostic information in NSCLC
than stage, age, performance status and gender, and this
might additionally be influenced by a different grading
and rate of apoptosis and mitosis as risk factors for
distant metastasis at least (Komaki et al. 1996; Ou et al.
2007).
2.1.3 Biological and Genetic Factors
Biological and genetic tumor factors have been
evaluated mostly in resected specimen, therefore data
on patients with advanced disease are rare. Never-
theless, some of those factors have been shown to
have independent prognostic significance. They are
rarely assessed in clinical routine practice: histologic
features, markers of tumor proliferation, markers of
cellular adhesion, and other molecular biological
markers.
The latter group includes regulators of cellular
growth (e.g., ras oncogene or protein, retinoblastoma,
epidermal growth factor receptor EGFR and EGFR
copy numbers well as EGFR gene mutations, erb-b2,
motility-related protein-1, and hepatocyte growth fac-
tor), regulators of the cell cycle and apoptosis (p53, bcl-
2, KRAS, p27), the nucleotide excision repair pathway
(excision repair cross-complementation group 1
ERCC1, ribonucleotide reductase messenger 1 RRM1,
breast cancer gene 1 BRCA1), and regulators of the
metastatic cascade (e.g., tissue polypeptide antigen
[TPA], cyclin D-1, and cathepsin).
Of those factors, especially EGFR mutations play
an important prognostic and predictive role, with
superior treatment outcomes in mutation-positive
subgroups receiving tyrosine-kinase-inhibitors of
EGFR (EGFR-TKI). However, response to EGFR-
TKI is not exclusive to patients with EGFR-mutation-
positive tumors, and the impact on overall survival is
not completely clear. Further prospective clinical
trials focus on this topic (Rossi et al. 2009).
p21 status, status of the serum assay for detection
of the cytokeratin 19 fragment, status of the
678
argyrophilic nucleolar organizer region, and p185
status have been significantly associated with prog-
nosis in about 80% of the studies, whereas Ki-67
status, vascular endothelial growth factor status, and
vessel invasion were positive correlated in only
50–60%. Data on mutation of the p53 suppressor gene
are also conflicting, but several systematic reviews
have confirmed its prognostic impact at least in
adenocarcinoma. Unfortunately, only a few reports
are based on prospectively designed studies thus
decreasing their value (Buccheri and Ferrigno 2004;
Coate et al. 2009). And, so far, none of these factors
can be really used for treatment decision. The ques-
tion of which molecular markers will prove to be the
most useful for selecting treatment for individual
patients remains unanswered.
Therefore, although well-developed and validated
genomic signatures could lead to personalized treat-
ment decisions, the practicing physician and the
patient are still left in doubt about the reliability and
medical utility of the signatures (Rossi et al. 2009;
Subramanian and Simon 2010). The importance of
standardization and prospective validation not only of
the markers but the techniques used in molecular and
biological markers can only be further emphasized,
which were immunohistochemistry, gene expression,
mutational analysis, and microarray (Goldstraw et al.
2011).
2.1.4 Angiogenesis, Growth Factors
and Carcinogenic Process
It is evident that angiogenesis is a relatively early
event during cancer pathogenesis, and it is at least in
part responsible to ensure tumor oxygenation, nutri-
tion, and to cause distant metastasis. Neoangiogenesis
as a major basis for tumor growth and metastasis has
been evaluated in surgical specimen. Microvessel
optical count was done in patients with stage I to IIIA
disease, and found to be a powerful independent
prognostic factor (Fontanini et al. 1998). This statis-
tical significance was confirmed by a large review of
several thousands of patient records by the European
Lung Cancer Working Party in 2002 (Meert et al.
2002).
In the previous years, an increasing number of
angiogenic cytokines have been identified being
involved in neoangiogenesis of lung cancer, with
vascular endothelial growth factors (VEGF) appar-
ently being the most important one. The prognostic
F. B. Zimmermann
importance of subgroups of VEGF has been validated
by a recent systematic review with metaanalysis in
2009 (Zhan et al. 2009). A higher level of VEGF in
blood and tumor tissue is strongly correlated with a
poorer outcome of the patient. Assessment of circu-
lating levels of VEGF may be valuable future tools
for treatment planning and monitoring treatment
effects and tumor relapse (Bremnes et al. 2006). Also,
both high VEGF-A and VEGF-C protein expression
have been associated with poor survival in the
majority of clinical trials on NSCLC (Reinmuth et al.
2010). With an increasing number of biomarker
studies there may be a chance to better characterize
the tumor, and thereby tailor an individualized perfect
treatment for each patient. Unfortunately, other types
of growth factors (VEGFR2, VEGFR3) seem not to
have an impact on prognosis and will not help in
treatment decision, whilst for further markers as
bFGF (basic fibroblast growth factor), hypoxia-
inducible factor (HIF), and metastasis-associated
protein 1 (MTA1) the data are still controversial or
too early to be safely interpreted (Bremnes et al.
2006; Zhan et al. 2009; Bonnesen et al. 2009; Wu
et al. 2011; Li et al. 2011b).
Matrix metalloproteinases 2 and 9 (MMP-2, MMP-
9) participate in many deregulated signaling pathways
that are used by the tumor to promote cancer cell
growth, angiogenesis, and apoptosis, especially deg-
radation of proteins in the extracellular matrix and
activation of growth factors. In a recent meta-analysis
on MMP-2 (Qian et al. 2010) and a single-center
evaluation on MMP-9 (Martins et al. 2009), the
prognostic value on overall survival either in NSCLC
for MMP-2 or in adenocarcinoma only for MMP-9
appeared significant. The integration of MMP-2
as a selection marker for a prospective trial to pro-
spectively evaluate its real value was demanded
(Qian et al. 2010).
2.1.5 Serological Tumor Markers
The value of standard tumor markers as predictive
parameter has been tested in several clinical trials.
Cytokeratin-19-fragments (Cyfra 21-1), tissue poly-
peptide antigen (TPA), cancer antigen 125, and car-
cinoembryonic antigen (CEA) have been evaluated as
valid prognostic determants, with cytokeratin frag-
ments almost certain. Unfortunately, the data are not
homogeneous, and the prognostic capability of CEA
was rather weak (Buccheri and Ferrigno 2004).
Prognostic Factors in Lung Cancer
In stage I disease, CEA may be used to indicate
adjuvant chemotherapy, but this has been shown
reliable only within small retrospective trials (Wang
et al. 2010; Hsu et al. 2007; Matsuoka et al. 2007).
Cyfra 21-1 has been evaluated in a multivariate
analysis, and was proven with a higher sensitivity to
predetermine the treatment outcome than CEA and
NSE (Picardo et al. 1996; Reinmuth et al. 2002).
More recent data do not support the value of Cyfra
21-1 as a prognostic indicator in stage I (Matsuoka
et al. 2007), and, therefore, this marker may be only
used to control the therapeutic efficacy of chemo- or
radiochemotherapy in more advanced disease. A new
marker, the carbohydrate antigen Sialyl Lewisx (SLX)
has been seen significantly linked with overall sur-
vival in resected stage I NSCLC, but has to be proven
prospectively in larger trials (Mizuguchi et al. 2007).
In principle, outside of clinical trials, none of the
tumor markers should be used for treatment decision
before initiating therapy, but only for follow-up.
2.2 Patient-Related Factors
2.2.1 Gender, Age and Ethnicity
Unfortunately, the literature is quite variable in the
conclusions about the prognostic value of gender and
age, and the strength of the association with survival
outcomes. Although reports on age in multivariate
analysis have been inconsistent, a younger age might
carry a better prognosis (Quejada and Albain 2004).
Albain and colleagues identified good performance
status, female sex, and age below 70 years as the most
important factors that were predictive of favorable
survival rates overall. Nevertheless, surgical, radia-
tion and perioperative intensive care techniques and
knowledge have increased reasonably in the previous
decades, resulting in lower treatment mortality even
in elderly patients. Due to raised comorbidity with
age, advanced age alone should not be the only reason
to withhold aggressive treatment but the presence of
comorbid conditions (Birim et al. 2006; Asmis et al.
2008). Scoring systems for risk assessment before
radical surgery and aggressive large-volume radio-
therapy would be helpful to better tailor individual
cancer treatment especially for elderly (Charlson
comorbidity index CCI; cumulative illness rating
679
scale for geriatrics CIRS-G) (Charlson et al. 1987;
Miller et al. 1992).
In several former studies the male sex was dis-
cussed as an adverse prognostic factor. A review in
1994 described significant evidence in 7 out of 19
studies with univariate analysis, and in 9 of 23
studies with multivariate analysis in favor of the
female sex (Buccheri and Ferrigno 1994). These data
were confirmed by an evaluation in a tumor register
population. Median survival was significantly better
for women than for men, and together with the
extent of tumor and weight loss gender was the
strongest independent predictor even in multivariate
analysis (Palomares et al. 1996). This may be
explained by the higher life expectancy of women
regardless of the presence of lung cancer, a lower
incidence of severe comorbidity of heart and lung,
less tobacco consumption, higher incidence of ade-
nocarcinoma, and less frequent pneumonectomies
(Birim et al. 2006). Furthermore, the hormonal and
metabolic situation in women seems to positively
influence the aggressiveness of lung cancer (Birim
et al. 2006). This may change with the increasing
incidence of lung cancer in women and the changing
smoking habits.
On the other hand, very recent data from the
Canada Clincal Trials Group indicated only a modest
effect of gender on progression-free survival for
women under chemotherapy, but no influence on
overall survival and quality of life, whereas a Japa-
nese analysis pronounced the significant positive
influence of female gender at least in never-smokers
(Wheatley-Price et al. 2010; Kawaguchi et al. 2010).
This heterogeneity is in contrast to the more homo-
geneously proven positive impact of female gender in
small-cell lung cancer, and therefore, treatment
decision in NSCLC should not be based on gender.
The importance of ethnicity and of socioeconomic
status as independent prognosticators has been shown
by a retrospective population-based study from the
cancer surveillance programs in Southern California.
Asians had the highest over survival, independent of
the type of treatment (Ou et al. 2009). A higher
socioeconomic status correlated well with a better
outcome, confirmed in a multivariate analysis and
thereby not influenced by surgical treatment or mar-
ital status (Ou et al. 2008).
680
2.2.2 Performance Status (Karnofsky Index
and Weight-Loss), Pulmonary Function
and Cardiovascular Disease, Smoking
Habits
Numerous studies investigated patient characteristics
as predictors of survival after surgical resection,
definite radio- or radiochemotherapy in non-small cell
lung cancer. Due to the fact that most patients with
early stage disease are asymptomatic, only few stud-
ies have systematically evaluated the prognosis of
patients related to clinical symptoms in stage I cancer.
They have been found to be less powerful predictors
of outcome, particularly in stage I disease, than in the
advanced disease setting, and, therefore, these factors
are not generally considered to be important for
clinical decision making. Nevertheless, hemoptysis,
coughing, and thoracic pain were identified as risk
factors for tumor recurrence and poor survival
(Harpole et al. 1995).
In locally advanced and irresectable cancer as well
as functional inoperable patients an increasing
amount of research has addressed the use of patient-
reported parameters. The majority of those patients
will show significant symptoms or other general
manifestations of illness such as weight loss or poor
performance status.
Karnofskys index of performance status (KPS) and
the Eastern Cooperative Oncology Group perfor-
mance status scale (ECOG PS) have been examined
within large trials, and ahead of 50 other factors, KPS
and weight loss within the previous 6 months were
the most important, besides the extent of disease
(Stanley 1980; Mandrekar et al. 2006; Li et al. 2011a,
b). Large clinical studies or reviews confirmed KPS as
well as ECOPG PS as one of the two most important
prognostic factors, with ECOG PS being the more
reliable and useful (Buccheri and Ferrigno 2004;
Kawaguchi et al. 2010). In recent trials, the role of
cancer related symptoms, quality-of-life scores, and/
or anxiety and depression measures have been
investigated more in depth. Those studies reported the
importance of quality of life, being a stronger deter-
minant than pure performance status (Langendijk
et al. 2000; Buccheri and Ferrigno 2004). Quality-
of-life scores and anxiety and depression assessments
may reflect the extent of disease and also the patients’
inherent characteristics or degree of emotional sup-
port that may predict better disease outcomes, possi-
bly through psychophysiologic mechanisms.
F. B. Zimmermann
Weight loss within the last 6 months before diag-
nosis has an important impact on survival, with total
proportional weight loss being the most significant one
(Buccheri and Ferrigno 2004; Mandrekar et al. 2006).
In resectable cancer, the prognostic value of pul-
monary function has been proven, with the estimation
of the absolute and predicted proportional postoper-
ative spirometry value being mostly predictive. These
values can be calculated by multiplying the observed
preoperative value with the percentage of postopera-
tively remaining lung tissue, or by performing a lung
perfusion scan (Birim et al. 2006). Cardiovascular
disease has been found in several retrospective trials
to be a relevant factor for postoperative morbidity and
mortality. Therefore, a preoperative evaluation should
be carried out in all patients at risk, using exercise
stress tests (Birim et al. 2006).
Actual data from Japan using a database of 4,954
patients showed that never-smoking status was a
marginal but significant favorable factor regarding
overall survival, not caused by response on chemo-
therapy or influenced by gender or younger age of
non-smokers. Different profiles of never-smokers with
lung cancer will enhance the idea that NSCLC in this
subgroup may be considered and treated as a dis-
tinctive disease (Kawaguchi et al. 2010).
2.2.3 Laboratory, Hematological
and Immunological Factors
Hematologic or biochemical markers might be associ-
ated with disease extent, and therefore have been eval-
uated in numerous trials regarding their prognostic
value. In a large study of 2,531 patients who were
enrolled in a variety of clinical trials, four prognostic
factors for patients receiving cisplatin chemotherapy
were identified that had significantly distinct survival
expectations: performance status, age, and hemoglobin
and serum LDH levels. Other studies employing sec-
ondary analysis of clinical trial information or after
retrospective evaluation of patient data outside of clini-
cal protocols have reached similar conclusions (Paes-
mans et al. 1995; Hespanhol et al. 1995; Takigawa et al.
1996; Mandrekar et al. 2006; Goldstraw et al. 2011).
In general, high white blood cell count, low
hemoglobin level, and LDH are certainly the strongest
prognostic factors, whether considered alone or in
combination with weight loss, performance status,
or tumor stage (Buccheri and Ferrigno 1994;
Mandrekar et al. 2006; Maione et al. 2009; Goldstraw
Prognostic Factors in Lung Cancer
et al. 2011), mainly in advanced stage tumors. Further
independent laboratory tests are calcium and albumin,
with decreased values predicting poor prognosis.
Thrombocytosis above 400.000/yl, tested in a spe-
cifically designed study, showed a strong correlation
with advanced disease and decreased survival even
after adjustment for stage and histological type of
tumor, sex and age of the patient (Pedersen and
Milman 1996). Based on these data, Mandrekar et al.
(2006) created a prediction equation for the prognosis
of patients with newly diagnosed stage IV NSCLC,
useful to design trials and compare results of phase-II
trials with each other.
2.2.4 Standardized Uptake Value
in FDG-PET
Several large retrospective evaluations (Al-Saraf et al.
2008; Agarwal et al. 2010) and an updated meta-anal-
ysis (Paesmans et al. 2010) have shown SUV being a
very interesting factor for predicting patient outcome,
with a strong correlation regarding overall survival and
cancer-specific survival as well. The results do not
allow concluding to an optimal threshold but only that
higher values of SUV imply higher hazards. It seems
that there is a continuous increase in risk with
increasing SUV (Paesmans et al. 2010).
2.3 Treatment-Related Factors
2.3.1 Clinically Resectable Disease
Several modern studies compared resection with
combined conservative modality treatments in stage
III NSCLC, showing no superiority of surgery in
regard to overall survival.
Nevertheless, when surgery is considered to be the
standard management of patients who are medically fit
for thoracotomy, to aim at both high local disease
control and acceptable overall survival rates (Sabiston
and Spencer 1995), complete resection is essential
(Birim et al. 2006). Lobectomy or pneumonectomy are
standard approaches, with wedge resection being
reserved for patients in poor condition even in stage I
NSCLC, due to inferior results possibly caused by close
resection margins or limited lymph node dissection
(Sabiston and Spencer 1995; Lee et al. 1999; Birim
et al. 2006; Nakamura et al. 2011). Tumor wedge
resection, segmental or atypical resection increases the
risk of local recurrence three to fivefold with a reduced
681
5-year survival rate, but not in very early stage NSCLC
(p T 1–2 N 0) where it gives the same results as
lobectomy (Graziano 1997; Jazieh et al. 2000; Na-
kamura et al. 2011). It has been clearly documented that
surgical procedure is a significant prognostic factor.
Of fatal prognostic significance is an incomplete
resection, either with gross disease remaining or with
positive microscopic resection margins, even when
additional postoperative therapy (radiotherapy or che-
moradiotherapy) is provided (Ginsberg et al. 1999),
suggesting the poor biological characteristics of the
tumor being both associated with locoregional extension
that causes microscopic residual disease and early sys-
temic spread. Perioperative blood transfusions, required
mainly in extensive dissections, is postulated to decrease
overall survival by mediated immunosuppression
favoring proliferation, distant spread, and migration of
tumor cells. Published data are incongruous, with
shortening time to recurrence, overall and recurrence-
free survival by 30% in some publications, and no sig-
nificant influence in others (Quejada and Albain 2004).
In marginal resectable situations, preoperative
chemotherapy may be considered, with proven pro-
longed survival rates, especially in patients with
responding tumors, making it a highly relevant
prognostic factor (Birim et al. 2006).
Primary radiotherapy with curative intent is mainly
recommended for patients who cannot undergo resec-
tion in curative intention, although no modern ran-
domized trials have directly compared surgery to
radiotherapy in early stage NSCLC (Ginsberg et al.
1999; Zimmermann et al. 2003, 2010). In this situation,
it is well known that treatment results depend on total
dose and fractionation schedule, with acceleration and
hyperfractionation to biological effective doses of more
than 70 Gy producing superior outcome in stage III
disease, whereas hypofractionated schedules with ste-
reotactic techniques produce high local control and
cancer-specific survival rates comparable to resection
(Sause 2001; Jeremic et al. 2002; Saudners et al. 1999;
Willner et al. 2002; Choi et al. 2001; Zimmermann et al.
2003, 2010). In this situation, total dose should be
chosen high enough (BED [100 Gy), to result in a
perfect long-lasting local tumor control of 90% or
higher (Olson et al. 2011).
2.3.2 Locally Advanced Disease
Patients without clinical symptoms or radiological
signs of systemic manifestations but irresectable
682
disease have been shown in a number of clinical trials
to have higher survival rates when they receive
induction chemotherapy followed by radiotherapy, or
even better concurrent chemoradiotherapy, compared
to radiotherapy alone (Stewart and Pignon 1995).
The same subgroup of patients has been shown to
experience higher survival rates when treated with
continuous hyperfractionated and accelerated radio-
therapy compared to conventional fractionation, and
when treated with higher doses of conventional radi-
ation compared to lower doses (Saudners et al. 1999;
Willner et al. 2002; Choi et al. 2001; Emami and
Perez 1993). In this situation, clinical tumor response
is a highly significant prognostic factor, as well as
tumor volme. Doses as high as justifiable and rea-
sonable should be aimed for, using modern radiation
techniques as IMRT and SBRT at least for a radiation
boost (Lee et al. 2011; Alexander et al. 2011).
The role of surgery in relation to induction che-
motherapy and radiotherapy is still investigational, as
is the role of combination chemoradiotherapy in more
symptomatic patients (Ginsberg et al. 1999). Never-
theless, in some situations neoadjuvant chemotherapy
can be considered, with increasing prognosis at least
for responders (Birim et al. 2006).
2.3.3 Metastatic Disease
For patients without substantial systemic manifesta-
tions of illness and under good condition (Karnofsky
Index [60), chemotherapy is known to improve
median survival time when compared to the best
supportive care alone (Stewart and Pignon 1995).
This has not been documented for patients with poor
performance status, where best supportive care is
recommended in general.
3 Small-Cell Lung Cancer
3.1 Tumor-Related Factors
3.1.1 Tumor Stage
In contrast to NSCLC, small-cell lung cancer is gen-
erally classified into a two-stage system—limited and
extensive disease—with limited disease (tumor con-
fined to one hemithorax (Veterans Administration
Lung Study Group VALG) or without distant metas-
tases (International Association for the Study of Lung
Cancer IASLC), respectively, being tested a definite
F. B. Zimmermann
and the most powerful prognostic factor in most of the
published series using the IASLC definition (Shepherd
et al. 2007; Micke et al. 2002; Paesmans et al. 2000;
Jorgensen et al. 1996). The median survival is around
15 months in limited in contrast to about 10 months in
extensive disease patients (Yip and Harper 2000), and
this has a major implication on treatment decision.
Besides this two class-system a lot of other prog-
nostic factors that describe the extent of tumor and the
number or location of metastatic sites involved have
been evaluated (vena cava syndrome, pleural effusion
or nodal involvement; involvement of different organs
like liver, brain, or bone) (Albain et al. 1990;
Würschmidt et al. 1995; Tamura et al. 1998; Bremnes
et al. 2003). Mediastinal involvement and the infil-
tration of several organs might decrease the prognosis
of the patient, as has been demonstrated regarding
long-term survival by a Canadian Group (Tai et al.
2003), but data are not consistent. Therefore, these
factors are not generally used as a basis for treatment
decision.
3.1.2 Histological Subtypes
Small-cell lung cancer can carry a mixture of different
tumor cells in upto 20% of the cases, large-cell car-
cinoma being the most commonly combined cell type.
This causes the pathological committee of the IASLC
to adopt three new subtypes of small-cell lung cancer:
small cell, mixed large and small cell, and combined
small cell carcinomas (Hirsch et al. 1988). Unfortu-
nately, several following studies could not document
a different clinical outcome for these three subgroups,
and the actual WHO classification abandoned the idea
of different subgroups (Brambilla et al. 2001).
Nevertheless, the high percentage of patients with
various combinations of small- and non-small cell
lung cancer might explain the divergent response to
chemotherapy, and support the idea of salvage
resection for locally low-responding cancer (Sheperd
et al. 1991). No histological factors are predictive of
prognosis in SCLC till now (Fissler-Eckhoff 2010).
3.1.3 Serological Factors (Tumor Markers)
Besides the tumor extent, simple laboratory parame-
ters like biochemical tests and serum tumor markers
have their predictive values.
Serological factors (tumor markers), produced by
tumor cells and released into the bloodstream,
have been evaluated in a number of different studies.
Prognostic Factors in Lung Cancer
Due to their low tumor-specificity only a few of them
have certain prognostic value: neuron specific enolase
(NSE) and cytokeratin-19-fragments (Cyfra 21-1).
NSE has been tested in several large trials, and a
significant correlation was found between elevated
NSE levels and poor prognosis both in univariate and
multivariate analyses, making it one of the most
powerful prognostic factors (Bremnes et al. 2003;
Jorgensen et al. 1996). Using NSE together with
performance status of the patient and tumor extent in
a simple algorithm produces a clearly defined prog-
nostic classification that can be used for treatment
decision (Jorgensen et al. 1996).
Cyfra 21-1 has been the most commonly studied
cytokeratin, and besides extensive disease and
increased levels of LDH and NSE, elevated levels to
more than 3.6 ng/ml significantly indicated a poor
outcome of the patient (Pujol et al. 2003).
Among the plentiful further tested serological
markers only the serum carcinoembryonic antigen
(CEA) has deserved to be mentioned: in univariate
analyses its value has been confirmed, whereas
chromogranin A (CgA), pro-gastrin releasing peptide
(ProGRP) and creatinine kinase-BB (CPK-BB) have
not yet been confirmed valid (Ferrigno et al. 1994;
Lamy et al. 2000; Sunaga et al. 1999).
3.1.4 Biological and Genetic Factors
The genetic deletion of a number of chromosomes is
discussed as the major impulse of the development of
human lung cancer, stimulating the activation of
proto-oncogenes and the loss of tumor suppressor
genes. In small-cell lung cancer, the activation of
genes of the myc family (c-myc, L-myc, N-myc)
seems to be notable (Rygaard et al. 1993). The
expression depends on tissue type, and corresponds to
the maturity and development of different cell lines.
The c-myc oncogene may play an important role for
the differentiation of the cell into many cellular pro-
cesses (proliferation, differentiation, apoptosis). It is
highly amplified in SCLC cell lines in vivo, indicating
its relation to tumor progression and aggressiveness of
the tumor (Bergh 1990). In clinical studies a high
amplification of c-myc strongly correlates with tumor
progression and a poor outcome of the patient (Salgia
and Skarin 1998).
The value of p53 antibody has been evaluated in
several clinical trials. It seems possible that the
presence of a high titer of p53 antibody (titer
683
ratio [5) is correlated with a survival advantage.
Unfortunately, in contrast to the prognostic value of
p53 antibodies in NSCLC the results from several
actual clinical trials are contradictory, so that the
value as prognosticator is not proven certain (Jassem
et al. 2001; Murray et al. 2000).
Further genetic and biological abnormalities con-
nected to the pathogenesis of small-cell lung cancer
are under investigation, as thymidylate synthase and
epidermal growth factor receptor (EGRF), but none
has already been established as a trustful marker
predicting the prognosis of a patient with small-cell
lung cancer. At least, it became obvious that due to
higher TS-levels in SCLC, a treatment with the
TS-inhibitor pemetrexed is not reasonable (Rossi
et al. 2009).
4 Patient-Related Factors
4.1 Performance Status (Karnofsky
Index and Weight-Loss)
The performance status describes the patients’ ability
of self-care and to perform normal activity including
his participation in social life. There are two different
schedules in use: the Karnofsky Scale of Performance
Status (KPS) (11 levels from 100 to 0) and the Eastern
Cooperative Oncology Group Scale of Performance
Status (ECOG PS) (5 levels). The value of both
schedules has been tested, with the ECOG PS being
easier to apply and of better discrimination of
patients’ prognosis (Buccheri et al. 1996). In numer-
ous and even very large clinical trials the performance
status—independent of the schedule used—was con-
firmed as a significant prognostic co-factor (Paesmans
2004; Buccheri and Ferrigno 1994; Osterlind and
Anderson 1986; Spiegelman et al. 1989; Albain et al.
1990; Rawson and Peto 1990).
Besides tumor extent and performance status
weight loss has been identified an important prog-
nostic factor also in small-cell lung cancer (Stanley
1980; Tamura et al. 1998; Bremnes et al. 2003).
A more complex determinant predicting the sur-
vival of patients with small-cell lung cancer is quality
of life, a multi-factorial concept considering all
physical, psychological, social, and functional status
of the patient. Quality of life tests have been tested
valid in several clinical studies, but are more difficult
684
to establish in clinical routine and, therefore, rarely
used besides clinical trials (Naughton et al. 2002;
Montazeri et al. 2001; Buccheri 1998).
4.2 Gender and Age
Gender was documented as a discriminating factor of
SCLC outcome, with the combination of female sex
and younger age (below 60 years) carrying the best
prognoses regarding response rates, median survival,
and 2-year survival rate. This observation was inde-
pendent of any other relevant prognostic variable
(Buccheri and Ferrigno 1994; Wolf et al. 1991;
Osterlind and Anderson 1986; Spiegelman et al. 1989;
Albain et al. 1990). It was repeatedly confirmed in
more recent trials, using different types of chemo-
therapy (Singh et al. 2005; Paesmans et al. 2000), but
should nevertheless not influence treatment decision
alone.
4.3 Laboratory, Hematological
and Immunological Factors
There is a long list of laboratory tests evaluated as the
possible prognostic factors in small-cell lung cancer:
lactate dehydrogenase (LDH), hemoglobin serum
concentration (Hb), albumin, alkaline phosphatase
(AP), sodium, calcium, creatininemia, bicarbonates,
bilirubinemia, erythrocytes, leucocytes, neutrophilia,
and thrombocytes.
Elevated LDH, tested in 10 of 13 multivariate and
three large trials with more than 500 patients each, is the
strongest hematological prognostic factor with high
accuracy predicting poor outcome. It seems to be even
more important than tumor markers (NSE), and is
recommended by different groups as the cheapest and
most valid marker for small-cell lung cancer as a
stratification criteria for clinical trials (Quoix et al.
2000; Rawson and Peto 1990; Osterlind and Anderson
1986). Of all the other factors mentioned before, the
results are more or less inhomogeneous: low serum
albumin concentration, normal sodium (Na) and uric
acid levels, decreased plasmatic level of hemoglobin,
leucocytosis, increased alkaline phosphatase (AP) and
serum bicarbonate were only positive in some of the
trials in which they were evaluated, and cannot be
integrated in clinical routine to found a treatment
F. B. Zimmermann
decision (Bremnes et al. 2003; Quoix et al. 2000;
Rawson and Peto 1990; Osterlind and Anderson 1986).
In principle, an elevated LDH should be seen as a
risk factor for poor survival and an indicator of a
larger tumor burden, at least demanding for a com-
plete assessment of tumor stage. Based on the work of
the Subcommittee for the Management of Lung
cancer in UK on almost 4000 patients, performance
status, disease stage, and AP, Na, aspartate amino-
transferase and LDH should be measured in all future
trials to assist comparisons between the clinical trials
(Rawson and Peto 1990). Together with performance
status and tumor stage, Na, AP, and LDH have been
combined as the Manchester Prognostic Score, and
later modified by a Japanese group into a new three-
group-classification (Kawahara et al. 1999). They can
differentiate 1-year survival rates of more than 50% in
the best versus 0% in the worst group, or median
survival rates of 16.0 versus 6.6 months, respectively.
These classifications can be used to design clinical
trials and to tailor individual treatment as well.
5 Treatment-Related Factors
The response to treatment has been found to be highly
significantly on survival of patients treated with
chemo- and radiochemotherapy. Complete responders
had a better survival than partial responders, who had
a superior outcome than non-responders (Lebeau et al.
1995; Ray et al. 1998; Paesmans et al. 2000).
In several randomized trials it has been docu-
mented that simultaneous radiochemotherapy, with
radiotherapy being administered early in the treatment
schedule, will improve the outcome of patients in
good condition compared to chemo- or radiotherapy
alone, and that altered fractionation of irradiation
might further enhance the results (Warde and Payne
1992; Murray et al. 1993; Jeremic et al. 1997; Work
et al. 1997; Lebeau et al. 1999; Turrisi et al. 1999;
Takada et al. 2002). In retrospective trials the
importance of total radiation dose has been pro-
nounced (Tai et al. 2003), but a randomized trial
comparing higher dose with hyperfractionated sche-
dule is still running and the answer lacking.
The value and the optimal timing of resection of
persistent tumor at the end of chemotherapy in
sequential protocols or after simultaneous radioche-
motherapy has only been evaluated in one randomized
Prognostic Factors in Lung Cancer
trials, and cannot be recommended. It might increase
local control, but without influencing overall survival
(Lad et al. 1994). In extensive disease, radiotherapy
should not be omitted in treatment responders, because
local tumor control and median survival can be
improved by additional irradiation (Jeremic et al.
1999).
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 Intensity-Modulated Radiation Therapy
and Volumetric-Modulated Arc Therapy
for Lung Cancer
Inga S. Grills and Victor S. Mangona

Contents 6 Outcomes .................................................................. 705

7 Conclusion ................................................................ 709
1 Introduction.............................................................. 692 References.......................................................................... 709
2 Technical Aspects .................................................... 692
2.1 Beam Modification.................................................... 692
2.2 Three-Dimensional Conformal Radiation Therapy... 693 Abstract
2.3 Intensity-Modulated Radiation Therapy ................... 693 Per 2010 estimates by the American Cancer
2.4 Intensity-Modulated Arc Therapy............................. 694
2.5 Volumetric-Modulated Arc Therapy......................... 695
Society, lung cancer has both the highest incidence
and mortality of all malignancies in the United
3 Potential Advantages of
States. Overall, outcomes, though improving,
Intensity-Modulated Radiation Therapy
and Volumetric-Modulated Arc Therapy: remain poor, and radiation therapy (RT) is an
Dose-Escalation and Toxicity Reduction .............. 696 important mainstay of locoregional therapy. The
3.1 Intensity-Modulated Radiation Therapy versus technical challenges of delivering biologically
Three-Dimensional Conformal Radiotherapy........... 696
effective doses of RT capable of achieving
3.2 Intensity-Modulated Radiation Therapy Planning
Studies........................................................................ 696 adequate local control are many and relate to
3.3 Toxicity and Intensity-Modulated Radiation target definition, respiratory tumor motion, tissue
Therapy ...................................................................... 696 heterogeneities and normal tissue tolerance.
3.4 Volumetric-Modulated Arc Therapy Experience ..... 700
Advancements over standard two-dimensional
4 Treatment Planning................................................. 700 RT, including three-dimensional conformal radia-
4.1 Simulation .................................................................. 701 tion therapy (3D-CRT), intensity-modulated radi-
4.2 Target Volumes (Gross Tumor Volume, Clinical
Target Volume, Planning Target Volume)............... 702 ation therapy (IMRT), and more recently
4.3 Inverse Planning ........................................................ 702 volumetrically-modulated arc therapy (VMAT),
5 Targeting and Verification ..................................... 703
in addition to four-dimensional (4D) CT simula-
5.1 Image-Guided Radiation Therapy............................. 703 tion and planning techniques, using biological
5.2 Biological Targeting with Positron Emission targeting via positron emission tomography (PET)
Tomography............................................................... 704 and 2 and 3-D image-guided delivery methods
5.3 Treatment Verification .............................................. 705
have aided the path toward achieving radiation
dose escalation while concurrently sparing organs
at risk (OAR) and reducing target miss. IMRT
planning studies have shown improvements over
I. S. Grills (&)
V. S. Mangona 3D-CRT with respect to tumor dose escalation and
Department of Radiation Oncology, OAR dose, particularly for locally-advanced dis-
William Beaumont Hospital,
ease. This, however, is potentially at the cost of
3601 West Thirteen Mile Road,
Royal Oak, MI 48073-6769, USA longer treatment times, monitor units, and volume
e-mail: igrills@beaumont.edu of lung receiving low dose, with some concern for

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 691
DOI: 10.1007/174_2011_283,  Springer-Verlag Berlin Heidelberg 2011
692
higher pneumonitis rates. Commercial planning
software and quality assurance measures now
allow for dynamically delivered VMAT, which
similarly may achieve higher tumor dose and lower
OAR dose while concurrently reducing treatment
times and monitor units and increasing target
conformality. Though IMRT and VMAT planning
studies and short-term, single-institution clinical data
are encouraging, long-term, multi-institutional stud-
ies comparing these techniques to 2D or 3D-CRT in
terms of locoregional control, survival, and quality of
life are lacking but should be supported.
1 Introduction
In the US, 2010 estimates by the American Cancer
Society suggest that lung cancer has both the highest
cancer incidence: 222,000 new cases per year (more
than both breast and prostate cancer) and highest
yearly cancer mortality: 157,000 deaths per year,
nearly as many as the next four leading causes com-
bined: colon, breast, pancreas, and prostate (American
Cancer Society: Cancer Facts and Figures 2010).
In patients with inoperable non-small-cell lung
cancer (NSCLC), radiation therapy remains the pri-
mary curative modality for both early-stage and
locally-advanced disease, despite chemotherapeutic
advances (Arriagada et al. 1991; Furuse et al. 1999;
Pisters 2000). Delivery of radiation therapy (RT) for
intrathoracic malignancies is technically challenging,
and conventional radiotherapy doses and techniques
have yielded unsatisfactory results. In early-stage
disease, local failure occurs in 60–70% of patients
with 2-year survival under 40% using standard-
fractionated RT (Armstrong and Minsky 1989;
Dosoretz et al. 1996; Kaskowitz et al. 1993).
In locally-advanced disease, 3-year local control (LC)
is approximately 20% with median survival under
18 months (Curran et al. 2003; Ataman et al. 2001).
Studies from the University of Michigan, radiation
therapy oncology group (RTOG), and Memorial
Sloan-Kettering Cancer Center (MSKCC) have
shown improved local control with dose-escalation
(Hayman et al. 2001; Narayan et al. 2004; Bradley
et al. 2005; Rosenzweig et al. 2005). In large tumors
(C100 ml), Rengan et al. showed a 36% decrease in
local failure with a 10 Gy increase in dose, and the
I. S. Grills and V. S. Mangona
Michigan group reached doses up to 102.9 Gy for
small solitary tumors (Rengan et al. 2004). Across
dose-escalation studies, however, the maximum tol-
erated dose for standard fractionated RT, without
chemotherapy, has been approximately 83–84 Gy.
Exceedingly high-biological effective doses (BEDs)
are now routinely administered for the treatment of
stage I NSCLC by way of stereotactic body radiation
therapy (SBRT) where a BED of [94–105 Gy has
shown higher rates of local control (Grills et al.
2010a; McGee et al. 2010; Onishi et al. 2010; Wulf
et al. 2005). In RTOG 0236, SBRT yielded a 3-year
LC rate of 98% (Timmerman et al. 2010), and
emerging data have shown SBRT to have comparable
results to sublobar (e.g. wedge) resection in terms of
local and regional recurrence (Grills et al. 2010b;
Welsh et al. 2010).
Even with the advent of three-dimensional confor-
mal radiotherapy (3D-CRT), escalating to tumoricidal
doses for larger tumors is highly constrained by the
potential for toxicity to the spinal cord, esophagus
(esophagitis/dysphagia), and normal lung (pneumoni-
tis). Furthermore, the amplified risk of ‘‘geographic
miss’’ due to respiratory tumor motion is a challenge
virtually unique to intrathoracic malignancies.
Particularly in locally-advanced disease, the advent of
intensity-modulated radiation therapy (IMRT) increa-
ses the potential for dose-escalation while sparing
organs at risk (OARs), but requires advanced technol-
ogies to account for respiratory tumor motion such as
four-dimensional computed tomography (4D-CT) and
is ideally administered using online 3D-image-guid-
ance for proper targeting and margin reduction.
In this chapter, we discuss technological advances
beyond 3D-CRT, particularly IMRT, intensity-modu-
lated arc therapy (IMAT), and volumetric-modulated
arc therapy (VMAT) and treatment planning, toxicity,
and clinical outcomes associated with these modalities.
2 Technical Aspects
2.1 Beam Modification
Upon exiting a treatment machine, beam modification
occurs by many methods for different purposes.
Custom blocks (e.g. historically lead or cerrobend)
shape beams for target conformality a job now most
commonly replaced by multi-leaf collimators (MLCs)
Intensity-Modulated Radiation Therapy and Volumetric-Modulated Arc Therapy for Lung Cancer
Fig. 1 A close-up photo of MLC leaves looking up into the
collimator head (Copyright  2010, Varian Systems, Inc. All
rights reserved.)
(Figs. 1, 2), which make IMRT possible. Flattening
filters improve dose homogeneity from central axis to
block edge. Wedges confer a linear gradient of dose
fluence across a beam in a single direction, whereas
physical compensators manipulate dose intensity in
two dimensions. Irradiation with wedges and/or
compensators is IMRT in its simplest form, radiation
with heterogeneous dose fluence across the beam.
Although no universally-accepted definition of
IMRT exists, Bortfield described IMRT in practice as ‘‘a
radiation treatment technique with multiple beams, in
which at least some of the beams are intensity-modu-
lated and intentionally deliver a non-uniform intensity to
the target. The desired dose distribution in the target is
achieved after superimposing such beams from different
directions. The additional degrees of freedom are
utilized to achieve a better target dose conformity and/or
better sparing of critical structures (Bortfield 2006).’’
2.2 Three-Dimensional Conformal
Radiation Therapy
Three-dimensional treatment planning became possi-
ble with the advent of computed tomography in the
1970s and the routine availability of computers in the
1980s. With 3D-planning, target volumes and organs
at risk (OARs) can be well-defined; and beam shapes,
directions, and energy levels can be appropriately
selected to give rise to increased conformity,
decreased margins, and target dose-escalation with
increased sparing of normal tissue. In practice,
3D-CRT implies that for each given beam angle, only
a single beam shape modifier (e.g. a cerrobend block
693
Fig. 2 An MLC portal outline (beams-eye view) as shown on
a computer display. This MLC is a tertiary system. The position
of the secondary jaws is shown. There are locations where the
leaves overlap the desired treatment outline and other spots
where they under lap producing a ‘‘scalloped’’ contour. The leaf
width is 1.0 cm projected to isocenter. Varian SHAPER
program software (Copyright  2010, Varian Medical Systems,
Inc. All rights reserved.)
or a single MLC portal) is allowed for each beam
position. If, for example, three different blocks (beam
shapes) were used at a single beam angle, the integral
dose fluence from the three beams would create a map
of variable dose fluence (Fig. 3) (McDermott and
Orton 2010), resulting in an individual IMRT beam.
2.3 Intensity-Modulated Radiation
Therapy
In practice, manually cutting blocks for multiple
beam segments and angles, then—in turn—manually
placing each block for each segment would require
great time, manual effort, and substantial potential for
error. The advent of computer-generated and manip-
ulated MLCs (Figs. 1, 2) is what made IMRT1
1
For the purposes of this chapter, the abbreviation ‘‘IMRT’’ by
default will refer only to fixed-field IMRT, whereby intensity-
modulated beams are delivered from multiple discrete, fixed
angles (using segmental or dynamic MLCs) without any gantry
rotation during beam-on time, thus excluding techniques such
as tomotherapy, IMAT, VMAT, etc. The unabbreviated term
‘‘intensity-modulated radiation therapy’’ may, however, confer
a broader connotation.
694
Fig. 3 Left intensity map of an IMRT beam superimposed on a
patient digital reconstructed radiograph (DRR). Right radiation-
induced epilation on the patient’s scalp from corresponding
Fig. 4 An intensity map
showing an IMRT beam with
1 cm 9 1 cm beamlets with
ten different greyscale
intensity levels (white less
intense, dark more intense)
(From McDermott and Orton,
color plate 17, The physics
and technology of radiation
therapy,  2010)
practical and logistically feasible, allowing large
numbers of ‘‘segments’’ (‘‘apertures’’). In segmental
IMRT, the most common form, the beam turns off
whenever the MLCs are in motion and is on only
when the MLCs are stationary, forming a static portal.
The initial beam segment for a given beam position
may be the ‘‘open-field’’ (e.g. which might be used for
a 3D-conformal plan). An electronic portal imaging
device (EPID) routinely takes a beam’s-eye-view
image through this segment for target verification.
Multiple ‘‘subportal’’ beams, with variable weights
are used to modify the initially-delivered open-field
beam. The resultant ‘‘IMRT beam’’ represents the
summation of dose from all beam segments (the open-
and sub-portals). The IMRT beam is therefore a series
of ‘‘beamlets,’’ with each beamlet providing a
different discrete intensity. At risk of oversimplifica-
tion, whereas a 3D-CRT beam represents a true
‘‘black and white’’ image (e.g. a beamlet is either
blocked or unblocked), the IMRT beam permits many
shades of gray (Figs. 4, 5). Such heterogeneous beam
I. S. Grills and V. S. Mangona
IMRT beam intensity (left) (From McDermott and Orton, color
plate 18, The physics and technology of radiation therapy, 
2010)
intensities delivered through multiple beam angles
allows dose-escalation to target volumes and sub-
volumes (e.g. simultaneous integrated boost), organ
sparing, and ultimately, ‘‘dose painting’’ (Figs. 6, 7)
superior to 3D-CRT (Brahme 1988).
2.4 Intensity-Modulated Arc Therapy
Yu et al. at William Beaumont Hospital first intro-
duced intensity-modulated arc therapy2 (IMAT) in
1995. This was a rotational radiation therapy delivery
technique in which the field shape changed dynami-
cally as the linear accelerator gantry rotated.
Gantry rotational speed and dose rate were constant
2
Notably, distinctions for IMAT and VMAT are not univer-
sally agreed upon. The term ‘‘arc therapy’’ will refer both to
IMAT and VMAT. As the term ‘‘VMAT’’ corresponds to
technological advances of IMAT, Yu et al. refer to VMAT
expressly as IMAT. Further, VMAT technology has been
trademarked with Elekta (VMATTM), Varian (RapidArcTM),
and Philips (SmartArcTM) and has also been referred to as
‘‘arc-modulated radiation therapy’’ (AMRT). Here forward, the
terms ‘‘volumetric-modulated arc therapy’’ and ‘‘VMAT’’ will
refer generically to the advanced IMAT technology inclusive of
variable gantry velocity and variable dose rate and exclusive of
arc therapy delivered with uniform dose rate and uniform
gantry velocity, which will be referred to as intensity-modu-
lated arc therapy or ‘‘IMAT.’’ Furthermore, tomotherapy will
be considered its own modality (not to be incorporated by
default with the terms ‘‘IMRT,’’ ‘‘arc therapy,’’ ‘‘IMAT,’’
or ‘‘VMAT.’’
Intensity-Modulated Radiation Therapy and Volumetric-Modulated Arc Therapy for Lung Cancer
Fig. 5 Comparison of conventional RT to IMRT. Three beams
are used to treat a target with an irregular shape. In the
conventional treatment (upper), the jaws are used to shape
the beams to correspond to the beam’s-eye-view shape of the
target. The resulting dose distribution is shown as homogenous
shading (upper-right). With IMRT (lower), the beam is
modulated in an attempt to reduce the dose to the ‘‘nooks and
crannies’’ representative of normal tissue. The resulting heter-
ogeneous dose distribution (lower-right) shows dose reduction
in these regions (From McDermott and Orton, Fig. 20.3, The
physics and technology of radiation therapy,  2010)
Fig. 6 The dose distribution in a geometric phantom (square
slabs in virtual water) illustrating the power of IMRT. Seven-
gantry angles and five intensity levels were used. The target
is the red annulus encompassing a cylindrical organ at risk
(e.g. spinal cord). The 100% isodose line wraps tightly around
both the inside and outside of the annulus giving high
conformity. Dose within the target, however, is quite hetero-
geneous with maximum dose of 148% the prescribed dose
(From McDermott and Orton, color plate 19, The physics and
technology of radiation therapy,  2010)
throughout treatment delivery. Multiple arcs with
varying field shapes created an intensity-modulated
arc. For treatment planning, arcs were planned using
set control points: IMRT beams at incremental angles
695
Fig. 7 The dose distribution in a geometric phantom with
three targets. The targets (red) are cylinders with axes
perpendicular to the page. A seven-field IMRT plan revealed
high conformity with only a single isocenter (intersection of
crosshairs). The maximum dose within the target is 115% the
prescribed dose (From McDermott and Orton, color plate 20,
The physics and technology of radiation therapy,  2010)
(Yu 1995; Yu et al. 1995). IMAT did not achieve
widespread use for several reasons: the arc sequenc-
ing was a lengthy process; accurate delivery was
inefficient with complex fields—often multiple
superimposed arcs were necessary—and available
computer power and memory at the time were inad-
equate for dose calculations at a fine resolution;
further, support from linear accelerator control soft-
ware was lacking (Otto 2008; Ramsey et al. 2001).
Achievable dose distributions, however, were con-
sidered comparable to helical tomotherapy while
using a standard linear accelerator (Cao et al. 2007).
2.5 Volumetric-Modulated Arc Therapy
In pursuit of single-arc IMAT plans with ideal plan
quality, Otto developed an algorithm that allowed for
a variable dose rate during arc delivery referred to as
VMAT2 (Otto 2008). Industrial advances allowed the
development of VMAT as a more dynamic radiation
delivery method. Similar to IMAT, the beam is on
during rotation of a standard linear accelerator gantry.
However, the dose rate, rotational gantry speed, MLC
position, and collimator angle, are all dynamically-
modulated during RT delivery. Thus highly confor-
mal treatment plans could be delivered in single to
multiple arcs. With VMAT, radiation treatment times
can average only 1.5–3 min/2 Gy fraction, substan-
tially lower than required for similarly complex
IMRT plans (Otto 2008). Though VMAT may be
696
planned as a near-to-full single rotation (e.g.
340–360) (Otto 2008; Scorsetti et al. 2010; Wolff
et al. 2009; Guckenberger et al. 2009; Clark et al.
2010; Ong et al. 2010), it can also be delivered as a
partial arc (e.g. 180) (Matuszak et al. 2010; McGrath
et al. 2010), dual (back-and-forth) partial arcs (Holt
et al. 2011), a full ? partial arc (Wolff et al. 2009),
and multiple arcs, both coplanar and non-coplanar
(Guckenberger et al. 2009; Clark et al. 2010). The use
of multiple arcs can provide further intensity modu-
lation or allow for more optimal normal tissue sparing
and avoid spreading low dose unnecessarily to other
areas of the body. The development of IMAT and its
progression to VMAT are well described in a review
by Yu and Tang (2011).
3 Potential Advantages of
Intensity-Modulated Radiation
Therapy and Volumetric-
Modulated Arc Therapy:
Dose-Escalation and Toxicity
Reduction
3.1 Intensity-Modulated Radiation
Therapy versus Three-Dimensional
Conformal Radiotherapy
As compared to 3D-CRT, IMRT has many inherent
potentially advantageous qualities. With heterogeneous
beam intensities, tumor heterogeneity can be increased,
allowing a higher maximum dose in the target as well as
sharper dose fall-off close to critical OARs leading to
normal tissue sparing (lung, esophagus, spinal cord,
etc.). Schwarz et al. (2005) showed that for large con-
cave tumors treated with IMRT the average dose
increase was as high as 35% compared to 3D-CRT. The
ability to spare cylindrical structures is well illustrated in
Fig. 6. Figure 7 illustrates the conformity to multiple
targets while using a single isocenter, a common sce-
nario in LA-NSCLC, where tumor and nodal gross
tumor volumes (GTVs) may be disjointed.
3.2 Intensity-Modulated Radiation
Therapy Planning Studies
In comparison to 3D-CRT, Liu et al. (2004) showed
that nine-field IMRT plans decreased mean lung dose
I. S. Grills and V. S. Mangona
(MLD) by 2 Gy and amount of lung receiving 20 Gy
(lung V20) by 8%. Grills et al. (2003) performed a
systematic planning analysis comparing IMRT to two
3D-CRT techniques: (1) optimized (numerous-field)
3D-CRT and (2) traditional limited-field (e.g. 2–3
beams) 3D-CRT. This study showed significant ben-
efit with IMRT, particularly in node-positive patients
and those with target volumes close to the esophagus.
With higher mean target doses secondary to IMRT
dose heterogeneity, tumor control probability (TCP)
was increased by 7–8%, whereas lung V20, lung
NTCP (normal tissue complication probability), and
esophagus NTCP were reduced by approximately 15,
30, and 55%, respectively. For GTVs within 1.5 cm
of the esophagus, IMRT reduced esophagus V50 by
40%. IMRT plans allowed for dose-escalation by
25–30% beyond that of comparably safe 3D-CRT
plans. A comparison of 3D-CRT to IMRT with
respect to critical organ dose for various planning
studies is included in Table 1.
3.3 Toxicity and Intensity-Modulated
Radiation Therapy
Sura et al. (2008) published the largest known toxicity
and outcome study of patients with NSCLC treated
exclusively with IMRT. This retrospective analysis
included 55 patients with inoperable stage I–II
(n = 16) and III (n = 39) NSCLC from 2001 to 2005
treated with 60 Gy in 2 Gy fractions at MSKCC.
Toxicity was scored using a modified RTOG toxicity
scoring system (Cox et al. 1995). The overall crude
rate of any pulmonary toxicity was 13%. Acute and
late (C4 months after RT start) toxicities are seen in
Table 2. Acute grade 1–2 esophagitis was common
(69%), but grade 3 rare (4%). All late esophageal
toxicity was grade 1–2 and occurred in 22% of
patients. Grade 2 or higher acute pulmonary toxicity
rates were 18% grade 2, 11% grade 3, and 0% grade
4–5. One patient had late grade 3 pulmonary toxicity,
and one died (grade 5 toxicity) secondary to treat-
ment-related pneumonitis (TRP) (Sura et al. 2008).
3.3.1 Sparing the Esophagus
The predominant increase in acute toxicity with
concurrent over sequential chemoradiotherapy for
locally advanced NSCLC is esophagitis, which can
ultimately become dose-limiting (Schwarz et al.
Intensity-Modulated Radiation Therapy and Volumetric-Modulated Arc Therapy for Lung Cancer 697

Table 1 Comparison of median/mean dose to organs at risk: 3D-CRT versus IMRT and VMAT
Organ Study N Patients Parameters 3D- IMRT VMAT Difference P
CRT
Spinal Bedford and 10 NR Dmax 10 Gy – 9 Gy -0.5 Gy NS
cord Warrington (2009)
Grills et al. (2003)a 9 N0 Dmax+3 mm 24 Gy 30 Gy – +5.6 Gy –
Grills et al. (2003)a 9 N2–N3 Dmax+3 mm 41 Gy 41 Gy – -0.6 Gy –
b
Lievens et al. (2011) 35 N2–N3 Dmax 47 Gy 45 Gy – -2.5 Gy –
Ong et al. (2010) 18 I Dmax 8 Gy – 11 Gy +2.9 Gy 0.014
Lungs Lievens et al. (2011) 35 N2–N3 V5 55% 45% – -10% \0.0001
Liu et al. (2004) 10 I–IIIB V5 NR NR – +8.0% 0.007
c c
McGrath et al. (2010) 21 I V5 NR – NR 4.2% RR 0.03
Murshed et al. (2004) 41 III–IV V5 52% 59% – +7% NS
d
Ong et al. (2010) 18 I V5 18% – 18% +0.2% NS
Bedford and 10 NR V10 40% – 34% –5.6% 0.03
Warrington (2009)
Liu et al. (2004) 10 I–IIIB V10 NR NR – –1.6% NS
c c
McGrath et al. (2010) 21 I V10 NR – NR 2.6% RR 0.01
Murshed et al. (2004) 41 III–IV V10 45% 38% – –7% \0.0001
McGrath et al. (2010)c 21 I V12.5 NR – NR 3.2% RRc 0.01
Bedford and 10 NR V20 21% – 24% +2.6% 0.02
Warrington (2009)
Grills et al. (2003)a 9 N0 V20 22% 19% – -2.8% –
a
Grills et al. (2003) 9 N2–N3 V20 29% 26% – -3.2% –
Lievens et al. (2011) 35 N2–N3 V20 28% 27% – -1.2% 0.06
Liu et al. (2004) 10 I–IIIB V20 NR NR – -8.0% 0.005
McGrath et al. (2010)c 21 I V20 NR – NR 4.5% RRc 0.02
Murshed et al. (2004) 41 III–IV V20 35% 25% – -10% \0.0001
Ong et al. (2010)d 18 I V20 4.9% – 5.4% +0.5% 0.025
Liu et al. (2004) 10 I–IIIB V30 NR NR – -8.9% 0.005
Liu et al. (2004) 10 I–IIIB Veff NR NR – -9.0% 0.005
Murshed et al. (2004) 41 III–IV Veff 71 Gy 58 Gy – -13 Gy \0.0001
Bedford and 10 NR MLD 14 Gy – 14 Gy +0.1 Gy NS
Warrington (2009)
Grills et al. (2003)a 9 N0 MLD 13 Gy 12 Gy – -1.8 Gy –
Grills et al. (2003)a 9 N2–N3 MLD 18 Gy 16 Gy – -1.8 Gy –
Liu et al. (2004) 10 I–IIIB MLD NR NR – -2.0 Gy 0.005
Murshed et al. (2004) 41 III–IV MLD 19 Gy 17 Gy – -2 Gy \0.0001
Lievens et al. (2011) 35 N2–N3 MLD 16 Gy 16 Gy – +0.1 Gy NS
Murshed et al. (2004) 41 III–IV Integral lung 19 Gy 16 Gy – -3 Gy \0.0001
dose
Grills et al. (2003)a 9 N0 NTCP 12% 11% – +1.1% –
a
Grills et al. (2003) 9 N2–N3 NTCP 21% 17% – -3.6% –
(continued)
698 I. S. Grills and V. S. Mangona

Table 1 (continued)
Organ Study N Patients Parameters 3D- IMRT VMAT Difference P
CRT
Esophagus Grills et al. (2003)a 9 N0 V50 5% 6% – +0.6% –
a
Grills et al. (2003) 9 N2–N3 V50 26% 19% – -7.6% –
Grills et al. (2003)a 9 N0 Mean dose 12 Gy 12 Gy – -0.2 Gy –
Grills et al. (2003)a 9 N2–N3 Mean dose 27 Gy 24 Gy – -2.9 Gy –
Lievens et al. (2011) 35 N2–N3 Dmax 93 Gy 79 Gy – -14 Gy \0.0001
Grills et al. (2003)a 9 N0 Dmax+3 mm 46 Gy 43 Gy – -3.4 Gy –
Grills et al. (2003)a 9 N2–N3 Dmax+3 mm 76 Gy 74 Gy – -1.6 Gy –
a
Grills 2003(2003) 9 N0 NTCP 5.2% 2.2% – -3.0% –
Grills et al. (2003)a 9 N2–N3 NTCP 41% 19% – -22% –
Heart Bedford and 10 NR Mean dose 9.9 Gy – 9.4 Gy NS –
Warrington (2009)
Grills et al. (2003)a 9 N0 D33 8.9 Gy 9.3 Gy – +0.4 Gy –
a
Grills et al. (2003) 9 N2–N3 D33 19 Gy 20 Gy – +0.8 Gy –
Grills et al. (2003)a 9 N0 D67 5.2 Gy 4.4 Gy – -0.8 Gy –
a
Grills et al. (2003) 9 N2–N3 D67 7 Gy 8 Gy – +1.5 Gy –
Grills et al. (2003)a 9 N0 D100 0.3 Gy 0.6 Gy – +0.3 Gy –
Grills et al. (2003)a 9 N2–N3 D100 0.9 Gy 1.6 Gy – +0.7 Gy –
Grills et al. (2003)a 9 N0 NTCP 0.1% 0% – -0.1% –
a
Grills et al. (2003) 9 N2–N3 NTCP 20% 11% – -9% –
3D-CRT 3D-conformal radiation therapy, IMRT intensity-modulated radiation therapy, VMAT volumetric-modulated radiation
therapy, Difference IMRT-3D-CRT or VMAT-3D-CRT, n number of patients, Dmax maximum dose, Veff = biologically effective
volume, +3 mm = volume of organ ? 3 mm expansion, NR not reported data, NS not statistically significant, I, II, III,
IV = AJCC stage, N nodal staging
a
Both plans with equivalent tumor control probability for PTVGTV. Lung dose calculations exclude gross tumor volume (GTV)
b
Liu 2004-both plans with dose-escalation with calculations using pencil-beam algorithm
c
Only VMAT relative (not absolute) reduction reported in this study. All variables were lower with VMAT in comparison
to 3D-CRT
d
Lung volume excludes planning treatment volume (PTV)

Table 2 Rate of early (\4 mos) and late (C4 mos) reactions in patients treated with IMRT (adapted from Sura et al. 2008)
Grade 0 (%) Grade 1 (%) Grade 2 (%) Grade 3 (%) Grades 4–5 (%)
Esophageal Early 27 47 22 4 –
Late 78 16 6 – –
Pulmonary Early 4 67 18 11 –
Late 23 57 16 2 –
Fatigue Early 18 49 31 – –
Nausea Early 73 22 6 – –
Cardiac Early 98 – – 2 –
Skin Early 45 44 7 4 –
Toxicity was scored using a modified RTOG toxicity scoring system (Cox et al. 1995)
Intensity-Modulated Radiation Therapy and Volumetric-Modulated Arc Therapy for Lung Cancer
2005; Liu et al. 2004; Grills et al. 2003; Chapet et al.
2005; Murshed et al. 2004). With twice-daily hyper-
fractionated regimens, severe acute esophageal tox-
icity can be as high as 40 to 60% (Werner-Wasik et al.
1999; Choy et al. 1998; Lau et al. 2001). In NSCLC
patients treated with either 3D-CRT or IMRT,
Shaitelman et al. (2009) found esophagitis to be lin-
early related to esophagus V10/20/30/40/50/55, mean
dose, and maximum dose. The strongest predictors of
grade C2 esophageal toxicity were esophagus
V10 [65% and esophagus Dmax (maximum dos-
e)[55 Gy. Multiple studies have shown the potential
for esophageal dose reduction with IMRT over
3D-CRT (Liu et al. 2004; Grills et al. 2003; Murshed
et al. 2004; Lievens et al. 2011). One of the planning
challenges in advanced stage NSCLC is the potential
for overlap of the planning target volume for tumor or
nodes with the esophagus. Chapet et al. (2005, 2006)
have shown that by relaxing homogeneity constraints
and using equivalent uniform dose (EUD) calcula-
tions, the planning target volume (PTV) excluding the
esophagus can be dosed to higher levels with potential
for better tumor control without increasing esophagus
NTCP. Similarly, IMRT has been used to boost PET-
positive disease using simultaneous integrated boost
(SIB) to doses 22% higher without significant change
in toxicity (Rebueno and Welsh 2009).
3.3.2 Pneumonitis: Worse with Intensity-
Modulated Radiation Therapy?
Although IMRT has numerous potential advantages
over 3D-CRT for NSCLC, IMRT plans require more
monitor units (MUs) per treatment and thus have risks
associated with increased total body exposure. Longer
treatment times may further increase the potential for
intrafraction variation. In the treatment of intratho-
racic malignancies, a significant concern is the
potential for increased lung toxicity—in comparison
to 3D-CRT—from spreading low dose throughout a
larger volume of normal lung. Reduced diffusing
capacity of carbon monoxide (DLCO) has been seen
in volumes of lung receiving C13 Gy (Gopal et al.
2003). Many studies have also consistently reported
the correlation between lung dose and TRP (Willner
et al. 2003; Fay et al. 2005; Schallenkamp et al. 2007;
Shi et al. 2010; Yom et al. 2007; Wang et al. 2006). In
a 3D-CRT dose-escalation study, high-grade TRP was
related to low-dose lung RT volumes: V5, V10, and V13
(Yorke et al. 2005). Schallenkamp et al. (2007) found
699
V10 and V13 to be most predictive of TRP (V5 was not
analyzed). Beaumont data further note V5 (cutoff
50%) and V10 (cutoff 45%) as the strongest predictors
for grade C3 pneumonitis (Shaitelman et al. 2009).
Wang’s multivariate analysis of 223 patients treated
with concurrent chemo radiation further support V5 as
the strongest predictor of TRP (cutoff 42%) (Wang
et al. 2006).
Yom et al. evaluated such parameters in patients
treated with IMRT (n = 68) as well as 3D-CRT
(n = 222) at MD Anderson, particularly predictors of
grade C3 TRP with LA-NSCLC receiving concurrent
chemotherapy. This study revealed a fourfold
decrease in TRP with IMRT over 3D-CRT (8 vs.
32%, P = 0.002). IMRT plans had higher V5 (63 vs.
57%, P = 0.011), similar V10 (48 vs. 49%, P = 0.87),
and decreased V15, V20…, V65 (P \ 0.05). The
12-month incidence of TRP for IMRT-treated patients
was significantly less with V5 B 70% (2 vs. 21%,
P = 0.02), suggesting a potential V5 threshold of
70 Gy (Yom et al. 2007). Interestingly, however, the
overall rates of TRP were lower with IMRT than with
3D-CRT despite higher V5 in the IMRT group, sug-
gesting that other factors may play a significant role in
determining risk for TRP in irradiated patients.
Shi et al. (2010) further expounded upon Yom’s
work, performing univariate and multivariate analyses
on 94 consecutive patients (11 who developed TRP)
treated with concurrent chemotherapy and IMRT.
Univariate analysis showed that COPD, FEV1, MLD,
lung NTCP, and lung V5–60 were all related to TRP.
Multivariate analysis revealed lung NTCP (cutoff
4.2%) and V10 (cutoff 50%) most significantly
associated with TRP.
3.3.3 Reducing Low Dose to Large Volume
With the increased low dose to larger lung volumes
with IMRT, attempts have been made to reduce low-
dose volumes, such as ‘‘hybrid-IMRT’’—whereby
static and IMRT treatments are used to decrease
contralateral lung V5, V13, and V20 (Mayo et al. 2008).
Restricting IMRT plans to five or fewer beams has
also been associated with reduction of low-dose vol-
umes (e.g. V5 and V10) (Liu et al. 2004). Three, five,
and seven-beam arrangements have been shown to
have similar MLD, V13, V20, and V30 (Chapet et al.
2006). A similar study, using beam angle optimiza-
tion to balance beam angle preference for both
tumor and lung, showed that five- and seven-beam
700
Fig. 8 Left ten-field non-coplanar beam 3D-CRT plan for SBRT. Right corresponding 1808 VMAT plan
angle-optimized plans achieved dose plans similar to
equispaced nine-field plans but with less MUs deliv-
ered (Liu et al. 2006). Further, all IMRT plans had
reduced V5, V10, V20, and MLD in comparison to
comparable 3D-CRT plans (Liu et al. 2006).
3.4 Volumetric-Modulated Arc Therapy
Experience
Toxicity and outcome data with IMAT and VMAT
techniques is notably sparse at the time of this writ-
ing. Bedford et al. (2008) reported treatment of one
patient with NSCLC treated to 50 Gy with single-arc
VMAT. Compared to a created 3D-CRT plan, the
VMAT plan had decreased lung V20 (31.5 vs. 34.8%),
MUs (271 vs. 377), treatment time (90 vs. 180 s), and
improved minimum PTV dose. In a later publication,
Bedford and Warrington (2009) used VMAT to replan
ten NSCLC patients originally treated to 65 Gy with
3D-CRT. Single-arc plans were created spanning
3408 at 108 intervals. Results are included in Table 1.
Notably, VMAT plans reduced lung V10, though PTV
coverage (93 vs. 91%, P = 0.1) and lung V20 were
slightly inferior (Bedford and Warrington 2009).
Scorsetti et al. (2010) reported a series of 24
consecutive patients with inoperable, stage III
NSCLC treated with 66 Gy using VMAT with two
partial arcs, avoiding entry through the contralateral
lung. These plans had excellent PTV coverage (PTV
D99 = 97 ± 2%) and met most planning objectives.
I. S. Grills and V. S. Mangona
Median follow-up was 6 months, in which time ten
(42%) had developed persistent cough requiring
medication and six (25%) developed grade 1–2
‘‘asymptomatic pneumonia.’’ There were no grade C3
adverse reported. Treatment time was 133 ± 7 s
(Scorsetti et al. 2010).
McGrath et al. recently reported on the utility of
VMAT for SBRT. In this study, 21 patients previ-
ously treated with non-coplanar 3D-CRT were
r-planned with a 1808 VMAT hemi-arc (Fig. 8),
oriented to avoid contralateral lung. VMAT improved
conformity (Table 3; Fig. 9) and decreased lung V5,
V10, V12.5, V20 (Table 1) with equivalent PTV cover-
age. Although VMAT plans resulted in marginal
increases in MUs compared to single-segment DMPO
plans (5.6%, P = 0.04), the treatment time was
markedly reduced (6 vs. 12 min, P \ 0.01) (McGrath
et al. 2010). A similar planning study from the
Netherlands showed that back-and-forth partial-arc
VMAT plans are comparable to non-coplanar limited-
segment IMRT for delivery of SBRT but require
significantly less treatment time, 6.5 vs. 23.7 min for
a single 18 Gy fraction (Holt et al. 2011).
4 Treatment Planning
Although the evolution away from elective nodal
irradiation to targeting only gross disease (tumor plus
involved lymph nodes) has been slow, it is now the
accepted standard of care for definitive management
Intensity-Modulated Radiation Therapy and Volumetric-Modulated Arc Therapy for Lung Cancer 701

Table 3 Conformity comparison: 3D-CRT versus IMRT and VMAT

Study Parameters 3D-CRT IMRT VMAT P
Liu et al. (2006) CI 100% 1.5 1.3a – –
McGrath et al. (2010) CI 95% 1.25 – 1.23 NS
McGrath et al. (2010) CI 80% 1.93 – 1.87 0.08
Ong et al. (2010) CI 80% 1.18 – 1.10 0.001
Ong et al. (2010) CI 60% 2.30 – 2.11 0.001
McGrath et al. (2010) CI 50% 5.65 – 5.19 0.01
Ong et al. (2010) CI 40% 4.86 – 5.00 NS
CI conformity index, CI x% = volume of x% isodose/PTV volume, NS not statistically significant
a
Using optimized seven-field IMRT

Fig. 9 Axial isodose comparison: 3D-CRT (left) versus VMAT (right). The VMAT plan (right) reveals improved conformity at
lower isodose lines

in NSCLC. IMRT allows the potential for further
dose-escalation to the target and is now permitted in
national cooperative group research protocols. RTOG
Protocol 0617 (ongoing) is the first RTOG protocol
permitting IMRT delivery. In this two-by-two phase
III randomized trial for stage IIIA–B NSCLC,
RT to either 60 Gy (standard arm) versus 74 Gy
(dose-escalated arm) is given concurrently with car-
boplatin/paclitaxel ± cetuximab followed by further
chemotherapy (Bradley et al. 2007).
4.1 Simulation
At our institution, patients are simulated supine in an
alpha cradle, arms above head using 4D-CT with
3 mm slices from the neck through the liver. Ten CT
phases are populated to correspond to different phases
of a complete respiratory cycle. CT-PET fusion—
ideally with the patient in the treatment position for
PET—is used in all cases for tumor and nodal target
volume delineation. As treatment delay can lead to
disease progression, if a staging PET has not been
performed within 6–8 weeks of treatment planning,
the PET is generally repeated for re-staging and
planning purposes (Mohammed et al. 2011a).
Although respiratory-gating and breath-hold strat-
egies may be preferential to an adaptive image-
guidance strategy in a capable patient, the superiority
likely holds clinical relevance if tumor excursion is
approximately 1.4 cm or greater (Hugo et al. 2007a),
quite rare in our experience. Furthermore, 4D-inverse
planning has resulted in plans comparable to real-time
target tracking methods (Zhang et al. 2008). Gating
or breath-hold strategies are not routinely employed
in our clinic. We do routinely assess for benefit of
702
abdominal compression in patients treated with
SBRT, though it has rarely been implemented due to
lack of observable benefit upon comparing 4D-CT
with and without abdominal compression in these
patients. Thus, we have favored free-breathing treat-
ment utilizing an ‘‘internal target volume’’ (ITV)
approach to account for tumor motion and have
implemented online image-guidance to decrease
planning treatment volumes. Treatment planning is
performed on the average phase CT scan, which
closely corresponds to the mean tumor position at the
time of online cone-beam CT soft tissue registration
(Hugo et al. 2007b).
4.2 Target Volumes (Gross Tumor
Volume, Clinical Target Volume,
Planning Target Volume)
As per the RTOG 0617 protocol, the gross tumor
volume (GTV) includes both primary tumor and
clinically positive lymph nodes (short axis [1 cm on
CT or PET SUV[3), but no elective nodal irradation.
If using an ITV approach to account for tumor
motion, the GTVITV is defined as the volume
encompassing the gross tumor throughout a complete
respiratory cycle. The clinical target volume (CTV)
includes an expansion from GTV to account for
microscopic extension, defined as a 0.5–1.0 cm
expansion of the entire GTV (or GTVITV) (Bradley
et al. 2007).
At Beaumont, as done on our in-house protocol for
LA-NSCLC, two separate GTV volumes are con-
toured on the maximal inspiration phase (phase 0%):
GTVprimary (the primary tumor) on lung windows and
GTVnodal (inclusive of clinically positive regional
lymph nodes) on mediastinal windows. The GTV is
contoured on a single phase of the respiratory cycle,
then propagated to the remaining nine phases fol-
lowed by physician verification of auto-propagations.
The union of the GTVprimary from all ten phases
constitutes the GTVITV-primary. As per our in-house
protocol guidelines, lymph nodes C2.0 cm (long axis)
on CT or 1.0–1.9 cm (long axis) with increased FDG
uptake are always included in GTVnodal. Non-FDG-
avid, subcentimeter lymph nodes are always exclu-
ded. Inclusion of FDG-avid subcentimeter lymph
nodes and non-FDG-avid 1.0–1.9 cm lymph nodes is
left to the treating physician’s discretion. To account
I. S. Grills and V. S. Mangona
for tumor microscopic extension, a 0.5–0.8 cm
(typically 0.5 cm) 3D-CTV margin (excluding bony
anatomy) is added to GTVITV-primary, creating a
CTVITV. Notably, a pathologic study of T1N0 ade-
nocarcinomas suggests a margin as small as 1.2 mm
from GTV (on lung windows) to CTV may be suffi-
cient for typical cases, but a 9 mm margin may be
required to cover 90% of tumors (Grills et al. 2007).
No CTV margin is added to the nodal GTV
(CTVnodal = GTVnodal). Similar to RTOG 0617, we
do not use elective nodal irradiation. For SBRT cases,
we use a smaller CTV expansion, 0.3–0.5 cm, given
the high-dose penumbra in such treatments (Grills
et al. 2007).
The planning target volume (PTV) accounts both
for internal tumor motion as well as setup error.
Various methods to account for tumor motion include
(1) an ITV approach, (2) a maximal intensity pro-
jection (MIP) approach, (3) automatic breath-hold, (4)
respiratory gating, and (5) fluoroscopy. RTOG 0617
recommends fluoroscopy to assess maximal respira-
tory excursion when 4D-CT is not available. With the
various approaches to account for tumor motion,
RTOG 0617 defines minimum CTV-to-PTV expan-
sions as small as 0.5 cm in all directions—with daily
bony registration and ITV planning—and up to
1.5 cm (superior–inferior) and 1.0 cm (axial) for
free-breathing (non-ITV) plans (Table 4).
4.3 Inverse Planning
As compared to conventional 3D-CRT, which is
forward-planned by choosing a beam angle/weight
and aperture size, IMRT is inversely planned by
providing the treatment planning computer with a
series of objectives and constraints for normal tissues
and target, subsequently allowing the computer to
generate segment apertures and weights and beam
weights that provide the ideal fluence map for a given
plan. Older IMRT planning systems required creation
of this ideal fluence map first followed by generation
of deliverable segments as a second step. More
modern software, however, allows for direct machine
parameter optimization (DMPO), where the genera-
tion of a fluence map and segments are done simul-
taneously considering the predefined constraints of
the treatment machine, substantially shortening the
required time for IMRT planning. Inverse treatment
Intensity-Modulated Radiation Therapy and Volumetric-Modulated Arc Therapy for Lung Cancer 703

Table 4 CTV to PTV expansions: RTOG 0617 (Bradley et al. 2007) and Beaumont methods
RTOG 0617 Beaumont
Free- Breath-hold/ ITV ITV 4D-Adaptive online IGRT
breathing respiratory protocol
gating
No ITV With daily No daily bone With daily With bone or soft (Includes ITV technique
(cm) imaging registration bony tissue registration and bone or soft tissue
(cm) (cm) registration (cm) registration)
(cm)
Superior– C1.5 C1.0 C1.0 C0.5 0.5 Superior: variablea
inferior Motion: Inferior: variablea
C1.0
Setup:
0.5
Axial C1.0 C0.5 C1.0 C0.5 0.5 Anterior: variablea
Posterior: variablea
Motion: Medial: 0.3 cm
C0.5
Setup: Lateral: 0.3 cm
0.5
RTOG radiation therapy oncology group, Motion internal tumor motion, ITV internal target volume, IGRT image-guided radiation
therapy
a
Margin in superior, inferior, anterior, and posterior directions determined according to the adaptive process

planning software takes the prescribed dose distribu-

tion and optimizes a plan by minimizing the ‘‘cost
function,’’ a function that quantifies variance from the
pre-determined dose–volume histogram (DVH)
objectives.
Dose constraints from RTOG 0617 (Bradley et al.
2007) and RTOG 0839 (Edelman et al. 2010) are
seen in Table 5. Although planning the best treat-
ment plan for a particular case inevitably involves
manual iteration, Craft et al. (2007) developed a
technique that generates a database of optimal plans
from which the user may select the plan felt clini-
cally preferential.
For arc therapy planning (either IMAT or
VMAT), MLC positions must be contiguous, and
incremental control points (e.g. every 6) are used
from which interval data can be interpolated.
Multiple inverse planning techniques have now been
developed for both single- and multi-arc treatments,
facilitating VMAT planning and delivery, thereby
allowing this new modality to become adapted into
clinical practice (Otto 2008; Luan et al. 2008; Wang
et al. 2008; Cao et al. 2009). At Beaumont, VMAT
plans are generated with SmartArc, integrated in
Pinnacle3 version 9.
5 Targeting and Verification
5.1 Image-Guided Radiation Therapy
In an effort to accurately target disease, escalate dose,
and spare organs at risk, two main targeting strategies
are routinely implemented: biological targeting with
positron emission tomography (PET) and image-
guidance. New 4D-imaging and planning techniques
further facilitate improvements in radiotherapy
administration. Harsolia et al. compared conventional
3D-CRT plans—using free-breathing planning CT
and fluoroscopy to assess tumor motion—to new 4D-
techniques using combinations of 4D-imaging, 4D-
planning, and image-guided radiation therapy (IGRT)
with oonboard 4D-conebeam CT (4D-CBCT) using
three strategies: (1) 4D-union technique, (2) 4D off-
line adaptive planning with a single correction (offline
adaptive radiotherapy (ART)), and (3) 4D-online
adaptive planning with daily correction (online ART)
(Harsolia et al. 2008). The 4D-union plan used an ITV
technique, defining GTVITV as the union of the GTV
phases with 5 mm expansions for CTV and PTV. The
ART process defines a probability density function
704 I. S. Grills and V. S. Mangona

Table 5 Dose constraints to organs at risk

RTOG 0617 (Bradley et al. 2007) RTOG 0839 (Edelman et al. Beaumont Beaumont
(60 vs. 74 Gy) 2010) (60 Gy) (2.0 Gy/day) (1.5 Gy BID)
Spinal cord Dmax \ 50.5 Gya Dmax \ 50.5 Gya Dmax(+3 mm) B Dmax(+3 mm) B 47
50 Gya Gya
Lungs (Excludes CTV) (Excludes CTV) (Excludes GTV) (Excludes GTV)
V20 \ 37% (or) V20 \ 37% (or) V20 B 30% (and) V18.7 B 30%
(and)
Dmean \ 20 Gy Dmean \ 20 Gy Dmean B 18 Gy Dmean B 17 Gy
b
Esophagus Dmean \ 34 Gy Dmax \ 40 Gy V50 B 30% V47 B 30%
Dmean B 25 Gy Dmean B 23.4 Gy
Dmax(+3 mm) B Dmax(+3 mm) B
75 Gy 70 Gy
Brachial Dmax \ 66 Gy Dmax \ 66 Gy Dmax B 66 Gy Dmax B 63 Gy
plexus
Heart D33 \ 60 Gyc D33 \ 60 Gy V50 B 50% V47 B 50%
D66 \ 45 Gyc D66 \ 45 Gy D33 B 66 Gy D33 B 62 Gy
D100 \ 40 Gyc D100 \ 40 Gy D100 B 40 Gy D100 B 37.5 Gy
BID twice daily fractions, Dmax maximum dose, Dmean mean dose, +3 mm = volume ? 3 mm margin, Vx proportional volume of
the region of interest receiving Cx Gy, Dy dose delivered to y% of the region of interest
a
Required constraint. For RTOG 0839, maximum dose is defined as maximum dose for contiguous volume C0.03 ml
b
constraint is strongly recommended
c
constraint recommended but not required

Table 6 Mean relative reduction compared to standard 3D-CRT plan (adapted from Harsolia et al. 2008)
Parameter 3D- 4D-union 4D-offline ART (single correction) 4D-online ART (daily correction)
CRT (%) (%) (%)
PTV volume – ;15 ;39 ;44
Lungs V20 (%) – ;21 ;23 ;31
Mean lung dose – ;16 ;26 ;31
3D-CRT 3D-conformal radiation therapy, ART adaptive radiation therapy, PTV planning target volume, online ART adaptive with
daily correction, offline ART adaptive plan with a single correction, V20 (%) = % volume of lungs excluding GTV receiving
C20 Gy

(PDF) of tumor position vs. time estimated by fluo-
roscopy and/or 4D-CT or 4D-CBCT to account for
tumor motion and interfraction variability of tumor
location. The offline ART process uses a single
adjustment after the first week of treatment,
accounting for individualized variability assessed
after five fractions. The online ART process used a
daily fluoroscopy-guided correction to account for
daily setup error, thus the PDF still accounted for
respiratory motion, but accounted for less setup error
than with the offline technique, further decreasing
the CTV-to-PTV expansion. IMRT plans decreased
PTV volume, mean lung dose, and lung V20, most
significant with daily online adaptive IGRT (Table 6;
Harsolia et al. 2008).
5.2 Biological Targeting with Positron
Emission Tomography
Since FDA approval of 18-fluorodeoxyglucose posi-
tron emission tomography (18FDG-PET) for staging
lung cancer, its utility has continued to expand
(Coleman and Tesar 1997). PET facilitates biological
targeting and is now used in all phases of radiation
therapy from staging to planning to follow-up. PET
Intensity-Modulated Radiation Therapy and Volumetric-Modulated Arc Therapy for Lung Cancer
has proven its role in NSCLC staging, with greater
sensitivity and accuracy than CT (Dwamena et al.
1999). PET helps define clinically positive lymph
node regions and define tumor extent, complementary
to the anatomic information provided by CT imaging
alone. Studies have shown that PET-to-CT (simula-
tion/planning CT) registration can result in smaller
target volumes secondary to improved GTV definition
but also upstaging, leading to increased target volume
(Giraud et al. 2001; Bradley et al. 2004; Erdi et al.
2002; Mah et al. 2002; Ung et al. 2000). With such
biological targeting afforded by PET, the risk of target
miss can be decreased while facilitating dose-escala-
tion by shrinking treatment volume, two key goals of
IMRT. As PET-CT scanners have become more
routinely available, patients have CT-simulation
immobilized in the treatment position and then pro-
ceed to the planning PET-CT. For planning, the
simulation acts as the primary data set to which the
CT portion of the PET-CT is merged, usually with
bony registration. PET has further been utilized to
assess tumor response to radiation therapy (Moham-
med et al. 2011b) and potentially predict local failure
(Mangona et al. unpublished abstract). Follow-up
PET-CT data from Wong et al. revealed significant
reduction in maximum SUV (standardized uptake
value) and CT size after treatment, with relative
reductions in maximal metabolic uptake greater than
size reduction (62 vs. 47%, P = 0.03) (Wong et al.
2007).
Recently, our SBRT and LA-NSCLC protocols
have implemented weekly on-treatment respiratory-
gated 4D-PET-CT. 4D-PET-CTs are performed
including gated and non-gated sequences 60 and
120 min after injection (early and delayed scans)
including both TOF (time-of-flight) and non-TOF
processing. By assessing early RT-tumor metabolic
response, on-treatment PET may potentially identify
patients who could ultimately benefit from some form
of additional treatment.
5.3 Treatment Verification
With increased conformity, decreased margins, and
intensity-modulation comes increased dependence on
quality assurance. IMRT and VMAT plans require
dosimetric verification prior to delivery (Ezzell et al.
2003). Traditionally, the plan can be delivered to a
705
phantom. Ion chambers and films are used to verify
the dose and spatial dose gradient, respectively.
Alternatively, individual beams can be assessed with
two-dimensional (2D) arrays of diodes such as the
MapcheckTM (Sun Nuclear). Electronic portal imag-
ing devices (EPIDs) serve to create beam’s-eye-view
portal images for user verification of beam position
and treatment setup. More recently, EPID images
have been shown to efficiently carry out the absolute
dosimetry for IMRT quality assurance with the added
benefit of improved spatial resolution lacking in
2D-diode arrays (Nelms et al. 2010). 3D-diode arrays
such as the Delta4 phantom have now come into
utility for quality assurance with IMRT and VMAT
treatments, obtaining accurate 3D-absolute dosimetry
without ionization chambers or film (Bedford and
Young 2009). Online volumetric (3D) pre-treatment
imaging (e.g. with online CBCT registration to the
planning CT) serves as an ideal method for target
verification at the time of treatment. This is particu-
larly important in the case of IMRT or SBRT where
the dose falloff between target and normal tissues is
sharp and the total number of treatment fractions may
be limited.
6 Outcomes
With the routine implementation of IMRT being rel-
atively recent, data from prospective clinical studies
treated with this modality are still maturing (RTOG
0617 is still open to accrual at the time of this writ-
ing). However, IMRT has shown ability to escalate
tumor dose while sparing normal tissue. In the ret-
rospective study from MD Anderson including
patients with LA-NSCLC treated with concurrent
chemoradiotherapy (mean dose 63 Gy), Yom et al.
(2007) analyzed outcomes of the subgroup receiving
IMRT (n = 68). For 6- and 12-month follow-up,
locoregional control (LRC) was 94 and 55%, disease-
free survival (DFS) 67 and 32%, and overall survival
(OS) 79 and 57%, respectively. The median follow-up
was only 8 months.
Sura et al. (2008) similarly reported the MSKCC
experience, including 55 patients with inoperable
stage I–IIIB disease treated with IMRT. The median
follow-up in this study was significantly longer,
21 months. Two-year local control (LC) rates were
50% (stage I–II, n = 16) and 58% (stage III, n = 29).
Table 7 Outcomes in NSCLC treated with IMRT and VMAT
706

Study n Time Patients Dose (Gy) Gpf RT Chemotherapy Follow-up Parameter Outcome
mean/median (Gy) Type median
(range) (range)
MSKCC (Sura 55 2001–2005 Inoperable 69.5 (60–90) 1.8–2.0 IMRT Sequential 21 months Local Control 2 year: 50%
et al. 2008) Stage (53%) (0–61) (Stage I–II)
I–IIIB Concurrent 2 year: 58%
(24%) (Stage III)
MD Anderson 68 2002–2005 Stage 63 (50.4–76) 1.8–2.0 IMRT Induction 8 months Locoregional Control 6 months:
(Yom et al. 2007) IIB–IV (29%) (0–27) 94%
Concurrent 12 months:
(100%) 55%
Belgium (Bral 40 2005–2008 Inoperable 70.5 (all) 2.35 Helical Sequential 14 monthsa LPFS 1 year: 66%
et al. 2010) Stage IIIa TT (82%)
Concurrent 2 year: 50%
(0%)
None (18%)
Milan (Scorsetti 24 2009 Inoperable 66 (50–66) 2.0 VMAT Concurrent 6 months Response at 3 months PR [ 50%:
et al. 2010) Stage III (46%) (RECIST(Therasse et al. 56%
Sequential 2000)) PR \ 50%:
(33%) 22%
None (21%) Stable
disease: 22%
Disease
progression:
0%
Beaumont 17 2008–2010 Stage III 66 (66–72, 54 1.5 IMRT Concurrent 12 months LR 1 year: 6%
(abstract) (McGee preoperative) BID (100%)
et al. 2010)
Beaumont 17 2008–2010 Stage III 66 (66–72, 54 1.5 IMRT Concurrent 12 months RR 1 year: 30%
(abstract) (McGee preoperative) BID (100%)
et al. 2010)
Beaumont 17 2008–2010 Stage III 66 (66–72, 54 1.5 IMRT Concurrent 12 months DM 1 year: 31%
(abstract) (McGee preoperative) BID (100%)
et al. 2010)
(continued)
I. S. Grills and V. S. Mangona
Table 7 (continued)
Study n Time Patients Dose (Gy) Gpf RT Chemotherapy Follow-up Parameter Outcome
mean/median (Gy) Type median
(range) (range)
Belgium (Bral 40 2005-2008 Inoperable 70.5 (all) 2.35 Helical Sequential 14 monthsa DMFS Median:
et al. 2010) Stage III TT (82%) 10.6 months
Concurrent
(0%)
None (18%) 1 year: 43%
MD Anderson 68 2002-2005 Stage 63 (50.4–76) 1.8–2.0 IMRT Concurrent 8 months DFS 6 months:
(Yom et al. 2007) IIB-IV (100%) (0–27) 67%
12 months:
32%
MSKCC (Sura 55 2001–2005 Inoperable 69.5 (60–90) 1.8–2.0 IMRT Sequential 21 months CSS 2 year: 63%
et al. 2008) Stage (53%) (0–61)
I–IIIB Concurrent
(24%)
MSKCC (Sura 55 2001–2005 Inoperable 69.5 (60–90) 1.8–2.0 IMRT Sequential 21 months OS Median:
et al. 2008) Stage (53%) (0–61) 25 months
I–IIIB 2 year: 57%
Concurrent 2 year: 55%
(24%) (Stage I–II)
2 year: 58%
(Stage III)
MD Anderson 68 2002–2005 Stage 63 (50.4–76) 1.8–2.0 IMRT Induction 8 months OS 6 months:
(Yom et al. 2007) IIB–IV (29%) (0–27) 79%
Concurrent 12 months:
(100%) 55%
(continued)
Intensity-Modulated Radiation Therapy and Volumetric-Modulated Arc Therapy for Lung Cancer
707
Table 7 (continued)
708

Study n Time Patients Dose (Gy) Gpf RT Chemotherapy Follow-up Parameter Outcome
mean/median (Gy) Type median
(range) (range)
Belgium (Bral 40 2005–2008 Inoperable 70.5 (all) 2.35 Helical Sequential 14 monthsa OS Median:
et al. 2010) Stage III TT (82% 17 months
Concurrent Median:
(0%) 21 months
(IIIA)
None (18%) Median:
12 months
(IIIB)
1 year: 65%
2 year: 27%
Beaumont 17 2008–2010 Stage III 66 (66–72, 54 1.5 IMRT Concurrent 12 months OS 1 year: 92%
(abstract) (McGee preoperative) BID (100%)
et al. 2010)
NSCLC non-small-cell lung cancer, IMRT intensity-modulated radiation therapy, VMAT volumetric-modulated radiation therapy, MSKCC Memorial Sloan-Kettering Cancer
Center, Gpf gray per fraction, BID twice daily, LPFS local progression-free survival, LR local recurrence, PR partial remission, RR regional recurrence, DFS disease-free survival,
DMFS distant-metastasis-free survival, CSS cause-specific survival, OS overall survival, TT tomotherapy
a
Median follow-up = 14 months in 16 survivors
I. S. Grills and V. S. Mangona
Intensity-Modulated Radiation Therapy and Volumetric-Modulated Arc Therapy for Lung Cancer
For all patients, median disease-free survival (DFS)
was 12 months, and 2-year DFS was 41%. Two-year
cancer-specific survival (CSS) and OS were 63 and
57%, respectively. Survival was similar in stage I–II
and stage III patients with a median of 25 months.
The largest published prospective trial of NSCLC
patients treated with IMRT is a Belgian trial of hyp-
ofractionated RT using helical tomotherapy (70.5 Gy,
2.35 Gy per fraction) in 40 consecutive patients with
inoperable IIIA (n = 16) and IIIB (n = 24) NSCLC
from 2005 to 2008. Patients were permitted induction
chemotherapy, but not concurrent with RT. Overall,
1- and 2-year local progression-free survival was 66
and 50%, respectively. Median time to distant
metastasis was 10.6 months, and 1-year distant-
metastasis-free survival (DMFS) was 43%. Median
OS was 21 versus 12 months for IIIA and IIIB disease
(P = 0.03) and 17 months for all patients. Two
patients (5%) died of acute pulmonary toxicity;
median follow-up in 14 survivors was 16 months
(Bral et al. 2010).
In Scorsetti’s VMAT study (limited follow-up) of
24 patients with large-volume, unresectable, stage III
NSCLC, patients received 66 Gy delivered with two
isocentric partial arcs. Using the RECIST (2000)
(Therasse et al. 2000) criteria for assessing response
to solid tumors, at 3-month follow-up, 14 (56%) had
partial remission [50%, five (22%) had partial
remission \50%, five (22%) had stable disease, and
no patients had evidence of disease progression
(Scorsetti et al. 2010).
At Beaumont, 17 patients from 2008 to 2010 were
enrolled to a prospective, hyperfractionated, dose-
escalation trial for patients with stage IIIA–IIIB
NSCLC using online 4D-adaptive CBCT image-
guidance. Non-surgical patients received 66–72 Gy,
preoperative patients 54 Gy. Fractions were 1.5 Gy
twice daily with a 6 h interfraction interval using
IMRT. With median follow-up of 12 months, pre-
liminary outcomes appear quite favorable with 1-year
incidences of local recurrence, regional recurrence,
and distant metastasis of 6, 30, and 31%, respectively.
A single patient who had developed distant metastasis
died of disease. With the remaining 16 patients cur-
rently still living, 1-year overall survival is 92%.
(McGee et al. 2010). A summary table of outcomes
for patients with LA-NSCLC treated with IMRT is
seen in Table 7.
709
7 Conclusion
Over the past ten years, technological advancements
have brought IMRT into routine clinical use with
inclusion in lung RTOG protocols since 2007. In this
technically challenging and prognostically poor dis-
ease, dose-escalation and normal tissue sparing have
been shown to be imperative for safely improving local
disease control while minimizing risk for potentially
severe acute and chronic toxicity. From the planning
perspective, IMRT has long proven its superiority to
3D-CRT for safe dose-escalation in properly selected
cases. As advancements such as biological targeting
improve our ability to define clinical targets and
advancements such as online image-guidance to reduce
target miss and PTV volumes, so may the full clinical
potential of IMRT—particularly in the setting of
LA-NSCLC—be better attained. Although still early in
clinical use, VMAT offers a new, promising way to face
the challenges set forth by lung cancer. With inverse-
planning algorithms and quality-assurance methods
available, its utility has grown rapidly in the past few
years. Initial studies have shown the potential for high
quality treatment plans with significantly curtailed
treatment time. Although lung cancer radiotherapy has
substantially improved in the past ten years, outcomes
with LA-NSCLC are still poor. Although the dosi-
metric advantages of IMRT are quite clear, clinical
outcomes of patients treated with IMRT continue to
mature with prospective data only recently appearing
as full articles in peer-reviewed journals. We have
optimism that technological advances (e.g. IMRT,
VMAT, 4D-image-guidance/planning) coupled with
future advances will translate into significant clinical
benefit for what continues to be the most common cause
of cancer-related death in the US and worldwide.
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07.025
 Image-Guided Robotic Stereotactic
Ablative Radiotherapy for Lung Tumors:
The CyberKnife
Billy W. Loo Jr. and Iris C. Gibbs
Contents
1 Introduction.............................................................. 715
2 The CyberKnife Image-Guided Robotic SABR
System ....................................................................... 716
3 Fiducial Marker Placement.................................... 716
4 Patient Positioning and Stabilization .................... 717
5 Treatment Planning................................................. 718
6 Treatment Delivery and Image Guidance ............ 719
7 Clinical Results of CyberKnife SABR for Lung
Cancer ....................................................................... 720
8 Conclusions and Future Directions ....................... 723
References.......................................................................... 723
B. W. Loo Jr. (&)
I. C. Gibbs
Department of Radiation Oncology,
Stanford University and Cancer Institute,
875 Blake Wilbur Drive: MC 5847,
Stanford, CA 94305-5847, USA
e-mail: BWLoo@stanford.edu
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_276, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
Stereotactic ablative radiotherapy (SABR) is a new
paradigm in radiation therapy, achieving high rates
of local tumor control with low toxicity through very
high dose intensity and conformity, and requiring
highly precise and accurate delivery. The Cyber-
Knife robotic radiosurgery system, originally
designed for frameless intracranial radiosurgery
using automated image-guidance, has unique char-
acteristics suitable for lung tumor SABR, including
dynamic tumor tracking capabilities. We review here
the technical characteristics and clinical outcomes of
lung tumor SABR using the CyberKnife system.
1 Introduction
Stereotactic ablative radiotherapy (SABR), also
called stereotactic body radiation therapy (SBRT), has
emerged as a promising treatment for early stage
non-small cell lung cancer, particularly for patients
unable to tolerate surgical resection, and possibly as an
alternative to surgery for some appropriately selected
patients. It has also proven useful for the treatment of
pulmonary oligometastases when an alternative to sur-
gical metastasectomy is desirable. High rates of local
tumor control, in some cases rivaling the historical
results of surgery, have been demonstrated with
acceptable toxicity and the practical advantage of a short
course of treatment. The CyberKnife image-guided
robotic radiosurgery system has unique technical char-
acteristics that make it well suited for SABR of tumors
that move with breathing, including lung tumors.
This chapter reviews the qualities of the CyberKnife
715
716
Fig. 1 The CyberKnife image-guided robotic stereotactic
ablative radiotherapy system at Stanford University, with major
hardware components labeled
platform for lung tumor SABR, and provides a
summary of clinical data using this system specifically.
2 The CyberKnife Image-Guided
Robotic SABR System
The key distinguishing feature of the CyberKnife ste-
reotactic radiotherapy system is the seamless integration
of fully image-guided stereotactic localization, elimi-
nating the need for rigid anatomic fixation to achieve
precise and accurate radiation delivery. The CyberKnife
was the first commercial platform to deliver modern
image-guided radiosurgery (IGRS), and remains the
system with the greatest degree of automated image
guidance. This capability has evolved from its original
application to intracranial stereotactic radiosurgery
(SRS), to SABR of tumors in the body. Its unique ability
to dynamically track targets that move with breathing,
such as in the thorax and upper abdomen, differentiates
the CyberKnife from other commercially available
image-guided platforms, which typically use either
respiratory manipulation or respiratory gating in order to
manage breathing-induced motion.
The major hardware components of the system are: a
compact 6 MV linear accelerator mounted on a com-
puter-controlled robotic manipulator, a pair of orthog-
onal X-ray sources and imaging panels, infrared
light-emitting diodes as external surface markers and an
optical camera that monitors their position, and a com-
puter-controlled patient couch (Fig. 1). Equally critical
B. W. Loo Jr. and I. C. Gibbs
is the software that integrates the functionality of the
hardware, including an inverse treatment planning
system for generating conformal targeting and normal
tissue avoidance plans, and the treatment delivery soft-
ware that analyzes the imaging data acquired during
treatment to determine the appropriate corrections to
apply to the couch and linac positions to maintain ste-
reotactic accuracy. A number of optional components
are available, including upgrades to the linac (with a
higher dose rate up to 1,000 MU/min) and the couch (full
six degree of freedom robotic positioning), an automatic
collimator changer, and a computer-controlled variable
aperture collimator. Of note, Monte Carlo dose calcu-
lation is available optionally, but as discussed below
should really be considered a requirement when treating
with curative intent in regions of heterogeneous tissue
density such as in or around the lungs, or adjacent to air
cavities as in the paranasal sinuses.
The key elements of producing ideal treatment
plans and safe treatment delivery include: (1) proper
placement of fiducial markers; (2) proper patient
positioning and stabilization; (3) appropriate target
delineation and margin design; (4) producing an
optimal dose distribution during treatment planning;
and (5) vigilant monitoring during treatment delivery.
3 Fiducial Marker Placement
Dynamic target tracking is an integral part of treating
tumors that move with breathing using the Cyber-
Knife. This process requires the implantation of
metallic fiducial markers in or around the tumor for
image-guided tracking. Markers may be delivered by
a number of routes, including CT-guided percutane-
ous needle placement, a bronchoscopic procedure, or
even endovascular delivery, prior to the initial simu-
lation (Kothary et al. 2009; Hong et al. 2010; Prévost
et al. 2008; Anantham et al. 2007). The fiducial
markers are ideally placed such that their projections
from the perspective of both of the in-room X-ray
imagers are distinct, i.e., non-overlapping and well
separated (by about 1 cm) while still being in close
proximity to the lesion to be treated. Three markers
are sufficient for unique spatial localization, but in
practice 4–5 are often placed in case of loss or sub-
optimal placement of markers. Implantation and
tracking of a single marker in the center of the tumor
has also been described (Brown et al. 2009).
Image-Guided Robotic Stereotactic Ablative Radiotherapy
The main challenge in the use of fiducial markers is
the invasiveness of the implantation approaches. In
fact, the main acute toxicity encountered in CyberKnife
SABR of lung tumors is implantation-related pneu-
mothorax. The CT-guided percutaneous approach in
particular carries the highest risk of pneumothorax,
although this is still a risk albeit small using broncho-
scopic approaches. Clinical studies of CyberKnife
SABR using percutaneous marker placement have
reported 19–45% rates of any pneumothorax, and
3–26% rates of pneumothorax requiring temporary
chest tube placement (Kothary et al. 2009; Hong et al.
2010; Le et al. 2006; Collins et al. 2009; Pennathur et al.
2009). These rates are similar to those of CT-guided
percutaneous needle biopsies, and are likely related to
the general frailty of this patient population with severe
comorbidities such as chronic obstructive pulmonary
disease making them medically inoperable.
By contrast, Erasmus Medical Center investigators
found no pneumothorax associated with endovascular
(pulmonary arterial) delivery of 87 vascular emboli-
zation coils in 23 patients (Prévost et al. 2008), but
cardiac arrythmia requiring pacemaker placement was
observed in one patient after intravascular coil
implantation in a subsequent study by the same group
(van der Voort van Zyp et al. 2009). Similarly, low
rates of 0–5.8% pneumothorax were found in patients
who underwent electromagnetic navigation broncho-
scopy or endobronchial ultrasound for endobronchial
implantation of various types of fiducial markers
(Anantham et al. 2007; Harley et al. 2010; Schroeder
et al. 2010). Also, retention of implanted fiducial
markers in lung tissue varies by marker type. For
example, the Stanford group found that percutane-
ously implanted platinum endovascular embolization
coils were much better retained than standard smooth
gold markers, and could successfully be tracked by
the CyberKnife after appropriate acceptance testing
(Hong et al. 2010). Likewise, similar coils were much
better retained than linear fiducial markers implanted
bronchoscopically (Schroeder et al. 2010).
4 Patient Positioning
and Stabilization
Classically, SRS for brain tumors has required invasive
fixation of the skull to a frame with a precisely known
spatial relationship relative to the isocenter of the
717
treatment system. Because the CyberKnife relies
entirely on image guidance for its accuracy, and
because it adapts dynamically to intrafractional chan-
ges in the target position, requirements for immobili-
zation are far less stringent. In fact, given the relatively
long treatment times with SABR using the CyberKnife,
less rigid immobilization is preferred: a higher priority
should be placed on patient comfort, which reduces the
likelihood of sudden large motions for which the sys-
tem cannot compensate other than by interrupting the
treatment. It makes more sense to think in terms of
patient position stabilization rather than immobiliza-
tion, as this is the more realistic and physiologic goal.
A commonly used device for position stabilization is
a custom molded cushion consisting of a bag filled with
foam beads, the shape of which is fixed upon evacua-
tion of air from the bag after forming it around the
patient (vacuum bag). The highest priority should be to
provide adequate support of the patient throughout the
duration of treatment, and a full body-length cushion is
desirable. Maximum rigidity of the mold is unneces-
sary, and can in fact be detrimental from the standpoint
of patient comfort and thus stability. For targets in the
body, it is generally dosimetrically advantageous to
place the upper extremities in the overhead position.
It is important to provide adequate support to the upper
extremities by building up an adequate mass of the
cushion material such that the patient expends no
further effort to maintain that position. Fatigue and pain
will impair positioning stability and may lead to
undesirable treatment interruptions.
The CyberKnife is designed to use many non-
coplanar beams, which contributes to the highly
conformal plans achievable with this system. However,
there are limits to the available beam directions based on
geometrical constraints. When the patient is supine,
beams are restricted to entering from approximately the
anterior hemisphere, because there is insufficient clear-
ance for the linac to be positioned under the patient to
deliver beams from those directions. Similarly, there is a
more subtle asymmetry in beam access when treating
lateralized targets because the base of the robotic
manipulator is positioned on one side or the other of the
couch, depending on the room configuration.
Therefore, while most patients are positioned supine,
for certain target locations, particularly very posterior or
lateral tumors, prone positioning can confer significant
advantages in dose distribution given the available beam
access on the CyberKnife. Prone positioning permits
718
treatment of posterior thoracic lesions while avoiding a
long path of entrance dose through the lungs that would
be required in the supine position (Ding et al. 2010). In
addition, for very lateral tumors that would be on the
opposite side of the couch relative to the robotic
manipulator when in the supine position, prone posi-
tioning can increase the beam access and improve the
dose distribution by moving the target to the side of the
robot. The use of a U-shaped cushion to support the face
without obstructing breathing may be used to facilitate
comfort in that position.
5 Treatment Planning
Treatment planning begins at simulation, where
patient positioning and image acquisition parameters
can have a substantial impact on the quality of the
plan and accuracy of treatment delivery subsequently.
X-ray computed tomography (CT) is the fundamental
imaging modality used for treatment planning.
Because of the non-coplanar beam arrangement, the
total axial field of view of the scan (in the superior–
inferior direction) should be sufficiently long to
include adequate tissue above and below the target
volume for accurate calculation of attenuation of
oblique beams. In addition, because the image guid-
ance is based on comparison of the images acquired
by the orthogonal in-room imagers with digitally
reconstructed radiographs (DRRs) generated from the
corresponding projections through the CT data,
acquisition of the CT with thin cuts (1.25 mm or finer
slice spacing) is needed to produce high-resolution
DRRs for optimal position and motion compensation.
One distinguishing feature of the CyberKnife
treatment planning system is that it uses inverse
optimization. This allows simultaneous conformal
targeting and normal tissue avoidance, and also per-
mits ‘‘dose painting’’, or simultaneously prescribing
different doses to high- or low-risk regions, for
example corresponding to gross and microscopic
tumor extension. User selected parameters include the
number and size of collimators, and exclusion of
beams through specified structures. A typical SABR
plan uses approximately 100–200 beams (Fig. 2).
The CyberKnife is designed to compensate for
breathing-induced target motion by dynamic tracking,
as discussed in detail below. Of note, a tumor tracking
plan can be created from a static (breath-hold) CT
B. W. Loo Jr. and I. C. Gibbs
scan. During treatment delivery, the robotic manipu-
lator follows the trajectory of the implanted fiducial
markers, ensuring that there is no geometric miss of
the target. However, the dose to the surrounding
normal structures can in principle be different from
that indicated by the static plan. If 4D CT simulation
is available, the treatment planning system can cal-
culate the dose on all the phases of the 4D CT data set
based on dynamic fiducial tracking, and deformably
propagate the doses to the reference phase, providing
an estimate of the dynamic dose distribution. This
feature is an optional addition to the treatment plan-
ning system. It is also possible to optimize the beam
weights based on organ motion over the phases of the
4D CT. However, this approach assumes that the
motion captured in the 4D CT scan (which effectively
represents a sampling of a single respiratory cycle in
time) is reproduced consistently during treatment,
generally an overly optimistic assumption.
A shortcoming of conventional dose calculation
algorithms is their poor modeling of dose build-up and
penumbra from lateral electron scatter when radiation
beams traverse interfaces between materials of sub-
stantially different density. The standard dose calcu-
lation algorithm in the CyberKnife treatment planning
system uses a pencil beam (electronic path length,
EPL) model that produces accurate dose distributions
for targets in regions of homogeneous density such as
the brain. However, it has significant inaccuracies
when used in regions of sharp density gradients such as
in or around the lungs or air sinuses in the head. Monte
Carlo dose calculation, which models the interactions
generated by individual photons to produce accurate
dose distributions when simulating many events, is
available as an optional addition to the treatment
planning system. When treating tumors in the lung, the
discrepancy in calculated dose (covering specified
volume of the target) between the EPL and Monte
Carlo algorithms is typically 10–20% but can exceed
80% depending on the size and location of the specific
target, with the largest discrepancies for small tumors
surrounded by air-filled lung parenchyma (Sharma
et al. 2010; Wilcox et al. 2010; van der Voort van Zyp
et al. 2010). The EPL calculation consistently over-
estimates the tumor coverage, but the degree of error is
not generalizable or predictable without doing an
actual comparative calculation. Thus the Monte Carlo
module should be considered a requirement for
definitive treatment of thoracic tumors.
Image-Guided Robotic Stereotactic Ablative Radiotherapy
Fig. 2 A typical lung tumor SABR treatment plan on the
CyberKnife. The upper left panel shows the available beams
(dark blue) as well as the beams used in the plan (light blue).
6 Treatment Delivery and Image
Guidance
Image guidance is in fact the key distinguishing fea-
ture of the CyberKnife treatment system. The degree
to which it is integrated into the delivery control
software and automated is what makes possible the
dynamic tumor tracking feature. The CyberKnife is
currently the only commercial platform that performs
dynamic tumor tracking.
At the beginning of treatment, in-room X-ray ima-
ges are acquired and compared to the DRRs to calculate
any required adjustment of the patient’s position. The
initial corrections are applied by moving the couch to
place the patient as closely as possible to the position of
719
The prescription isodose line (green) conforms in all planes to
the planning target volume (red), while lower isodose lines
avoid normal structures such as the esophagus and spinal canal
the original simulation. Subsequent changes in the
patient’s position or breathing-induced target motion
are compensated for by adjustments to the linac
position using the robotic manipulator. The dynamic
marker-based tumor tracking is then initiated (using the
Synchrony Respiratory Tracking System).
Two separate imaging systems are employed in the
tumor tracking schema (Schweikard et al. 2000,
2004). The first is the pair of X-ray imagers that
acquires orthogonal images of the fiducial markers,
which are compared to the DRRs to obtain three-
dimensional localization of each of the markers as
well as their center of mass. The image analysis
software automatically extracts the projections of
the markers from the images. Of note, the in-room
imagers produce intermittent static images rather than
720
continuous images. The second is an optical camera
that continuously monitors the position of three
infrared light emitting diodes that are placed on the
external surface of the patient’s chest at the beginning
of the treatment session, and move as the patient
breathes. The trajectories of the external markers
follow the breathing cycle, including variations in the
breathing pattern. The key to dynamic tracking with
this arrangement is the correlation of the intermittent
X-ray localization of the internal markers with the
continuous signal of the external markers.
Prior to the initiation of treatment, a series of
10–15 X-ray images is acquired, timed such that the
internal marker coordinates from the various portions
of the breathing cycle are all sampled, as determined
by the signal from the optical camera. A correlation
model is then built, which generates a continuously
calculated position of the center of mass of the
internal fiducials from the external marker coordi-
nates. It is this calculated/predicted position that the
beam follows dynamically.
Intermittent X-ray images continue to be acquired
throughout the delivery, as often as at the beginning
of every beam. Each new measurement of internal
marker position is compared to the corresponding
predicted position, and the correlation error is calcu-
lated. Treatment continues as long as the correlation
error is below a user-defined threshold, generally
3 mm. This threshold is thus an approximate upper
bound to the tracking error of the system. If it is found
to be exceeded, treatment stops, additional images are
acquired, and if necessary, the correlation model is
rebuilt from the new images. Otherwise, the correla-
tion model is simply updated with the newest data
point. Gradual changes to the breathing pattern
throughout treatment are accommodated in this way.
The clinical accuracy of the Synchrony system was
assessed retrospectively in 44 patients, finding a
maximum correlation model error of 2.5 mm
(standard deviation) (Hoogeman et al. 2009).
An optional marker-less tracking capability is also
available for treatment of selected lung tumors
(the XSight Lung Respiratory Tracking System).
Tumor localization is accomplished using automated
real-time image segmentation of the in-room X-ray
images based on the contrast of the tumor itself. Thus
the system is best used for lesions with sufficient
contrast in density from the surrounding anatomy to
be clearly visualized on both the in-room X-ray
B. W. Loo Jr. and I. C. Gibbs
imagers, i.e., those located in the lung periphery at
least 1.5 cm in size, and that do not overlap other
dense anatomical structures, such as the spine, dia-
phragm, and heart in the projection views. As such,
marker-less tracking may be applicable to a minority
of lung tumors currently. Furthermore, its accuracy
remains to be rigorously validated clinically, and
presently all of the publications on this subject pertain
to measurement of its performance in artificial set-
tings, although early clinical reports of favorable
tumor control when using this method provide indi-
rect evidence of its accuracy (Brown et al. 2009).
A typical lung tumor SABR plan is delivered in
60–90 min owing to the sequential delivery of
approximately 100–200 non-coplanar beams. Options
are available for a higher output linac with a dose rate
up to 1,000 MU/min, a treatment couch capable of
full 6 degree of freedom robotic positioning, and a
variable aperture collimator, which together can
reduce treatment times by as much as 20–30%,
making the treatment times comparable to those of
other linac-based SABR treatment systems.
While the most unique strength of the CyberKnife
system is its automated image-guided motion com-
pensation, this in no way diminishes the importance
a highly skilled and attentive treatment team. A
potential pitfall is the temptation to allow the entire
treatment session to proceed automatically with
almost no user interaction. Because errors in auto-
mated image analysis, such as fiducial marker
extraction, can and do occur, manual inspection of the
images displayed during the treatment and interrup-
tion for reimaging when necessary are crucial to
ensure that treatment is delivered appropriately.
Ultimately, the treating physicians and therapy staff,
rather than the technology itself, are the most
important determinants of quality treatment and
technical accuracy.
7 Clinical Results of CyberKnife SABR
for Lung Cancer
A large, rapidly growing literature has emerged in
recent years documenting the high promise of SABR
for early lung cancer using a wide range of treatment
platforms. Notable for being a prospective coopera-
tive group trial in a uniform population of medically
inoperable patients with peripherally located early
Image-Guided Robotic Stereotactic Ablative Radiotherapy
lung cancer, the Radiation Therapy Oncology Group
(RTOG) 0236 study demonstrated 98% local control
(within the primary tumor) and 87% local–regional
control (within the ipsilateral lobe, hilum, and medi-
astinum, consistent with the surgical definition of
local control) at three years with an intensive regimen
of 60 Gy in three fractions (or approximately 54 Gy
with proper heterogeneity corrections) (Timmerman
et al. 2010). Similarly, a prospective multi-institu-
tional study by the Nordic Study Group of SBRT
demonstrated 92% primary tumor control at three
years (Baumann et al. 2009).
With respect to SABR using the CyberKnife spe-
cifically, to date there have been 22 peer-reviewed
English language publications reporting the clinical
outcomes of lung tumor SABR with this platform,
including updates of previously reported series
(Brown et al. 2009; Le et al. 2006; Collins et al. 2009;
Pennathur et al. 2009; van der Voort van Zyp et al.
2009; Whyte et al. 2003; Nuyttens et al. 2006; Brown
et al. 2007; Brown et al. 2007; Brown et al. 2007;
Collins et al. 2007; Muacevic et al. 2007; Pennathur
et al. 2007; Brown et al. 2008; Coon et al. 2008; Ahn
et al. 2009; Pennathur et al. 2009; Brown et al. 2010;
Vahdat et al. 2010; van der Voort van Zyp et al. 2010;
van der Voort van Zyp et al. 2010; Unger et al. 2010).
The majority of these comprise the experiences of five
major centers: Stanford University, Erasmus Medical
Center in Rotterdam, University of Pittsburgh,
Georgetown University, and the CyberKnife Center
of Miami.
In 2003, the first published report of lung tumor
SABR using the CyberKnife was of the preliminary
results and feasibility analysis of a prospective phase I
dose escalation trial conducted by Stanford University
and Cleveland Clinic that was in fact the first pub-
lished North American clinical trial of SABR for lung
cancer (Whyte et al. 2003). Twenty-three patients
with primary NSCLC (15 patients) or single lung
metastases (8 patients) were treated in a single frac-
tion of 15 Gy (the starting dose level of the Phase I
trial). In the early period of this study, motion man-
agement was achieved by respiratory breath-hold
technique or an early version of respiratory-tracking
techniques that required very long treatment times.
The updated results of the completed phase I study at
Stanford University included 32 patients (20 NSCLC,
12 metastases) treated with 15, 20, 25, or 30 Gy in a
single fraction (Le et al. 2006). There were three
721
possible treatment-related deaths, all in patients who
had received prior or subsequent chemotherapy and
two of three in patients who had received prior tho-
racic radiotherapy. Pulmonary toxicity was encoun-
tered at doses 25 Gy or higher, mainly in patients
with central tumors or PTV greater than 50 mL (cm3),
leading to the conclusion that 25 Gy single fraction
SABR for small lung tumors is safe in properly
selected patients. No significant changes in pulmon-
ary function testing (PFT) were found in 17 patients
who had pre- and post-treatment PFT. With respect to
tumor control, local control appeared to be better with
higher doses (91% at 1 year for doses C25 Gy) and
primary lung cancer histology (as opposed to metas-
tases). However, subsequent analysis of outcomes in
this series found the main predictor of local control
with single fraction SABR to be tumor volume, with
excellent local control of tumors smaller than 12 mL
but inadequate control of larger tumors in the dose
range tested: the Kaplan–Meier estimate of local
control at 11 months was 100% for tumors \6 mL,
93% for tumors 6–12 mL, and 47% for tumors
[12 mL (Brown et al. 2010). More recently, a pre-
liminary analysis of a tumor volume-adapted dosing
strategy in which small tumors (\12 mL) were trea-
ted with single fractions of biologically effective dose
(BED) \100 Gy and larger tumors (C12 mL) were
treated with more dose intensive multi-fraction regi-
mens of BED C100 Gy found equally high 1-year
local control rates of 91.4 and 92.5%, respectively in
83 patients with 97 tumors at a median follow-up of
13.5 months (Chang et al. 2009; Trakul et al. 2010).
Figure 3 shows an example of the treatment response
following CyberKnife SABR of a peripheral lung
tumor.
Investigators from Erasmus Medical Center
reported a retrospective series of 70 patients with
inoperable early stage peripheral NSCLC (39 T1
tumors; 31 T2 tumors) treated with either 45 or 60 Gy
in three fractions (1 treated to 36 Gy) (van der Voort
van Zyp et al. 2009). The median follow-up was 15
months. There was a trend toward improved local
control with higher radiation dose, with 2 yr actuarial
local control of 96% in those treated with 60 Gy
versus 78% in those treated with 45 Gy (P = 0.197).
The four local recurrences were in patients with T2
tumors. Actuarial overall survival was 83 and 62% at
first and second years, respectively, with 19 deaths
during follow-up (6 from lung cancer, 13 from
722
Fig. 3 Peripherally located
stage I NSCLC in a medically
inoperable patient, treated
with CyberKnife SABR to
a dose of 50 Gy in four
fractions. There was a
complete response with minor
tissue retraction surrounding
the implanted markers
(arrow), and no evidence
of disease 26 months after
treatment
intercurrent illness), yielding cause-specific survival
rates of 94 and 86% at 1 and 2 years, respectively.
Late toxicities included grade 3 pneumonitis in three
patients, and grade 3 thoracic pain in four patients
with lesions near the chest wall. An analysis by the
same institution of a subgroup of 38 octagenarians
with stage I NSCLC found 100% 2 year local control
and 1- and 2-year overall survival of 65 and 44%,
respectively, which are favorable results in this
especially frail patient population (van der Voort van
Zyp et al. 2010). In addition, a quality of life analysis
of 39 patients on a prospective phase II trial of
4860 Gy in 36 fractions found maintenance of quality
of life and significant improvement in emotional
functioning after SABR along with 97% local control
and 62% overall survival at 2 years and no severe
([grade 3) treatment-related toxicity (van der Voort
van Zyp et al. 2010).
The University of Pittsburgh group reported their
retrospective experience treating 100 patients, 46 with
primary NSCLC, 35 with locally recurrent tumors
after prior therapy, and 19 with pulmonary metastasis
(Pennathur et al. 2009). The majority (72 patients)
were treated with 20 Gy in a single fraction, while 28
received 60 Gy in three fractions. With a median
follow-up of 20 months, median time to local pro-
gression was 22 months and median overall survival
B. W. Loo Jr. and I. C. Gibbs
was 24 months. There was a statistically significantly
longer time to local progression with the higher dose.
University of Pittsburgh investigators are also coor-
dinating a multi-institutional phase II clinical trial of
CyberKnife SABR for medically inoperable early
lung cancer, which continues to accrue patients
(ClinicalTrials.gov 2008).
Georgetown University investigators reported a
series of 20 medically inoperable patients with small
peripheral stage I NSCLC treated with CyberKnife
SABR to an average dose of 53 Gy (range 42–60 Gy)
in 3 fractions over a 3–11 day period (Vahdat et al.
2010). The mean tumor volume in this series was
10 mL (range 4–24 mL). With a median follow-up of
43 months, the 2 year actuarial survival was 90% and
local control was 95%. No regional and three distant
recurrences were observed. Chest wall discomfort
occurred in 8 of 12 patients with tumors near the
pleura and 1 case of subacute grade 3 pneumonitis
was encountered in a patient who had received radi-
ation concurrently with gefitinib (Collins et al. 2009).
They also reported the outcomes of 20 patients with
large hilar tumors (median gross tumor volume
73 mL) treated more modest doses of 30–40 Gy in
five fractions, finding an estimated 1-year local
control of 63%, suggesting a palliative rather than
definitive benefit of such regimens in this setting
Image-Guided Robotic Stereotactic Ablative Radiotherapy
(Unger et al. 2010). One patient with gross endo-
bronchial tumor invasion developed a fatal fistula
after treatment.
The CyberKnife Center of Miami group reported a
retrospective series of 31 patients with Stage IA or IB
NSCLC with tumors ranging in volume from 0.6 to
71 mL treated to doses of 60–67.5 Gy in 3–5 frac-
tions (Brown et al. 2009). After a median follow-up
time of 27.5 months, actuarial local control rates of
93.2 and 85.8% were observed at 1 and 4.5 years,
respectively, and the overall survival was 93.6 and
83.5% at 1 and 4.5 years, respectively. There were no
observed grade 3 or higher toxicities.
In summary, the clinical outcomes of CyberKnife
SABR of pulmonary tumors are very consistent with
the promising results reported in the broader literature
of SABR for lung tumors.
8 Conclusions and Future Directions
SABR has been shown to be effective and feasible for
the treatment of medically inoperable early stage
NSCLC, and the CyberKnife system employs novel
solutions to some of the technical challenges involved
in these complex treatments. Treatments of high
biologically effective doses (e.g., 60 Gy in three
fractions) have yielded excellent local control results,
particularly for smaller, peripheral tumors. Additional
studies are needed to optimize the dose for large and
centrally located tumors. Given the favorable results
that are competitive with results historically observed
after surgery for these tumors, ongoing trials aim to
study this treatment modality in operable patients,
including multi-center cooperative group trials being
conducted by the RTOG and the Japan Clinical
Oncology Group (JCOG). In addition to these, the
international Lung Cancer STARS (Stereotactic
Radiotherapy vs. Surgery) trial, coordinated by the
M.D. Anderson Cancer Center and sponsored by
Accuray, Inc., will study in a randomized fashion the
comparative effectiveness of fractionated SABR
(nominally 60 Gy in three fractions for peripheral
lesions, and 60 Gy in four fractions for central
lesions) using the CyberKnife system specifically
versus surgical lobectomy for stage I NSCLC
(ClinicalTrials.gov 2009). In parallel, technological
improvements in hardware and software should lead
to faster delivery times and improved marker-less
723
tracking of tumors to reduce the need for invasive
marker placement. Rigorous clinical and technical
evaluation will be important to validate the accuracy
of these enhancements.
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 Advances in Radiation Oncology
of Lung Cancer
Deepak Khuntia and Minesh P. Mehta

Contents Abstract
A variety of advanced radiation technologies are
1 Basics of Tomotherapy............................................ 725 currently available that have changed the way we
1.1 Helical Delivery......................................................... 725 practice Radiation Oncology. In this chapter, the
1.2 Planning Parameters .................................................. 726
1.3 Image Guidance......................................................... 727
authors will review one such technology, Helical
tomotherapy. Basic operations and planning, appli-
2 Clinical Application................................................. 728
cations in stereotactic body radiotherapy, and
2.1 Stereotactic Body Radiotherapy for NSCLC ........... 728
2.2 Unresectable NSCLC ................................................ 728 locally advanced lung cancer, as well as devel-
2.3 Hippocampal Sparing Whole Brain Radiation ......... 730 oping and future applications in hippocampal
3 Future Directions..................................................... 730 sparing whole brain radiation, adaptive radiation,
3.1 Adaptive Radiotherapy and theragnostic radiation delivery will also be
and Real-Time Planning............................................ 730 discussed.
4 Conclusion ................................................................ 732
References.......................................................................... 732
1 Basics of Tomotherapy

1.1 Helical Delivery

Tomotherapy is the ‘‘slice-by-slice’’ delivery of inten-

sity modulated radiation therapy, originally pioneered
by Mark Carol as ‘‘serial tomotherapy’’, and com-
mercialized as the NOMOS system. Helical tomo-
therapy, which replaces the ‘‘serial slice-by-slice
Disclosures Dr. Khuntia serves on the advisory board of
Radion Global and has received the speakers honorarium delivery’’ (which requires multiple couch position
for Tomotherapy. Dr. Mehta serves as a consultant for adjustments), represents a substantial degree of
Tomotherapy, and holds stock options in Tomotherapy.
sophisticated refinement over this approach, by
D. Khuntia (&) utilizing helical delivery on a couch in continuous
Western Radiation Oncology, slow-motion, and is currently commercially available
125 South Drive, Mountain View, as Tomotherapy Hi-Art and Tomotherapy HD
CA 94040, USA (Tomotherapy, Inc., Madison, WI). This represents
e-mail: khuntia@wradonc.com
just one of several image guided radiotherapy (IGRT)
M. P. Mehta delivery devices available in the market place. To-
Northwestern University,
676 N St. Clair, Suite 1800, Chicago, motherapy, however, differentiates itself from the
IL 60611, USA other devices wherein it is a dedicated IGRT-IMRT

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 725
DOI: 10.1007/174_2011_277, Ó Springer-Verlag Berlin Heidelberg 2011
726 D. Khuntia and M. P. Mehta

Fig. 1 Primary components of a helical tomotherapy unit

(courtesy of Rockwell Mackie, PhD)

Fig. 2 Helical Tomotherapy Hi-Art

system incorporates megavoltage CT for IGRT, and
delivers radiation with multiple coplanar rotational
radiation beamlets, and the ability to collect exit dose
from the patient, mapped back to the daily megavolt-
age CT imaging allows precise documentation and
calculation of the daily delivered dose (Mackie et al.
1999, 2003). The technology of tomotherapy dates
back to the 1990s with the original Peacock System
(Nomos, Sewickley, PA) where rotational delivery is
accomplished using a fan beam generated from fast-
moving, actuator-driven multileaf collimators (MLC).
This technology has evolved into what is now known
as Tomotherapy Hi-Art and Tomotherapy HD (Helical Fig. 3 Multi-leaf collimator within gantry of a Tomotherapy
and Direct). Tomotherapy Direct refers to the ability to Hi-Art system. Each MLC has an incredibly fast transit time of
deliver radiation with limited or fixed gantry positions 20 ms. The rapid rotation and modulations allow for conformal
radiation delivery
emulating a 3D plan or a forward planned IMRT.
With the current Tomotherapy Hi-Art device, the
MLC modulates the beam in the range of 300 cm/s 1.2 Planning Parameters
which allows incredible modulation of the beam,
exceeding any currently available commercially Each Tomotherapy system includes its own proprie-
available radiation technology (Figs. 1, 2, 3). The tary treatment planning system. The system, as a
beam delivers radiation through a ring gantry system, whole, is one of the most forgiving planning systems
similar to a diagnostic helical spiral CT scanner. and also one of the easiest to learn. Treatment plan-
There are multiple advantages to a ring gantry system, ning is based primarily on three parameters: field
including increased stability, faster rotation, simple width, pitch, and modulation factor. Further, each
coplanar delivery, and no possibility of rotational col- rotation is divided into 51 separate beam projections
lisions. Further, because of the intense modulation with each projection having its own leaf opening and
capable with this system, a single low energy (6 MV) is closing pattern which transcends over seven degrees
sufficient. This allows for less neutron contamination of arc. The first planning parameter is field width.
and less shielding requirements. Field width can have a significant impact on both
Advances in Radiation Oncology of Lung Cancer
conformality and treatment time. Specifically, field
width refers to the width of each slice of delivery
along the Y dimension of the 85-cm field length. Field
sizes of 1, 2.5, and 5 cm can be used; 1-cm field sizes
will allow for significant conformality when high
precision is needed [such as in stereotactic body
radiotherapy (SBRT)], but comes at the expense of
treatment time. A very large treatment field (such as
total marrow irradiation) may be better treated with a
5-cm field width.
Pitch refers to the field width the couch moves per
rotation. For example, if the field width is 5 cm and the
pitch is 0.5, the table will move 2.5 cm per rotation. In
other words, pitch refers to how loose or tight the
spiral of radiation delivery is. As one decreases the
pitch, there could be an increase in the number of
rotations that could increase the treatment time.
However a short pitch may allow for improved
resolution in the dose distribution, as the spiral is tight.
Finally, modulation factor is the third treatment
planning parameter. This refers to the maximum leaf
opening time divided by the average leaf opening
time of the MLC. A high-modulation factor allows
more flexibility in the leaf opening time, resulting in
more conformal plans, but can come at the expense of
longer treatment delivery times.
1.3 Image Guidance
Image-guided radiotherapy (IGRT) uses online
imaging just prior to treatment delivery to improve
the probability that the patient is positioned accurately
and reproducibly for every treatment fraction
(Dawson and Jaffray 2007). Currently, different IGRT
systems use portal films, electronic portal images,
infrared cameras, conebeam CT, radiofrequency
beacons via implanted fiducials, ultrasound, or MVCT
(as is the case with Tomotherapy), and MR imaging
on-board is being investigated. Typically, the stan-
dard practice has involved checking portal films
approximately once in every five fractions. This
makes it difficult to see variations compared to the
planning session which may be a result of human
error in setup, patient anatomy changing due to
weight loss or edema, or even changes in the tumor.
By using daily MVCT for image guidance (Fig. 4),
there is less uncertainty in patient positioning, so
tighter planning target volume (PTV) expansions can
727
Fig. 4 Megavoltage (MVCT) taken prior to treatment delivery
for a stereotactic lung radiotherapy delivery of 12 Gy in a
single fraction. An additional four fractions will be delivered.
The grey box represents the planning kilovoltage CT with the
purple boxes representing the daily MVCT image. Adjustments
are made to endure that the patient is setup in a similar position
as the planning scan
be incorporated which will yield less normal tissue
dose. Further, if there is a dramatic change in a
patient’s anatomy, this will allow the physician to
identify the changes earlier and apply a new radiation
plan if warranted (Siker et al. 2006).
The changes seen on MVCT can vary based on
the disease site being treated (Schubert et al. 2009).
Head and neck and brain treatments have smaller
shifts than lung, for example, as there tends to be
little motion with brain/neck treatments as these are
fixed structures and have very good immobilization.
The lung, however, can have considerable motion
and the currently available immobilization devices
cannot restrict motion to the same degree as in the
head and neck. Therefore, image guidance is critical
in the chest, and becomes even more critical when
hypofractionated schedules are employed. Schubert
et al. (2009) found that variations in systemic errors
and the magnitude of random errors were higher for
lung cancer than any other disease site. As tomo-
therapy is a fully integrated IGRT system, there is
considerable advantage in this technology in man-
aging thoracic tumors. Further, it causes very low
radiation exposure to the patient (1.5 cGy) compared
to other 3D IGRT techniques such as conebeam CT
(Shah et al. 2008).
728
2 Clinical Application
Tomotherapy is uniquely qualified as a premier
radiation delivery device for patients with lung
cancer. As described below, there is a changing par-
adigm in lung cancer, focusing on dose-escalation,
including the approach of dose-per-fraction escala-
tion, based on biologic rationale, and made possible
by a changing technological landscape. In the 3D
conformal radiotherapy era, Radiation Oncologists
were limited to moderate doses of radiation due to the
lack of conformality with these techniques. Modern
delivery techniques, especially as available with
Tomotherapy, have allowed safe dose escalation that
has resulted in improvements in local control, survival
and reduced toxicity (Adkison et al. 2008).
2.1 Stereotactic Body Radiotherapy
for NSCLC
Stereotactic Body Radiotherapy (SBRT) refers to
precise 3D volume positioning of targets outside the
brain, taking motion into account, to deliver extre-
mely high doses of radiation conformally in five or
fewer fractions. In order to successfully deliver SBRT
to lung tumors, proper selection is mandatory.
Generally, these tumors must be peripheral in location
as clinical trials have shown a higher incidence of life
threatening toxicity for central tumors (though other
fractionation regimens are being investigated for this
group) (Timmerman et al. 2006; Chi et al. 2011).
Because lung tumors can move up to 5 cm (especially
for tumors near the diaphragm), it is important that a
method exists to limit this motion or track the tumor
and gate treatment delivery. Tomotherapy accom-
plishes this by immobilizing the patient (typically in
an abdominal compression device) and planning the
patient using a 4D CT scan and targeting the motion
envelope. MVCT is used to ensure that the tumor is
adequately targeted during treatment.
One of the earliest SBRT experiences using helical
tomotherapy was reported by Hodge and colleagues at
the University of Wisconsin (Hodge et al. 2006). In their
series, patients received a total of 60 Gy in five fractions
over a ten day period. The PTV was defined as the
motion envelope plus a 6 mm expansion for microscopic
extension and setup error with daily MVCT IGRT. The
D. Khuntia and M. P. Mehta
Fig. 5 The figure above represents the dose escalation model
described by Mehta and colleagues. On the Y-axis, the tumor
control probability is represented while the X-axis represents
time. As can be seen, maximum TCP is realized at 25 fractions
(5 weeks). (Mehta and Scrimger et al. 2001)
mean tumor regression was 72% and all the patients in
the original series were locally controlled with no grade
two or higher pulmonary toxicity. Others have found
similar local control rates in excess of 90% using SBRT
techniques for unresectable lung cancer (Nagata et al.
2005; Timmerman et al. 2006; Yoon et al. 2006).
2.2 Unresectable NSCLC
It has been generally accepted that a dose-response
relationship exists for non-small cell lung cancer
based on several prospective clinical trials and data-
base analyses (Perez et al. 1980; Kong et al. 2005;
Belderbos et al. 2006; Yuan et al. 2007). However,
until recently, safe delivery of significantly escalated
doses was difficult to achieve. There have been at
least two helical tomotherapy-based series in unre-
sectable locally advanced NSCLC that have shown
initial promise for this difficult disease. Mehta and
colleagues described a hypofractionated dose-per-
fraction escalation model keeping the number of
fractions constant (25) in order to combat accelerated
repopulation which can retard the gains from dose
escalation associated with treatment prolongation
(Mehta et al. 2001). Based on the biological param-
eters utilized, and as can be seen from Fig. 5, the
maximal tumor control probability is likely to be
Advances in Radiation Oncology of Lung Cancer
Fig. 6 Typical dose escalation plan in a patient treated on the
UW phase I dose escalation trial. The dose volume histogram is
shown below. This patient received 3 Gy 9 25 fractions. Very
achieved when treatment is delivered over 25 frac-
tions, permitting one to utilize this schedule as a
baseline and escalating beyond it by increasing frac-
tional dose, rather than the number of fractions.
The phase I study reported by Adkison et al.
(2008) from the University of Wisconsin binned
patients into separate ‘‘dose-volume-risk’’ bins, and
escalated fractional doses from 2.28 to 3.62 Gy per
fraction 9 25 fractions. Patients were placed into a
variety of ‘‘Bins’’ based on predicted mean dose to the
lung and esophagus (Fig. 6). At the time of initial
reporting in 46 patients, no grade three or higher
toxicities had occurred. In this study, the use of
concurrent chemotherapy was prohibited though non-
gemcitabine containing regimens which were allowed
neoadjuvantly or adjuvantly. An impressive 47%
2-year OS was seen, despite having over 80% of
patients as Stage III or higher disease.
729
low doses are realized to the esophagus and lung with this plan
(Adkison et al. 2008)
Song et al. (2010) retrospectively reviewed 37
NSCLC patients treated with hypofractionated radiation
to 60-70.4 Gy with 2-2.4 Gy per fraction to the gross
disease delivered with helical tomotherapy, in con-
junction with concurrent chemotherapy. The authors
reported incredibly high 2-year local control and sur-
vival rates of 63 and 56%, respectively. Acute esopha-
gitis grade 3 or higher was seen in five patients and grade
3 or higher pneumonitis was seen in seven patients. Four
treatment-related deaths were reported. A multivariate
risk analysis demonstrated an association between the
volume of lung receiving low doses of radiotherapy and
the development of pulmonary toxicity, and the authors
advocated that no more than 60% of the contralateral
lung volume should receive 5 Gy or higher dose. The
patient cohort included in their report had very advanced
disease, including supraclavicular bulky N3 adenopathy
with poor performance status. The two studies also
730
Fig. 7 Typical hippocampal whole brain radiation therapy plan. Here, the goal is to keep the mean dose to the hippocampus under
10 Gy and preferably under 7–8 Gy. This is best accomplished with helical tomotherapy
differed in their GTV to CTV expansion margins, with
the Song study utilizing more generous expansion
margins. Regardless, the control rates were impressive,
and this is clearly a group of patients that likely could not
be treated safely with 3D techniques.
2.3 Hippocampal Sparing Whole Brain
Radiation
Given the fact that a significant proportion of
patients with lung cancer develop brain metastasis,
whole brain radiation therapy (WBRT) is an
important treatment for many of these patients
(Khuntia et al. 2006). WBRT has been shown to
improve local control as well as delay decline in
neurocognitive function (NCF) (Aoyama et al.
2007). However, there may be adverse effects on
NCF associated with WBRT and prospective efforts
are being made to minimize these (DeAngelis et al.
1989; Chang et al. 2009) The RTOG recently com-
pleted a study (RTOG 0614) evaluating the drug
memantine to preserve cognitive function in patients
undergoing WBRT, and results are awaited. A cur-
rent RTOG trial, RTOG 0933, is evaluating the use
of IMRT to reduce the dose to the peri-hippocampal
stem cell compartments involved in neurogenesis
essential for memory functions (Monje et al. 2002;
Mizumatsu et al. 2003; Monje et al. 2003). By
reducing the dose to the hippocampus, it may be
possible to preserve these radiosensitive stem cell
D. Khuntia and M. P. Mehta
compartments, and possibly reduce the likelihood of
cognitive decline.
Considerable work has been done over the last
several years attempting to delineate the feasibility
of hippocampal sparing WBRT. Investigators have
shown that the likelihood of isolated recurrences
within the hippocampus is small (Gondi et al. 2010).
Further, atlases have been created to help standard-
ize the contouring of the hippocampus so that this
technique might be broadly, but reproducibly applied
(Gondi et al. 2010). Patients requiring prophylactic
cranial radiation or those with very good perfor-
mance status requiring WBRT may have the most to
gain from such an approach. Unfortunately, the
ability to deliver such exquisite plans where the
whole brain receives 30 Gy or more while the hip-
pocampus receives mean doses of 10 Gy or less is
very difficult to accomplish. Helical tomotherapy has
been shown to be able to accomplish some of the
most conformal radiation plans in this setting
(Fig. 7).
3 Future Directions
3.1 Adaptive Radiotherapy
and Real-Time Planning
Adaptive radiotherapy refers to the ability to change
the radiation delivery based on anatomic variation in
a patient from one day to another. This has
Advances in Radiation Oncology of Lung Cancer
Fig. 8 The image on the left shows the treatment planning
volume of a patient with small cell lung cancer outlined in red.
After just 1 week of radiation (15 Gy of radiation in ten
fractions, with twice daily treatments), there has been a
particular importance in patients where the external
anatomy changes (such as a patient that has lost a lot
of weight during the course of treatment) or even in
patients that have rapidly responding tumors such as
small cell lung cancer (Fig. 8). Tomotherapy differs
from other delivery devices in that the image guided
MVCT images can be used for replanning. This
application, known as Planned Adaptive, is proprie-
tary to Tomotherapy. Further, investigations are
underway that will allow the use of advanced con-
touring software using deformable registration algo-
rithms to re-contour a patient’s altered anatomy in a
matter of seconds. Advanced planning tools have
already been developed (currently available as a
research module only) that can replan an optimized
treatment to this volume in just a few minutes. This
entire process, completed in a few minutes would
allow the assessment of the patient with an MvCT to
determine whether plan adaption is necessary, per-
form auto-contoured deformable image fusion,
recalculate a new plan, and deliver it, all within
minutes. This can therefore allow for frequent, and if
necessary, even daily re-planning for certain
731
dramatic reduction in tumor (now outlined in blue with the
original volume still in red.) Tomotherapy allows for
re-planning to be accomplished from the daily MVCT so that
a new plan can be delivered the following day
situations. Tomotherapy is therefore uniquely quali-
fied to develop adaptive radiation therapy protocols
given its image guidance and treatment planning
software capabilities.
Further, this technology will allow for biologi-
cally adapted radiotherapy, tailored to the response
biology of a patient’s tumor, a process referred to as
theragnostic radiotherapy. For example, it would be
quite possible to develop dose-prescription models
that track early alterations in resistance processes
such as hypoxia or proliferation, or response pro-
cesses such as cell death, measured at a voxel-level
using advanced PET or MR imaging; these altera-
tions can be converted to voxelized prescription
functions, based on prospective evaluation of change
in function versus local control/relapse rates. An
initial agnostic radiotherapy prescription can be
altered based on patient- and tumor-specific changes
in these imaging studies, permitting an extremely
sophisticated form of dose painting. Tomotherapy is
one of the best radiation treatment modalities suited
for this type of adaptation (Bentzen and Gregoire
2011).
732
4 Conclusion
In the last decade, advances in stereotactic body
radiotherapy for medically inoperable lung cancer
have yielded local control rates approaching or
exceeding 90%. Several trials, such as RTOG 0618
are now exploring the use of SBRT in medically
operable stage I and II NSCLC. This approach will
need to become even more sophisticated as we gar-
ner a better understanding of the toxicities associated
with it, such as chest wall pain, trachea-vascular
complications, etc., but also because the recent NCI-
sponsored trial of screening high-risk patients with
CT scans has demonstrated survival improvement,
thereby ensuring that within a short period of time,
CT-screening will become routine. This will lead to
the diagnosis of early stage lung cancer in many
medically inoperable patients, for whom such body
stereotactic approaches will become critical.
For patients with more locally advanced disease,
dose escalation has resulted in improvement in local
control as well as survival (Yuan et al. 2007). Fur-
ther investigations are underway (RTOG 0617)
attempting to validate the role of high doses of
radiation with concomitant chemotherapy, and
advanced technologies such as tomotherapy are
ideally suited to precisely and safely deliver highly
conformal thoracic radiation.
Adaptive radiotherapy will likely be the next
advance in radiation therapy. Lung cancer patients are
ideal candidates for this as their tumors can indeed
change both anatomically and biologically. Techno-
logical advances in computer processing, exit beam
dosimetry from MVCTs, and software updates in
deformable registration will allow for rapid transla-
tion of new plans perhaps on a daily basis to deliver
the ultimate adaptive radiation delivery.
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 Image-Guided Radiotherapy in Lung Cancer
Percy Lee and Patrick Kupelian

Contents
1 Introduction.............................................................. 735
2 Image-Guided Target Delineation Using
Functional Imaging.................................................. 736
3 Lung Tumor Motion ............................................... 737
4 Treatment Room Planar Imaging ......................... 738
5 Fiducial Markers ..................................................... 739
6 Treatment Room Volumetric Imaging.................. 740
7 Conclusion ................................................................ 741
References.......................................................................... 741
Abstract
Technological advances in image guidance have led
to improvements in outcome for lung cancer patients
treated with radiation therapy. In particular advance-
ments in 2-Dimensional to now 3 and 4-Dimensional
treatment planning as well as the use of functional
imaging such as FDG-PET/CT have allowed for
more accurate targeting of radiation therapy to areas
of disease while limiting collateral damage to
surrounding normal tissue. Patient specific margins
are now applied to individual patients and are
substantially less than what has been used in the
previous era. This has allowed for radiation dose-
escalation to the tumor while maximally sparing the
surrounding organs at risk and has translated into
improved tumor control and decrease in toxicities
clinically. In-treatment room stereoscopic X-ray
imaging with or without implanted fiducial markers
as well as volumetric kilovoltage or megavoltage
cone-beam CT have allowed clinician to reliably
deliver the planned treatment daily to the intended
target despite the smaller margins of error. Image-
guidance is an important evolving component of
radiation therapy for lung cancer and is an area of
intense research interest.

1 Introduction

P. Lee (&)
P. Kupelian The recent technological advances in radiation ther-

Department of Radiation Oncology, apy have dramatically improved outcomes in lung
University of California at Los Angeles, cancer patients treated with radiation. In the era of
200 UCLA Medical Plaza, Ste. B265,
Los Angeles, CA 90095-6951, USA two-dimensional (2D) radiation therapy, tumor con-
e-mail: percylee@mednet.ucla.edu trol was poor, and dose was limited due to the

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 735
DOI: 10.1007/174_2011_287, Ó Springer-Verlag Berlin Heidelberg 2011
736
increased toxicity necessitated by the poor imaging
quality during planning and treatment, and the
requirement to include a large volume of normal tis-
sue in the treatment fields. Three-dimensional (3D)
conformal radiotherapy has incrementally improved
our outcomes due to better tumor and organ spatial
delineation, but was still unable to account for real-
time tumor motion. More recently, the use of hypo-
fractionated radiation therapy or stereotactic body
radiation therapy (SBRT) using sophisticated image-
guidance has drastically reduced the overall treatment
time as well as improved the tumor control rates to
greater than 90% in medically inoperable stage I non-
small cell lung cancer (NSCLC) (Timmerman et al.
2010). This has been possible due to combined
advances in functional and anatomical imaging,
improved accuracy and precision of radiation therapy
delivery devices, advent of four-dimensional (4D) CT
planning where individualized tumor motion can be
accounted for and characterized, as well as on-board
stereoscopic and volumetric imaging in the radiation
therapy treatment room prior to radiation delivery.
The main reasons for local failure after radiation
therapy are (1) inadequate staging imaging to identify
all areas of gross and microscopic disease; (2) geo-
graphic misses due to tumor motion as a result of
respiration during treatment delivery; and (3) inade-
quate planned radiation dose due to nearby dose-
limiting objects at risk (OARs). Image-guided radiation
therapy (IGRT) based on functional planning imaging
such as positron emission tomography/computed
tomography (PET/CT) as well as 4D CT to account for
individualized tumor and organ motion, and in-room
image-guidance such as stereoscopic imaging or volu-
metric cone beam CT (CBCT) has allowed radiation
oncologist to dose-escalate the radiation to the intended
target, while reducing dose to OARs, thereby reducing
treatment-related toxicities. A dose–response relation-
ship for tumor control likely exists for NSCLC as seen
in the radiation therapy oncology group (RTOG) 7301.
Trial for stage III NSCLC that established 60 Gy in 30
fractions as the standard dose (Perez et al. 1986). In
medically inoperable stage I NSCLC, with very con-
formal SBRT approaches and IGRT, very high bio-
logical doses (up to 20 Gy per fraction) can be delivered
to peripheral tumors to achieve excellent local control
(80–90%) suggesting that local control is possible when
sufficiently high doses are delivered (Timmerman et al.
2010; Onishi et al. 2004; Xia et al. 2006).
P. Lee and P. Kupelian
2 Image-Guided Target Delineation
Using Functional Imaging
In 3D conformal radiotherapy, delineation of the
gross tumor volume (GTV) is done primarily with
anatomically based CT imaging. Limitations of CT-
based imaging to identify the GTV include variability
in window and level settings, motion artifact, indis-
tinct tissue boundaries between tumor and lung
atelectasis that have similar density, and inability to
identify pathologically involved lymph nodes less
than 1 cm. By compensating for these inadequacies
using excessive large margins, one adds excessive
treatment toxicities. On the other hand, undercon-
touring is likely to lead to inadequate dose to the
intended target, and local failure due to geographic
miss. For example, using CT-based treatment plan
often leads to undercontouring of involved lymph
nodes less than 1 cm. One study found that up to 44%
of nodes involved were less than 1 cm in diameter,
and 18% of patients with pathologically involved
mediastinal lymph nodes did not have any nodes
larger than 1 cm (Prenzel et al. 2003).
Functional imaging such as flurodeoxyglucose
(FDG)-PET/CT is quite useful for disease staging and
treatment volume delineation for radiation therapy
(Bradley et al. 2004; Mac Manus and Hicks 2007).
Most commonly, an FDG-PET/CT can assist in
detecting occult involved mediastinal and hilar lymph
nodes less than 1 cm and distinguish collapsed lung
from tumor (Fig. 1). There are also limitations for
PET-based image-guided treatment planning. The
spatial resolution of PET is relatively poor ([1 cm),
poor temporal resolution due to tumor and organ
motion as well as non-tumor related nonspecific
uptake due to inflammation. Specifically for radio-
therapy planning, there are many unanswered ques-
tions such as how to best use FDG-PET guided
imaging for planning. Mainly, several approaches
have been proposed for defining FDG-based GTV: (1)
visual interpretation of the FDG-PET/CT imaging; (2)
using a percentage such as 40–50% of the maximal
uptake as the threshold for target delineation; or (3)
using an absolute threshold such as a standard uptake
value (SUV) of greater than 2.5 to segment the GTV.
Despite its limitations however, the use of FDG-PET/
CT in radiation treatment planning has significantly
improved radiation target delineation, and reduced
Image-Guided Radiotherapy in Lung Cancer
Fig. 1 Top axial CT slice of a patient with medically inoperable,
centrally located, stage I squamous cell carcinoma of the left
lower lobe causing collapse of the left lower lobe. Bottom PET
image of the equivalent axial slice demonstrating FDG avidity of
only the tumor and not the collapse left lower lobe. PET was used
for stereotactic body radiation therapy image-guided treatment
planning to target the FDG-avid tumor only
geographic misses compared to CT-based treatment
planning. Currently, investigation is ongoing to
develop other novel PET tracers that are specific for
other biological pathways of cancer, such as hypoxia,
cell proliferation, angiogenesis, apoptosis, and gene
expression. These novel functional imaging tools may
further assist in image-guided radiation therapy
planning in the near future. A possibility in the future
is to use functional information such as radioresistant
subvolumes within the GTV and dose-escalated the
radiation using intensity-modulated radiation therapy
approaches to these subvolumes.
3 Lung Tumor Motion
Lung tumor motion is a major obstacle in accurate
treatment delivery for thoracic malignancies. Respi-
ratory-induced target motion (also known as intra-
fraction tumor motion), can add significant amount of
737
geometric uncertainty to the radiation treatment.
In the era of 3D conformal radiotherapy, excessive
large margins were used due to uncertainty regarding
the extent of the tumor motion. However, the devel-
opment of 4D CT with multislice detectors and faster
imaging reconstruction has facilitated the ability to
obtain images while patients breathe and assess tumor
and organ motion (Nehmeh et al. 2004a, b). One
approach to designing individualized target volume
based on the 4D CT is by contouring the lung tumor
in the extreme phases of respiration (end inspiration
and end expiration) during normal breathing. Using
this approach, an internal target volume (ITV) can be
defined. The ITV is defined as the GTV plus an
internal margin (IM) to account for intra and inter-
fractional tumor motion from respiration. Most lung
tumors have a respiratory excursion of less than
5 mm. However, a minority, approximately 10%, of
lung tumors move more than 10 mm and occasionally
motion of 40 mm can be seen, especially in lowerlobe
tumors near the diaphragm (Liu et al. 2007). The use
of an ITV allows patient-specific IM to be applied
rather than population-derived values, the latter can
substantially underestimate or overestimate the IM.
Tumor motion in the thorax has been assessed in
multiple studies. In one study, the 3D motion of the
20 lung tumors was assessed by implanting a 2-mm
gold fiducial marker in or near the tumor. The 3D
position of the implanted markers was determined
using two in-room fluoroscopy imaging processor
units. The system provided coordinates of the gold
marker during beam-on and beam-off time in all
directions (Seppenwoolde et al. 2002). On average,
lower lobes tumor had the greatest motion in the
cranial–caudal dimension (12 ± 2 mm). The lateral
and anterior–posterior directions were small both for
upper and lowerlobe tumors (2 ± 1 mm). Since the
tumor spends more time in the exhalation than in the
inhalation phase, the time-averaged tumor position
was closer to the exhale position. In another study,
using a baseline free-breathing CT scan, the patient’s
couch position was fixed where each tumor showed
its maximum diameter on the image. For 16 tumors,
over 20 sequential CT images were taken every 2 s,
with a 1-s acquisition time occurring during free
breathing (Shimizu et al. 2000). In the sequential CT
scanning, the tumor was not visible in the examina-
tion slice in 21% (75/357) of cases. There were sta-
tistically significant differences between lowerlobe
738
tumors (39.4%; 71/180) and upperlobe tumors (0%;
0/89; P \ 0.01) and between lowerlobe tumors and
middle-lobe tumors (8.9%; 4/45; P \ 0.01) in the
incidence of the disappearance of the tumor from the
image. Michalski et al. (2008) evaluated the repro-
ducibility of respiration-induced lung tumor motion
by obtaining 23 pairs of 4D CT scans for 23 patients.
The group confirmed that the largest extent of respi-
ration-induced motion was along the cranio-caudal
direction, which ranged from \0.5 to 3.59 cm.
Furthermore, three patients had dissimilar respiratory-
induced motion on repeated 4D CT imaging. The
authors concluded that target motion reproducibility
was seen in 87% of cases, and advised verification of
target motion during treatment.
Another aspect of tumor motion relates to its
potential for deformation during the respiration cycle.
Wu et al. (2009) evaluated the extent of tumor
deformation, along with motion in the 3D for 30
patients with early stage NSCLC. They evaluated the
overlap index after accounting for translation of only
image registration, after accounting for translation
and rotation, and also after accounting for transla-
tions, rotation, and deformation. The overlap index
increased only by 1.1 and 1.4%, respectively, when
one accounted for rotation and rotation plus defor-
mation. These results were independent of GTV size
and motion amplitude. The authors concluded that the
primary effect of normal respiration on tumor motion
was the translations of tumors and while tumor rota-
tion and deformation played a minimal role.
4 Treatment Room Planar Imaging
Most of the beneficial effects of IGRT are seen in the
treatment room. As previously mentioned, due to
setup uncertainty and lack of image-guidance, large
planning margins were traditionally added to ensure
that the target is encompassed in the PTV due to setup
uncertainty and tumor motion. This can lead to a
substantial amount of unnecessary irradiation to nor-
mal tissue causing excessive toxicities, or limiting the
dose to the tumor that led to local recurrence. For
example, adding a 0.5-cm thick shell to a spherical
GTV of 4.5 cm in diameter nearly doubles its volume.
Traditionally, electronic portal imaging devices
(EPIDs) acquiring 2D orthogonal views were used to
align and verify treatment position and isocenter
P. Lee and P. Kupelian
(De Neve et al. 1992). Typically, the source energy of
the linear accelerator with megavoltage (MV) energy
was used to produce these EPIDs. This produced
image of poor quality and high imaging dose, while
providing no soft tissue information. Alignment can
be verified using EPIDs either on a daily basis or on
another schedule.
More recently, some of the limitations for onboard
megavoltage EPIDs have been overcome by the use
of kilovoltage (kV) X-ray source to produce kilo-
voltage EPIDs. The source is offset at right angles to
the gantry of the linear accelerator head, opposite to a
flat-panel detector. Kilovoltage EPIDs produces
superior image quality over megavoltage EPIDs while
delivering a lower imaging dose to the patient.
Orthogonally mounted EPIDs in room can be used
to track bone and fiducial markers in real time
(Seppenwoolde et al. 2002; Shirato et al. 2000). The
Cyberknife system (Accuray, Sunnyvale, CA) mounts
a 6-MV miniature linear accelerator source on a
robotic arm and is equipped with an in-room
orthogonal EPIDs system. The robotic arm is able to
move and track a moving lung tumor by tracking
either implanted fiducial markers or soft-tissue cor-
relate, and make adjustments to the beam. Similarly,
the ExacTrac/Novalis Body System (BrainLAB AG,
Heimstetten, Germany) has flat-panel detectors built
in the treatment room that detects kilovoltage sources
from the floor. Treatment adjustments and tracking
can be performed when internal surrogate markers are
used (Fig. 2). These stereoscopic IGRT approaches
are particularly useful for treatment of tumors in the
central nervous system, or spine applications as bone
is readily detected with these images in realtime and
are stable surrogate markers. One advantage of planar
IGRT over volumetric-based IGRT such as CBCT is
the speed at which images are acquired and adjust-
ments can be made. For both Accuray and BrainLab
systems, an automated 2D/3D co-registration algo-
rithm is applied to align a 3D CT patient data set with
2 kV-images. When properly calibrated such that the
exact position of the kilovoltage tubes and detectors
are known with respect to the machine’s isocenter, it
is possible to generate DRRs from planning CT at the
same positions as the kilovoltage images are acquired
and compare with the acquire kilovoltage images. An
automated registration algorithm based on gradient
correlation is used, and corresponding shifts in 3D are
derived.
Image-Guided Radiotherapy in Lung Cancer 739

Fig. 2 Top DRR to

kilovoltage matching using
spine anatomy using paired
oblique stereoscopic imaging
in the treatment room. Bottom
DRR to kilovoltage matching
using implanted fiducial
markers in the left upper lobe
lung tumor during image-
guided SBRT

such as pneumothorax, bleeding, or infection.

5 Fiducial Markers
For these planar IGRT systems to be able to gate or
track the tumor during radiation treatment, radi-
opaque markers need to be implanted in or near the
intended target. The fiducial markers act as internal
radiologic landmarks and are assumed to move with a
constant relationship to the targeted tumor during
therapy. The main disadvantage of using a marker-
based system for IGRT is the risk of complications
A secondary disadvantage is the delay in the therapy
in order for the markers to be placed and stabilized in
the patient’s body. For the thorax, marker implanta-
tion can be done either transcutaneously or trans-
bronchially. One study reported marker implantation
in 15 patients performed transcutaneously and eight
patients transbronchially (Kupelian et al. 2007). Eight
of the 15 transcutaneous implants developed pnemo-
thoraces, six of which required the placement of a
chest tube. None of the patients who underwent
740
transbronchial implantation developed pneumothorax.
The authors concluded that in their patient population
with many elderly patients with emphysema, trans-
cutaneous marker implantation led to a high compli-
cation rate compared to the transbronchial approach.
Kothary et al. (2009) reported a similar study of
percutaneous fiducial implantation in 132 patients
(139 implants) . Of the 139 implantations, 44 were in
the lung. Pneumothoraces were seen in 20 of 44 lung
implantations (45%); a chest tube was required in
only seven of the 44 lung implantations (16%). Of the
139 implantations, 133 were successful with six
procedures leading to marker migration (4.3%). The
authors concluded that percutaneous fiducial implan-
tation is safe and effective with acceptable risks
similar to conventional percutaneous organ biopsy.
Thus, it would appear that the risk of complications
from percutaneous marker implantation is high
dependent on the patient population as well as the
experience of the operator. Nevertheless, implanting
fiducial markers require extra effort and time, and
delays initiation of treatment.
Overall, stereoscopic kilovoltage-imaging has some
distinct advantages and disadvantages. Volumetric
data assessment is difficult based on the planar images.
The system will always require an internal surrogate to
identify the target, track, or gate the treatment, be it
bony anatomy, or radiopaque markers. Complications
from marker implantation and marker migration after
implantations are always valid concerns. The limita-
tions of the planar imaging, however, are compensated
by the simultaneous stereoscopic image acquisitions
allowing for six degrees of freedom positioning
assessment, especially when combined with a robotic
couch system (Novalis) or robotic arm (Cyberknife),
which makes the process efficient and faster than
obtaining volumetric imaging. Also, this system oper-
ates independent of the treatment allowing image
acquisition during treatment, and real-time assessment
of target motion in order to compensate for intrafrac-
tional tumor and organ motion.
Due to the limitations of a marker-based system in
planar-based IGRT, groups have evaluated the feasi-
bility of using respiratory surrogates without internal
fiducials. One study evaluated the feasibility for
markerless tracking of lung tumors in SBRT (Richter
et al. 2010). EPID movies were acquired during SBRT
treatment given to 40 patients with 49 lung targets, and
retrospectively analyzed via 4D CT and EPID in the
P. Lee and P. Kupelian
superior–inferior direction for intra- and inter-frac-
tional variations. Tumor visibility was sufficient for
markerless tracking in 47% of the EPID movies.
Another study compared two respiratory surrogates for
gated lung radiotherapy without internal fiducials
(Korreman et al. 2006). Video clips were acquired after
six patients had fiducial markers implanted in lung
tumors to be used for image-guided SBRT. The posi-
tions of the markers in the clips were measured within
the video frames and used as the standard for tumor
volume motion. Two external surrogates, a fluoro-
scopic image correlation surrogate and an external
optical surrogate were compared to the standard. In
four out of the six cases, fluoroscopic image correlation
surrogate was superior to the external optical surrogate
in the AP-views. In one of the remaining two cases, the
two surrogates performed comparably. In the last case,
the external fiducial surrogate performed best. The
authors concluded that fluoroscopic gating based on
correlations of native image features may be adequate
for respiratory gating.
6 Treatment Room Volumetric
Imaging
More recently, the implementation of in-room volumet-
ric imaging has extended the possibilities of image
guidance. The availability of volumetric imaging with
kilovoltage or megavoltage helical CT or cone-beam CT
(CBCT) scans has allowed the evolution of image guid-
ance for lung cancers in three fundamental ways: (1) as an
alternative method for guidance not relying on implanted
fiducials, (2) assessment of anatomic variations in soft
tissues during a treatment course (e.g. relative location of
tumor and relevant organs at risk, changes in tumor size),
and (3) the future possibility of assessing dosimetric
variations in radiation delivery either on a daily basis or
cumulatively throughout a treatment course.
For tumor localization, in-room CT scans are ade-
quate to localize lung tumors even though images are
typically inferior in quality compared to multi-slice
kilovoltage helical CT scans. In addition, these are
essentially ‘‘slow’’ scans that will give an ‘‘average’’
position of a mobile tumor. Motion ‘‘tracking’’ is not
easily implemented at this stage using in-room CT
scans. However, the fact that the scans provide the
‘‘average’’ position of a mobile lung tumor makes such
scans adequate for initial positioning of patients on a
Image-Guided Radiotherapy in Lung Cancer
Fig. 3 In-room megavoltage CT scan of the chest demonstrating changing tumor size throughout a treatment course
regular basis throughout a treatment course, eliminat-
ing both systematic and random errors in initial set ups.
Even if gating is not performed on the basis of breathing
cycle signals, a motion envelope can be safely designed
around this ‘‘average’’ tumor position. Implanted
fiducials and the associated implantation potential
toxicities are therefore avoided. This avoidance of
additional procedures, such as trans-cutaneous or trans-
bronchial metallic fiducial implanation, in this group of
patients with typically poor general health is an
important advantage of volumetric imaging.
In-room volumetric imaging also allows for a
better evaluation of anatomic variations throughout a
course of treatment beyond the simple location of an
intrathoracic tumor (Fig. 3). Information about tumor
progression or response, relative position of primary
lesions versus lymph node changes that could be
affected by deformations or rotations, development or
resolution of atelectatic areas can be obtained. These
are situations that cannot be assessed without volu-
metric imaging. One such important future applica-
tion of tumor response assessment in patients with
locally advanced lung cancer is the ability to identify
individual patients who have significant tumor
response at some point throughout treatment and
subsequently might benefit from implementation of
adaptive therapy approaches. Such approaches will
push dose escalation beyond currently used doses.
Finally, the availability of soft tissue images does
facilitate potential dosimetric evaluations of delivered
therapies. Megavoltage CT scans versus kilovoltage
conebeam CT scans present different challenges with
741
respect to being utilized for dose evaluations.
However, they do enable assessment of dosimetric
implications of shrinking tumor, changing shapes, and
deforming organs.
7 Conclusion
Image guidance in the treatment of lung cancer is
performed with a variety of techniques ensuring the
accuracy of radiation delivery. These techniques are
essential to major advances in lung cancer treatments
such as stereotactic body radiotherapy delivering
ablative doses. It is important to realize that these
techniques are still works in progress. Future appli-
cations utilizing in-room images are being developed,
such as adaptive therapy. Overall, image guidance has
resulted in significant refinement of radiation delivery
techniques and is an integral part of future advances in
lung cancer radiotherapy.
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 Proton Therapy for Lung Cancer:
State of the Science
David A. Bush

Contents
1 The Clinical Problem .............................................. 744
2 Physical Characteristics of Proton Radiation
Therapy..................................................................... 744
3 Treatment-Planning Considerations
and Comparisons ..................................................... 746
4 Considerations in Delivering Proton Beams
for Lung Cancer ...................................................... 748
5 Clinical Outcomes.................................................... 748
6 Conclusion ................................................................ 750
References.......................................................................... 750
Abstract
Proton radiation for cancer offers to the physician
the ability to conform the high-dose region to
the tumor while reducing the dose of radiation to
adjacent normal tissues. In lung cancer this results
in the ability to deliver higher doses to the targeted
volume while yet permitting greater sparing of
uninvolved and critical normal tissues: lung, heart,
esophagus, and spinal cord. Studies comparing the
distribution of radiation dose show that proton
radiation is superior to photon radiation for lung
cancer, even when factors such as respiratory
motion are considered. Clinical experience con-
firms the feasibility of proton radiation for early-
stage non-small-cell lung cancers; clinical trials
are being performed in locally advanced tumors.
Evidence accumulated thus far indicates that
proton radiation should be further explored.

Abbreviations

BID Twice-daily treatment

CGE (sometimes expressed as GyE) Cobalt gray
equivalent, a means of expressing the
proton dose in relation to Gray units
(cf below) while allowing for the slightly
higher radiobiologic effect of protons
(i.e., 1.1 in relation to cobalt)
D. A. Bush (&) CTV Clinical target volume
Department of Radiation Medicine, GTV Gross tumor volume
Loma Linda University Medical Center, Gy Gray, standard radiation dose. A common
11234 Anderson Street, Loma Linda,
California 92354, USA daily fraction of photon-beam radiation
e-mail: dbush@dominion.llumc.edu is 2 Gy (or 200 centigray (cGy)); a

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 743
DOI: 10.1007/174_2011_256, Ó Springer-Verlag Berlin Heidelberg 2011
744
30-fraction course of radiation at that dose
rate equates to a total dose of 60 Gy
IMPT Intensity-modulated proton therapy
IMRT Intensity-modulated radiation therapy
NSCLC Non-small-cell lung cancer
PTV Planned target volume
SBRT Stereotactic body radiation therapy
1 The Clinical Problem
Although death rates have declined in men and
recently have stabilized in women, presumably due to
reductions in cigarette smoking, lung cancer remains
one of the leading causes of cancer death in North
America (Jemal et al. 2010). Non-small-cell lung
cancers (NSCLC) predominate over the small-cell
variant and are usually associated with a poor prog-
nosis because most patients have locally advanced or
metastatic disease when first seen. The only NSCLC
subgroup associated with a better than 50% 5-year
survival rate consists of individuals having peripher-
ally located T1 or T2 tumors without evidence of
nodal or distant metastases (Mountain 1997). More
than 80% of patients, however, present with more-
advanced stages of disease.
The goal of definitive radiotherapy is to eradicate
intra-thoracic disease while respecting the radiation
tolerance of nearby normal structures by minimizing
the dose to such structures. Various photon (X-ray)
techniques have been employed to effect a therapeutic
advantage, among them are hyperfractionation (mul-
tiple treatments per day); accelerated fractionation
(shorter treatment periods); and dose escalation
(Byhardt et al. 1993; Kong et al. 2005; Rosenman
et al. 2002; Saunders et al. 1997). Most innovative
techniques have focused on conformal treatment
delivery with computer-assisted three-dimensional
therapy planning and, in some cases, intensity-mod-
ulated photon radiotherapy (IMRT) or stereotactic
body radiation therapy (SBRT), in which more-com-
plex treatment-planning and delivery can allow the
radiation oncologist to have better control of doses to
healthy tissues (Grills et al. 2003; Murshed et al.
2004). The intent has been to deliver higher doses to
target volumes in an effort to improve local tumor-
control within the constraints of surrounding normal-
D. A. Bush
tissue regions such as the heart, lung, esophagus, and
spinal cord. Tumor-control rates with photon radia-
tion therapy, however, continue to be disappointing,
in part because of dose-limiting constraints associated
with these normal structures.
2 Physical Characteristics of Proton
Radiation Therapy
Because protons (hydrogen ions) have mass (1835
times that of an electron) and an electric charge, the
physician can control the beam in three dimensions
and thus can deposit radiation doses more accurately
within target volumes while minimizing—or, often,
eliminating—the radiation dose to surrounding non-
targeted tissues. Mass reduces the extent to which the
particle scatters as it passes through tissue; charge
enables interaction with orbiting electrons within
targeted cells, and hence the ionization required to
begin the process of cell destruction; and beam energy
enables the radiation oncologist to control depth of
penetration. The ability to spare normal tissues is
important. The greater the extent to which the phy-
sician can reduce or eliminate the dose to normal
tissues, the lesser is the likelihood that treatment may
need to be compromised or halted because of unac-
ceptable side effects. The ability to reduce or elimi-
nate radiation dose to normal tissues, thanks to the
reduced lateral scatter and sharp dose fall-off of the
proton-beam, not only allows one to deliver the total
needed dose but also yields opportunities to deliver
higher doses without increasing side effects.
The importance of reducing the volume integral
dose to normal tissues has long been noted. In studies
spanning more than 40 years, Philip Rubin and sev-
eral collaborators identified the clinicopathologic
courses of radiation injury in organs and tissues
throughout the body, and also identified tolerance
doses for those organs. Tolerances were identified in
ranges of total doses in which severe or life-threat-
ening complications were likely to occur within five
years of therapeutic radiation; i.e., severe sequelae
would likely occur in 5% of patients treated at the
lower end of the range (TD5/5) and in 50% of patients
treated to the dose at the top of the range (TD50/5)
(Rubin et al. 1978). Although organs and tissues were
separated into categories according to their
Proton Therapy for Lung Cancer: State of the Science 745

Fig. 1 Percent dose deposited per depth in tissue for photon

beams of various energies, and a proton-beam (shown in red)

importance for survival, no ‘‘safe’’ dose (TD0/5) was

identified for any organ; rather, in a classic series of
graphs, Rubin and Casarett (1968) demonstrated that
sublethal doses of radiation initiate a course that can
eventuate in clinical manifestations of radiation
injury, some of which progress to lethality. Studies
such as these highlight the desirability of avoiding
radiation exposure to normal tissues whenever pos-
sible, yet paradoxically, the present ‘‘gold standard’’
of photon radiotherapy, IMRT, increases the volume
of tissues exposed to low doses.
In later studies, Rubin et al. demonstrated early
and persistent elevation of cytokine production fol-
lowing pulmonary irradiation. The temporal rela-
tionship between elevation of specific cytokines and
histological and biochemical evidence of fibrosis
illustrated the continuum of response which, the
Fig. 2 Planning comparison of a single lateral field with a X-
authors speculated, underlies pulmonary radiation ray (left) and proton-beam (right)
reactions and supports the concept of a perpetual
cascade of cytokines, produced immediately after
radiotherapy and persisting until expression of path- treatment of similar target volumes with photon
ologic and clinical late effects (Rubin et al. 1995). beams, these properties permit sparing the treated
Proton-beam therapy offers a means to reduce the lung, opposite lung, heart, esophagus, and spinal cord,
volume integral dose. Protons demonstrate a Bragg in turn allowing for safe dose escalation.
peak: the deposited dose is relatively low upon Because local tumor-control rates are generally
entrance and increases slowly until reaching the pre- poor with conventional photon radiation treatment,
scribed depth in tissue; there, the bulk of the dose is and because evidence exists to indicate that higher
deposited within the targeted volume and no dose is doses may improve tumor-control, investigators have
deposited in distal tissues. The radiation oncologist anticipated a role for proton radiation therapy in
can spread out the Bragg peak to encompass the target patients with lung cancer. Fowler (2003), using bio-
volume while still retaining a relatively low entrance logical modeling, estimated that significant improve-
dose and sparing tissues distal to the direction of ments in local tumor-control and survival are likely to
travel (Fig. 1). In NSCLC, and in contrast to supervene with proton radiotherapy. Because of the
746
normal-tissue-sparing properties of proton beams, not
only does an opportunity exist to achieve effective
disease control without increased normal-tissue
complications, it also may be possible to decrease the
severity of toxicity that is seen in comparable treat-
ment regimens with photons. Accordingly, clinical
investigations of proton and other heavy-charged-
particle treatments for lung cancer are being con-
ducted around the world.
3 Treatment-Planning
Considerations and Comparisons
As noted, proton beams exhibit a Bragg peak, which
yields normal-tissue sparing not possible with photon
beams. This capability persists despite special dosi-
metric circumstances for treating lung cancer with
protons; these circumstances differ from those asso-
ciated with proton therapy elsewhere in the body. For
example, lung cancers are invariably surrounded by
aerated pulmonary parenchyma, in which an essen-
tially water-density-equivalent tumor is surrounded
by substantially less-dense lung tissue. Aerated lung
tissue possesses reduced stopping power compared to
other soft tissues, thus affecting the stopping distance
or distal edge of a spread-out Bragg peak; this can
cause proton beams to travel some distance beyond
the distal edge of the intended target volume, a situ-
ation that is not typically seen in tumors located in
other parts of the body. Additionally, when lung tar-
gets are selected for treatment, the physician needs to
consider physiologic internal target motion, which
depends greatly on the region of the lung in which the
tumor is located: tumors located near the diaphragm,
for example, will show the largest extent of move-
ment owing to respiration. The simplest method
to account for such motion is to measure the
three-dimensional excursion of the tumor and expand
the treatment volume to encompass all possible tumor
positions. For small tumors, with motion parameters
of less than 1 to 2 cm, this method is adequate: the
technique has been used for patients with peripheral
lung tumors of 1 to 4 cm in size at Loma Linda
University Medical Center (LLUMC) for more than a
decade, with an excellent safety profile and a low
incidence of radiation pneumonitis (Bonnet et al.
2001). For larger tumors, and when motion
D. A. Bush
parameters are greater, respiratory monitoring with
beam gating, or respiratory control or compensation,
perhaps via a patient positioning device that moves
the patient during treatment in a way that allows the
target to remain still relative to the treatment beam,
may be employed to significantly reduce the dose to
normal lung tissue.
Reports by Engelsman and colleagues (Engelsman
and Kooy 2005; Engelsman et al. 2006) compared
computerized treatment plans using various tech-
niques to account for respiratory motion in planning
proton treatments. Target expansion utilizing treat-
ment planning in which the planning CT data set
includes multiple phases of the respiratory cycle (the
fourth dimension of 4D planning) was found to pro-
vide the most reliable target coverage. Intrinsic pul-
monary or treatment-related factors, such as pleural
effusion or atelectasis, may also cause uncertainties in
the stopping region of the Bragg peak, and thus need
to be accounted for in therapy planning. If the radi-
ation oncologist suspects that such changes may occur
during the treatment course, she or he may find it
necessary to repeat chest imaging and create a new
therapy plan for any significant anatomic changes.
This practice is referred to as adaptive treatment
planning.
Using four-dimensional computed tomography,
Zhao et al. (2007) investigated dosimetric errors caused
by lung tumor motion in order to find an optimal method
of designing patient compensators and apertures for a
passive-scattering beam delivery system and treating
the patient under free breathing conditions. In their
study, the maximum intensity projection method was
compared to patient-specific internal margin designs
based on a single breathing phase at the end of inhale or
middle of exhale. They found that maximum intensity
projection provided superior tumor dose distribution
compared to patient-specific internal margin designs.
Clearly, great care must be taken in planning
proton therapy for lung cancer. This care is accentu-
ated by the proton beam’s energy-deposition sensi-
tivity to variations in density caused by respiratory
motion. Even allowing for such factors, however,
proton-beam dosimetry improves upon that obtain-
able with photon beams (Fig. 2). The tissue-sparing
capability of the proton-beam is most apparent in the
treatment of early NSCLC (Fig. 3), but significant
sparing also may be achieved when using protons to
treat locally advanced disease.
Proton Therapy for Lung Cancer: State of the Science
Fig. 3 Dose distribution (Top) for a stage I lung cancer treated
with proton-beam shown in axial (left) and sagittal views
(right). Beams include a right lateral, right posterior oblique
and posterior arrangement. Colored contours represent the
Chang et al. (2006) have published a formal
comparison between proton and photon treatment
planning. They analyzed ten patients with inoperable
Stage I lung cancer, comparing proton treatment plans
to three-dimensional (3D) conformal photon plans at
two total dose levels (66 and 87.5 Gy). Analysis
revealed an approximately 50% reduction in non-
target lung dose when protons where used. The nor-
mal lung tissue-sparing effect seemed to be increased
with the high-dose plans, indicating an additional
benefit for dose escalation when proton beams are
used. Fifteen patients with Stage III lung cancer were
also analyzed, comparing 3D photon, IMRT, and
proton-beam plans at two total dose levels (63 and
74 Gy). Again results showed a substantial reduction
in the non-target lung dose, and again, the proton
benefit seemed to be more evident with the higher-
747
percentage of the total prescribed dose. Dose–volume histo-
gram (Bottom) for the same plan. Note the great disparity on
dose delivered to the CTV in comparison to that received by the
spinal cord, heart, esophagus, and lung
dose plans. Doses to the heart, esophagus, and spinal
cord were also found to be significantly reduced. This
study suggests that protons can achieve higher total
doses to the target volumes, with more significant
normal-tissue sparing, than 3D conformal radiation
therapy or IMRT.
Another planning comparison indicates that protons
offer a therapeutic advantage in more-challenging
Stage I cases as well. Register et al. (2010) evaluated 15
patients with centrally or superiorly located (within
2 cm of critical structures) SBRT (50 Gy in 4
fractions). They compared the plans used for those
patients with treatment plans for passive-scattering
proton therapy and intensity-modulated proton therapy
(IMPT). Both forms of proton plans, but notably the
IMPT variant, offered superior sparing of critical nor-
mal structures in these presentations.
748
Similarly, a study by many of the same investi-
gators (Zhang et al. 2010) compared dose–volume
histograms (DVHs) for patients with extensive Stage
IIIB NSCLC treated with IMRT, passively scattered
protons beams, and IMPT. The latter spared more
lung, heart, spinal cord, and esophageal tissue, even
with dose escalation. Compared with passively scat-
tered protons, IMPT allowed further dose escalation,
from 74 Gy to a mean maximal tumor dose of
84.4 Gy while all parameters of normal-tissue sparing
were kept at lower or similar levels. They concluded
that IMPT offered opportunities to pursue individu-
alized radical radiotherapy for such patients.
4 Considerations in Delivering
Proton Beams for Lung Cancer
Today, most heavy-charged-particle-beam treatment
facilities utilize a beam scattering system and passive
beam-shaping devices, such as an aperture to shape
the perimeter of the particle beam and a tissue com-
pensator to shape the distal edge or Bragg peak region
to be in contour with the distal edge of the target.
Such devices are designed carefully, to avoid unnec-
essarily over-radiating pulmonary tissue while
allowing for factors such as altered stopping power in
aerated tissue and physiologic motion (Moyers et al.
2001). Scanning-beam technology, essential to IMPT,
is under development at several treatment centers;
most authorities believe this will provide enhanced
target coverage and normal-tissue protection not
achievable with passive beam-shaping methods
commonly used at present. However, the application
of this technology for treating intra-thoracic targets
presents a significant challenge owing to physiologic
internal motion and potentially unreliable radiologic
path lengths. Until there is a thorough understanding
and reliable control of these variables, it is likely that
scattered beams will continue to be utilized for lung
cancer treatment.
No standardized treatment techniques or beam
arrangements exist for using heavy-charged-particle
beams in patients with lung cancer. The largest
experience is from LLUMC, where proton beams have
been employed since 1995. For patients with solitary
pulmonary nodules, the beam arrangements employed
have been relatively simple, typically consisting of
D. A. Bush
lateral, posterior, and posterior oblique beams. Fre-
quently the lateral beam is preferred, as it typically
will provide the lowest volume of normal lung tissue
exposed. This is in distinct contrast to photon beams,
which will continue through the mediastinum into the
contralateral lung. Lateral proton beams, however, are
very useful for lung cancer treatment, as the Bragg
peak allows the beams to stop without irradiating tis-
sues distal to the tumor; this location frequently is at
the mediastinal pleural surface, thus completely
sparing the mediastinum and contralateral lung. Mul-
tiple treatment beams per day have been utilized;
hypofractionated treatment courses have been
common.
Treatment techniques in patients with locally
advanced lung cancer can be significantly more
challenging. Mediastinal lymph nodes usually are
targeted; then, other sensitive normal-tissue structures
come into play, such as the heart, esophagus, and
spinal cord. Such patients are being treated with
protons and chemotherapy at LLUMC under a clinical
trial. Beam arrangements typically used for such
patients include anterior beams, which stop short of
the spinal cord, along with lateral and posterior
oblique beams. When beams are designed to limit the
dose to the esophagus or spinal cord, it is generally
preferred that the edge of the aperture be used to
protect these structures. If a beam is designed to stop
short of a critical normal-tissue region, great care is
taken to account for physiologic motion and incon-
sistent tissue densities within the chest.
5 Clinical Outcomes
The proton-beam has been the most commonly used
particle beam for treating patients with lung tumors.
The largest reported experience has been with early-
stage NSCLC at LLUMC: patients with clinical Stage
I disease, who are either medically inoperable or
refuse a recommended surgical intervention, are
treated on a clinical trial. The latest report includes 68
patients treated with either 51 CGE or 60 CGE in ten
fractions over a two-week course (Bush et al. 2004).
The area targeted for treatment includes the gross
tumor volume (GTV) as well as a planned target
volume (PTV) that includes additional margin for
respiratory motion. There was no size constraint, and
Proton Therapy for Lung Cancer: State of the Science
Fig. 4 Dose distribution for a patient with stage III lung
cancer treated with proton-beam. Contours represent the lung
tumor and involved nodes (red) and sub-clinically involved
mediastinal nodes (light blue). Distribution shows the percent
of the total dose. The beam arrangement includes a left lateral
and posterior to the CTV (46 CGE) and a left posterior oblique
to the GTV (30 CGE)
centrally located tumors were included; SBRT series
usually exclude the latter. Typically, two to four
beams are utilized for treatment, with at least two
fields being treated each day. Various beam weigh-
tings have been employed, generally with preference
given to lateral beams to minimize lung exposure
(Fig. 3). In this series the median lung v20 was 7%
and the median v60 was 2%. The therapy has been
exceptionally well tolerated, with a low incidence
of grade 1 pneumonitis and no reported grade 3
toxicities.
Disease-specific survival at three years was 73%.
Patients with T1 tumors have achieved local control
in 87% of cases; those with tumors larger than 3 cm
(T2) have had local failures up to 50% at three years,
which has led to a third dose escalation: the current
regimen delivers 70 CGE in 10 equally divided
fractions over two weeks. Although no survival or
local control data are yet available at this dose level,
there does not appear to be any difference in tolerance
after treating nearly 40 patients at this escalated total
dose. No decline of post-treatment pulmonary func-
tion (FEV1 or PO2) has been observed (Bonnet et al.
2001).
In Japan, Nihei et al. (2006) reported on 37
patients with Stage I non-small-cell lung cancer
treated with protons. Most patients received between
80 and 88 Gy equivalent, utilizing fraction sizes
ranging from 3.5 to 4.9 Gy. The reported two-year
local–regional relapse-free survival rate for T1 tumors
was 79%; for T2 tumors the rate was 60%. They
identified six cases of grade 2 and 3 pulmonary
749
Fig. 5 Dose–volume histogram for the total of the irradiated
lung associated with the treatment plan shown in Fig. 4
toxicity, with the majority of these being seen in
patients with larger tumors. Shioyama et al. (2003)
have reported on 28 patients with Stage I non-small-
cell lung cancer treated with proton beams to a
median dose of 76 Gy at 3 Gy per fraction. Patients
with T1 tumors had a 70% overall survival rate at
5 years, while patients with T2 tumors had a signifi-
cantly lower survival rate (approximately 16%). Pul-
monary toxicity was reported as minimal. A recent
report from Nakayama et al. (2010) reaffirms that, in
their experience, proton radiation therapy was effec-
tive and well tolerated in medically inoperable
patients with Stage I NSCLC.
Studies now underway at LLUMC utilize proton-
beam radiotherapy in conjunction with chemotherapy
for treating locally advanced lung cancers. Neo-adju-
vant and concurrent chemotherapy is administered with
proton therapy, which is given as a concomitant boost.
The dose to the sub-clinically involved mediastinum is
46 CGE in 2 CGE fractions with a GTV, BID boost of
30 CGE during the last three weeks of treatment.
It should be noted that the mediastinal CTV is
omitted from most IMRT trials, owing to concerns for
pulmonary toxicity. Despite the much larger target
volumes and dose escalation in such cases, significant
sparing of normal pulmonary tissues still is achieved
(Figs. 4 and 5). In the most recent evaluation of
ongoing results in 19 patients, no Grade 3 or 4 esoph-
ageal toxicities were observed; Grade 3 leukopenia was
seen in two patients; Grade 3 thrombocytopenia
occurred in one individual.
Two Phase II clinical trials are currently underway,
testing the use of proton radiotherapy in combination
with concurrent chemotherapy for locally advanced
(Stage III), inoperable NSCLC. Studies at the
University of Florida (ClinicalTrials.gov identifier:
NCT00881712) and the University of Texas M.D.
Anderson Cancer Center (ClinicalTrials.gov
750
identifier: NCT00495170) are evaluating proton
radiation in combination with Paclitaxel and Carbo-
platin. These safety/efficacy studies are similar, yet
differ in some details. In the Florida study, the pri-
mary outcome measure is to determine whether
reduced acute toxicity from combined concomitant
chemotherapy and radiotherapy occurs, compared to
previous cooperative group trials; disease control,
median overall survival, and 5-year survival are
identified as secondary outcome measures. In the
M.D. Anderson study, median survival time is the
primary outcome measure, with local control, pro-
gression-free survival, disease-specific survival, and
disease-free survival as secondary outcomes. That
study also seeks to determine whether grade 3 and
higher toxicities are reduced; whether pre- and post-
treatment PET/CT are useful in predicting clinical
outcome; and whether a biomarker can be used for
predicting treatment response and toxicities. Patients
in the Florida study receive 80 CGE at 2 CGE per
fraction to PET-positive deposits of gross primary
disease and PET-positive deposits of gross nodal
disease measuring more than 15 mm; 60 CGE at 2
CGE per fraction to PET-positive deposits of gross
nodal disease measuring less than 15 mm; and 40
CGE in 2 CGE per fraction to full nodal stations
containing foci of PET-positive gross disease, or
anatomically adjacent to nodal stations containing
PET-positive gross disease.
6 Conclusion
Evidence shows that dose escalation can provide
improved local tumor-control in NSCLC, and treat-
ment-planning comparisons reveal that proton treat-
ment can further reduce the dose to lung tissues even
when compared to advanced photon treatments such
as IMRT and SBRT. Clinical results indicate that lung
cancer treatment with protons is feasible and has
demonstrated a high level of local tumor-control for
small lesions in reported trials. Severe treatment-
related toxicity has been minimal in both early and
locally advanced cases, thus allowing for further dose
escalation if clinically indicated.
The evidence required to bring new technology
into clinical practice is poorly defined. Historically,
new technology that demonstrates improved dose
D. A. Bush
delivery to the intended target and/or decreases the
dose to surrounding healthy tissues has been sufficient
evidence for many. The proton-beam would seem to
meet these criteria today. Evidence and experience
accumulated thus far, therefore, warrant the continued
exploration of proton therapy for lung cancer. It is
highly likely that the modality has not yet reached its
full potential in the treatment of such tumors. The
next advance likely will be in the routine clinical use
of IMPT. As has been noted above, comparisons of
IMPT plans with scattered-beam proton plans and
IMRT plans show a therapeutic advantage for the
former. Clinical application of IMPT will require
reliable control of the variables associated with
physiologic internal motion and potentially unreliable
radiologic path lengths, but it is highly likely that
such control will be achieved as has occurred with
IMRT. At that point, IMPT may become an effective
clinical tool for treating NSCLC, as well as large and
irregular tumor volumes in other anatomic sites.
Acknowledgments I would like to thank William Preston
EdD for manuscript editing and preparation.
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 Carbon Ion Radiotherapy
in Hypo-Fractionation Regimen and Single
Dose for Stage I Non-small-Cell Lung Cancer
T. Miyamoto, N. Yamamoto, M. Baba, and T. Kamada
Contents
1 Introduction.............................................................. 754
2 Hypo-Fractionation Irradiation .............................
2.1 Materials and Methods ..............................................
2.2 Results........................................................................
2.3 Discussion ..................................................................
2.4 Conclusions................................................................
3 Single-Dose Irradiation ...........................................
3.1 Patients and Treatment..............................................
3.2 Staging .......................................................................
3.3 Results and Discussion..............................................
References.......................................................................... 761
T. Miyamoto (&)
N. Yamamoto
M. Baba
T. Kamada
Research Center Hospital for Charged Particle Therapy,
National Institute of Radiological Sciences (NIRS),
4-9-1 Anagawa, Inage-Ku, Chiba 263-8555, Japan
e-mail: t-miyamoto@min-iren-c.or.jp
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_257, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
It has been more than one decade since we started
carbon ion radiation therapy (CIRT) for non-small-
755 cell lung cancer (NSCLC) in November 1994.
755 From 1994 to 1999, we conducted a phase I/II
756 clinical trial for stage I NSCLC with CIRT and
757
demonstrated an optimal dose of 90 GyE in 18
758
fractions over 6 weeks and 72 GyE in 9 fractions
759 over 3 weeks for achieving more than 90% local
759
759 control with minimal pulmonary damage. In the
759 following phase II study from 1999 to 2003, the
total dose was fixed at 72 GyE in 9 fractions over
3 weeks and at 52.8 GyE for stage IA and at
60 GyE for stage 1B in 4 fractions over 1 week.
Targets were irradiated from four oblique direc-
tions. A respiratory-gated irradiation system was
used for all irradiation sessions. On these two
phase II schedules combined, the 5-year local
control rate for 131 primary tumors of 129 patients
was 91.5%. The local control rate for T1 and T2
tumors was 96.3 and 84.7%, respectively. While
there was significant difference in control rate
between T1 and T2, there was no significant
difference in histology between squamous and
non-squamous type. The 5-year cause-specific
survival rate of the patients was 67.0% (IA: 84.4,
IB: 43.7), and their overall survival was 45.3%
(IA: 53.9, 1B: 34.2). No adverse effects greater
than grade III occurred in the lung. In this way, the
treatment period and fractionation were shortened
and lessened from 18 fractions over 6 weeks to 9
fractions over 3 weeks and further to 4 fractions
over one week. Finally it reached a single dose.
Since 2003, 210 patients have already been treated
753
754
with CIRT in single dose increasing 28, 32, 34, 36,
38, 40, 42, 44, 46, and 48 GyE. Compared with the
previous fractionation regimen, CIRT in single-
dose is demonstrating low morbidity and high
QOL. The 5-year local control rate of 131 tumors
with doses more than 36 GyE was higher than
80%. The 5-year cause-specific and overall sur-
vival rate of 131 patients were 1.5 and 52.6%,
respectively. Of the whole evaluate, we will finally
recommend that CIRT in single dose is the best for
the treatment of the peripheral type of stage I
NSCLC.
1 Introduction
In 1998, lung cancer became the leading cause of
cancer-related death in Japan, as in the Western
countries. Surgery plays a pivotal role in the curative
treatment for non-small-cell lung cancer (NSCLC),
but it is not necessarily the best treatment for elderly
persons and/or patients with cardiovascular and pul-
monary complications. Conventional radiotherapy as
an alternative, however, produces a 5-year survival
rate in merely 10–30% (Jeremic et al. 2002) of the
patients treated due to poor control of the primary
tumor. These results were quite inferior to those by
surgery (Mountain 1997; Naruke et al. 2001)
Recently, new modalities such as stereotactic radio-
therapy (Nagata et al. 2005; Onishi et al. 2004) and
proton radiotherapy (Bush et al. 1999; Shioyama et al.
2003) have been tried but have not yet been demon-
strated as valid alternatives.
Heavy particle beams penetrate the body and
abruptly stop to form a Bragg peak as energy is lost;
A great deal of energy is deposited to cause dense
ionization of high linear energy transfer (LET) (Kanai
et al. 1997). These physical properties help achieve
excellent dose-localization for deep-seated tumors,
sparing critical normal organs while high LET exerts
a powerful biological effect. It can be expected that
heavy particle beams can improve tumor control
without increasing toxicity.
In 1984, the Japanese government decided to
construct the Heavy Ion Medical Accelerator in Chiba
(HIMAC) at our Institute: National Institute of
Radiological Sciences (NIRS). HIMAC was com-
pleted in November 1993 (Hirao et al. 1992).
T. Miyamoto et al.
Table 1 Results of phase I/II study on CIRT for stage I
non-small-cell lung cancer
Adverse effects on lung
(1) Minimum damage on lung (Grade 3 radiation pneumonitis
was 2.7%)
(2) Influenced by dose, respiration movement, and port
direction and number
Local control
(1) Dose dependent, but less dependent to tumor size and
histological type
(2) More than 90% by optimal dose and evidenced by
pathological CR
Survival
(1) Influenced by local control state and tumor size
(2) Less decreased by node and intralober (PM1) metastasis
(3) More decrease by local failure, pleuritis carcinomatosa
and distant metastasis
For clinical use, carbon ion beams were selected
based on preclinical experiments (Kanai et al. 1999).
Dose escalation is essential to improve the effec-
tiveness of carbon ion radiation therapy (CIRT) for
lung cancer. Yet this increases the risk of pulmonary
toxicity. The phase I/II clinical trials with CIRT for
stage I NSCLC were initiated in October 1994 and
concluded in February 1999. The additional purpose
was to develop correct, reliable, and safe irradiation
techniques for CIRT. As a result of two successive
dose escalation phase I/II studies, a regimen of
90 GyE (Gray equivalents) in 18 fractions over
6 weeks (NIRS protocol number: #9303) and 72 GyE
in 9 fractions over 3 weeks (#9701) were chosen as
the optimal dose (Miyamoto et al. 2003), and the
following results (Table 1) were obtained: (1) The
local control rate was dose dependent, and reached
more than 90% at 90 GyE with a regimen of 18
fractions over 6 weeks and 72 GyE with a regimen of
9 fractions over 3 weeks. Both the doses were deter-
mined to be optimal. It was found that setting the
provisional target by allowing for the difference with
CT value can prevent marginal recurrence (Koto et al.
2004). (2) The damage on lung was minimum,
showing that Grade 3 radiation pneumonitis occurred
in 2.7%. Respiratory-gated and 4-portal oblique irra-
diation excluding opposed ports proved successful in
reducing the incidence of radiation pneumonitis.
(3) The survival was strongly influenced by the
local control and tumor size in the primary lesion.
Carbon Ion Radiotherapy in Hypo-Fractionation Regimen and Single Dose
(4) The early detection of nodal and intralobar
metastasis followed by irradiation with carbon beams
can prevent the survival rate from further decreasing.
(5) The local failure, distant metastasis, and pleuritis
carcinomatosa caused to decrease the survival.
2 Hypo-Fractionation Irradiation
Following the phase I/II study, we have conducted
two successive phase II studies: the total dose was
fixed at 72 GyE in 9 fractions over 3 weeks (#9802)
(Miyamoto et al. 2007a, b) and at 52.8 GyE for stage
IA and at 60 GyE for stage IB 4 fractions over one
week (#0001) (Miyamoto et al. 2007a, b). Using the
two hypo-fractionation regimen, the phase II trial was
initiated in April in 1999 and closed in December in
2003 accruing a total number of 129 patients.
2.1 Materials and Methods
2.1.1 Carbon Ion Beams, HIMAC
and Treatment Systems
Carbon ion beams with 290, 350 and 400 MeV/
nucleon energy were generated in the HIMAC syn-
chrotron and delivered through its transport system to
the irradiation system in the treatment room. In this
system, the beams are broadened and shaped to a
three-dimensional (3-D) tumor contour. For 3-D dose
delivery, the key technology is to spread out a sharp,
monoenergetic Bragg peak (SOBP) of carbon ion
beams by using a range modulator to cover the tumor
thickness (Kanai et al. 1997, 1999). The reference
point was set so as to be the center of SOBP. In this
procedure, the patients were immobilized with cus-
tom-made devices in a semi-cylindrically shaped
rotary capsule set on a CT couch or a treatment couch.
CT planning is performed using the HIPLAN (Endo
et al. 1996), which was specifically developed for 3-D
treatment planning with respiratory-gated CT images.
Patient positioning and verification are performed
using the patient set-up devices, digital reconstructed
radiographs (DRR), online portal fluoroscopic radio-
graphs and metal markers made of iridium-wire as a
landmark. A respiratory-gated irradiation system was
developed and employed to minimize respiratory
movements of the tumor and reduce treatment volume
(Minohara et al. 2000).
755
The carbon ion radiation dose was expressed in
terms of Gray equivalents (GyE). The GyE values are
calculated by multiplying the physical dose with the
relative biological effectiveness (RBE), which is
approximately 3.0 at 0.8 cm from the distal end of the
SOBP (Kanai et al. 1997, 1999).
2.1.2 Patients
Patients with a peripheral type of stage I NSCLC who
were inoperable or refused surgery were eligible for
this study. Primary tumor had to be histologically
proven and measurable. The patient’s performance
status (PS) was between 0 and 2 according to the
WHO criteria. The patient had to have no history of
radiotherapy to the target, and no prior chemotherapy
within 4 weeks of therapy. They had to have no
intractable infection and active multiple cancers. Each
patient gave his/her written informed consent,
approved by the Ethics Committee at our Institute.
After therapy, the patients’ progress was verified
twice a year by the members of the Working Group
for Lung Cancer.
One hundred and twenty nine patients with 131
primary lesions were enrolled into this study. The 51
primary tumors of 50 patients were treated by carbon
beam irradiation alone using the fixed total dose of
72 GyE in 9 fractions over 3 weeks (#9802). The
remaining 79 patients had 80 stage I tumors. The IA
stage tumors were treated with the fixed dose of
52.8 GyE and the IB tumors with the fixed does of
60 GyE in 4 fractions over one week (#0001). The
patients had an average age of 74.5 years. The gender
breakdown was 92 males and 37 females. The tumors
consisted of 72 of T1 and 59 of T2. The average
tumor size was 31.5 mm in diameter. By type of
cancer, there were 85 adenocarcinomas, 43 squa-
mous cell carcinomas, 2 large cell carcinomas and
1 adenosquamous cell carcinoma. Medical inoper-
ability stood at 76% (Table 2).
2.1.3 Treatment
The targets were usually irradiated from four oblique
directions without prophylactic elective nodal irradi-
ation (ENI). A greater than 10 mm margin was set
outside gross target volume (GTV) to determine the
clinical target volume (CTV). The planning target
volume (PTV) was set by adding an internal margin
(IM) to the CTV. The IM was determined by extend-
ing the target margin in the head and tail directions by
756 T. Miyamoto et al.

Table 2 Treatments and Characteristics of 129 patients with stage 1 NSCL (1999.4–2004.9)
Protocol no 9802 0001 Total
Fractionation total dose (GyE) 9fr/3w 72 4fr/1w 52.8 (T1), 60 (T2) –
Patient number 50 79 (77)* 129 (127)*
Lesion number 51 80 131
Age 74 75 74.5
Gender
Male 38 54 92
Female 12 25 37
PS
0 0 8 8
1 50 68 118
2 0 3 3
T factor (stage)
T1 (IA) 30 42 72
T2 (IB) 21 38 59
Tumor size (mm) 30.9 32.1 31.5
Histology
AD 32 53 85
SQ 19 24 43
L 0 2 2
Ad-Sq 0 1 1
Refusal of surgery 14 17 31 (24%)
Medical inoperability 36 62 98 (76%)
*The two patients were twice treated in the protocol firstly 9802 and the 0001 secondly

a width of 5 mm, resulting in the successful preven-
tion of marginal recurrence caused by respiration
movement (Koto et al. 2004). Figure 1 shows the dose
distribution map for a representative case.
2.1.4 Statistical Analysis
Local control and survival were assessed by the
Kaplan–Meier method. For statistical testing, the
long-rank test was used.
2.2 Results
All patients were followed until death with a median
follow-up time of 50.8 months ranging from
2.5 months to 70.0 months. The local control rate for
the 131 primary lesions was 91.5% (Fig. 2). The local
control rate for the T1 (n = 72) and T2 (n = 59)
tumors was 96.3 and 84.7% and for squamous
cell type (Sq) (n = 43) and non-squamous cell type
(non-Sq) (n = 88) was 87.1 and 93.8%, respectively.
While there was significant difference (p = 0.0156)
in tumor control rate between T1 and T2, there was no
significant difference (p = 0.1516) between squa-
mous and non-squamous in T1 ? T1, and in the both
T1 and T2. However, with respect to squamous cell
type the local control was 100% for T1 (n = 17) and
78.0% for T2 (n = 26), and there was near significant
difference (p = 0.0518). The local control of non-
Squamous tumors was 95.3% for T1 (n = 55), and
91.0% for T2 (n = 33), and there was no significant
difference (p = 0.3364).
The 5-year cause-specific survival rate of the 129
patients was 67% (Fig. 2), breaking down into 84.8%
for the stage IA and 43.7% for the stage IB tumors.
The 5-year overall survival rate was 45.3% (Fig. 2),
breaking down into 53.9% for the stage IA and 34.2%
for the stage IB tumors.
The toxicity of CIRT to the skin and lung
was assessed according to the RTOG (acute) and
Carbon Ion Radiotherapy in Hypo-Fractionation Regimen and Single Dose 757

Fig. 1 a Axial image: dose

distribution for tumor (right
lower lobe) receiving a total
carbon ion dose of 60 GyE
from 4 directions (4-portals).
Yellow line: PTV red line:
96% of the prescribed dose
orange line: 90%, green line
50%, blue line 30%, and
violet line: 10%. b Coronal l
image. c Sagittal image

Local Control (n=131)& Survival(n=129) 126 patients were at grade 1 and 3 patients were at
1.0 grade 2. No more than grade 3 reactions were
Local Control and Survival rate

Local Control (5y) 91.5%

Cause-specific(5y) 67.7%
observed.
0.8
The cause of death was assessed. Sixty-two out of
0.6 Overall (5y) 45.3% 129 patients (48.8%) were dead at that time, with 31
dying of the lung tumor treated with CIRT. Five of
0.4
the patients died due to primary recurrence and 26
0.2 patients due to metastasis and dissemination. For the
remaining 31 patients, intercurrent diseases were the
0.0
cause of death.
0 10 20 30 40 50 60
Month after treatment

Fig. 2 Five-year local control (blue), cause-specific (red), and 2.3 Discussion
overall (green) survivals in 129 patients with 131 stage I
NSCLC after start of CIRT on the following two phase-II In the present study, we used the fixed total dose of
regimen combined: the total dose was fixed at 72 GyE in 9 72 GyE in 9 fractions over 3 weeks, and of 52.8 GyE
fractions over 3 weeks (#9802) and at 52.8 GyE for stage IA
and at 60 GyE for stage 1B in 4 fractions over 1 week (#0001) for stage IA and 60 GyE for stage IB 4 fractions over
one week. Using this schedule which was optimized
RTOG/EOTRC (late) as shown in Table 3. The early in the phase I/II study by CIRT (Miyamoto et al.
skin reaction was assessed for 131 lesions and the late 2003), we conducted a phase II clinical trial for 129
skin reactions for 128 leisions. In acute reaction 125 patients with stage I NSCLC.
lesions were at grade 1 and 6 at grade 2. In late As a result, the local control, cause-specific, and
reaction 126 lesions were at grade 1, one at grade 2 overall survival rates for 129 patients were 91.5, 67.0,
and one at grade 3. The lung reaction was clinically and 45.3%, respectively. And toxicity in skin, lung
assessed for 129 patients. There were 127 patients at and bone was of a minimum.
grade 0 and 2 patients at grade 2 in early reaction. Local recurrence out of 131 primary cancers of
There were 126 patients who were followed up for 129 patients occurred in 9 cases (6.8%). The average
late effect. Among them, 7 patients were at grade 0, recurrence time was 17.2 months in an average
758 T. Miyamoto et al.

Table 3 Adverse effects by CIRT

Early reaction (RTOG) Late reaction (RTOG/EORTC)
Lesion no 0 1 2 3 4B Lesion no 0 1 2 3 4B
Skin 9802 51 0 50 1 0 0 51 0 49 1 1 0
0001 80 0 75 5 0 0 77* 0 77 0 0 0
Total 131 0 125 6 0 0 128 0 126 1 1 0
Lung 9802 50 49 0 1 0 0 50 0 48 2 0 0
0001 79 78 0 1 0 0 76* 7 68 1 0 0
Total 129 127 0 2 0 0 126 7 116 3 0 0
*3 cases were not observed due to the early death

ranging from 7 to 39 months. According to the pre-
vious study, the observation period required to
determine the local control of the irradiated lesions
was at least 3 years after therapy. However, the
present study suggests that a longer observation time
is needed. Prolonged survival guarantees more reli-
able observation of local control results.
For the correct assessment of local control of the
patients who could not be observed for such a long
time as they died of metastasis/dissemination or
intercurrent disease, a histological approach by
repeating bronchoscopy was performed and proved to
be no viable tumor cells in the collected specimens
(Miyamoto et al. 2007a, b). And this definite tumor
control by CIRT was also observed in autopsy and
operated cases (Yamamoto et al. 2003). Such high
and definite tumor control appears to be an out-
standing feature of CIRT which may be primarily due
to the radiobiological nature of the high LET beams,
and may contribute to a higher survival rate for stage I
NSCLC. The failure in local control for a primary
tumor directly influences the poor survival of stage I
NSCLC patients (Miyamoto et al. 2003, 2007a, b).
There were 20 loco-regional recurrences (15.7%):
7 regional nodes, 1 intrabronchial metastasis and 3
intralobar pulmonary metastases (PM1) in addition to
9 primary recurrences. Their incidence was close to
that of surgery (7.5%) (Harpole et al. 1995), 11%
(Martini et al. 1995). When the 11 regional metastasis
were diagnosed after the first CIRT for a primary
tumor, the second CIRT was given to the 9 regional
recurrences and photon therapy to two recurrences.
All of the regional recurrences could be controlled by
re-treatment irradiation, and the patients were found
to have the same survival as the patients without
primary recurrence. Martini et al. (1995) reported any
resections less than lobectomy and no lymph node
dissection had adverse effects on recurrence and sur-
vival. On the contrary, our treatment strategy for
regional recurrence is thought to have been validated
as the standard surgical procedure for stage I NSCLC.
With clinical stage I NSCLC, our 5-year overall
survival results were somewhat inferior to the surgical
ones (Miyamoto et al. 2007a, b; Yamamoto et al.
2003). The survival difference may be due to age
difference between the two groups. The incidence of
death due to recurrence in the surgical group was 29
or 36% whereas that of death due to intercurrent
diseases was 19% or a few % (Martini et al. 1995). On
the other hand, there was more frequent intercurrent
death (60%) than recurrence death (40%) with our
patients. Generally speaking, such a high frequency of
intercurrrent death might be due to the advanced age
of our patients who were 10 years older on average
than the surgical patients.
Compared with pulmonary damage reported in
stereotactic radiotherapy for stage I NSCLC (Nagata
et al. 2005; Onishi et al. 2004), the incidence and
severity in our patients seem to be clearly low. These
less adverse effects for the lung were achieved as a
result of the small irradiated volume (V20 #9802) T1
(n = 30) mean 5.5% (2.3–11.6), T2 (n = 39) mean
6.4% (1.0–12.3), #0001 T1 (n = 41) mean 4.8%
(1.1–13.2) T2 (n = 21) mean 7.6% (2.6–13.9)
achieved with excellent dose distribution by carbon
ion beams due to the formation of a Bragg peak
contrast with X-ray as a permeating beam.
2.4 Conclusions
By conducting the phase II study using a total dose of
72 GyE in a regimen of 9 fractions over 3 weeks
and 52.8 GyE for stage IA and 60 GyE for stage IB
Carbon Ion Radiotherapy in Hypo-Fractionation Regimen and Single Dose
4 fractions over one week the following results were
obtained: (1) The higher local control rate of 91.5%
was achieved. In addition, there was statistical diff-
erence in the local control rate for T1 and T2 and near
significant for squamous cell carcinoma and non-
squamous cell carcinoma of T2. (2) The damage on
lung was minimum, showing no Grade 3 radiation
pneumonitis. (3) The cause-specific survival rates
were equal to that of surgery while the overall sur-
vival was less than that of surgery due to high inci-
dence in intercurrent death due to an advanced age
and complication. CIRT, which is an excellent new
modality in terms of a high QOL and ADL, is a valid
alternative to surgery for stage I cancer, especially for
elderly and inoperable patients.
3 Single-Dose Irradiation
Throughout the 10 years of CIRT for clinical stage I
NSCLC as already described, the treatment period
and fractionation were shortened and lessened from
18 fractions over 6 weeks to 9 fractions over 3 weeks
and further to 4 fractions over one week. Finally it
reached a single dose (Miyamoto 2004). Till now, 210
patients have already been treated with single-dose
CIRT (#2010) with doses increasing 28, 32, 34, 36,
38, 40, 42, 44, 46, 48 and 50 GyE since April 2003.
The single dose CIRT therapy has been demonstrated
to lead to low morbidity and a high QOL. The efficacy
of single dose CIRT close to that of the previous
fractionation regimen with increasing dose and
attained the same level of local control and survival
rate with doses more than 36 GyE.
3.1 Patients and Treatment
Patient eligibility was same as that of the previous
fractionation regimen. Until the present time, 201
patients were treated with single-dose CIRT. Among
them, 198 patients who had elapsed 6 months after
therapy were documented for analysis. An average
age was 74.2 year-old. The number of male to female
was 144–54. There were 134 adenocarcinoma, 62
squamous cell carcinoma, 3 large cell carcinoma and
one mucoepitheloid cancer. The number T1 and T2
was 108 and 85, respectively. These characteristics of
patients were almost same to those of the previous
759
patients shown in Table 2. Irradiation is performed in
B room equipped with vertical and horizontal ports. A
patient immobilized in rotary capsule is rotated at +20
and -20° and irradiated in order from each port
within 15 min, and completed from 4-ports within 1 h
and a case was shown after therapy in Fig. 3. As
phase I/II study, a dose of 28 GyE for 6 patients (pts),
32 GyE for 27 pts, 34 GyE for 34 pts, 36 GyE for 18
pts, 38 GyE for 14 pts, 40 GyE for pts 20, 42 GyE for
15 pts, 44 GyE for 44 pts, and 46 GyE for 20 pts was
delivered.
3.2 Staging
For staging, CT scan of the chest and upper abdomen,
enhanced MRI scans of the brain, bone scans and
bronchoscopy were routinely performed. Regional
lymph nodes greater than 1 cm in the short axis on the
contrast-enhanced CT images were taken to serve as
evidence of positive metastasis. A 11C-Methionine
PET scan was routinely taken for confirmation as
previously (Yasukawa et al. 1996). However, there
were some false positive cases by PET scan. Since
2005, we adopted EBUS (endobronchial ultrasound-
guided transbronchial needle aspiration) to exclude
the false positive node by PET scan (Nakajima et al.
2008).
3.3 Results and Discussion
For adverse effects, there was no grade III for early
(198 pts) and late (128 pts) lung reaction and in early
(198 pts) and late (198 pts) skin reaction. The 5-year
local control rate, cause-specific and overall survival
of 131 patients who received a dose of 36–46 GyE
was 80.5, 71.5, and 52.6%, respectively as shown in
Fig. 4. The local control rate of T1 (78 patients) and
T2 (53 patients) was 86.7 and 78.4% and three years
later, it was 82.8 and 78.4%, respectively. This study
is on-going, now. These results are further improving
with increasing dose. Recently, we could determine
an optimal single-dose of CIRT for the treatment of
peripheral type of stage I NSCLC, and all of the
results will be published.
The massive single dose technique for uterine
cancer was first initiated in the 1920s in Germany
after the First World War (Ludwig Seitz and Hermann
760
Fig. 3 In B room equipped with vertical and horizontal ports,
a patient immobilized in rotary capsule is rotated at +20° and
-20° and irradiated in order from each port within 15 min. The
irradiation was completed from 4-ports within one hour (the
Wintz 1920). In an attempt to concentrate on the
tumor control dose in the cancer, Ludwig Seitz and
Hermann Wintz used a method involving irradiation
from multiple portals to improve spatial dose distri-
bution and control the radiation dose to within the
tolerance dose of the normal tissue. This method is
called the Erlangen technique that constitutes the
basic rationale for present-day radiotherapy. Since the
beam used at the time had a poor depth/dose ratio and
the dose measurement techniques available were still
not sufficiently sophisticated, visceral injuries and
other side-effects occurred quite frequently. After
this, improvements have been made until the present
T. Miyamoto et al.
upper left and middle). Dose-distribution curve for stage IB
adenocarcinoma of the lung treated with single-dose CIRT
from four oblique directions (the right) and the tumor response
(the lower) before and after 6 years at irradiation was shown
by using a drawn-out dose fractionation regimen with
few adverse effects. The present standard technique is
a fractionation regimen in which the required radia-
tion dose is spread into fractions over a certain period
of time. The goal is to achieve the highest possible
local control within the permissible range of radiation
injury, especially late injuries. However, this is a
substantially palliative method of radiotherapy. Now
that we have been able to apply carbon ion beams that
have a superior depth dose distribution for radio-
therapy and select the treatment for stage I lung
cancer, our single-dose regimen is a revival of the
technique using a heavy particle beam created as the
Carbon Ion Radiotherapy in Hypo-Fractionation Regimen and Single Dose 761

at more than 36.0GyE (n=131) Acknowledgments We thank the following doctors who par-
ticipated in this long-term study: Hideki Nisimura, Masasi
1 Koto, Toshiyuki Sugawara, Tomoyasu Yasiro, Naoki Hirasawa,
Local Control and survival rate

Kenji Kagei, Mio Nakajima, Toshio Sugane, Kyousan Yosik-

.8 awa, Susumu Kandatsu, Hidefumi Ezawa and Kennosuke
Kadono. We also thank the doctors who constantly supported
.6 and advised: Hirohiko Tujii, Jun-etsu Mizoe, Suhou Sakata,
Kozo Morita, Takeshi Iinuma, and Toru Matzumoto, and
.4 Takehiko Fujisawa of the Working group for lung cancer.

.2 Local control(5 years) : 80.5%

Cause-specific (5 years) : 71.5% References
0 Over all (5 years) : 52.6%

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 Novel Cytotoxic Agents in Combination
with Radiation in the Management
of Locally Advanced Non-Small Cell
Lung Cancer: Focus on Pemetrexed
and Nab-Paclitaxel [Abraxane]
Corey J. Langer

Contents
1 Introduction.............................................................. 765
2 Pemetrexed ............................................................... 766
3 Abraxane................................................................... 768
4 Conclusions ............................................................... 770
References.......................................................................... 770
Abstract
The treatment of locally advanced, unresectable
non-small cell lung cancer (NSCLC) remains
challenging. Radiation therapy (RT) combined with
chemotherapy is more effective than RT alone, and
concomitant chemoradiation has yielded improved
survival compared to sequential chemotherapy and
RT, but at the cost of heightened toxicity, especially
esophagitis. The majority of randomized chemora-
diation trials have featured cisplatin or carboplatin
based chemotherapy, usually in combination with
either etoposide or paclitaxel, with median survival
times of 16–18 months, and 5 year survival rates of
15 to 20% at best. In this chapter, we describe recent
studies employing pemetrexed and nab-paclitaxel,
each of which has been extensively investigated in
advanced disease, the former yielding improved
progression-free and overall survival in adenocarci-
noma both in the frontline and maintenance setting,
the latter yielding superior response rates in
squamous cell carcinoma compared to conventional
paclitaxel in chemo-naïve patients. Both agents have
demonstrated safety and efficacy in LA-NSCLC in
conjunction with RT. Whether these agents will ever
prove superior to either etoposide or paclitaxel in this
setting will require careful, phase III testing.

1 Introduction
C. J. Langer (&) In fit patients with minimal weight loss (i.e., less
Abramson Cancer Center,
than 5–10% from baseline) and intact PS (ECOG PS
University of Pennsylvania,
Philadelphia, PA 19104, USA 0-1), concurrent chemoradiation with a platinum-
e-mail: corey.langer@uphs.upenn.edu based combination has emerged as the standard

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 765
DOI: 10.1007/174_2011_314, Ó Springer-Verlag Berlin Heidelberg 2011
766
approach in locally advanced NSCLC (Furuse et al.
1999; Curran et al. 2010; Aupérin et al. 2007). In the
absence of significant comorbidity, hearing loss, or
renal compromise, in patients who can readily tol-
erate an acute fluid load, the use of the etoposide–
cisplatin combination with XRT, both started on
day 1, is generally favored. The minimum ‘‘accep-
ted’’ dose of radiation in this setting is 60 Gy,
although multiple studies are now evaluating doses
of 74 Gy and higher using newer technology. In
frailer or older patients, and in those with significant
co-morbidity including renal insufficiency (creati-
nines of 1.5–3.0), hearing loss, congestive heart
failure, or severe COPD, cisplatin is often discarded
in favor of carboplatin, and many will substitute
paclitaxel for etoposide. Choy et al. (2002) investi-
gated regimens featuring carboplatin AUC 2 weekly
and paclitaxel 45–50 mg/m2 weekly, both initiated
on day 1 of thoracic radiation, followed by two
cycles of full-dose chemotherapy once radiation was
completed; and Movsas et al. (2005) assessed this
approach in the cooperative group setting.
Many have argued that carboplatin-based therapy
is inferior to cisplatin in the treatment of LA-NSCLC,
but recent data from Japan in a combined modality
trial [West Japan Oncology Group Trial (WJTOG
0105)] evaluating various concurrent chemoradiation
regimens suggests de facto therapeutic equivalence
(Yamamoto et al. 2010). Investigators led by
Nobuyuki Yamamoto compared their erstwhile stan-
dard of MVP with weekly carboplatin in combination
with either irinotecan or paclitaxel during XRT; in
each arm, those without disease progression or unto-
ward toxicity went on to receive two cycles of full-
dose chemotherapy during the ‘‘consolidation’’ period
using the same agents administered during XRT. The
paclitaxel–carboplatin regimen resulted in less toxic-
ity, fewer dose reductions or omissions, and equiva-
lent, if not superior, survival at 5 years: 19.5% versus
17.5% for MVP and 17.8% for irinotecan/carboplatin.
In fairness, this study also compared second-gen-
eration with third-generation chemotherapy; but this
may be the only phase III trial to attempt to address
the platinum question, which, to be frank, arises
constantly. Regardless, a platinum backbone grafted
onto XRT is the standard for combination therapy in
LA-NSCLC. Whether newer agents such as peme-
trexed or abraxane can do as well or better than
established agents in LA-NSCLC remains to be seen.
C. J. Langer
2 Pemetrexed
Based on a phase III trial showing equivalent
response rate, PFS, and survival with considerably
less toxicity compared to docetaxel, pemetrexed, a
synthetic, multi-targeted antifol, was first approved in
the second line setting in advanced NSCLC (Hanna
et al. 2004). More recently, it was approved for first-
line treatment in advanced non-squamous NSCLC
based on a phase III trial showing a survival advan-
tage for pemetrexed–cisplatin compared to gemcita-
bine–cisplatin (Scagliotti et al. 2008). In addition, the
JMEN study demonstrated a >5 months survival
advantage for maintenance therapy with pemetrexed
in a similar population of non-squamous cell NSCLC
compared to intravenous placebo in patients whose
disease had stabilized or responded to first-line
treatment with a platinum-based combination
(Ciuleanu et al. 2009). As a result of these studies, use
of pemetrexed in advanced NSCLC has expanded
globally.
Pre-clinical data suggest additivity, if not synergy
for pemetrexed with radiation. Due to its effective-
ness, ease of administration, and relatively mild tox-
icities observed in advanced non-small cell lung
cancer, pemetrexed has also been explored in locally
advanced NSCLC. A study led by Seiwert et al.
(2007) was among the first to assess the role of
pemetrexed and platinum in combination with radia-
tion in locally advanced NSCLC. As a phase I effort,
this study included patients with oligo-metastatic
disease as well as esophageal cancer. Treatment was
administered every 21 days. Regimen 1 included
pemetrexed (200–600 mg/m2), while regimen 2 fea-
tured pemetrexed (500 mg/m2) with escalating car-
boplatin doses (AUC = 4 ? 6). Both regimens
included concurrent radiation, escalated from 40 to
66 Gy. Thirty patients (18 with locally advanced
NSCLC and 12 metastatic with dominant local
symptoms) were enrolled. All but one had an ECOG
PS of 0 or 1. All dose levels were tolerable for regi-
men 1 (n = 18: 15 NSCLC and three esophageal
cancers) and regimen 2 (n = 12: all NSCLC). In
regimen 1, one dose-limiting toxicity consisting of
grade 4 esophagitis/anorexia occurred at 500 mg/m2.
Grade 3 neutropenia was the main hematologic tox-
icity and occurred in three of 18 patients. In regimen
2, one dose-limiting toxicity consisting of grade 3
Focus on Pemetrexed and Nab-Paclitaxel
esophagitis occurred at a pemetrexed dose of
500 mg/m2 and carboplatin dose of AUC = 6. Grade
3/4 leukopenia was the main hematologic toxicity and
occurred in four of 12 patients. Four complete
responses (two pathologically proven) and eight partial
responses were observed in those receiving regimen 2.
When systemically active chemotherapy doses were
reached, further dose escalation was discontinued, and
a phase II dose-range was established: pemetrexed
500 mg/m2 in combination with carboplatin
AUC = 5–6. The authors concluded that this regimen
was feasible and have since exported it to the coop-
erative groups. Of note, in contrast to many other
regimens, systemically active chemotherapy doses
of pemetrexed and carboplatin could be given
concurrently with XRT, without untoward toxicity.
To further determine efficacy, safety, and
optimal dosing, the cancer and leukemia Group B
study 30407 recently completed evaluating this
regimen in patients with unresectable stage III
NSCLC. Govindan et al. (2009) mounted a ran-
domized phase II trial of pemetrexed and carboplatin
in combination with radical thoracic radition
(70 Gy). Half the enrollees also received cetuximab
[C225]. In addition to two full cycles of carboplatin
and pemetrexed during XRT and two administered
after completion of XRT, all patients were assigned
to receive four additional cycles of single-agent
pemetrexed 500 mg/m2 as consolidation. Due to the
timeframe in which the trial was designed and
conducted, all histologies were allowed. Although
the overall incidence of grade 3/4 toxicities was
fairly high, they were generally tolerable and
essentially similar in both arms, with the exception
of skin rash: 4% in the non-cetuximab arm versus
41% in the cetuximab arm. There was no obvious
exacerbation of esophagitis or pulmonary toxicity
compared to other similar trials incorporating plati-
num combinations. Median survival proved to be
22 months in both arms. Because data in patients
with advanced NSCLC showed a survival benefit for
pemetrexed predominantly in nonsquamous NSCLC
(Scagliotti et al. 2008), the results were analyzed by
histology. For squamous versus nonsquamous his-
tology, median OS was 18 months and 22 months
and 18-month OS proved 48 and 56%, respectively.
These differences were not statistically significant,
but suggest a potential preferential advantage for
pemetrexed in non-squamous histology.
767
Choy et al. (2010) have adopted a similar regimen
looking at combination pemetrexed with either cis-
platin or carboplatin in combination with XRT.
Patients with inoperable stage IIIA/B NSCLC were
randomized to pemetrexed 500 mg/m2 every 21 days
combined with carboplatin AUC = 5 (PCb) or cis-
platin 75 mg/m2 (PC) intravenously every 21 days for
3 cycles. All points received concurrent RT 64–68 Gy
(2 Gy/day, 5 days/week, days 1–45). Consolidation
pemetrexed 500 mg/m2 IV every 21 days for 3 cycles
began 3 weeks after completion of chemoradiation.
The primary endpoint of this ongoing trial was 2-year
overall survival; secondary endpoints included tox-
icity, response rate, time to progression, and median
survival. Since June 2007, 72 patients have been
evaluated: 34 received PCb: 38 received PC. Average
dose compliance was 89% or higher for each agent.
Average dose compliance for CRT was 91.2% for
those receiving PCb and 85.5% for those receiving
PC. Dose interruptions occurred in 23 patients.
Amongst 15 patients evaluable for response in the
PCb arm, there was one CR (6.7%) and six patients
with PR (40.0%); seven patients (46.7%) had stable
disease and one had PD (6.7%). The PC arm featured
20 evaluable patients, of whom one (5.0%) had a CR,
11 (55%) had a PR, five (25.0%) had SD, and three
(15.0%) had PD. The authors of this abstract justifi-
ably concluded that pemetrexed and radical thoracic
RT in combination with either carboplatin or cisplatin
appeared well-tolerated in the treatment of locally
advanced NSCLC.
Other studies have evaluated pemetrexed and tho-
racic RT exclusively in combination with cisplatin. A
study led by Brade et al. (2011) was restricted to good
prognosis patients with \5% weight loss and good
performance status. Enrollees received two cycles of
pemetrexed (300, 400, or 500 mg/m2 on days 1 and 22
for dose Levels 1, 2, and 3/4, respectively) and cis-
platin (25 mg/m2 days 1–3 for dose Levels 1–3;
20 mg/m2 days 1–5 for dose Level 4) concurrent with
thoracic radiation (61–66 Gy in 31–35 fractions).
Consolidation consisted of two cycles of pemetrexed/
cisplatin (500 mg/m2, 75 mg/m2) 21 days apart, after
concurrent therapy. Between January 2006 and
October 2007, 16 patients were accrued. No dose-
limiting toxicities were observed. Median radiation
dose was 64 Gy (range, 45–66 Gy). Rates of signifi-
cant Grade 3/4 hematologic toxicity were 38 and 7%,
respectively. One patient experienced Grade 3 acute
768
esophagitis, and two experienced late grade 3 esoph-
ageal strictures, successfully managed with dilatation.
One patient experienced Grade 3 pneumonitis. The
overall response rate was 88%. At median follow-up of
17.2 months, 1-year overall survival was 81%. Long-
term PFS and OS are still pending. The authors con-
cluded that full-dose systemic pemetrexed was safe in
combination with full-dose cisplatin and thoracic
radiation in Stage IIIA/B NSCLC, and that pemetrexed
was, in fact, the first third-generation cytotoxic agent
tolerable at full dose in this setting. Phase II study
evaluating dose Level 4 is ongoing.
Another ongoing, global, randomized Phase III
trial titled PROCLAIM [H3E-MC-JMIG] in the
context of chemoradiation compares pemetrexed–
cisplatin followed by single-agent pemetrexed during
the consolidation period with standard chemoradia-
tion (ClinicalTrials.gov. NCT00686959; H3E-MC-
JMIG). Eligibilty stipulates fit patients with stage
IIIA/B non-squamous, non-small cell lung cancer
patients. Enrollees are allowed up to 10% weight
loss from baseline. Patients in the investigational
arm receive pemetrexed 500 mg/m2 plus cisplatin
75 mg/m2 every three weeks for 3 cycles during
concurrent thoracic radiation to 66 Gy followed by
consolidation with pemetrexed 500 mg/m2 for 4
cycles. In the standard arm, patients receive cisplatin
and etoposide for 2 cycles during concurrent thoracic
radiation followed by two additional cycles of con-
solidation, with clinician’s choice of either cisplatin/
etoposide, cisplatin/vinorelbine, or carboplatin/pac-
litaxel. The primary endpoint is overall survival;
accrual of 900 patients is planned (ClinicalTrials.
gov. NCT00686959; H3E-MC-JMIG). As of 2/28/11,
316 individuals have been enrolled. To date, no
untoward or unusual toxicities have been noted. The
role of pemetrexed in LA-NSCLC will likely be
determined by the results of this trial. If it is formally
approved in this setting based on survival, there
is little doubt that this agent will supplant etopo-
side in the therapy of locally advanced, unresectable
NSCLC.
Meanwhile, ClinicalTrials.gov. lists at least ten
ongoing studies evaluating pemtrexed in combina-
tion with radiation in locally advanced NSCLC, as
well as other settings. Of note, a randomized phase
II sequencing trial, being conducted in Amsterdam,
assigns ‘‘good prognosis’’ patients to either induction
therapy with pemetrexed–cisplatin for 3 cycles
C. J. Langer
followed by concurrent radiation and pemetrexed for
2 cycles or to concurrent radiation and pemetrexed
for 2 cycles, followed by three cycles of consolida-
tion cisplatin-pemetrexed (ClinicalTrials.gov. NCT0
0497315). A separate trial orchestrated by the
Intergroupe Francophone de Cancerologie Thoraci-
que assesses concurrent pemetrexed 500 mg/m2 and
cisplatin 75 mg/m2 IV every 3 weeks for 4 cycles in
combination with C225 and full dose RT (66 Gy;
2 Gy/fx) (ClinicalTrials.gov. NCT01102231). Eligi-
bility stipulates stage III, non-squamous cell NSCLC
and performance status 0–1. An aborted trial con-
ducted the Hoosier Oncology Group grafted single-
agent pemetrexed onto standard dose thoracic RT
(60 Gy) in poor prognosis patients with compro-
mised PS or >10% baseline weight loss. (Clinical-
Trials.gov. NCT00497315. Unfortunately, only eight
patients were enrolled between 8/08 and 12/10
leading to discontinuation of this study. Finally,
there is some suggestion that pemetrexed may help
reduce the incidence of CNS metastases. The Line-
berger Cancer Center of UNC, led by Stinchcombe
and colleagues is assessing concurrent pemetrexed
and WBRT in NSCLC patients with newly diag-
nosed brain metastases (ClinicalTrials.gov. NCT00
280748 UNC-LCCC 0409). Thirty patients with KPS
of 70 or greater were accrued between 5/05 and
6/09. The results are not yet available.
3 Abraxane
Abraxane [nab-paclitaxel] or ABI007 is a novel,
solvent-free 130 nm nanoparticle albumin-bound
formulation of paclitaxel, designed without the dose-
limiting solvent Cremophor EL used in the standard
solvent-based paclitaxel. Like paclitaxel, it is also
a radiosensitizer. A dose-finding study showed a
higher maximum tolerated dose for nab-paclitaxel
compared to solvent-based paclitaxel and linear
pharmacokinetics (Ibrahim et al. 2002; Nyman et al.
2005). Nab-paclitaxel is well tolerated without ste-
roid or H1/H2 blocker premedication when given at
doses higher than standard solvent-based paclitaxel;
it has produced significant tumor response in patients
with non-small cell lung cancer (Green et al. 2006),
metastatic breast cancer (Ibrahim et al. 2005), and
head and neck and anal canal cancers (Damascelli
et al. 2001).
Focus on Pemetrexed and Nab-Paclitaxel
Preclinical xenograft studies have shown that cel-
lular transport of nab-paclitaxel differs from that of
standard solvent-based paclitaxel. Albumin is trans-
ported via a gp60-mediated mechanism into endo-
thelial cells and via a secreted protein acidic and rich
in cysteine (SPARC)–mediated mechanism into
SPARC-overexpressing tumor cells, resulting in
selective nab-paclitaxel accumulation in tumors
(Desai et al. 2006; Sparreboom et al. 2005; ABI 007.
Drugs 2004) with a 33% higher intra-tumoral con-
centration of paclitaxel following administration of
ABI-007compared with an equal dose of cremophor-
based paclitaxel in the MX-1 xenograft model
(Sparreboom et al. 2005). In addition, elevated
expression of Cav-1 has been identified in various
tumor types including breast, prostate, lung, pancre-
atic, renal, and esophageal cancer. Caveolin-1 over-
expression has been linked to tumor aggressiveness
and poor patient prognosis. Albumin-bound nano-
particles (e.g. Abraxane) may help exploit Caveolin-1
to deliver more drug selectively to tumors. The
unique formulation also enables paclitaxel to traverse
the circulation more seamlessly than standard paclit-
axel wedded to a cremaphor vehicle. As a conse-
quence, nano-particle technology can help reduce the
toxicities typically associated with paclitaxel,
including neuropathy, myalgias, and arthralgias.
Abraxane was first approved in metastatic and
recurrent breast cancer on the basis of a phase III trial
comparing this agent to standard paclitaxel (Gradishar
et al. 2005). Abraxane achieved a superior overall
response rate and a significantly longer time to tumor
progression (P = 0.029). The incidence of peripheral
neuropathy was somewhat higher, but easily managed
and more rapidly reversible, compared to standard
paclitaxel. There was also a lower incidence of neu-
tropenia. The much shorter infusion schedule also
favored abraxane over paclitaxel [10–30 min com-
pared to 3 h].
A recent phase III trial enrolling over 1,000
patients with advanced NSCLC compared weekly
abraxane in combination with carboplatin (nab–PC)
administered every 3 weeks to standard paclitaxel and
carboplatin (PC) every 3 weeks; the results showed
therapeutic equivalency between the two regimens
and improved response rate in squamous cell carci-
noma (Socinski et al. 2010). Baseline and histologic
characteristics were well balanced. Dose intensity of
paclitaxel was higher in nab–PC compared to PC
769
(82 vs. 65 mg/m2/wk). With respect to overall
response rate (ORR), nab–PC was superior to PC both
by independent radiographic review [33 vs. 25%,
P = 0.005; 1.31 response ratio (RR), 95% CI: 1.08,
1.59], and by investigator review [37 vs. 30%,
P = 0.008; 1.26 RR, CI: 1.06, 1.50]. Histologic
analysis showed significantly improved ORR for nab–
PC (n = 228) versus PC (n = 221) in squamous cell
carcinoma (SQC) patients (41 vs. 24%, P \ 0.001,
IRR; 1.67 RR). Nab–PC was well tolerated, with
significantly improved safety profile, including
reduced neurotoxicity and hematologic toxicity ver-
sus. PC. Longterm PFS and OS data are still pending,
but this phase III trial has rekindled interest in the use
of abraxane concurrently with radiation, although
there remains a relative paucity of trials investigating
this strategy.
In preclinical models, such as murine ovarian
carcinoma [OCa-1], abraxane results in radio-sensi-
tization of the tumor without increased normal tissue
damage (Wiedenmann et al. 2007). In one study, mice
bearing syngeneic ovarian or mammary carcinomas
were treated with nab-paclitaxel, radiation, or a
combination of both. Nab-paclitaxel was administered
at 90 mg/kg, 1.5 times the maximum tolerated dose
for solvent-based paclitaxel. Endpoints included
antitumor efficacy (growth delay, radiocurability, and
cellular effects) and normal tissue toxicity (gut and
skin). Nab-paclitaxel demonstrated single-agent anti-
tumor efficacy against both tumor types and acted as a
radiosensitizer. Combined with radiation, nab-paclit-
axel produced supra-additive effects when given
before radiation. Nab-paclitaxel significantly increased
radiocurability by reducing the dose yielding 50%
tumor cure (TCD50) from 54.3 to 35.2 Gy. Tumor
histology following nab-paclitaxel treatment was
characterized by pronounced necrotic and apoptotic
cell death and mitotic arrest. Nab-paclitaxel did not
increase the normal tissue radio-response. These
improved effects were achieved without increased
normal tissue toxicity to either rapidly or slowly
proliferating normal tissues, although the drug dose
was 50% higher than the maximum tolerated dose of
solvent-based paclitaxel.
Work by Harari et al. (2010) has demonstrated
similar promise. Optical imaging using phase display
technology showed that HVGGSSV-guided nab-
paclitaxel selectively targeted irradiated tumors and
showed 1.48 ± 1.66 photons/s/cm2/sr greater radiance
770
compared with SGVSGHV-nab-paclitaxel, and
1.49 ± 1.36 photons/s/cm2/sr greater than nab-paclit-
axel alone (P \ 0.05). Bio-distribution studies showed
a more than fivefold increase in paclitaxel levels
within irradiated tumors in HVGGSSV-nab-paclitaxel
treated groups compared with either nab-paclitaxel
or SGVSGHV-nab-paclitaxel at 72 h. Both Lewis
lung carcinoma and H460 lung carcinoma murine
models showed significant tumor growth delay for
HVGGSSV-nab-paclitaxel compared with nab-paclit-
axel, SGVSGHV-nab-paclitaxel,and saline controls.
HVGGSSV-nab-paclitaxel treatment induced a sig-
nificantly greater loss in vasculature in irradiated
tumors compared with unirradiated tumors, nab-
paclitaxel, SGVSGHV-nab-paclitaxel, and untreated
controls.
In the clinical realm, an ongoing phase I/II trial in
LA-NSCLC at Vanderbilt-Ingraham Cancer Center
(ClinicalTrials.gov. NCT00544648), is evaluating
carboplatin (AUC 2) IV over 30 min following
nab-paclitaxel, once/week 9 7 weeks, in combina-
tion with 3D conformal radiotherapy or intensity-
modulated radiation therapy (IMRT), 2.0 Gy/day 9
5 days/week for 33 days during weeks 1–7 (total
dose = 66 Gy). The starting dose for nab-paclitaxel
is 40 mg/m2. The primary endpoint is determination
of the maximum tolerated dose (MTD) of paclitaxel
albumin-stabilized nanoparticle formulation when
given concurrently with carboplatin and radiation
followed by two courses of paclitaxel albumin-
stabilized nanoparticle formulation with carboplatin
as consolidation. Once the MTD is established, the
phase II component of the study will determine
progression-free survival in patients with stage III
unresectable non-small cell lung cancer treated.
Secondary objectives focus on overall survival as well
as biocorrelatives including tumor specimen analysis
for the secreted protein acidic and rich in cysteine
(SPARC) gene expression.
A separate trial in poor prognosis patients with
locally advanced NSCLC will evaluate induction
therapy with carboplatin and weekly nab-paclitaxel,
followed by concurrent full dose radiation and erl-
otinib (ClinicalTrials.gov. NCT00553462). While this
study does not assess the radiosensitizing properties
of nab-paclitaxel directly, it attempts to mitigate
toxicity by incorporating this agent in the induction
setting prior to definitive RT in patients who might
have trouble tolerating standard treatment. Enrollees
C. J. Langer
are considered poor risk based either on NCI CTC
performance status (PS) 2 or C10% weight loss
within the past 3 months.
4 Conclusions
Pemetrexed has established its role in phase II and
phase III trials in LA-NSCLC. It is clear, at this point,
that this agent can be combined at full systemic
dose with either carboplatin or cisplatin with
respectable PFS and OS in cooperative group studies
in LA-NSCLC and acceptable toxicity. Whether
pemetrexed and platinum can supplant etoposide
and cisplatin will be determined by the results of
an ongoing phase III trial that is enrolling well.
Nab-paclitaxel, while clearly radiosensitizing in pre-
clinical and xenograft models, is much further behind
in clinical trials integrating this agent with XRT in
LA-NSCLC. Assuming the results of phase III testing
in advanced NSCLC leads to its approval, then interest
in investigating this agent in LA-NSCLC will grow.
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 Novel Targeted Agents
and Radiopharmaceuticals in Lung Cancer
Martin J. Edelman and Nadia Ijaz
Contents
1 Overview ................................................................... 773
2 Epidermal Growth Factor Receptor ..................... 775
2.1 EGFR Monoclonal Antibodies.................................. 775
2.2 EGFR Tyrosine Kinase Inhibitors ............................ 777
3 Vascular Endothelial Growth Factor.................... 778
3.1 VEGF Antibodies ...................................................... 778
3.2 VEGFR TK Inhibitors ............................................... 779
4 PARP Inhibitors ...................................................... 780
5 Proteasome Inhibitors ............................................. 780
6 HDAC Inhibitors ..................................................... 781
7 mTOR Inhibitors ..................................................... 782
8 IGF-IR Inhibitors .................................................... 782
9 Cyclooxygenase-2 Inhibitors................................... 783
10 ALK Targeted Inhibitors........................................ 784
11 Aurora Kinase and Polo-like
Kinase Inhibitors ..................................................... 784
12 Hedgehog Pathway Inhibitors................................ 785
13 Radiopharmaceuticals ............................................. 785
References.......................................................................... 787
M. J. Edelman (&)  N. Ijaz
University of Maryland Greenebaum Cancer Center,
Rm. N9E08 22 S. Greene Street, Baltimore,
MD 21201, USA
e-mail: medelman@umm.edu
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_312, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
The use of chemotherapy in addition to radiation
has unquestionably improved outcomes in both
small cell and non-small cell lung cancer.
However, as in advanced disease, a plateau in
efficacy has been reached. Over the past several
decades numerous receptors and pathways respon-
sible for normal cellular growth, maintenance and
development have been identified. Derangements of
these pathways frequently result in cancer, perpet-
uate cancer or result in resistance to treatment with
chemotherapy and/or radiation. New agents target-
ing these pathways are now becoming available.
Many of these have the potential to potentiate
existing agents and/or radiation. In addition,
radiation can itself be targeted by coupling radio-
isotopes to a moiety that will bind with receptors
that are aberrantly expressed in cancer.
1 Overview
Many commonly employed antineoplastic agents
including the platinums, vinca alkaloids, and taxanes
have been incorporated into chemoradiotherapy reg-
imens that have improved the potential for cure in
patients with locally advanced (stages IIIa, b) non-
small cell lung cancer (NSCLC). Platinum and eto-
poside combined with radiotherapy is the standard,
and potentially curative, approach for limited stage
(stages I–IIIB) small cell lung cancer. The extensive
research done along the lines of molecular structures
and biochemical pathways over the past several dec-
ades has resulted in numerous new agents with
773
774 M. J. Edelman and N. Ijaz

Table 1 Novel targets and Class Agent(s)

agents currently under clinical
investigation VEGF Bevacizumaba
Sorafeniba
Sunitiniba
Vandetaniba
Cediranib
Epidermal growth factor receptor (EGFR) Cetuximab (C225)a
Panitumumaba
Erlotiniba (OSI 774)
Gefitiniba (ZD 1839)
PARP inhibitor Veliparib (ABT-888)
Iniparib (SAR240550, BSI-201)
Olaparib
PF1367338 (AG-014699)
MK 4827
AZD2281 (KU-0054436)
Proteasome inhibitors Bortezomiba
Carfilzomib
MLN-9708
CEP-18770
HDAC inhibitors Vorinostata
Etinostat
COX-2 Celecoxiba
Apricoxib
ALK inhibitor Crizotinib (PF1066)
IGF-R inhibitors Figitumumab
IMC-A12
RI-507
AMG-479
SCH-717454
INSM-18
OSI-906
XL-228
Hedgehog pathway inhibitors GDC-0449
PF-04449913
TAK-441
IPI-926
LDE225
mTOR inhibitors Sirolimusa
Everolimusa
Radaforolimus
(continued)
Novel Targeted Agents and Radiopharmaceuticals in Lung Cancer
Table 1 (continued) Class
Polo-like kinase inhibitors
Aurora kinase inhibitors
a
FDA approved for at least one indication
potential benefit for the treatment of cancer. These
‘‘targeted’’ drugs act through pathways necessary for
the development and continued growth of malignan-
cies. Many of them have the potential for combination
with existing agents as well as with radiation. Some
of these agents are still in the early phase of devel-
opment while others are in standard clinical use. None
has yet to be conclusively demonstrated to be of use
in combination with radiotherapy in lung cancer,
Table 1.
This chapter will discuss some of the many novel
agents and pathways that are currently under inves-
tigation in NSCLC. It will focus on the potential of
these agents to be employed with radiotherapy.
Targeted radiopharmaceuticals are also discussed.
In many cases, these agents are just entering clinical
trials and information is limited. Ongoing studies are
listed with their National Clinical Trials number
(clinicaltrials.gov) to allow the reader to determine
the status of the study.
2 Epidermal Growth Factor Receptor
Constitutive activation of the epidermal growth factor
receptor (EGFR) may be a critical step in malignant
proliferation, angiogenesis, and metastasis (Wood-
burn 1999). The initial impetus to target the EGFR
was based upon its frequent overexpression in many
malignancies including NSCLC and the association of
overexpression with poor prognosis. As a conse-
quence of the development of agents targeting the
775
Agent(s)
BI 6727 (Volasertib)
TAK 960
NMS-1286937
AT9283
AS703569
CYC116
PF-03814735
MLN8237
LBH589B
SNS 314
AMG900
GSK1070916A
EGFR, activating EGFR mutations were discovered
and found to occur in approximately 10% of patients
with NSCLC. These mutations are both prognostic
and predictive of response to EGFR tyrosine kinase
inhibitors (TKIs) (Lynch et al. 2004; Paez et al.
2004). Two major families of agents, antibodies, and
TKIs, have been developed that target the EGFR.
Two antibodies are approved that target the external
domain (cetuximab, panitumimab) and two TKIs
(gefitinib and erlotinib) target the ATP binding site of
the internal domain.
2.1 EGFR Monoclonal Antibodies
The monoclonal antibodies (MAbs) are directed at the
extra-cellular domain of the EGFR receptor and
include drugs such as cetuximab (C225), pani-
tumumab and matuzumab (EMD 72000). Cetuximab,
a chimerized antibody of the IgG1 subclass, was
originally derived from a mouse myeloma cell line.
The chimerization process resulted in an antibody
with a relative affinity five-fold greater than the
murine monoclonal antibody (Mendelsohn et al.
1990). Cetuximab blocks binding of EGF and TGFa
to EGFR and inhibits ligand-induced activation of this
tyrosine kinase receptor. Cetuximab also stimulates
EGFR internalization, effectively removing the
receptor from the cell surface for interaction with
ligand (Baselga et al. 1993). Cetuximab binds spe-
cifically to the epidermal growth factor receptor
(EGFR, HER1, c ErbB-1) on both normal and tumor
776
cells, and competitively inhibits the binding of EGF
and other ligands, such as TGFa. Binding of cetux-
imab to the EGFR blocks phosphorylation and acti-
vation of receptor-associated kinases, resulting in
inhibition of cell growth, induction of apoptosis, and
decreased matrix metalloproteinase and vascular
endothelial growth factor (VEGF) production.
Cetuximab has shown to enhance the activity of
cytotoxic drugs in colorectal cancer and radiotherapy
in head and neck cancer. Single agent activity has also
been demonstrated in colorectal cancer. Cetuximab is
approved for the treatment of colorectal cancer also
approved in combination with radiotherapy for the
treatment of head and neck cancer. Panitumumab is a
high-affinity fully human IGG2 monoclonal antibody
against EGFR. Compared with cetuximab, it is much
less likely to cause severe infusion reactions, does not
require premedications nor a loading dose. It is cur-
rently approved as a single agent in advanced colo-
rectal cancer in Kras wild type disease.
Two phase III trials of cetuximab in combination
with chemotherapy have been performed in NSCLC
with variable results. In the United States, a random-
ized multicenter phase III trial BMS099 evaluated
Cetuximab and first-line taxane/carboplatin chemo-
therapy as first-line treatment in advanced NSCLC
(Lynch et al. 2010). Six hundred and seventy six
chemotherapy-naïve patients with advanced stage
NSCLC were enrolled. There was no requirement to
demonstrate EGFR expression. Patients were ran-
domly assigned to cetuximab and taxane/carboplatin
versus taxane/carboplatin. The taxane was at the
investigator’s discretion and could be either paclitaxel
or docetaxel. The primary end point was progression-
free survival assessed by independent radiologic
review committee. The median progression-free sur-
vival (as determined by the IRRC) was 4.40 months
with cetuximab/TC versus 4.24 months with TC
(hazard ratio [HR] = 0.902; 95% CI, 0.761 to 1.069;
P = 0.236). Median overall survival was 9.69 months
with cetuximab/TC versus 8.38 months with TC
(HR = 0.890; 95% CI, 0.754 to 1.051; P = 0.169).
ORR-IRRC was 25.7% with cetuximab/TC versus
17.2% with TC (P = 0.007). The safety profile of this
combination was manageable and consistent with its
individual components. The addition of cetuximab to
TC did not significantly improve the primary end
point, though there was significant improvement in the
overall response rate. An analysis of specimens from
M. J. Edelman and N. Ijaz
the trial failed to identify any predictive biomarkers
(Khambata-Ford et al. 2010). In contrast, the FLEX
trial combined cisplatin, vinorelbine, and cetuximab
versus cetuximab alone in a population of advanced
lung cancer patients selected for EGFR expression by
immunohistochemistry (though the degree of expres-
sion was not specified) and found that the EGFR
inhibitor resulted in a significantly improved overall
survival (Pirker et al. 2009). One thousand one hun-
dred and twenty five patients were randomly assigned
to chemotherapy plus cetuximab (n = 557) or che-
motherapy alone (n = 568). The experimental arm
demonstrated superior survival (median 11.3 vs.
10.1 months; HR = 0.871; P = 0.044). Recently pre-
sented data indicate that the benefit see with cetuximab
is dependent upon the degree of EGFR experiment
(Pirker et al. 2011).
None of the targeted agents has been evaluated as
thoroughly with radiotherapy as cetuximab. A phase
III trial in head and neck cancer has demonstrated
superiority of cetuximab combined with radiotherapy
versus radiotherapy alone and has led to its approval
in combination with radiotherapy (Bonner et al.
2006). The efficacy and safety of cetuximab were
studied in combination with radiation therapy in a
randomized, controlled trial of 424 patients with
locally or regionally advanced squamous cell carci-
noma of the head and neck versus radiation alone.
Four hundred twenty-four patients with Stage III/IV
SCCHN of the oropharynx, hypopharynx, or larynx
with no prior therapy were randomized (1:1) to
receive cetuximab plus radiation therapy (211
patients) or radiation therapy alone (213 patients).
Radiation therapy was administered for 6–7 weeks as
once-daily, twice-daily, or concomitant boost. Start-
ing one week before radiation, cetuximab was
administered as a 400-mg/m2 initial dose, followed by
250 mg/m2 weekly for the duration of radiation
therapy (6–7 weeks). Cetuximab was administered
1 h prior to radiation therapy, beginning week 2.
The patient characteristics were similar across the
study arms. 56% of the patients received radiation
therapy with concomitant boost, 26% received once-
daily regimen, and 18% twice-daily regimen. The
main outcome measure of this trial was duration of
locoregional control, which was superior for the
combination of cetuximab with radiation (24.4 vs.
14.0 mo, HR = 0.68, P = 0.005) with an advantage
also demonstrated for the secondary endpoint of
Novel Targeted Agents and Radiopharmaceuticals in Lung Cancer
overall survival (49.0 vs. 29.3 mo, HR = 0.74,
P = 0.03).
Two major studies have been reported that evalu-
ate cetuximab in combination with chemoradiother-
apy in locally advanced NSCLC, with conflicting
results. RTOG 0324 (n = 93) combined carboplatin,
taxol, radiotherapy, and cetuximab in treatment of
inoperable stage III patients. There was no selection
based upon EGFR status. The median survival of
22.7 months is among the best ever demonstrated for
a cooperative group study population. Importantly,
other than rash, there was little evidence that the use
of cetuximab was associated with increased toxicity
(Blumenschein et al. 2011). Another cooperative
group study, CALGB 30407, evaluated carboplatin,
pemetrexed, cetuximab, and concurrent radiotherapy
versus carboplatin, pemetrexed, and concurrent
radiotherapy. Similar to the RTOG trial, other than
increased skin rash, there was no difference in tox-
icity. However, survival on the two arms was similar
and the addition of cetuximab was not felt to be
beneficial (Govindan et al. 2009). Currently, a ran-
domized phase III trial is in progress (RTOG 0617,
NCT00533949) is testing the addition of cetuximab as
well as radiation dose to chemoradiotherapy in locally
advanced, inoperable NSCLC.
2.2 EGFR Tyrosine Kinase Inhibitors
The EGFR TKIs were the first targeted therapies to
have become established for the treatment of lung
cancer. Gefitinib, erlotinib, and related quinazoline
molecules are small molecule inhibitors of the intra-
cellular domain of the EGFR (Woodburn 1999). Only
one agent, erlotinib, is fully approved for the treat-
ment of NSCLC in the United States. Gefitinib, ini-
tially granted approval in the US, is currently
approved in many European and Asian countries. The
initial trials with both agents were negative. The
drugs were combined with standard platinum based
chemotherapy in unselected populations as first-line
chemotherapy for advanced NSCLC. Four random-
ized trials with this design were negative (Giaccone
et al. 2004; Herbst et al. 2004; Gatzemeier et al. 2007;
Herbst et al. 2005). It is an interesting distinction, that
despite the common target of the two classes of anti-
EGFR agents is the demonstrated benefit of EGFR
antibodies in addition to cytotoxic chemotherapy in
777
contrast to the lack of benefit from the addition of
EGFR TKIs to cytotoxics. Ultimately, approval for
erlotinib resulted from the BR.21 trial conducted by
the National Cancer Institute of Canada Clinical
Trials Group which compared erlotinib to placebo in
previously treated patients with NSCLC (Shepherd
et al. 2005). The results of this study led to approval
of erlotinib for the treatment of NSCLC after pro-
gression on 1 or 2 prior chemotherapy regimens. This
trial demonstrated improved response rate, time to
progression, survival, and quality of life compared
with placebo. A similar, larger trial termed, Iressa
Survival Evaluation in Lung Cancer (ISEL) compared
gefitinib with placebo. This study produced similar
results in terms of response and quality of life; how-
ever, the 1-year survival endpoint failed to reach the
statistically defined criteria for superior survival and
resulted in withdrawal of approval in the United
States, though the drug is still approved in many parts
of Europe and Asia. Subsequent studies have evalu-
ated gefitinib versus carboplatin/paclitaxel in first-line
therapy and against docetaxel in second line therapy
and found the agent to be active and well tolerated.
Erlotinib is also approved for use in the maintenance
setting after initial benefit from platinum based che-
motherapy (Cappuzzo et al. 2010).
Since the initial studies versus placebo that dem-
onstrated the activity of the EGFR TKIs, a number of
studies have been performed that have expanded and
further refined the role of these drugs. Most impor-
tantly, and as a direct result of the observation that
some patients (i.e. scant or never smokers, women,
Asians), experienced truly dramatic benefit in terms
of both radiographic response and progression-free
survival, activating mutations (primarily in exons 19
and 21) in the EGFR were discovered. Retrospective
analyses as well as prospective studies have now been
performed that confirm the importance of these
mutations. The Iressa Pan-Asia Study (IPASS)study
tested gefitinib versus chemotherapy as initial therapy
in scant or never smokers with advanced NSCLC
(Mok et al. 2009). There was a clear progression-free
survival advantage for gefitinib, though no overall
survival advantage, apparently due to cross-over.
Retrospective analysis demonstrated that the benefit
was mostly due to treatment of patients with acti-
vating mutations. Prospective studies have now been
accomplished in patients with activating mutations
demonstrating unprecedented response rates and
778
progression-free survival (Maemondo et al. 2010).
At this time, the optimal use of these agents in
advanced disease, i.e. initial use, in maintenance or at
time of relapse in mutated patients is controversial,
though the current trend is to employ them as soon as
possible.
Both EGFR inhibitors are well tolerated compared
with other antineoplastic agents. Toxicities, including
rash and diarrhea, were described for both agents,
with a somewhat greater frequency described for
erlotinib. However, the rate of treatment discontinu-
ation for toxicity was very low for both drugs. In the
National Cancer Institute of Canada BR.21 trial, only
5% of patients discontinued erlotinib treatment for
toxicity compared with 2% of patients in the placebo
arm. Of note, the rate of interstitial lung disease (ILD)
was very low and possibly unrelated to the use of
erlotinib. Both the patients treated with erlotinib and
those treated with placebo experienced a 0.8% inci-
dence of ILD. This is in contrast to the Japanese
experience where uncontrolled trials indicated a 4 to
10% incidence of ILD, and may represent toxicity
unique to the Japanese patient population (Lynch
et al. 2010; Khambata-Ford et al. 2010).
The role of EGFR TKIs in combination with
radiotherapy is less clear. Preclinical evidence supports
the potential use of these agents in combination with
radiation (Chinnaiyan et al. 2005). To date, small
studies have demonstrated the feasibility of this
approach (Choong et al. 2008; Wang et al. 2011). In
addition to the concomitant use of the agents, another
approach is to use EGFR TKIs as maintenance treat-
ment. SWOG 0023 evaluated gefitinib in patients with
locally advanced NSCLC with stable or responding
disease after concurrent chemoradiation. Surprisingly,
they not only failed to demonstrate an advantage for
this approach, but actually demonstrated a significant
decrease in overall survival (Kelly et al. 2008).
3 Vascular Endothelial Growth Factor
VEGF is a potent endothelial angiogenic factor
expressed in a wide variety of tumors. Aberrant sig-
naling via this pathway is frequently associated with
neoangiogenesis in tumors. In NSCLC, high levels of
VEGF expression indicate a poor prognosis, sug-
gesting that treatment geared toward this pathway
might be effective target for therapy.
M. J. Edelman and N. Ijaz
3.1 VEGF Antibodies
Bevacizumab was the first antiangiogenesis agent to
gain approval by the US FDA and is currently
approved for use in five malignancies: breast cancer,
colon cancer, ovarian cancer, glioblastoma multi-
forme, and NSCLC. It a recombinant humanized
monoclonal antibody that binds and neutralizes
VEGF, thereby preventing its interaction with the cell
surface VEGF receptor and blocking the VEGF
pathway.
A preliminary randomized phase II study demon-
strated improved survival for patients with advanced
NSCLC treated with bevacizumab15 mg/kg in com-
bination with carboplatin/paclitaxel as initial therapy
(Johnson et al. 2004). Of concern, there were six cases
of significant hemoptysis, four of them fatal. These
cases were confined to patients with squamous his-
tology. This study informed the design of the eastern
cooperative oncology group (ECOG) 4599 study
which excluded patients with squamous histology,
brain metastases, anticoagulation or other history of
bleeding or thrombotic events (Sandler et al. 2006).
In this selected population, the trial demonstrated
prolonged overall and progression-free survival
bevacizumab was added to carboplatin/paclitaxel.
However, an unplanned subset analysis by the ECOG
investigators indicated that patients over 70 years of
age who received bevacizumab experienced increased
myelotoxicity and no survival benefit (Ramalingam
et al. 2008).
The phase III AVAstin In Lung cancer (AVAiL)
trial showed that combining bevacizumab (7.5 or
15 mg/kg) with platinum based chemotherapy
improved progression-free survival for ‘‘bevacizumab-
eligible’’ patients with advanced NSCLC, but not
overall survival (Reck et al. 2009). This study enrolled
1,043 patients who were randomly assigned to receive
cisplatin 80 mg/m2 and gemcitabine 1,250 mg/m2
for up to six cycles plus low-dose bevacizumab
(7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or
placebo every 3 weeks until disease progression
(placebo, n = 347; low-dose, n = 345; high-dose,
n = 351). For unspecified reasons, the primary end
point was amended from overall survival to progres-
sion-free survival while the trial was in progress. PFS
was significantly prolonged; the hazard ratios for pro-
gression-free survival were 0.75 (6.7 vs. 6.1 months for
placebo; P = 0.003) in the low-dose group and 0.82
Novel Targeted Agents and Radiopharmaceuticals in Lung Cancer
(6.5 vs. 6.1 months for placebo; P = 0.03) in the high-
dose group compared with placebo. Objective response
rates were 20.1, 34.1, and 30.4% for placebo, low-dose
bevacizumab, and high-dose bevacizumab, respec-
tively. However, no significant differences were
observed in overall survival. Interestingly, this trend
has been noted with bevacizumab in combination with
chemotherapy in a number of other settings, including
in the adjuvant treatment of colorectal cancer and in
breast cancer. The increase in progression-free survival
without an overall survival advantage may imply that
treatment with bevacizumab results in accelerated
repopulation of tumor cells or induction of resistance.
It should also be noted that the mechanism of bev-
acizumab is unclear. Though an effect on angiogenesis
was the basis of its development, some have postulated
that benefit may result from a normalization of vascu-
lature and increased delivery of chemotherapy (Tong
et al. 2004). In addition, preclinical evidence indicates
that the benefits of bevacizumab may be dependent
upon the specific chemotherapy regimen employed
(Shaked et al. 2008).
Overall, in combination with chemotherapy,
bevacizumab is generally well tolerated. The most
common adverse events include hypertension and
proteinuria. Hemorrhage, though uncommon, can be
fatal. Other less common events include reversible
posterior leukoencephalopathy syndrome (RPLS) and
organ perforation.
The excitement generated by the positive ECOG
4599 study led to several attempts to combine bev-
acizumab with radiation and chemoradiotherapy in
locally advanced lung cancer. The Sarah Cannon
group evaluated bevacizumab in combination with
chemotherapy in locally advanced NSCLC and lim-
ited stage SCLC. The trials were halted after five
patients experienced tracheoesophageal fistulas or
other life threatening GI toxicity (Spigel et al. 2010).
In the SCLC trial, 2 of 29 patients developed TE
fistulae (one fatal) and a third died of GI hemorrhage.
In the NSCLC trial, 2 of 5 patients developed TE
fistulae. The SouthWest Oncology Group (SWOG
0533) performed a pilot trial combining cisplatin/
etoposide and radiotherapy followed by consolidation
docetaxel and the addition of bevacizumab in locally
advanced NSCLC (NCT00334815). Bevacizumab
was added in three ways, at the initiation of
chemoradiotherapy, at day 15 of chemoradiotherapy
and with docetaxel alone after completion of
779
chemoradiotherapy. Patients were stratified based
upon the risk of toxicity due to bevacizumab. The
‘‘high risk’’ stratum (any of the following: squamous
histology, tumor cavitation, location of tumor near a
major vessel or a history of hemoptysis) was closed
due to unacceptable toxicity. The University of North
Carolina is performing a Phase I/II Trial of induction
carboplatin/paclitaxel with bevacizumab followed by
concurrent thoracic conformal radiation therapy with
carboplatin/paclitaxel, bevacizumab and erlotinib
locally advanced NSCLC (NCT00280150). Of the
first 21 patients enrolled, one experienced a grade 5
hemorrhage. At this time, the trial is still active.
Though investigations continue, it is clear that the
combination of bevacizumab with chemoradiotherapy
has the potential for significant toxicity and is unli-
kely to be of benefit in the broad patient population.
3.2 VEGFR TK Inhibitors
Numerous small molecule TKIs have been developed
that inhibit one or more of the VEGF receptors. These
include sunitinib, sorafenib, vandetanib, cediranib, and
axitinib. Sorafenib and sunitinib have been licensed for
the treatment of renal cell carcinoma and vandetanib
has received approval for thyroid cancer. Some, for
example sunitinib and axitinib have been demonstrated
to have single agent activity in NSCLC (Socinski et al.
2008; Schiller et al. 2009). However, no phase III trial
has demonstrated a survival advantage for the concur-
rent administration of these agents with chemotherapy.
In fact, due to increased toxicity, some have been
inferior to placebo. For example, a study comparing
carboplatin/paclitaxel to carboplatin/paclitaxel/so-
rafenib demonstrated a median OS for standard therapy
of 10.7 versus 10.6 months for the experimental arm
(HR = 1.15; 95% CI, 0.94 to 1.41; P = 0.915). A pre-
specified exploratory analysis revealed that patients
with squamous cell histology had greater mortality
with sorafenib (HR = 1.85; 95% CI, 1.22 to 2.81)
(Scagliotti et al. 2010). A sequential approach, with
initial administration of chemotherapy followed by
single agent sunitinib is currently under investigation
by the CALGB (CALGB 30607, NCT00693992)
The side effects of these agents are similar to bev-
acizumab and include hypertension, proteinuria,
increased risk of neutropenia, and RPLS. Some carry
additional toxicities, such as stomatitits (sunitinib).
780
A study of sorafenib in combination with 45 Gy of
radiotherapy (3 Gy fractions) in patients with ‘‘poor
prognosis NSCLC for whom thoracic radiotherapy is
indicated’’ has been completed at MD Anderson, but
the results have not been reported (NCT00543335).
Similarly, a phase I study of sunitinib in combination
with radiotherapy is underway at Thomas Jefferson
University (NCT00437372).
4 PARP Inhibitors
Perhaps the most exciting agents under development
from the standpoint of their potential for future use
with radiation are the poly ADP ribose polymerase
(PARP ) inhibitors. PARP is an important component
of the DNA repair pathway, providing the scaffold for
replacing damaged or missing bases. The PARPs, the
most abundant of which is PARP1, are a family of
about 18 nuclear enzymes that polymerize poly
(adenosine diphosphate–ribose) on substrate proteins
to regulate processes such as DNA repair, gene tran-
scription, and chromatin architecture. PARP1 is
involved in the repair of single-strand breaks. Inhi-
bition of PARP results in double-strand breaks, which
normal cells can repair through a process of homol-
ogous recombination. In cells with defective homol-
ogous recombination, such as those with BRCA1or
BRCA2 deficiency, PARP inhibition leads to persis-
tent double-strand breaks, inducing cell death through
apoptosis as well as autophagy (Carey and Sharpless
2011). Preclinical work has demonstrated the poten-
tiation of DNA damaging chemotherapy and radio-
therapy with PARP inhibitors in cell lines (including
the NSCLC line A549) and in a head and neck cancer
xenograft model (Calabrese et al. 2004; Khan et al.
2010). Utilizing a murine lung cancer xenograft
model, potentiation of radiotherapy by the PARP
inhibitor ABT-888 was demonstrated with cytotox-
icity due to both apoptosis and autophagy (Albert
et al. 2007). In glioma cell lines the PARP inhibitor
KU-0059436 increased radiosensitivity in a replica-
tion-dependent manner which was enhanced by
fractionation (Dungey et al. 2008). The authors
hypothesized that PARP inhibition increased the
incidence of collapsed replication forks after ionizing
radiation, generating persistent DNA double-strand
breaks and consequent apoptosis. Liu et al. (2008)
demonstrated that the radiation potentiating effects of
M. J. Edelman and N. Ijaz
PARP inhibition occur to a similar degree in both
oxygenated and hypoxic cells.
Phase I studies in combination with DNA damag-
ing chemotherapy agents such as platinums and
temozolamide have been reported and demonstrated
good tolerability (Plummer et al. 2008). Proof of
principle for this approach has come through a ran-
domized phase II trial in previously treated ‘‘triple
negative’’ breast cancer, an entity with frequent
BRCA1/2 deficiency (O’Shaughnessy et al. 2011).
A phase III study with a similar regimen
(NCT00938652), but in a different patient population
is reportedly negative. However, subset analysis
appears to confirm the earlier findings and there
seems little doubt that this agent will eventually enter
routine use. Surprisingly, there are relatively few
studies evaluating PARP inhibitors in combination
with radiotherapy. The University of Chicago Con-
sortium has activated a phase I study combining
ABT-888 with low-dose weekly carboplatin/paclit-
axel and radiotherapy regimen for the treatment of
locally advanced NSCLC. In addition, a phase I study
of ABT-88 in combination with whole brain radiation
for solid tumor brain metastases, including lung
cancer, is currently in progress (NCT00649207).
5 Proteasome Inhibitors
Bortezomib (Velcade, PS-341) represents the first
proteasome inhibitor to have shown anti-tumor
activity. The drug is a tripeptide with pyrazinoic acid,
phenylalanine and l with boronic acid. The boron
atom reversibly binds with high-affinity and speci-
ficity at the catalytic site of the 26S proteasome that
degrades ubiquitinated proteins. It blocks the nuclear
factor-kappa B (NF-kB), leading to increased apop-
tosis, and inhibition of tumor cell adhesion to the
stroma along with having anti angiogenic properties.
While multiple signaling pathways are involved,
proteasome inhibition prevents degradation of pro-
apoptotic factors, leading to programmed cell death in
neoplastic cells.
Currently, bortezomib is approved for the treat-
ment of multiple myeloma. Its role in other malig-
nancies in general and lung cancer in particular is
yet to be fully established. Bortezomib has been
studied either as a single agent or in combination with
various chemotherapy drugs (erlotinib, carboplatin/
Novel Targeted Agents and Radiopharmaceuticals in Lung Cancer
gemcitabine etc.) in lung cancer but has failed to
demonstrate sufficient activity to warrant further
studies (Lynch et al. 2009; Davies et al. 2009).
There is considerable preclinical rationale for the
combination of bortezomib and other proteasome
inhibitors with radiation (Edelman 2005). A phase I
trial of bortezomib given at days 1, 4, 15, and
18 in addition to carboplatin (AUC = 2)/paclitaxel
50 mg/m2 with concurrent radiotherapy (61 Gy over
6 weeks) as induction treatment for locally advanced
(Stage IIIa, selected IIIb) has been reported as a tri-
modality approach to lung cancer (Edelman et al.
2010). Bortezomib was administered during the
6-week induction chemoradiotherapy. Surgical
resection was attempted in the patients with medias-
tinal sterilization. Bortezomib was well tolerated,
with no unexpected toxicities during the induction
phase. However, there were three postoperative
deaths, two from pneumonitis and one from failure of
the bronchopulmonary flap and so the trial was halted
as a consequence of these toxicities. Although the
relationship of these events to the use of bortezomib
was not completely clear, it was felt that the contin-
uation of this trial was inappropriate. However, there
was a high incidence of complete pathologic response
and so it appears that cautious exploration of this agent
in the non-operative setting is appropriate. A non-
operative study utilizing a similar regimen
(NCT00093756) has been conducted by the North
Central Cancer Treatment Group, but has not yet been
reported.
A number of second generation proteasome
inhibitors (e.g., carfilzomib) are currently in devel-
opment. Some of these agents are irreversible inhib-
itors, in contrast to borezomib or have different
chemical attributes that may convey unique activity
(Kuhn et al. 2011; Dick and Fleming 2010). At least
one (MLN-9708) is oral. No data exist regarding their
potential activity in lung cancer either alone, or with
chemotherapy or radiation.
6 HDAC Inhibitors
Histone deacetylases (HDAC) are a group of novel
anticancer agents that have been shown to effect cell
differentiation, proliferation, cell-cycle arrest, and
apoptosis (Kim and Bae 2011). They also inhibit cell
migration, invasion, and angiogenesis in many cancer
781
cell lines. There are 18 HDACs generally divided into
four classes based on homology to yeast HDACs.
HDACs remove the acetyl groups from the lysine
residues of histone. They have many protein sub-
strates in addition to histones that are involved in
regulation of gene expression, cell proliferation, and
mitotic cell death. Inhibition of HDACs cause accu-
mulation of acetylated forms of these proteins, thus
altering their function. Vorinostat (suberoylanilide
hydroxamic acid), is the first HDAC inhibitor
approved for clinical use in the treatment of the
cutaneous T-cell lymphoma. It inhibits the zinc-con-
taining classes I, II, and IV, but does not affect the
NAD (+)-dependent class III, enzymes.
Histone deacetylase inhibitors constitute a prom-
ising treatment for cancer therapy due to their
potential wide spectrum of activity and relatively low
single agent toxicity. Randomized phase II and phase
III studies used carboplatin and paclitaxel in combi-
nation with either vorinostat or placebo for first-line
therapy of advanced NSCLC have been completed. In
the US, an NCI sponsored randomized phase II trial,
patients with previously untreated stage IIIB or IV
NSCLC were randomly assigned to carboplatin (AUC
6 mg/ml x min) and paclitaxel (200 mg/m2 day 3)
with either vorinostat (400 mg by mouth daily) or
placebo. Vorinostat or placebo was given on days 1
through 14 of each 3-week cycle to a maximum of six
cycles. The response rate was 34% with vorinostat
versus 12.5% with placebo (P = 0.02). There was a
trend toward improvement in median progression-free
survival (6.0 vs. 4.1 months; P = 0.48) and overall
survival (13.0 vs. 9.7 months; P = 0.17) in the vori-
nostat arm (Ramalingam et al. 2010a). While the
investigators concluded that this was a potentially
promising approach, a company sponsored phase III
trial employing a different schedule was negative.
There are several studies evaluating the role of
HDAC inhibitors with radiotherapy in NSCLC. A
dose-escalation study of single agent vorinostat with
radiation for the palliation of locally advanced
NSCLC is being conducted at Yale (NCT00821951).
A phase I/II study combining vorinostat with carbo-
platin/paclitaxel and XRT in locally advanced disease
is in progress at the Fred Hutchison Cancer Research
Center (NCT00662311). Stanford investigators are
evaluating the role of vorinostat in combination with
stereotactic radiosurgery for brain metastases due to
NSCLC (NCT00946673).
782
7 mTOR Inhibitors
The mammalian target of rapamycin (mTOR) is an
intracellular serine/threonine protein kinase posi-
tioned at a fundamental point in many cellular sig-
naling pathways and has been identified as a major
culprit in tumorigenesis. Several inhibitors of mTOR,
including temsirolimus, everolimus, and ridaforoli-
mus (formerly deforolimus) have been developed and
assessed for their safety and efficacy in patients with
cancer. Temsirolimus is an intravenously adminis-
tered agent approved in the United States for the
treatment of advanced renal cell carcinoma. Everoli-
mus is an oral agent approved for the treatment of
advanced renal cell cancer after failure of treatment
with sunitinib or sorafenib. Additionally, there is
recent evidence of significant single agent activity in
pancreatic neuroendocrine tumors (Yao et al. 2011).
Ridaforolimus is a newer agent currently under
investigation. Clearly, mTOR inhibitors, either alone
or in combination with other anticancer agents, have
demonstrated activity in cancer and the potential to
provide anticancer activity in numerous tumor types.
Everolimus demonstrated limited single agent
activity in a study of previously treated small cell
lung cancer patients (Tarhini et al. 2010). In contrast,
some promise for everolimus (10 mg daily) was
demonstrated in a multicenter phase II trial (n = 85)
of patients with previously treated NSCLC (Soria
et al. 2009). A phase I study evaluating the combination
of everolimus and docetaxel for refractory/relapsed
NSCLC has been completed and a phase II trial is
currently accruing (Ramalingam et al. 2010b).
A trial combining everolimus with gefitinib has been
completed for patients with relapsed NSCLC
(NCT00456833). The 13% partial response rate did not
appear to be much greater than gefitinib alone and did
not warrant further development (Price et al. 2010).
Both agents are under active investigation as a
potential radiosensitizers in lung cancer. In vitro
evidence indicates that the PI3kinase/AKT pathway is
upregulated with radiotherapy and that inhibition of
the mTOR pathway is radiosensitizing (albeit using
prostate and breast cancer models) (Cao et al. 2006;
Albert et al. 2006). Phase I studies combining
temsirolimus with radiotherapy (NCT00796796) and
everolimus with radiotherapy (NCT01167530) che-
moradiotherapy (NCT01063478) are now in progress
M. J. Edelman and N. Ijaz
at a number of sites. In addition, everolimus is being
evaluated in combination with whole brain radio-
therapy for the treatment of CNS metastases from
NSCLC (NCT00892801).
8 IGF-IR Inhibitors
The insulin-like growth factors (IGFs: IGF-1 and
IGF-2) are mediators of growth hormone and they
play major role in cell growth, differentiation, sur-
vival, and metastasis. The effects of the IGFs are
mediated by the IGF-1 receptor (IGF-1R), a tyrosine
kinase receptor with homology to the insulin receptor
(IR). The IGF-binding proteins (IGFBPs) are another
component of the IGF system comprising of a class of
six soluble secretory proteins. They represent a
unique class of naturally occurring IGF-antagonists
that bind to and sequester IGF-1 and IGF-2, inhibiting
their access to the IGF-1R. Deregulation of the IGF
system is a well recognized element in the progres-
sion of multiple cancers, increasing the tumorigenic
potential of breast, prostate, lung, colon and head and
neck squamous cell carcinoma (Gridelli et al. 2010).
Currently, both antibodies and small molecule
inhibitors targeting the IGF pathway are in develop-
ment. Figitumumab (CP-751,871) is a fully human
immunoglobin G monoclonal antibody against IGF-
1R that has demonstrated promising activity in
NSCLC when combined with carboplatin/paclitaxel
in a phase II trial. It has an effective half-life of
approximately 20 days, and it has been generally well
tolerated in clinical studies when given alone or in
combination with chemotherapy and targeted agents
(Karp et al. 2009a). Mild to moderate asymptomatic
hyperglycemia is observed with figitumumab therapy.
A randomized phase II study compared paclitaxel
(200 mg/m2), carboplatin (AUC = 6), and fig-
itumumab (20 mg/Kg) or paclitaxel and carboplatin
alone for 3 weeks for a total of 6 cycles. The study
appeared to demonstrate and advantage for patients
with squamous cell carcinoma (Karp et al. 2009b).
However a phase III trial in lung cancer was discon-
tinued due to excessive deaths but others are still in
progress (Jassem et al. 2010). In vitro evidence indi-
cates that inhibition of IGF-1R results in radiosensi-
tization (Cosaceanu et al. 2004). No studies of these
agents, either alone with radiation or as part of che-
moradiotherapy have been reported to date.
Novel Targeted Agents and Radiopharmaceuticals in Lung Cancer
9 Cyclooxygenase-2 Inhibitors
Cyclooxygenase-2 (COX-2) is an enzyme of the ara-
chidonic acid cascade. It is upregulated and overex-
pressed in many tumors, including lung cancer as well
as in newly formed blood vessels within tumors. The
mechanism by which COX-2 overexpression affects
NSCLC is unclear. It is believed that prostaglandin E2
(PGE-2), a downstream product of COX-2, promotes
tumor growth and invasion by stimulation of VEGF
production, inhibits immune surveillance, and upreg-
ulates bcl-2 and various matrix metalloproteinases.
COX-2 overexpression is considered a marker of poor
prognosis in NSCLC (Lee et al. 2007).
The availability of selective COX-2 inhibitors (e.g.,
celecoxib), coupled with the potential role of COX-2
overexpression, has made COX-2 a rational target in
NSCLC. Despite considerable preclinical evidence,
the results of clinical trials in lung cancer have been
mixed. Altorki demonstrated that carboplatin/paclit-
axel when administered pre-operatively could induce
COX-2 and that this effect was abrogated by celecoxib
with an accompanying improvement in response
(Altorki et al. 2003). However, a large (n = 561)
phase III study in an advanced disease (NVALT) did
not demonstrate an advantage for celecoxib when
added to carboplatin/docetaxel in advanced disease
(Groen et al. 2009). There was a borderline improve-
ment in the objective response rate with celecoxib
compared to placebo (32 vs. 27%). However, there
was no improvement in either progression-free or
overall survival 4.5 versus 4.1 and 8.2 versus
8.3 months, respectively.
Cancer and Leukemia Group B investigators
evaluated inhibitors of two eicosanoid pathways
COX-2 (celecoxib) and 5-lipoxygenase (zileuton)
added to carboplatin/gemcitabine in a randomized
phase II trial (Edelman et al. 2008). Though the study
was negative, a pre-defined analysis found that while
high COX-2 expression was a negative prognostic
marker for overall survival for patients not receiving
celecoxib, it was a positive prognostic marker for
patients with moderate to high levels of COX-2
expression who did receive celecoxib in addition to
chemotherapy. Multivariate analysis confirmed the
interaction of COX-2 and celecoxib on survival. This
study, and several others utilized either COX-2
expression evaluated by immunohistochemistry or
783
urinary PGE-M (a stable, and major downstream
metabolite). These studies also indicate that if COX-2
inhibitors are to have any benefit, that benefit will
likely be confined to those with tumors that are driven
by COX-2. A phase III study (CALGB 30801) is
currently in progress in patients selected for COX-2
expression on the basis of immunohistochemistry.
Preclinical studies show that COX-2 inhibitors
enhance in vitro cell radiosensitivity and in vivo
tumor radioresponse. MD Anderson investigators
evaluated the use of celecoxib with radiotherapy in
poor prognosis patients with localized or locally
advanced NSCLC. The trial had three cohorts: (1)
locally advanced NSCLC with obstructive pneumo-
nia, hemoptysis, and/or minimal metastatic disease
treated with 45 Gy in 15 fractions; (2) inoperable
early-stage NSCLC treated with definitive radiation
of 66 Gy in 33 fractions; and (3) patients who
received induction chemotherapy but who were not
eligible for concurrent chemoradiotherapy trials.
These patients received 63 Gy in 35 fractions. Cele-
coxib was administered orally on a daily basis 5 days
before and throughout the course of radiotherapy with
doses escalated from 200, 400, 600, to 800 mg/d. The
main toxicities were grades 1 and 2 nausea and
esophagitis, and they were independent of the dose of
celecoxib or radiotherapy schedule. A maximal
tolerated dose was not reached in this study. The
treatment resulted in local progression-free survival
of 66.0% at 1 year and 42.2% at 2 years. A multi-
center phase I/II study (RTOG 0213) of celecoxib
plus radiotherapy in locally advanced NSCLC in
patients with intermediate prognostic factors that
failed to complete accrual. A Dutch randomized
phase II/III study compared standard radiotherapy for
stage II/III patients with celecoxib 400 mg bid (begun
1 week before radiation) versus placebo with the
drugs continuing for one year. Unfortunately, the
study failed to accrue and was closed when only 41
patients had been randomized (De Ruysscher et al.
2007). There were no significant differences between
the arms, however, overall, one year and two year
survival numerically favored the use of celecoxib.
In a single-institution phase II study concurrent
chemoradiation with paclitaxel and carboplatin
alongwith with 400 mg of celecoxib was given-twice-
daily until disease progression occurred in patients with
stage IIIA or IIIB (Mutter et al. 2009). The overall
objective response rate seen was 42.9%, and the median
784
overall survival time was 203 days. In contrast to
nonresponders, those patients with complete and partial
responses had a significant decrease in the level of
urinary PGE-M. Patients with very high levels of PGE-
M before initiation of therapy also responded poorly to
therapy. The trial was terminated because it did not
meet the predetermined goal of 80% overall response
rate. In unselected patients, the addition of celecoxib to
concurrent chemoradiotherapy with inoperable stage
IIIA/B NSCLC did not improve survival. This study
also showed that urinary PGE-M appears to be a
promising biomarker for predicting response to COX-2
inhibition in NSCLC (Liao et al. 2005).
At this time apricoxib, a new more potent selective
COX-2 inhibitor is currently under investigation in a
variety of malignancies, including NSCLC (Edelman
2011). These studies select patients based upon uri-
nary PGE-M suppression. If there is to be a future for
COX-2 inhibitors in lung cancer, either in combina-
tion with chemotherapy or radiation, it is likely that it
will emerge from the studies currently underway in
these enriched populations.
10 ALK Targeted Inhibitors
Transforming rearrangements of the anaplastic lym-
phoma kinase (ALK) gene have recently been
described in NSCLC. A certain subset of patients with
NSCLC have an inversion in chromosome 2 that
juxtaposes the 50 end of the echinoderm microtubule-
associated protein-like 4 (EML4) gene with the 30 end
of the ALK gene, resulting in the fusion oncogene
EML4-ALK. At least seven ALK gene rearrangement
variants have been described involving different
EML4-ALK breakpoints or rarely other non-EML4
fusion partners. ALK rearrangements may be identi-
fied in tumor tissue by reverse transcription-poly-
merase chain reaction or fluorescent in situ
hybridization. The orally administered small molecule
tyrosine kinase inhibitor crizotinib (PF02341066),
originally under development as an inhibitor of c-met,
is also a potent inhibitor of ALK phosphorylation and
signal transduction. This inhibition is associated with
G1-S phase cell-cycle arrest and induction of apop-
tosis in positive cells in vitro and in vivo.
Crizotinib has demonstrated dramatic antitumor
benefit with little toxicity and is well tolerated in
patients with ALK-rearranged NSCLC. Tumors with
M. J. Edelman and N. Ijaz
EML4-ALK fusion oncogene or its variants have a
phenotype similar to that of EGFR mutation positive
patients, i.e. adenocarcinoma histology, younger age
at presentation, and patients with never or light
smoking history.
A phase I dose-escalation study with crizotinib
demonstrated substantial activity in patients with
advanced NSCLC harboring the EML4/ALK trans-
location (Kwak et al. 2010). There was a confirmed
radiographic response rate of 57% and a disease
control rate of 87% at eight weeks. The estimated
probability of progression-free survival at six months
was 72%. The most common side effects were fati-
gue, nausea/vomiting, diarrhea, and visual distur-
bances associated with the transition from dark to
light. There are currently trials evaluating crizotinib
in first-line, second line and subsequent therapy.
Approval of the agent for routine clinical use is likely
to occur within the next 1–2 years. As the agent is
also an inhibitor of c-met, it may also find a role in
patients with EGFR mutations who have developed
resistance to EGFR TKIs as a consequence of c-met
amplification. As c-met inhibitors may potentiate
radiotherapy either through direct toxicity or an
antiangiogenic mechanism, crizotinib (as the first
agent to be approved with this activity) should be
evaluated in this role (Welsh et al. 2009; Hu et al.
2009).
11 Aurora Kinase and Polo-like
Kinase Inhibitors
A number of recently described proteins that form a
‘‘mitotic spindle apparatus’’ that synchronizes the
movement of tubulin and consequently chromosomal
segregation. These proteins include the aurora kina-
ses, polo-like kinases, kinesin spindle proteins, sur-
vivin and others. In addition to the function of
chromosomal segregation, cytokinesis and other key
cellular functions mediated by tubulin are also gov-
erned by these proteins (Andrews et al. 2003).
Overexpression of these proteins, particularly the
aurora kinases has been demonstrated to be associated
with malignancy in general and lung cancer in par-
ticular (Smith et al. 2005). There are three types of
aurora kinase, A, B, and C. Aurora kinase A and B are
essential for normal progression of all types of cells
through mitosis. Aurora C is expressed exclusively in
Novel Targeted Agents and Radiopharmaceuticals in Lung Cancer
the testis and co-localizes with aurora-B. Aurora-A
dysregulation is commonly associated with the
development of cancer. Interestingly, amplification of
aurora-A has been demonstrated to result in resistance
to paclitaxel as well as radiation (Anand et al. 2003;
Guan et al. 2007).
A plethora of inhibitors to the aurora kinases (both
selective for A or B as well as dual inhibitors) and
polo-like kinases have entered clinical trials, Table 1.
Single agent toxicity data have been relatively
similar, with both classes of agents limited by dose
dependent neutropenia. There is considerable ratio-
nale for evaluating these agents in combination with
chemotherapy and radiation. Polo-like kinases are
involved in DNA damage repair and inhibition has
been demonstrated to result in enhancement of radi-
ation and chemotherapy cytotoxicity (Gerster et al.
2010; Zhou and Bai 2004). Aurora-B kinase inhibitors
have been demonstrated to sensitize cells to radiation
(Tao et al. 2009). Sensitization to chemotherapy and
radiotherapy may be schedule dependent and clinical
evaluation of these agents will require careful atten-
tion to the timing of administration relative to radia-
tion and/or chemotherapy. At this time, there is
relatively little data regarding activity in lung cancer
and no clinical studies have yet evaluated the agents
in combination with radiotherapy.
12 Hedgehog Pathway Inhibitors
The Sonic Hedgehog (Shh) pathway plays an impor-
tant role in embryogenesis, stem cell maintenance,
tissue repair, and tumorigenesis (Yang et al. 2010).
Intercellular signaling proteins of the Hh family have
come to be recognized as mediators of fundamental
processes in embryonic development and is a major
regulator for stem cell maintenance, cell differentia-
tion, tissue polarity, and cell proliferation. The key
molecules in this pathway include: (1) smoothened
(SMO)—a seven member transmembrane domain, (2)
patched (PTC)—a transmembrane protein which
serves at the receptor for Hh, (3) Gli—a family of
downstream transcription factors that regulate target
gene expression by direct association with a specific
consensus sequence located in the promoter region of
the target genes. In the absence of Hh, the Hh receptor
PTC suppresses SMO activity and repressor forms of
Gli (GliR) are generated, leading to downregulation of
785
Hh target genes. In the presence of Hh ligands (Shh, Ihh
or Dhh), PTC is unable to affect SMO signaling, leading
to enhanced formation of activated forms of Gli (GliA)
and upregulation of Hh target genes. Gene mutations
(PTC, SMO) or abnormal over expression of Hh
ligands may lead to elevated expression of Hh target
genes. Abnormalities of the Hh pathway occur in both
NSCLC and SCLC, but seem to be particularly com-
mon in small cell lung cancer (Gialmanidis et al. 2009;
Vestergaard et al. 2006).
Cyclopamine is a naturally occurring steroidal
alkaloid which inhibits Hh ligand dependent and
independent pathways via direct interaction with Smo
(Kubo et al. 2004). GDC-0449 is an orally administered
analogue of cyclopamine which has shown activity and
excellent tolerability as a single agent in tumors har-
boring mutations associated with activation of the Hh
signaling pathway (i.e, basal cell carcinoma, medullo-
blastoma) (Von Hoff et al. 2009; Rudin et al. 2009). The
agent demonstrated a favorable pharmacokinetic pro-
file, with high, sustained, plasma concentrations and a
terminal half-life of greater than seven days. No dose-
limiting adverse events were observed at the three dose
levels (150, 270, or 540) studied.
Currently, there are several trials underway in lung
cancer. GDC-0449 is being tested by the ECOG in
combination with cisplatin/etoposide in extensive
small cell lung cancer (NCT00887159). No trials are
currently underway combining these agents with
radiotherapy. However, such studies are logical as the
Hh pathway is upregulated in response to radiation
and is therefore a logical target (Chen et al. 2011).
13 Radiopharmaceuticals
A relatively unexplored approach in lung cancer is the
use of radiopharmaceuticals. Broadly defined, these
are agents with a specific targeting moiety coupled to
a radionuclide. Table 2 describes the basic terminol-
ogy for radiopharmaceuticals and some of the char-
acteristics of the most widely evaluated radionuclides
(Milenic and Brechbiel 2004). Part of the attraction of
these agents is that this approach allows for a real
time assessment of the presence of a target through
the use of related imaging diagnostics or in some
cases the agent itself. This approach has been vali-
dated for the treatment of B-cell non-Hodgkins
lymphoma where two agents (yttrium 90 ibritumomab
786
Table 2 Radionuclide terminology and examples
Term Definition Examples
Alpha particle 2 protons ? 2 neutrons (He nucleus) Bi211
212
Bi
At211
Beta particle electrons Yt90
a
Re188
a
Lu177
a 131
I 8days
a
also emits gamma radiation (photons)
Adapted from Millenic and Brechibel (Price et al. 2010)
and iodine-131 tositumomab) have been approved.
Both agents couple a radioisotope to a CD-20 anti-
body, which is highly specific for B-cells.
In general, all agents share certain features. There
is a targeting moiety, such as an antibody or a
receptor analogue, coupled to a molecule capable of
binding the radionuclide chosen. Binding can be
directly to the protein (halogenation) at a tyrosine
group, or through chelating agents that bind to the
protein and to the radionuclide. Most radionuclides
for therapeutic purposes are either alpha or beta
emitters. The characteristics of the radionuclide are
critical determinants of potential applicability and
activity. Too short a half-life will prohibit generalized
use of the agent. Too long a half-life increases the
potential toxicity to the patient and others. The path
length and energy imparted by the radionuclide will
determine the potential activity and toxicity. Beta
emitters generally deposit energy at some distance
from the decay event. However, the amount of energy
is relatively low. In comparison, the alpha emitters
deliver a large amount of energy, but the path length
is short. Longer path lengths allow for effects on
tumor cells that may not express the target, too long a
path length increases the risk of bystander organ
toxicity. Most agents that have entered clinical eval-
uation are renally excreted and hence the kidney
becomes the dose-limiting organ, though some degree
of marrow toxicity is also frequently observed.
There are several unique aspects to the use of ra-
diopharmaceuticals including the ability to image the
tumor (which can assist with determining the appro-
priateness of treatment) as well as determining the
dose. For the two licensed agents, the radionuclide is
a beta emitter. Agents in which the radionuclide is a
M. J. Edelman and N. Ijaz
Half-life Tissue range (mm) Energy (mEv)
46 min 0.04–0.1 5.87
1h 0.04–0.1 6.09
7.2 h 0.04–0.1 5.87
2.7days 2.76 2.3
17 h 2.43 2.1
6.7days 0.4 0.50
0.28 0.81
gamma (photon) as well as beta emitter have the
advantage of the potential for dual use as both as an
imaging as well as a therapeutic agent. A typical
paradigm is to administer either a small dose of the
agent (if a gamma emitter) or a Tc99 labeled version
of the agent to determine the avidity of the target
as well as the distribution which allows for determi-
nation of the dose based upon the target uptake as
well as the potential limits of normal tissues.
In solid tumor oncology there are relatively few
tumor specific surface antigens that lend themselves
to this approach. One such specific antigen is the
somatostatin receptor family. There are at least five
SSTRs that can be exploited for this purpose. SSTR2
is frequently expressed in both small cell and NSCLC
as well as on peritumoral neovasculature (O’Byrne
et al. 2001).
P2045 is an agent that couples Re188 to a somato-
statin fragment specific for SSTR2. The approach had
its origins in a Tc99 labeled diagnostic agent developed
prior to the advent of FDG-PET that demonstrated good
ability to distinguish between benign and malignant
solitary pulmonary nodules on the basis of the presence
of somatostatin receptors. A phase I trial has been
reported that demonstrated the feasibility and tolera-
bility of this approach (Edelman et al. 2009). However,
the study was terminated due to concerns regarding the
potential long-term renal toxicity of the agent. Given
the poor prognosis for advanced lung cancer patients,
this was probably excessively cautious and develop-
ment of this agent is to be resumed in the near future.
A number of similar molecules have also been
developed. The somatostatin receptor is frequently
expressed on neuroendocrine carcinomas. Conse-
quently, small cell lung cancer has been a disease of
Novel Targeted Agents and Radiopharmaceuticals in Lung Cancer
particular interest for this approach. Studies in a
murine small cell lung cancer model have been
reported that compared the unlabeled somatostatin
analogue with the radionuclide labeled agent dem-
onstrating considerable activity utilizing the radiola-
beled agent in contrast to no activity for the parent
compound (Schmitt et al. 2004).
Other targeting molecules can clearly be utilized,
though relatively few have been developed. Of par-
ticular relevance to lung cancer, an EGFR antibody
labeled with Re188 has been developed (Chopra
2008). Clinical experience outside of the somatostatin
analogues however, is quite limited. In addition, most
agents that have entered the clinic have been tested
utilizing a single administration. Relatively few have
been evaluated for repeated dosing, the most common
approach for both standard radiotherapy as well as
chemotherapy. In addition, combination with che-
motherapy agents has only rarely been explored, even
in preclinical models.
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 Translational Research in Lung Cancer
Deepinder Singh, Kevin Bylund, and Yuhchyau Chen

Contents
1 Introduction.............................................................. 794
2 Tumor Markers of Non-small
Cell Lung Cancer .................................................... 794
2.1 Molecular Markers of Prognosis............................... 794
2.2 Predictive Tumor Markers and Molecular
Targets........................................................................ 796
3 Small Cell Lung Cancer Serum Markers ............
3.1 Chromogranin A ........................................................
3.2 Neuron-Specific Enolase ...........................................
3.3 Pro-Gastrin-Releasing Peptide ..................................
4 A Chemoradiation Model of Translational
Investigation for Stage III Non-Small Cell
Lung Cancer............................................................. 802
4.1 National Institutes of Health Roadmap
for Translational Medicine........................................ 802
4.2 Translational Investigation Model of Taxane
Chemoradiation for NSCLC ..................................... 802
5 Summary................................................................... 804
References.......................................................................... 805
D. Singh  K. Bylund  Y. Chen (&)
University of Rochester Medical Center,
601 Elmwood Ave, Box 647,
Rochester, NY 14642, USA
e-mail: Yuhchyau_Chen@urmc.rochester.edu
Abstract
Translational research has become an important
initiative emphasized by the National Institute of
Health (NIH) in recent years, with goals of
bringing benchtop research to the bedside through
clinical trials, and translating clinical trials to the
recommended care in clinical practice. Much
progress has been made in the translational
801 research of lung cancer. Molecular predictive
801
801 tumor markers, such as mutation of epidermal
801 growth factor receptor (EGFR), markers of DNA
repair (excision repair cross-complementing group
1 gene product [ERCC1]; regulator subunit of
ribonucleotide reductase [RRM1]; human MutS
homologue 2 [hMSH2], human MutL homologue
1 [hMLH1]), and echinoderm microtubule-associ-
ated protein-like 4-anaplastic lymphoma kinase
(EML4-ALK) have been identified to predict
response to molecular targeting agents for non-
small cell lung cancer (NSCLC). Serum proteomic
profiling was found to predict response to EGFR
tyrosine kinase inhibitor (TKI) treatment of
NSCLC. Serum markers such as chromogranin
A (CgA), neuron-specific enolase (NSE), and pro-
gastric-releasing peptide (ProGRP) may aid diag-
nosis, detection of disease progression or recur-
rence, and monitoring therapy for small cell lung
cancer (SCLC). We present two clinical trial
designs that are based on preclinical investigations
that offer the rationale and hypotheses for taxane-
based chemoradiation treatment to maximize chest
tumor control and to target distant micrometastasis
for stage III NSCLC. While stage III NSCLC in
general is associated with[50% chest failure and a

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 793
DOI: 10.1007/174_2011_296, Ó Springer-Verlag Berlin Heidelberg 2011
794
median survival of 14–17 months after chemora-
diation treatments, the outcome of this transla-
tional approach has yielded a 97% in-field tumor
control in study U1597, and 32 months overall
survival in study U1500.
1 Introduction
Translational research for lung cancer is evolving.
Progress has been made concerning molecular markers
of lung cancer, which include tumor genetic markers,
tumor protein markers, and secreted proteins in the
serum of lung cancer patients. Molecular markers can
provide the prognosis of tumors expressing such mark-
ers, or predict the response to treatment for certain types
of therapy. The latter is often associated with therapeutic
agents that directly target the molecular markers within
the tumor cells. The progress and success in molecular
targeting have formed the basis of many new drug
developments by pharmaceutical companies. This
approach has proven to be effective in ‘‘personalized
medicine’’ regarding lung cancer treatment in recent
years. We summarize the current state of translational
research in molecular markers of lung cancer and
describe a model in translational chemoradiation treat-
ment of locally advanced non-small cell lung cancer
(NSCLC) in the context of the National Institutes of
Health (NIH) roadmap with the translational emphasis
from bench top to clinic (Westfall et al. 2007) (Fig. 1).
2 Tumor Markers of Non-small Cell
Lung Cancer
Numerous molecular markers for NSCLC have been
investigated in recent decades, including epidermal
growth factor receptor (EGFR) family (c-erb-B1,
c-erb-B2, c-erb-B3 and c-erb-B4), CD82, Ki-67,
p120, p53, bcl-2, CD31 MIA-15–5, p21, PCNA,
Ki-67, p185new protein, RB protein, blood group A,
K-ras mutation, K-ras p21 protein, H-ras p21 protein,
angiogenic marker factor viii, adhesion molecule
CD-44, sialyl-Tn, blood group AMRP-1/CD9 gene,
KA11/CD82, laminin receptor, FOS, JUN, cyclin A,
TGF-a, amphiregulin (AR), and others (Chen and
Gandara 2006). Some molecular markers were
found to have prognostic values when investigated
D. Singh et al.
individually, but lost the values when multiple factors
were examined at the same time (Chen and Gandara
2006). Here, we summarize and update K-ras and
p53, the two major prognostic molecular markers for
NSCLC, as well as review the current state of gene
signature prognostic factors in NSCLC.
2.1 Molecular Markers of Prognosis
2.1.1 Ras Oncogenes p21
The ras oncogene family encodes guanosine triphos-
phate-binding proteins with a 21 kD (p21) molecular
weight. The proteins are localized at the inner surface
of the cell membrane and are involved in the trans-
duction of growth signals. There are three well-
characterized members of the ras oncogene family:
H-ras, K-ras, and N-ras (Barbacid 1987). The onco-
genic potential of ras genes is triggered by point
mutations occurring mainly in either codon 12, 13, or
61. A ras gene mutation is detected in 10–30% of
NSCLC cases, and 80–90% of ras mutations occurred
at codon 12 of the K-ras gene (Rodenhuis et al. 1987;
Bos 1989; Slebos et al. 1990; Mitsudomi et al. 1991;
Sugio et al. 1992). The mutations are frequently
observed in smokers, are more frequent in adenocar-
cinoma than in squamous cell carcinoma (SCC), and
are absent in small-cell lung cancer (SCLC)
(Rodenhuis et al. 1987; Mitsudomi et al. 1991;
Greatens et al. 1998; Brose et al. 2002; Riely et al.
2009). Several investigators have reported that K-ras
mutations are a poor prognostic factor in NSCLC, and
the absence of H-ras p21 expression was among the
nine independent predictors for recurrence, while
other researchers found no negative prognostic value
to the K-ras mutation. More recently, Mascaux et al.
(2005) performed a meta-analysis of more than 53
studies, which evaluated the K-ras mutation and
outcomes in patients with NSCLC. They identified K-
ras mutations or p21 overexpression by PCR assay as
a negative prognostic factor for NSCLC (hazard ratio
[HR] for death was 1.35; 95% confidence interval
[CI], 1.16–1.56), and even worse HR for adenocar-
cinoma (HR 1.40; 95% CI 1.18–1.65). Notably,
investigations of ras using immunohistochemical
stain (IHC) showed no prognostic values in the meta-
analysis (HR 1.08; 95% CI 0.86–1.34). The major
criticism of such meta-analysis was that it was not
based on prospectively designed studies, and the
Translational Research in Lung Cancer
Fig. 1 The National Institutes of Health (NIH) roadmap for
medical research includes two major research arenas (bench
and bedside) and two translational steps (T1 and T2). Histor-
ically, moving new medical discoveries into clinical practice
(T2) has been haphazard, occurring largely through continuing
medical education programs, pharmaceutical detailing, and
guideline development. The expansion of the NIH Roadmap
authors did not perform multivariate analyses to
include other clinical prognostic variables such as
tumor stage, performance status, and weight loss.
A large trial that has prospectively assessed K-ras
mutations was conducted as part of the Eastern
Cooperative Oncology Group study E3590. Patients
with stage II–IIIA NSCLC were randomized to
receive postoperative radiation therapy or radiation
therapy and chemotherapy (Schiller et al. 2001). The
study found no correlation of survival or disease-free
survival with K-ras mutations. Tumors from 197
patients were available for K-ras mutational analysis
out of the 488 patients enrolled. Mutations were
identified in 24% (44/184 cases), with 4.8% (3/63
cases) in SCC and 33% in non-SCC histology
(P \ 0.05). Median survival was 30 months among
the 44 patients with the K-ras mutation (95% CI:
34–64 months), and 42 months among the 140
patients with wild type K-ras (P = 0.38). There was a
trend toward significance for patients on the chemo-
radiation arm of the study. Seventy patients on the
chemoradiation arm who had wild type K-ras
had a median survival of 42 months, compared with
25 months among the 20 patients with K-ras mutations
795
(blue) includes an additional research arena (Practice-based
research) and translational step (T3) to improve incorporation
of research discoveries into day-to-day clinical care. The
research roadmap is a continuum, with overlap between sites of
research and translational steps (Westfall et al. 2007, with
permission)
(P = 0.09). In multivariate analysis, the K-ras
mutation was not an independent prognostic factor,
suggesting that it did not carry a distinct prognosis in
this population of resected NSCLC.
2.1.2 p53 Tumor Suppressor Gene
p53 is a tumor suppressor gene (TSG) encoding a
53 kD nuclear phosphoprotein with a transcriptional
activator, which controls cell proliferation by regulat-
ing a G1-S checkpoint before DNA synthesis, through
the cyclin- dependent kinase (CDK) pathway (Cordon-
Cardo 1995). In response to DNA damage by ionizing
radiation and a variety of chemical agents or carcino-
gens, p53 induces cells to repair damage or promote
apoptosis (Yin et al. 1992; Hartwell 1992; Farmer et al.
1992). Mutations of the p53 gene are the most common
findings in human cancer cells of all types (Greenblatt
et al. 1994). The p53 gene is the most commonly
mutated TSG in human malignancies, and these affect
90% of SCLC and 50% of NSCLC (Mayne et al. 1999).
Most mutations occur in evolutionary conserved p53
exon 5–8. p53 mutations correlate with smoking and
most are of the type G to T transversions expected from
tobacco smoke carcinogens.
796
More evidence linking smoking damage with p53
is that a major cigarette-smoking carcinogen known
as benzopyrene selectively forms adducts at the p53
mutation hot spot (Kohno and Yokota 1999). The
types of p53 mutations are varied and include mis-
sense, nonsense, and splicing abnormalities as well as
larger deletions. The most common mutations are of
the missense type, which often prolongs the half-life
of the p53 protein to several hours, leading to
increased levels detectable by IHC, which can be used
for surrogate assay of p53. It is still controversial
whether these mutations detected in p53 affect
survival.
The prognostic significance of p53 remains unclear
as studies have showed conflicting findings. There are
at least three published works on p53 meta-analyses.
Mitsudomi et al. (2000) performed a meta-analysis of
43 articles. p53 alteration was detected either by
overexpression of the protein (IHC) or as mutation by
the DNA studies. They found that the incidence of
p53 alteration in DNA studies was 37% (381/1,031)
and the incidence of protein overexpression was 48%
(1,725/3,579 cases). The incidence of p53 overex-
pression and mutation in adenocarcinoma (36 and
34%, respectively) was lower than that in SCC (54
and 52%, respectively). p53 alteration had a signifi-
cant negative prognostic effect for adenocarcinoma
but not for SCC. They concluded that p53 alteration
either by protein overexpression or by DNA mutation
was a significant marker of poor prognosis in patients
with pulmonary adenocarcinoma. Steels et al. (2001)
did a meta-analysis of 74 eligible papers. The studies
were categorized by histology, disease stage, treat-
ment, and laboratory technique. Combined hazard
ratios suggested that an abnormal p53 status had an
unfavorable impact on survival for all tumor stages
(I–IV) and for both SCLC and adenocarcinoma.
Huncharek et al. (2000) published a meta-analysis of
eight studies investigating p53 mutations involving a
total of 829 patients. They did not find the p53
mutation as a prognostic marker in NSCLC, and felt
that selection bias, smoking history, race, geographic
location of the study, and socioeconomic status might
have been the confounding factors. Testing the
prognostic value of p53 in a prospective study by the
above-mentioned large trial of E3590, the study did
not find the correlation of survival or disease-free
survival with p53 protein expression and p53 muta-
tion (Schiller et al. 2001).
D. Singh et al.
2.1.3 Gene Expression Profiles
Gene expression profiling of resected lung tumors was
made possible by microarray technologies and real-
time reverse-transcriptase polymerase chain reaction
(RT-PCR) analysis. Gene expression profiles have
revealed the underlying heterogeneity of NSCLC
classified by conventional histopathology, thus
offering the possibility of molecular taxonomy
(Bhattacharjee et al. 2001). Further, several studies
have reported the prognostic value of discrete gene
signatures in association with survival outcome for
operable NSCLC. These gene expression profiles
were generated from resected NSCLC with mostly
stage I tumors. Prognostic gene signatures included
3–6 genes (Lau et al. 2007; Chen et al. 2007; Boutros
et al. 2008), 20–64 genes (Guo et al. 2008; Lu et al.
2006; Sun et al. 2008), 125 genes (Larsen et al. 2007),
and more than 2,000 genes in the scenario of
metagenes (Potti et al. 2006). All of these gene
signatures have shown prognostic value for cancer
survival independently or in combination with clinical
factors. The largest gene signature set is the meta-
gene, which is a collection of gene expression profiles
that are computer generated and randomly assigned
sets of 25–200 genes. The signatures contain 100
metagenes, which encompass more than 2,000 dis-
tinct genes. In theory, this large size allows for a
much greater predictive power for disease recurrence
than fewer numbers of genes. Initially it was reported
with an accuracy of 72–93% in different patient
groups with stage IA NSCLC (Potti et al. 2006).
However, the original report was retracted in March
2011 due to failure to reproduce results supporting the
validation of the lung metagene model described in
the article by Potti et al. (2011). Nonetheless, the
prognostic value of global gene profiling remains an
area of active research interest.
2.2 Predictive Tumor Markers
and Molecular Targets
2.2.1 Epidermal Growth Factor Receptor
Proto-oncogenes: c-erb-B1
c-erb-B1 (EGFR) is the proto-oncogene encoding the
EGFR protein. EGFR is a member of the erb-B family
of tyrosine kinase receptor proteins, which also
include erb-B2 (HER-2/neu), erb-B3, and erb-B4
(Franklin et al. 2002). Intracellular signaling is
Translational Research in Lung Cancer
Fig. 2 Schematic
presentation of epidermal
growth factor receptor
(EGFR) activation. On
extracellular ligand (EGF)
binding, the receptor
dimerizes, allowing the
cytoplasmic EGFR-tyrosine
kinase (TK) to activate in a
tail-to-head fashion. The
locations of regions within
EGFR-TK are indicated on
the exon boundary map
(Kumar et al. 2008, with
permission)
triggered by the binding of ligands, such as epidermal
growth factor (EGF), resulting in the dimerization
of EGFR molecules or heterodimerization with
other closely related receptors, such as HER-2/neu.
Phosphorylation of the receptors through their tyro-
sine kinase domains leads to intracellular signal
transduction and the activation of proliferative signals
and DNA synthesis (Fig. 2) (Yarden and Sliwkowski
2001; Jorissen et al. 2003; Kumar et al. 2008). In
NSCLC, EGFR is more commonly overexpressed
than HER-2/neu, and has been observed in 40–80% of
cancer specimens (Franklin et al. 2002; Arteaga 2003;
Berger et al. 1987). The prognostic value of EGFR
overexpression analyzed by IHC stains and by fluo-
rescence in situ hybridization (FISH) in lung cancer
has been a controversial issue. Some reports indicated
that EGFR overexpression was associated with a poor
prognosis (Volm et al. 1992; Ohsaki et al. 2000; Cox
et al. 2000), while others have shown no prognostic
association (Greatens et al. 1998; Rusch et al. 1997;
Pfeiffer et al. 1996; Fontanini et al. 1998; D’Amico et
al. 1999; Pastorino et al. 1997). Hirsch et al. (2003)
has reported analyses of the gene copy number of
EGFR using the FISH technique as well as the protein
expression using IHC stain. In this report, EGFR
protein overexpression was observed in 62% of
NSCLC with more frequency in SCC (82%) than non-
SCC (44%), and in 80% of the bronchioloalveolar
carcinomas. They found that EGFR overexpression
correlated with increased gene copy number per cell,
but neither EGFR overexpression nor high gene copy
797
number had any significant influence as an indepen-
dent prognostic factor. Poor prognosis was observed
in tumors with high gene copy numbers combined
with a low EGFR score by IHC. There is no data to
support or confirm whether high EGFR gene copy
number or overexpression correlates with survival
improvement after EGFR inhibitor therapy, thus
such information is not useful in routine practice
(Ramalingham et al. 2011).
In contrast to the lack of prognostic and predictive
value of protein overexpression and gene copy num-
ber, the somatic mutation of EGFR gene in the tyro-
sine kinase domain was found to be predictive for
tumor response to treatment by EGFR tyrosine kinase
inhibitors (TKIs): gefitinib (Iressa) and erlotinib
(Tarceva). EGFR mutations are present in approxi-
mately 10–15% of Caucasians and in nearly 40% of
Asians. Patients with EGFR mutations are highly
responsive to EGFR TKI treatment. Two early studies
support the concept of molecular targeting to specific
markers in predicting tumor responses, but did not
address the impact on survival. Lynch et al. (2004)
found that a subgroup of patients who had mutations
in the EGFR gene by either in-frame deletions or
amino acid substitutions around the ATP-binding
pocket of the tyrosine kinase domain had clinical
responsiveness to gefitinib. Likewise, Paez et al.
(2004) found somatic mutation in the kinase domain
(exons 18 through 24) in 5/5 patients who responded
to gefitinib, and none in four patients who did not
respond to gefitinib. Most of the patients with the
798
mutations were women, non-smokers, and those with
bronchioloalveolar tumors. Somatic mutations of
EGFR were more frequent in adenocarcinomas (21%)
than other NSCLC (2%), more frequent in women
(20%) than in men (9%), and more frequent in
patients from Japan (26%) than patients from the US
(2%). The highest fraction of EGFR mutations was
found in Japanese women with adenocarcinomas
(57%) (Kris et al. 2003; Fukuoka et al. 2003).
The benefit of EGFR TKIs for NSCLC patients has
subsequently been established in randomized clinical
trials using erlotinib versus placebo in patients that
have progressed after 1 or 2 cycles of chemotherapy
for advanced-stage NSCLC. The NCI Canada BR21
trial found a significant improvement in overall sur-
vival and progression free survival with erlotinib
treatment, leading to FDA approval for the treatment
of refractory NSCLC (Brown and Shepherd 2005).
A similar study was carried out with gefitinib, but this
revealed no difference in overall survival when
compared with placebo treatment (Thatcher et al.
2005). However, in this latter study, significant sur-
vival benefit was noted for patients who have never
smoked and patients of Asian ethnicity treated with
gefitinib in a subset analysis.
Recent large studies conducted in Asia and Spain
further confirmed the role of EGFR mutations as a
major predictor of outcome to treatment by EGFR
TKIs (Rosell et al. 2009; Mok et al. 2009; Lee et al.
2009; Mitsudomi et al. 2010; Maemondo et al. 2010).
Findings from these large studies led to the paradigm
shift in using EGFR TKIs for first line therapy in
patients with advanced stage NSCLC, with the benefit
limited to only patients with known EGFR mutations.
The study by Mok et al. (2009) was a randomized
phase 3 study for those who had advanced pulmonary
adenocarcinoma, and who were non-smokers or for-
mer light smokers to receive gefitinib versus carbo-
platin plus paclitaxel chemotherapy in East Asia.
Twelve-month rates of progression-free survival were
24.9% in the gefitinib arm, and 6.7% in the carbo-
platin–paclitaxel arm. The study showed superiority
of gefitinib in the intention-to-treat population (HR
0.74; 95% CI: 0.65-0.85; P \ 0.001). Likewise,
Mitsudomi et al. (2010) conducted a phase 3 study
(WJTOG3405) in the Japanese population for
stage IIIB/IV NSCLC or postoperative recurrence
harboring EGFR mutations. Patients were randomly
D. Singh et al.
assigned to receive gefitinib or cisplatin plus docetaxel
for 3–6 cycles. The gefitinib group had significantly
longer progression-free survival compared with the
cisplatin plus docetaxel group, with a median pro-
gression-free survival time of 9.2 months (95% CI
8.0–13.9) versus 6.3 months (range 5.8–7.8; HR 0.489,
95% CI 0.336–0.710, log-rank P \ 0.0001). Again, it
was found that patients with NSCLC who were selected
by EGFR mutations had longer progression-free sur-
vival if they were treated with gefitinib than if they were
treated with cisplatin plus docetaxel. Maemondo et al.
(2010) randomly assigned 230 patients with metastatic
NSCLC and EGFR mutations without prior chemo-
therapy to receive gefitinib or carboplatin plus paclit-
axel. In the planned interim analysis of the first 200
patients, progression-free survival was significantly
longer in the gefitinib group than in the standard-
chemotherapy group (HR for gefitinib group, 0.36;
P \ 0.001), resulting in early termination of the study.
The gefitinib group had a significantly longer median
progression-free survival than the chemotherapy group
(10.8 vs. 5.4 months) (HR 0.30; 95% CI 0.22–0.41;
P \ 0.001), as well as a higher response rate (73.7 vs.
30.7%, P \ 0.001). The median overall survival was
30.5 months in the gefitinib group and 23.6 months in
the chemotherapy group (P = 0.31).
2.2.2 Markers of DNA Repair: Excision
Repair Cross-Complementing Group 1
Gene Product and Regulatory Subunit
of Ribonucleotide Reductase
The excision repair cross-complementing group 1
gene product (ERCC1) and the regulatory subunit of
ribonucleotide reductase (RRM1) have been reported
as being prognostic of outcome and predictors of
therapeutic efficacy in patients with NSCLC. Both
ERCC1 and RRM1 are critical to the nucleotide
excision repair (NER) of the DNA repair pathway.
Expression of these genes can both protect the host
from the development or progression of cancer, and
protect tumors from the effects of chemotherapy. Low
ERCC mRNA expression and low RRM1 mRNA
expression have been correlated with improved sur-
vival in advanced NSCLC after treatment with cis-
platin-based chemotherapy and decreased survival in
early stage NSCLC with no adjuvant treatment
(Rosell et al. 2004; Simon et al. 2008; Bepler et al.
2008; Souglakos et al. 2008; Zheng et al. 2007).
Translational Research in Lung Cancer
2.2.3 Excision Repair Cross-Complementing
Group 1 Gene Product
ERCC1 encodes a DNA-repair protein, a member of
the NER complex. In particular, the ERCC1 protein
forms a heterodimer with xeroderma pigmentosum
(XPF) group A protein, and functions to create the 50
incision of damaged DNA. It is a highly conserved
protein, and plays a rate-limiting role in the NER
pathway. ERCC1 polymorphisms have been impli-
cated in carcinogenesis (Chen et al. 1998). However,
ERCC1 function can also predict the capacity of
tumor cells to repair after cytotoxic treatment, as NER
is the primary mechanism for removing platinum–
DNA adducts from the tumor DNA (Reed 1998).
ERCC1 function and the NER pathway have also
been shown in vitro to explain the synergy between
cisplatin and gemcitibine (Yang et al. 2000).
A retrospective study evaluated ERCC1 mRNA
expression in 56 patients with advanced (stage IIIB or
IV) NSCLC (Lord et al. 2002). These patients were
treated with cisplatin and gemcitibine. The study
demonstrated ERCC1 expression to be a significant
predictor of overall survival, with ERCC1 low-
expressing patients surviving 61.6 weeks as compared
to 20.4 weeks in the ERCC1 high-expressing group,
although improved tumor response to chemotherapy
could not be shown. Subsequent retrospective studies
using cisplatin and gemcitibine have confirmed an
overall survival either singly (Ceppi et al. 2006;
Hwang et al. 2008; Li et al. 2010) or in combination
with low RRM1 expression (Rosell et al. 2004). Other
studies, which have used other cisplatin-based thera-
pies, have shown no increase in overall survival with
low expression of ERCC1 (Booton et al. 2007; Fujii et
al. 2008), although a differential tumor response was
seen (Fujii et al. 2008).
The International Adjuvant Lung Cancer Trial
(IALCT), which randomized patients to receive cis-
platin-based chemotherapy after a complete resection
of stage I–III NSCLC, showed a small but statistically
significant improvement in overall survival with the
addition of chemotherapy (44.5 vs. 40.4% at five
years) (Arriagada et al. 2004). However, when this
study was retrospectively analyzed for ERCC1 pro-
tein expression, it was found that only patients with
low ERCC1 expression derived benefit from the
adjuvant therapy, while low RRM1 scores trended to
indicate benefit from adjuvant chemotherapy
(Olaussen et al. 2006; Bepler et al. 2011). The first
799
prospective randomized clinical trial testing the con-
cept of customized chemotherapy in NSCLC has been
completed, which assessed the role of ERCC1 in
treatment planning. The phase 3 study had 346
patients with stage IV NSCLC and they were evalu-
ated after being randomized to receive either doce-
taxel and cisplatin or a tailored regimen based on
ERCC1 mRNA levels (docetaxel and cisplatin for low
ERCC1 levels, and docetaxel plus gemcitibine for
higher ERCC1 levels). A significant improvement in
the objective response rate was seen in the arm
receiving the tailored treatment. However, there was
no difference in disease-free survival and overall
survival in the study arms (Cobo et al. 2007).
2.2.4 Ribonucleotide-Diphosphate
Reductase M1
The ribonucleotide-diphosphate reductase M1
(RRM1) gene is the large regulatory subunit of ribo-
nucleotide reductase, which catalyzes the production
of deoxyribonucleotides from ribonucleotides prepa-
ratory to DNA synthesis during the S phase of the cell
cycle. RRM1 is also essential for NER, as it provides
the bases needed for restoration of the complimentary
DNA strand. RRM1 also plays a role in cell migration
and metastases. The gene is encoded on 11p15.5, and
is thought to be a TSG. In fact, RRM1 transgenic
mice were significantly less likely to develop car-
cinogen-induced lung tumors (Gautam and Bepler
2006). It is the dominant molecular determinant of
gemcitabine efficacy.
A phase II study was performed in 53 patients with
previously untreated NSCLC who were stratified in
treatment based on real-time quantitative PCR mRNA
levels of ERCC1 and RRM1 (Simon et al. 2008).
Treatments by different combinations of double agent
chemotherapy were based on low level versus high
level of ERCC1 and RRM1, showing feasibility of
this approach. In contrast to the expression in
advanced stage lung cancer, low RRM1 and ERCC1
expression appears to predict worse clinical outcomes
in patients with earlier stage disease. A study of 187
patients with early stage NSCLC who received no
adjuvant therapy after surgery showed that RRM1 and
ERCC1 were both determinants of survival (Zheng et
al. 2007). This apparent paradox may be explained by
the fact that intact DNA repair mechanisms in early
stage lung cancer may either prevent or compromise
the gathering of further genomic mutations and
800
progression of disease. Thus, ERCC1 and RRM1 may
both predict patients with early stage tumors that do
not require further therapy, and also inform appro-
priate chemotherapy for patients with more advanced
cancers (Gazdar 2007).
2.2.5 Echinoderm Microtubule-Associated
Protein-Like 4-Anaplastic Lymphoma
Kinase Translocation
The echinoderm microtubule-associated protein-like
4-anaplastic lymphoma kinase (EML4-ALK) fusion-
type tyrosine kinase is an oncoprotein found in 4–5% of
NSCLCs. The EML4-ALK fusion gene is generated by
small inversion within the chromosome two short arm,
encoding a 1,059-amino acid fusion protein. The
N-terminal portion is identical to the human EML4
(Pollmann et al. 2006) and the C-terminal portion is the
same as the intracellular domain of human ALK (Morris
et al. 1994). The EML4-ALK translocation is most
common in younger males, never smokers, and patients
with adenocarcinoma. EML4 NSCLC occurs most
commonly in clinical subgroups, which share many of
the clinical features of NSCLC likely to harbor EGFR
mutation (Shaw et al. 2009). With rare exceptions, EML
and EGFR mutations are mutually exclusive. EML
translocation tends to occur in younger patients and
those with locally advanced disease, while this rela-
tionship has not been reported for EGFR-mutant
NSCLC (Inamura et al. 2009). There is currently no
standard method for detecting EML4 in NSCLC, and
several methods including PCR, IHC, and FISH are
being evaluated. The challenge remains to incorporate
and disseminate wide spread use of diagnostic testing for
identifying this patent subset (Sasaki et al. 2010).
As a molecular target, ALK inhibitors lead to
apoptosis in vitro and tumor shrinkage in vivo.
Patients with tumor mutations may represent a very
effective therapeutic strategy (Sasaki et al. 2010).
ALK-targeted therapies are in advanced clinical
development of EML4-ALK NSCLC. PF-02341066
(crizotinib) is an orally bio available ALK inhibitor
currently under clinical development. Initial findings
demonstrated a remarkable 53% response rate and
disease control rate of 79% (Kwak et al. 2009). These
dramatic findings have led to two clinical trials of
PF-023410066. A randomized phase 3 trial that
compares PF-02341066 with standard second line
chemo premetrexed or docetaxel in second line
EMLALK NSCLC cancer patients is underway.
D. Singh et al.
2.2.6 Human MutS Homologue 2 and
Human MutL Homologue 1
The human MutS homologue 2 (hMSH2), and human
MutL homologue 1 (hMLH1) genes are key compo-
nents in DNA mismatch repair processes for the
recognition and replacement of erroneous base pairs.
Mismatch repair reduces mutations at DNA replica-
tions, but is also thought to be involved, as an adjunct
to NER, with error-free repair of DNA inter-strand
crosslinks (Wu et al. 2005). Dysfunction of these
genes can lead to microsatellite instability, or errors in
replicating repeating DNA sequences. Clinically,
mutations in these genes constitute hereditary non-
polyposis colorectal cancer types 1 (for MSH2) or
type 2 (for MLH1), wherein patients carry a high risk
for various gastrointestinal, genitourinary, and repro-
ductive system cancers.
Certain polymorphisms in the hMLH1 and hMSH2
genes have been shown to be associated with a
decreased or increased risk of developing NSCLC
(Jung et al. 2006; Hsu et al. 2007; Kim et al. 2010; Lo
et al. 2011; Shih et al. 2010). In particular, decreased
expression of the hMLH1 gene was seen more in
SCLC, and decreased expression of the hMSH2
was more common in adenocarcinoma of NSCLC
(Xinarianos et al. 2000). In early stage NSCLC, with
no adjuvant therapy, MLH1 and MSH2 protein
expression has not been shown to be prognostic
(Cooper et al. 2008). However, hMLH1 gene inacti-
vation (Xinarianos et al. 2000), and in general,
microsatellite instability (Woenckhaus et al. 2003) are
associated with the risk of lymph node metastases.
This indicates that mismatch repair defects can play a
role in the development and progression of NSCLC.
The data are less clear, as in other DNA repair
genes, as to whether inhibition of MSH2 correlates
with improved survival in lung cancer patients
requiring chemotherapy. A retrospective analysis of
the IALCT showed that patients with low MSH2
protein levels (about 38% of the whole) had trends
towards improved survival, and that no benefit was
seen when MSH2 was high. Chemotherapy prolonged
overall survival significantly for patients with tumors
expressing low levels of both MSH2 and ERCC1, and
also for low levels of MSH2 and p27 (a cell cycle
protein) (Kamal et al. 2010). Another study of 179
patients did not show any association of hMLH1 or
hMSH2 expression with disease outcomes in stage III
NSCLC (Skarda et al. 2006). A third study showed
Translational Research in Lung Cancer
improved survival for cases with low expression of
hMLH1, but not hMSH2 (Scartozzi et al. 2006). Data to
date indicate that decreased activity of the mismatch
repair pathway can be associated with development and
progression of NSCLC. In more advanced disease,
decreased activity in this pathway does not correlate
robustly with an increased response to cytotoxic
chemotherapy. This may indicate that although such
cells may have a decreased ability to repair chemo-
therapy-induced defects, this is balanced by a muta-
genic phenotype, allowing for phenotypic selection.
2.2.7 Serum Proteomic Profiling
Serum proteomic profiling that utilizes the matrix-
assisted laser desorption/ionization mass spectrometry
(MALDI) reveals many different proteins in the blood
at the time of sample collection. It has been shown
that serum proteomic profiles of blood samples from
NSCLC patients can predict which patients are more
likely to benefit from EGFR TKI treatment (Meyer-
son and Carbone 2005). Some clinical trials have
been conducted and validated this observation
(Amann et al. 2010; Taguchi et al. 2007).
3 Small Cell Lung Cancer Serum
Markers
SCLC is characterized by rapid growth and the
propensity for early metastases. It is known to be
associated with neuroendocrine differentiation due to
its cell origin. SCLC has shown positive expressions
by IHC stain with neuroendocrine markers such as
Neuron Specific Enolase (NSE, an isoform of the
ubiquitous enolase enzyme), chromogranin A (CgA),
synaptophysin, creatinine kinase BB, bombesin
(Gastrin-Releasing Peptide [GRP]), and neural cell
adhesion molecule (NCAM) (Berendsen et al. 1989;
Erisman et al. 1982; Yamaguchi et al. 1983). Some of
these neuroendocrine molecules are released into the
blood of SCLC patients. Translational investigation of
SCLC has been focused on these serum markers. At
present, SCLC serum markers are considered more
useful for diagnosis, detection of disease progression
or recurrence, and monitoring of therapy, but less
useful for the prognosis or prediction of response to
therapy for SCLC. The serum markers with more
specificity to SCLC are CgA, NSE, and Pro-gastrin-
releasing peptide (Pro-GRP).
801
3.1 Chromogranin A
CgA is a 49 kD acidic-soluble protein ubiquitously
present in neuroendocrine tissues and serves as a
suitable circulating marker of neoplasms of neuro-
endocrine origin. The ability of serum CgA to dis-
tinguish neuroendocrine and non-neuroendocrine
tumors either in situ or by serum level titration has
been suggested (Drivsholm et al. 1999).
3.2 Neuron-Specific Enolase
NSE is a neuronal form of the glycolytic enzyme
enolase, which was first found in extracts of brain
tissue, and was later shown to be present in amine
precursor uptake and decarboxylation (APUD) cells
and neurons of the diffuse neuroendocrine system, but
not in other peripheral cells. Neuroendocrine neo-
plasias (APUDomas) (including islet-cell tumors,
pheochromocytomas, medullary thyroid carcinomas,
SCLC, and APUDomas of the gut, pancreas, and
lung) reacted strongly with antisera to NSE (Tapia et
al. 1981).
3.3 Pro-Gastrin-Releasing Peptide
GRP is a gut hormone that is present in nerve fibers,
as well as in the brain and neuroendocrine cells in the
fetal lung (Drivsholm et al. 1999; Miyake et al. 1994).
It was originally isolated from the porcine stomach
and is the mammalian counterpart of amphibian
bombesin. It is elevated in the plasma of patients with
SCLC, but its regular use as a diagnostic marker is not
preferred because of its instability in the serum with a
half-life of approximately 2 min (Yamaguchi et al.
1983). In contrast, serum ProGRP, a more stable
precursor of GRP, has been shown to be a specific
tumor marker of SCLC (Miyake et al. 1994).
While all three markers are useful in the diagnostic
performance of SCLC, various studies have shown
that serum ProGRP is superior to other markers in its
ability to differentiate SCLC and NSCLC. Studies
also found that serum CgA has better diagnostic
sensitivity than NSE in SCLC (61 vs. 57%), espe-
cially in limited disease. In contrast, NSE reflected
disease extent more accurately than CgA. It has also
been shown that the CgA assay is not affected by
802
hemolysis, whereas NSE serum levels greatly
increased in hemolysed sera. CgA assays via this
method are a reliable procedure in the diagnosis of
SCLC, whereas NSE is the suitable marker of choice
in staging and monitoring of the disease (Holdenrie-
der et al. 2008; Wójcik et al. 2008). In a large retro-
spective study examining the single and combined
diagnostic value of NSE, ProGRP, serum carcino-
embryonic antigen (CEA), and cytokeratin fragment
19 (CYFRA21-1), ProGRP reached the highest diag-
nostic efficacy for SCLC with 57% true positive
results at a specificity of [99% (Gruber et al. 2008).
Serum markers have also been used for monitoring
first-line chemotherapy in the management of SCLC
(Holdenrieder et al. 2008). A study assessing Pro-GRP,
NSE, CYFRA 21-1 and lactate dehydrogenase (LDH)
levels at the time of diagnosis and during chemotherapy
and radiotherapy of SCLC patients with limited stage of
disease, found elevated levels of ProGRP, NSE, CYFRA
21-1, and LDH in 79.9, 57.8, 23.4, and 12.5% of patients,
respectively. Before the second chemotherapy course,
all tumor marker levels except LDH decreased signifi-
cantly in comparison with the pretreatment levels.
However, only ProGRP levels showed a progressive
decrease during consecutive course of therapy, while
NSE and DYFRA 21-1 fluctuated within reference
ranges. Changes of Pro-GRP level seem to be more
precise than NSE as a tool for monitoring therapy in
SCLC patients with limited disease (Wójcik et al. 2008).
4 A Chemoradiation Model
of Translational Investigation
for Stage III Non-Small Cell Lung
Cancer
4.1 National Institutes of Health
Roadmap for Translational Medicine
For decades, the NIH has been funding basic biomed-
ical research that aims to understand how living
organisms work. The initiative of the NIH roadmap
(Fig. 1), has increased the focus on the need to
‘‘translate’’ basic research more quickly into human
studies, and then into tests and treatments that can
improve clinical practice for the benefit of patients
(Westfall et al. 2007). Here we describe a translational
investigation that has successfully brought the
‘‘benchtop’’ observations to the ‘‘bedside’’ of clinical
D. Singh et al.
trials in the investigation of taxane-based chemoradi-
ation treatment for stage III NSCLC. This project has
discovered the differential effects between paclitaxel
and docetaxel in the ‘‘radiosensitizing effect’’ versus
the ‘‘cytotoxic effect’’, and has applied these differen-
tials to maximally target the chest tumor control and
distant micrometastasis control of stage III NSCLC.
4.2 Translational Investigation Model
of Taxane Chemoradiation for NSCLC
Locally advanced stage III NSCLC constitutes
20–30% of patients who present with NSCLC.
Treatment of stage III NSCLC remains a challenge to
oncologists. Despite aggressive chemoradiation
combination treatment, the outcome is quite poor with
a high intrathoracic failure rate at approximately 50%
and a high rate of distant metastasis at approximately
80% (Morton et al. 1991; Schaake-Koning et al. 1992;
Mattson et al. 1988; Gandara et al. 1991; Marino et al.
1995; Arriagada et al. 1991; Sause et al. 2000; Curran
et al. 2000; Furuse et al. 1999, 2000). The median
survival time using cisplatin-based chemoradiation is
only 14–17 months from large randomized trials of
chemoradiation treatments. To improve the local
tumor control rate, the Radiation Therapy Oncology
Group (RTOG) is currently conducting a four-arm
phase III randomized clinical trial (RTOG 0617)
using concurrent chemotherapy (carboplatin/paclit-
axel), with or without cetuximab (monoclonal anti-
body against EGFR), and radiation, to compare
standard dose radiation of 60 Gy versus high dose
radiation to 74 Gy. In addition to adding molecular
targeted agents such as cetuximab to improve on the
control of distant metastasis, many other clinical trials
have applied newer chemotherapeutic agents and
tested different chemoradiation sequences. Thus far,
there is no major therapeutic breakthrough in
improving the treatment outcome of stage III NSCLC
(Chen and Okunieff 2004).
A translational investigation was conducted at the
University of Rochester by bringing preclinical
benchtop findings to the development of two
sequential clinical trials using taxane-base chemora-
diation regimens. The two studies targeted chest
tumor control and distant micrometastasis control,
yielding promising results (Chen et al. 2001, 2003,
2010).
Translational Research in Lung Cancer
Fig. 3 Clonogenic survival curves of human lung cancer cell
line NCI520. Cells were treated with either a paclitaxel (Taxol)
or b docetaxel (Taxotere) at two different drug concentrations
(50 or 100 nM) for 3 h. After drug treatments, cells were either
irradiated immediately or irradiated 24 h later. Radiation doses
were 2, 4, 6, and 8 Gy versus sham radiation (0 Gy). Both
paclitaxel treated cells and docetaxel treated cells showed more
4.2.1 Preclinical Studies Of Lung Cancer Cell
Lines
Taxanes are the ideal radiation sensitizers due to the
cell cycle effect in arresting cancer cells in the most
sensitive phase of the cell cycle of G2/M (Sinclair
1966). Investigators at the University of Rochester
conducted preclinical studies using lung cancer cell
lines and investigated effects of paclitaxel and doce-
taxel on the cytotoxic effects versus radiation sensi-
tizing effects of these taxanes. The preclinical data
revealed the following: (i) after paclitaxel treatment, a
minimum of 4 h is necessary for cell cycle progression
to G2/M phase of the cell cycle, the most radiosensitive
phase of the cell cycle (Chen et al. 2001); (ii) pulsed
treatment of taxane sustains G2/M cell cycle arrest
(Chen et al. 2003); (iii) delaying radiation after taxane
treatment led to better radiosensitizing effects than
immediate radiation after drug treatment (Chen et al.
2001, 2003, 2010), and (iv) docetaxel demonstrates a
much more potent cytotoxic effect than paclitaxel
(Chen et al. 2001, 2010) (Fig. 3).
4.2.2 Translating Preclinical Studies to
Clinical Trials
Translating the preclinical information to the design
of two sequential clinical studies (U1597 and U1500)
led to novel approaches in the combination of taxane-
803
cell death (steeper slopes) if radiation is delayed at 24 h,
supporting better radiosensitizing effect by delaying radiation
after drug treatments. For sham irradiated cells (0 Gy), there is
more cell death in the docetaxel treated cultures (Y axis of B)
than the paclitaxel treated cultures (Y axis of A), demonstrating
that docetaxel is significantly more cytotoxic (Chen et al. 2001,
2010)
based chemotherapy and radiation therapy for the
treatment of stage III NSCLC. Based on preclinical
information regarding the cell cycle and apoptotic
effects of paclitaxel on lung cancer cell lines, U1597
applied concurrent pulsed low-dose, radiosensitizing
paclitaxel chemoradiation to treat stage III NSCLC.
To optimize radiosensitization by paclitaxel without
increasing toxicity, a chemoradiation combination
was conducted in a schedule dependent manner with
paclitaxel delivered on alternating days (three times
per week, M, W, F) at low doses (15, 20, and 25 mg/
m2 in the phase I dose-escalation study). Daily radi-
ation was delayed to allow for cell-cycle progression
of cancer cells into G2/M phase of the cell cycle, the
most radiosensitive phase of the cell cycle. The
pulsed low-dose paclitaxel schedule allowed for rapid
clearance of drug from the plasma to minimize tox-
icity (Chen et al. 2008). This phase I study (U1597)
yielded a 100% gross tumor response rate, a three-
year survival of 30%, and low rates of grade 3 or 4
toxicities (Chen et al. 2001, 2003, 2008). The inves-
tigators contoured the tumors on 104 pre-treatment
and post-treatment chest CT scans, and modeled the
kinetics of clinical tumor response (Zhang et al. 2008).
Data showed that the bulk of the tumor shrinkage
occurred within 4–6 weeks post-treatment, and larger
tumors shrunk faster (Fig. 4). This is dramatically
804
Fig. 4 The tumor response kinetics model is developed from
104 chest CTs of patients treated on U1597, employing pulsed
low-dose paclitaxel (Taxol) chemoradiation treatment for stage
III NSCLC. a Mathematic model of tumor response kinetics.
Estimates of the model parameters and their standard deviation
different from the expected kinetics of NSCLC in that
tumor shrinkage after chemoradiation is expected to be
slow and may take several months to reach nadir. This
study yielded an in-field (radiation port) tumor control
of 97% at 5 years (Chen et al. 2003).
To target distant micrometastasis upfront, the
second study (U1500) employed one-cycle induction
chemotherapy of docetaxel and cisplatin, followed by
low-dose, pulsed docetaxel chemoradiation. The
hypothesis of U1500 was that for targeting micro-
metastasis, a single cycle of full-dose chemotherapy
should suffice, while two or three cycles of induction
chemotherapy will delay local therapy. This is based
on thoughts by Goldie (1987) that ‘‘it can be stated
that as a general biological principle that there are
many compelling reasons why chemotherapy should
be directed at minimal tumor burdens.’’ One-cycle
induction chemotherapy in targeting potential
distant micrometastasis instead of the conventional
2–3 cycles would not delay chest local therapy using
concurrent radiosensitizing chemoradiation. There-
fore, U1500 was conducted with one cycle of cisplatin
(75 mg/m2) and docetaxel (75 mg/m2) followed by
low-dose sensitizing docetaxel (12.5 to 15 mg/m2,
twice per week on Monday and Thursday), and con-
current daily chest radiation to 64.8 Gy. The result
showed an overall response rate of 69%, which was
lower than the pulsed paclitaxel study of U1597
(100%), but had a much better survival rate than the
U1597 study. The 3-year overall survival was 45%
compared to 30% in U1597 (Chen et al. 2003, 2010).
D. Singh et al.
are shown in the table insert. The volume reduction over time
shows early rapid tumor shrinkage within the first 4–6 weeks.
b The rate of tumor shrinkage versus the initial tumor volume
correlation shows that larger tumors shrink faster for tumors
treated by pulsed paclitaxel chemoradiation (unpublished data)
Median survival was 32 months in U1500 and was
11 months in U1597.
The clinical outcome of these two studies support
that while the addition of one-cycle full-dose che-
motherapy of docetaxel/cisplatin improved survival
of patients, pulsed low-dose radiosensitization
‘‘paclitaxel’’ was more effective than ‘‘docetaxel’’ in
sensitizing radiation for gross chest tumor control.
5 Summary
The emphasis of the NIH roadmap has yielded
increasing success in translating benchtop research to
clinical trials. Translation research in NSCLC has
revealed that most molecular prognostic factors tested
by IHC are not useful. After rigorous testing, K-ras
mutation is associated with poor prognosis, but its
prognostic value has not been observed in a pro-
spective clinical study for patients with stage II and
IIIA NSCLC population (Schiller et al. 2001). On the
other hand, major progress has been made with
molecular markers in predicting response to particular
treatments, and in some cases survival outcome as
well. Findings in the predictive molecular markers
such as EGFR mutations, ERCC1, RRM1, EML4-
ALK translocations, hMSH2, and hMLH1, have been
applied to pharmaceutical targets for personalized
therapy in molecular targeting approaches to the
treatment of NSCLC. Serum proteomics have been
found to be predictive in the treatment response to
Translational Research in Lung Cancer
EGFR TKI in NSCLC, while serum markers such as
CgA, NSE, and Pro-GRP have the potential value in
the diagnosis and monitoring therapy response for
SCLC. The taxane-based chemoradiation model we
presented here supports that the translational investi-
gation to the design of clinical trials that are
hypothesis based and are built upon preclinical
findings may have higher probability of yielding the
desirable clinical outcome.
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 Clinical Research in Radiation Oncology
of Lung Cancer: Why We Fail(ed)?
Branislav Jeremić
Contents
1 Introduction.............................................................. 809
2 Clinical Research Generals .................................... 810
3 Technological Addictions ........................................ 810
4 Clinical Failures....................................................... 812
5 Controversial Issues ................................................ 813
6 Possible Solutions..................................................... 817
References.......................................................................... 817
B. Jeremić (&)
Institute of Lung Diseases, Sremska Kamenica, Serbia
e-mail: nebareje@gmail.com
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_222, Ó Springer-Verlag Berlin Heidelberg 2011
Abstract
Clinical research in radiation oncology of lung
cancer can bring important advances in the field of
optimized treatment approaches in this disease.
However, such a research has been a subject of many
controversies, in particular in the light of lack of
adequate number and quality of clinical trials which
could have changed our standard policies. To
address the comprehensive issue of clinical research
in radiation oncology of lung cancer, several aspects
will be considered: clinical research generals,
technological addictions, clinical failures, and some
of existing, rather controversial issues identified.
Finally, some of possible solutions for the current,
grossly unfavorable, situation will be discussed.
1 Introduction
Lung cancer remains one of the most important health
problems worldwide. This is not so, only because of its
high morbidity and mortality (as the major cancer
killer in both sexes), but also due to the fact that dismal
figures obtained nowadays reflect largely inadequate
efforts to optimize our prevention, screening, early
diagnosis, treatment, and palliation efforts in this dis-
ease. Radiation therapy remains one of the corner-
stones of modern therapeutic endeavours due to its
high effectiveness as both curative and palliative
approach given either alone or in combination with
other therapeutic modalities (surgery, chemotherapy)
in the majority of patients with this disease.
However, our ability to theoretically consider all
possible avenues to optimize radiation therapy and then
809
810
practically apply it in daily clinic has been very low.
Hence, improvements have been only incremental and
suffice to say, inadequate, having in mind that each year
more than one million patients are newly diagnosed with
this disease. The vast majority of lung cancer patients do
not benefit from any of these ‘‘improvements’’ irre-
spective of geography, race or social status/income.
Therefore, lung cancer must be considered as one of the
major battlegrounds in clinical research of oncology,
since clinical research can bring important discoveries
and help improve our ability to more successfully eval-
uate more general oncological principles in this disease.
This also relates to continuous and very much evolving
evaluation of the place and the role of radiation therapy
in the field of clinical research in thoracic oncology.
To address the comprehensive issue of clinical
research in radiation oncology of lung cancer, several
aspects will be considered: clinical research generals,
technological addictions, clinical failures, and some
of existing, rather controversial issues identified.
Finally, some of possible solutions for the current,
grossly unfavorable, situation will be discussed.
2 Clinical Research Generals
General observations can be easily understood if one
tries to answer the following questions: who does
clinical research, how one does it and finally, when
one does it? Putting events (e.g. clinical trials
designed and performed) into a chronological order,
instant observation is that the vast majority of clinical
research in radiation oncology of lung cancer (and
very much with other treatment options) through
clinical trials is mostly done within single-institu-
tional setting and less within the group setting and
even less within the intergroup setting. This, unfor-
tunately, leads to less patients enrolled per study and
that, ultimately, leads to poorer (lower) clinical evi-
dence such studies can bring. Therefore, it must be
clearly said that this type of approach leads to inferior
quality of clinical research and hampers implemen-
tation into a general clinical practice of radiation
oncology of lung cancer. Similarly, when answering
to a question how one does it, again, more phase I and
II trials are observed and less phase III trials are
performed. For example, if one takes as an example of
what two of the major groups (RTOG and EORTC)
have done in the last 30 years in the field of e.g.
B. Jeremić
combined radiochemotherapy in locally advanced
nonsmall cell lung cancer, only a few prospective
phase III clinical trials have been successfully per-
formed, fully analyzed and fully published (Belderbos
et al. 2007; Curran et al. 2000; Sause et al. 1995;
Schaake-Koning et al. 1992). As probably the most
extreme example is the case of extensive disease
small cell lung cancer where we have had a single
prospective randomized trial ever reporting on the
role of curative thoracic radiation therapy in this
disease. As an additional evidence supporting these
statements is the fact that after publication of (Jeremic
et al. 1999) on radiation therapy in extensive disease
small cell lung cancer, 10 years passed before two
studies opened up for patient accrual in the US and
The Netherlands, respectively. Finally, when one
remains in the same time period (e.g. last three decade),
it must be clearly observed that what and when have
driven researchers is less the idea itself, but, unfortu-
nately, more fashion and trend. Hence, we have seen an
avalanche of induction chemotherapy studies in the
1980s of the last century (Dillman et al. 1990; Le
Chevalier et al. 1992; Clamon et al. 1999; Vokes et al.
2002; Belani et al. 2005a) and many of the consolida-
tion chemotherapy studies in the 1990s of the last
century (Lau et al. 2001; Gandara et al. 2006; Sekine
et al. 2006; Hanna et al. 2008), all asking very similar
questions, with very similar design, majority of which
were not asking strategically different question from
their predecessors. Changing a regimen consisting of
70 mg/sqm of paclitaxel given every week with
100 mg/sqm of cisplatin given every 3 weeks to a
regimen consisting of 60 mg/sqm of paclitaxel given
once a week with 50 mg/sqm of cisplatin given twice a
week meant very little, if anything. Indeed, it mostly
brought nothing to the overall scientific improvements
in this field, not to mention that thousands of patients
have been exposed to meaningless clinical research that
‘‘misused’’ millions of dollars and Euros worldwide.
3 Technological Addictions
Radiation oncology is technology driven and tech-
nology dependent profession. It was so since the
advent of X-rays and it will definitely remain so in the
foreseeable future. The level of this dependency is
very much related to several factors. Some of them
are inherent to national health care systems (due to
Clinical Research in Radiation Oncology of Lung Cancer: Why We Fail(ed)?
billing specifics), while some are related to the pro-
fessional and/or scientific level of an institution.
While free-standing/private institutions usually see
technological advances as a driving force for more
patients expecting that patient flow remain crucially
dependent on offering the latest available technology
(and assuming that these technologies work well
against cancer), academic institutions are usually
inclined towards newer technologies also due to
enormous capacity for research such technologies
usually bring early in the phase of the development.
In both cases mindset towards ‘‘new’’ (presumably
also being better!) is what actually drives clinicians
and scientists and that is the fact worldwide. Let us
briefly take the matter of introduction and subsequent
use of intensity modulated radiation therapy in the
clinical practice worldwide, especially in the US. Due
to the fact that it had found fast way to overall and
legal approval, with very favorable billing profile, this
technology became so widely available that majority
of institutions started almost indiscriminately using it
in majority of tumor sites. Logical question (evidence
vs. type of the proof needed) one may ask is whether we
actually have had ‘‘evidence’’ to support this? Without
going into a detail what ‘‘evidence’’ actually means, we
faced the fact that only a few clinical trials have actually
compared in a prospective randomized fashion this
technology with already available technologies such as
2D or 3D radiation therapy. In spite of being rather
complex and time consuming application (evidence vs.
challenge), clinicians nevertheless continued with its
use in clinic, largely based on the fact that ‘‘isodose
distribution’’ (or DVH or else) achieved with it was
better than with other technologies’’. Again, one can
rightly point out that what we actually do is nothing but
using a surrogate (in this case computer screen repre-
sentation of physical calculations done on phantoms) of
the real life (clinic, better to say) as definite measure of
comparison between the two. So, what is done this way
it is nothing but the third in a row of hurdles, one may
call evidence versus intention. Whichever evidence we
confront with any comparator, the ultimate question, in
every single tumor site, would simply remain whether
there are Clinically Meaningful benefits for this and
other more advanced cases to justify its discriminate
use in daily clinic.
One may also point out the active influence of
industry in this regard. While this author fully
understands and supports active engagement of
811
industry in the field of clinical research of radiation
oncology in lung cancer, sometimes this influence is
at least hard to understand. While marketing aspects
bring necessary flavour to the overall happenings in
the field, sometimes they do the harm. I will here
briefly describe the situation occurring during one of
the major European meetings which occurred several
years ago. During evening session organized as a pure
marketing event for hundreds of guests, one machine
company marketed their product using the slogan:
‘‘Problem solving for tumor motion’’. What made this
slogan a bit inaccurate was not the machine itself, or
its future and potential capabilities (to be clinically
proven) but rather supporting the slogan by identify-
ing a person saying so, an unusual matter in a sci-
entific world, at least in such marketing aspect.
Finally, what made this approach really problematic
was that the person (radiation oncologist) whose
name was used to support this marketing effort never
did anything serious in the field of lung cancer and
was actually known as head and neck person due to
good achievements in the field of head and neck
radiation oncology. It was obvious that company
embarking on this task had nobody from the field of
lung cancer able to say those words, likely because
real professional in the field would not uncondition-
ally support unproven technologies, no matter how
promising they look. Contrary to this technology,
another one was popularized much less over the
years. In spite of several vendors being active in the
field, offering different products, various stereotactic
applications proved to be extremely and almost
identically efficient in the treatment of both primary
(early) and metastatic nonsmall cell lung cancer. This
became obvious when one looks at how different dose
prescriptions, fractionation patterns and immobiliza-
tion devices have been used worldwide, all leading to
very similar results.
Finally, technological addictions will also have an
inadvertent influence on radiobiological aspects of
contemporary clinical fractionation. With more ori-
entation towards larger dose per fraction and, hence,
shorter regimens, these hypofractionated regimens
would prove as unexplored territory for combined
radiochemotherapy and I particularly refer to con-
current radiation therapy and chemotherapy. What we
mostly practice today is based on our experience
gathered when ‘‘classic’’ radiobiology modelling and
clinical studies were combined to gather knowledge
812
that serves as the cornerstone of the current evidence-
based decision–making process. That said, standard
dose fraction radiation therapy and chemotherapy as
we have used it and still use, may mean little in the
future when large dose per fraction and fewer times
available (over the course of combined radiation
therapy and chemotherapy) to administer chemo-
therapy concurrently with radiation therapy. While
this may lead to fewer concurrent regimens in the
future, it may also lead to somewhat higher incidence
of both acute and late toxicity such ‘‘hybrid’’ regi-
mens may lead to due to larger dose per fractions and
less time to fractionated total chemotherapy dose.
4 Clinical Failures
The term ‘‘clinical failures’’ is used here to describe
our failures to observe events during clinical studies
performed in the past and to use then-gathered
knowledge to optimize subsequent studies. In partic-
ular, this is referred to the time component to use
gathered knowledge to optimize future attempts via
clinical studies. These failures can broadly be sepa-
rated into patient-related, tumor-related, and history
of the disease-related.
Of patient-related observations, it was frequently
observed that patients with performance status of less
than 50% and/or those with pronounced weight loss
(i.e. [5%) are those suffering from more toxicity,
having more treatment interruptions and/or dose
reductions, all leading to poorer local control and
ultimately, inferior survival. Hence, it may come as a
surprise that although more recent studies tried as
much as possible to exclude these patients from var-
ious dose-intensification trials, we do not have more
clinical studies concentrating on those, rather unfa-
vorable, prognostic group with only a few exemptions
to this statement. Similarly, elderly have largely been
neglected adequate access to clinical trials, possibly
due to a fear that they could not tolerate intensive
therapeutic interventions. While there are no firm data
supporting this, rather nihilistic view, there are also
not many prospective randomized clinical trials spe-
cifically addressing various aspects of treatments
administered in the field of radiation oncology of lung
cancer, where radiation therapy was given either
alone or in combination with chemotherapy. These
observations may fall into a group of explanations of
B. Jeremić
why we do not have more patients enrolled into
clinical trials since the vast majority of clinical trials
are continuously used to ask various questions about
optimization via intensification of radiation therapy
and/or chemotherapy.
Of tumor-related factors, stage, histology, and
location can be used to provide necessary framework
for statements above. Stage III nonsmall cell lung
cancer is one of the focuses of clinical investigations
in the field of lung cancer. Even with the most recent
staging revision (Goldstraw et al. 2007), it still has 11
different T and N combinations. While we continue
this, rather surgical, staging system, it is unknown
why radiation oncologists do not embark on first
evaluating and then using more tumor volume-, rather
than tumor size-driven staging system(s). This is
especially so since we are living for, at least, the last
20 years, in an era of powerful computers which
enabled easy 3D reconstruction of various volumes
and, hence, fast computation of volumetrics. While
occasional work had been done mostly concentrating
on T volumes, N volumes seem as almost completely
neglected matter. Regarding histology, it has been
speculated for many years about more ‘‘local’’ char-
acter of the squamous cell carcinomas than other
nonsmall cell carcinomas (e.g. adenocarcinoma, large
cell carcinoma). If this is so, why then efforts have not
been appropriately made towards optimization of
our endeavours by using more local (e.g. radiation
therapy dose escalation with/without radioenhancing
administration of chemotherapy) treatment options in
this setting and, contrary to that, more/higher doses of
chemotherapy given with radiation therapy in ade-
nocarcinomas and large cell carcinomas due to their
presumably larger metastatic potential? Similarly,
some observed more ‘‘local’’ character of peripheral
lung cancers, especially early stage ones. Therefore,
different approaches could have been explored in
addressing these issues and helped gain insight about
differences in both biological behavior of tumors
located differently as well as design clinical trials
addressing different therapeutic options tailored
according to these characteristics.
Of those observations that could have easier
changed our reality by using them in clinic, events in
locally advanced nonsmall cell lung cancer and
extensive disease small cell lung cancer could nicely
serve as supporting background. In locally advanced
nonsmall cell lung cancer, induction chemotherapy
Clinical Research in Radiation Oncology of Lung Cancer: Why We Fail(ed)?
followed by radical radiation therapy became stan-
dard treatment option in the 1990s of the last century.
In order to optimize it, various intensification
attempts have been made, including administration of
concurrent radiochemotherapy after induction che-
motherapy. What all of these studies clearly identified
is insufficient local control obtained when one starts
the treatment with induction chemotherapy, no matter
how much you eventually intensify the second (con-
current) part of the combined treatment with either
higher radiation therapy dose or more drugs/doses,
some of which belong to the third generation drugs.
What was occasionally discussed in the literature
became obvious with the study of (El Sharouni et al.
2003) who compared CT scans pre-and post-induction
chemotherapy, with emphasis on the time from the
last induction chemotherapy cycle to the time of
radiation therapy treatment planning CT was actually
done. That way they have been able to measure an
increase in gross tumor volumes (GTV) and subse-
quently define volume doubling times. During the
waiting period (for the planning CT scan and start of
RT), a total of 41% of all tumors became incurable,
with the ratio of GTVs being in the range of 1.1–81.8!
Tumor doubling times ranged 8.3–171 days, with the
median of 29 days. When translated into more clini-
cal language, these findings clearly say that even if
one may have thought (due to insufficient CT-based
imaging) that response occurs (and that it matters),
there is actually an opposite development, with sur-
viving tumor clonogens repopulating fast, leading
tumors to regrow to the state of incurability. When
applied to observations of various clinical studies,
whatever you do after you start with chemotherapy, it
became widely known that failure is inevitable and
comes fast. With this approach, one can only achieve
more toxicity (Vokes et al. 2002; Akerley et al. 2005;
Socinski et al. 2008) and even if you use the modern
radiation therapy tools such as 3D radiation therapy
and attempt treatment intensification by escalating the
total dose, again, one cannot achieve better outcomes.
Indeed, impressive 12% mortality in the most recent
CALGB attempt (Socinski et al. 2008) to combine
induction chemotherapy with subsequent radiation
therapy and concurrent chemotherapy led investiga-
tors to early stopping the trial. Interesting, though, is
that even nowadays, after successful publication of
three meta analyses which clearly showed superiority
of concurrent radiation therapy and chemotherapy
813
over induction chemotherapy and radiation therapy,
there are still clinicians embarking on this hazardous
and inferior treatment option, driven, obviously, by
other than evidence-based motives. Similarly, by
observing patterns of failure in extensive disease
small cell lung cancer treated with chemotherapy
alone, (Jeremic et al. 1999) designed and executed a
prospective clinical trial that successfully integrated
radical chest radiation therapy in combined modality
approach. While this study was praised as pioneering
one, researchers continued to practice chemotherapy
alone in this disease. It took about 10 years after full
publication of the date of (Jeremic et al. 1999) to
embark on similar studies evaluating the role of
radiation therapy in this disease.
5 Controversial Issues
They can broadly be divided into pressure from
industry (largely discussed above), hospital/depart-
mental workflow, and some personal issues. Hospital/
departmental workflow was and still seems to be one
of the major problems in clinical research in the field
of lung cancer worldwide. They include sometimes
existing waiting lists which adversely influence time
to start with radiation therapy treatments and, before
it, treatment planning activities. In the past, this was
frequently discriminatory issue, which was mostly
used by medical oncologists and/or pneumologists as
the driving force to start combined treatment with
administering chemotherapy first. While the nature of
the work of medical oncologists/pulmonologists
dealing with lung cancer remains the domain of
chemotherapy from the onset, with a paradigm, ‘‘the
more of it, the better of it’’, radiation oncologists
have, unintentionally, I assume, added to these fail-
ures by accepting the policy that we ‘‘should do
something’’ while patient is waiting for planning CT
scan, as part of the preparation before the radiation
therapy will start. We have indeed done/achieved
something! Several clinical trials clearly showed that
any intensification of the latter/major part of the
combined treatment approach via concurrent radio-
chemotherapy is not effective, once you have started
with induction chemotherapy. Several studies of
CALGB (Vokes et al. 2002; Akerley et al. 2005;
Socinski et al. 2008), showed that there is no com-
pensation for insufficient start (with chemotherapy).
814
Other attempts, such as the use of three daily fractions
of radiation therapy, also proved to be ineffective. All
in all, whatever you do after you start with chemo-
therapy, failure is inevitable and comes fast. With this
approach, you can only achieve more toxicity such as
12% mortality in the most recent CALGB (30105)
(Socinski et al. 2008) attempt to combine induction
chemotherapy with subsequent radiochemotherapy
that led investigators to early stopping the trial.
Waiting lists remain to be an unpleasant reality in
radiation oncology departments in various regions all
over the world. While one can instantly pinpoint at
them as one of the sources of potential obstacle for
implementing e.g. concurrent radiation therapy and
chemotherapy, there are measures to overcome it,
either completely, or at least significantly. This is
especially so if one continues to use long and pro-
tracted regimens in the treatment of metastatic disease
or even locally advanced incurable cases. Therefore,
there is little justification and sympathy for those
radiation oncologists which continue to use e.g.
30 Gy in 10 fractions for a single painful bone
metastasis (instead of using 8 Gy in a single fraction)
and, at the same time, complain about existing wait-
ing lists. To extend this, some of brain metastasis
patients could effectively be treated with 20 Gy in
five fractions and some of locally advanced incurable
lung cancer with either 10 Gy in a single fraction or
17 Gy in two fractions given with 1 week split. While
billing issues still dominate as one of the reason for
favoring more protracted regimens, hospital/depart-
ment management should prioritize access to radia-
tion therapy-based on cost-effectiveness, at least.
In addition, worldwide experience with routes of
patient referral for lung cancer treatment remains
unfavorable for radiation oncologist. In spite of the
fact that radiation oncologists actively working in the
field of stereotactic radiation therapy have seen more
referrals directly to them, largely due to excellent
results achieved with this treatment technique, this is
not the case when more standard (here meant as three-
dimensional conformal radiation therapy or intensity
modulated radiation therapy) approach in both early
and locally advanced nonsmall cell lung cancer and
most of limited disease small cell lung cancer patients
is considered. There, besides official and visible
tumor boards, there seems to exist an invisible one,
materialized in the fact that patients are first referred
to either thoracic surgeon and/or medical oncologist/
B. Jeremić
pneumologist. While this presents no problem for
doubtful cases, those with definite diagnosis needed,
or those of borderline cases, it remains absolutely
unknown why fully staged patient with stage III
nonsmall cell lung cancer, having a performance
status score of e.g. 80%, no weight loss, squamous
histology and no pulmonary reserve compromised
(provided that all of these had been previously
investigated and confirmed) is not sent to radiation
oncologist who would then be responsible for the
overall treatment plan including chemotherapy. This
is even more so in inoperable cases with serious lung/
heart issues when neither surgery nor chemotherapy
would be offered. Including another specialist leads
only to loosing additional time, as well as it will
obscure clear picture and undermine efforts of one
efficient treatment option, namely radiation therapy.
Perhaps, radiation oncologists should go more to
public, inform it about standards of care, engage in
continuous discussions with other potential sources of
patient referrals (e.g. general physicians, respiratory
physicians working outside academic/university hos-
pital/centres) and bring more awareness to non-radi-
ation oncology community about opportunities of
modern radiation oncology in the field of lung cancer.
Some of the controversial issues are actually per-
sonal in nature. We all occasionally witness evidence-
based versus expert-based opinions. Unfortunately,
even some of the most prestigious institutions all over
the world suffer from this disease including also
inherent specifics of medical profession and division
between ‘‘big’’ specialities (e.g. surgery, internal
medicine) and presumably ‘‘smaller’’ (e.g. radiation
oncology). I am sure all of thoracic radiation oncol-
ogists occasionally witnessed unpleasant situations in
daily clinic or during tumor board meetings where
this has occurred. Collateral damage may well be our
residents, who are primed with this type of really
unacceptable behavior for which there should be only
a zero tolerance. Extension to this is its soft version
materialized in frequent existence (among radiation
oncologists) of ‘‘non-believers’’ in evidence-based
principles. Some people simply do not believe evi-
dence they are presented with. Usually, this is not
related to ‘‘constructive’’ (better said, productive)
criticism, based on scientific merits, but rather finding
excuses of how to interpret existing evidence. Even
softer version of non-believing in existing evidence is
seen in some of our colleagues who request always
Clinical Research in Radiation Oncology of Lung Cancer: Why We Fail(ed)?
more evidence than is present and/or needed. Excuses
goes from: (1) ‘‘this is only a second trial confirming
that A is better than B’’, through (2) ‘‘logistics of our
clinic prevent us of implementing this approach (e.g.
bid fractionation)’’ to (3) ‘‘the statistical power of that
particular study is not strong enough’’. Even in cases
of existing meta-analyses and multiple large confir-
matory trials there may be an obstacle to implement
what is already proven. Several years ago, (Langer
et al. 2005) report on the chemotherapy characteris-
tics practiced in nonmetastatic lung cancer in the U.S.
during the Patterns of Care Survey survey in 59
radiation therapy institutions. Informations have been
sampled during a period 2000–2002. Only 6% of
patients received hyperfractionated (b.i.d.) radiation
therapy in small cell lung cancer, only 22% received
prophylactic cranial irradiation and only 49% patients
underwent CT-based treatment planning. Signifi-
cantly more patients older than 70 years were treated
at large nonacademic facilities compared with smaller
nonacademic or academic institutions, surprising
finding for non-treating institutions since a large body
of data exists on the effectiveness of radiation therapy
in elderly or simply a finding underlining the lack of
radiation therapy studies in this patient population.
Some 5% patients with small cell lung cancer do not
receive chemotherapy, while 18% of stage I nonsmall
cell lung cancer patients receive radiation therapy/
chemotherapy and this percentage goes up to 34% for
stage II nonsmall cell lung cancer. Of additional
importance is that 33% of locally advanced nonsmall
cell lung cancer receives only radiation therapy.
Induction chemotherapy is still widely practiced,
while trend seems to have favored consolidation
chemotherapy as well. These examples are perfect
show of practice of non-evidence-based medicine in
lung cancer as they also nicely match observation
from the choice of timing of radiation therapy/che-
motherapy in small cell lung cancer, choice of drugs,
etc. They all fortify general impression that although
combined radiation therapy and chemotherapy are
practiced by the majority of institutions in majority of
locally advanced nonsmall cell lung cancer and small
cell lung cancer patients, there are still tremendous
variations in practice, most of which are not sub-
stantiated by the existing evidence. It remained
unknown whether perhaps group affiliation of the
sampled radiation therapy facilities influenced the
practice, because it is likely to expect that academic
815
and large non-academic institutions/practicing physi-
cians would feel some heat for non-recruiting patients
into the juicy clinical studies investigating novel
drugs or combinations. Another matter is how fast this
can be observed in daily routine. It is hard completely
to digest authors explanation that e.g. LAMP study
(Belani et al. 2005b) widely influenced practice in the
US being published only as an abstract in the year
2002 (and had, therefore, only several months of its
limited abstract life to exert influence on troublesome
behavior of practicing physicians in this Patterns of
Care Study, published in 2004) while, on the other
side, RTOG 9410 (Curran et al. 2000) did not exert
such an influence, being published in the same way
(abstract) in the year 2000! Speed of such an imple-
mentation is more than debatable.
Sometimes, however, evidence is confusing, even
when coming from three meta-analyses as we have
recently seen when focusing on the issue of timing of
administration of radiation therapy and chemotherapy
in limited-disease small cell lung cancer. While one
may assume that all three analyses showed the same
outcome, based on the same data from the available
literature, however, they do not show that. If one
roughly compares their conclusions, the meta analysis
by (Huncharek and McGarry 2004) showed the
highest differential survival advantage for early ver-
sus late radiation therapy and chemotherapy, a sys-
tematic review by (Fried et al. 2004) showed a
somewhat smaller but nevertheless significant
advantage for early radiation therapy and chemo-
therapy (greater at 2 years than at 3 years), while a
systematic review by (Pijls-Johannesma et al. 2004)
concluded that ‘‘the optimal integration of radiation
therapy and chemotherapy in limited disease small
cell lung cancer is unknown’’. How does one recon-
cile these findings? Is it simply 2 outweighing 1? Not
necessarily. There are a number of facts which need to
put into the right perspective, especially in the review
of (Pijls-Johannesma et al. 2004) which give addi-
tional insight into this matter. It is, therefore, that,
sometimes ‘‘meta-analysis of the meta-analyses’’,
may be needed, although this could rightly be criti-
cised as additional example of expert-based medicine!
(Jeremic B. 2006). Basically, there are various dif-
ferences in these three analyses. Some of them are
inherent to the characteristics of the accepted studies,
such as a different definition of the ‘‘limited disease
small cell lung’’ which included more or less of the
816
‘‘distant’’ intrathoracic nodal areas, as well as differ-
ent radiation therapy and chemotherapy characteris-
tics. Others are inherent in the analyses themselves,
such as a different definition of ‘‘early’’ and ‘‘late’’
radiation therapy and chemotherapy. These led to
different inclusion and exclusion criteria which
resulted in different numbers of patients being inclu-
ded into these analyses, enhancing great heterogeneity
among the studies, a usual finding when a meta-
analysis is done. Also, although all used meta-analytic
approach, there were differences in statistical inter-
ventions and subgroup analyses, and outcomes used
(local control, toxicity). Finally, none of the three
analyses used individual patient data. Contrary to
the two analyses (Huncharek and McGarry 2004;
Fried et al. 2004) observing significant advantage
for ‘‘early’’ radiation therapy and chemotherapy over
the ‘‘late’’ radiation therapy and chemotherapy, the
review of (Pijls-Johannesma et al. 2004) was not
supportive of these findings. Since that review (2004)
indicated no difference between the ‘‘early’’ and the
‘‘late’’ schedules, one must turn to other outcome
measures to have better perspective about therapeutic
benefit of these two approaches. Interestingly, toxicity
data showed that there was no difference between
outcomes for ‘‘early’’ and ‘‘late’’ schedules regarding
various types of toxicity, except that leucopoenia was
significantly higher in the ‘‘late’’ group. This finding
would favor ‘‘early’’ administration of radiation
therapy and chemotherapy having better overall out-
come than ‘‘late’’ radiation therapy and chemother-
apy. Finally, a subgroup analysis might be done to
focus on an important issue (e.g. fractionation or type
of chemotherapy) or when a seemingly inappropriate
study (due to different reasons) was excluded from an
analysis, the improved homogeneity of the remaining
studies instantly led to a favorable effect of ‘‘early’’
radiochemotherapy. It is obvious that more ‘‘consol-
idation’’ efforts should be directed towards bringing
the highest level of evidence to the community of
thoracic oncologists and that we should, perhaps, pay
additional effort and add additional forces to sys-
tematically address issues of importance for our
profession.
A number of controversial issues could also
directly be connected with the clinical trial issues.
While we have already mentioned that very few
prospective phase III trials are produced (designed
and executed) by radiation oncologists, another issue
B. Jeremić
is that even those that are with clear outcomes and
great potential for improving overall approach in lung
cancer are frequently poorly implemented in practice.
One good example is aforementioned hyperfraction-
ation trial in limited disease small cell lung cancer.
Another good example may well be the so-called
CHART (continuous hyperfractionated accelerated
radiation therapy) which produced significant
improvement in treatment outcome when compared to
standard radiation therapy in inoperable nonsmall cell
lung cancer (Saunders et al. 1999). Due to its poor
implementation, even in the UK, the National Health
Service (NHS) there had to officially urge institutions
to adopt such an approach. Also, as we mentioned
above, some of the trials implemented in clinical
practice are not those representing standards of
treatment as various Patterns of Care Studies have
shown (Movsas et al. 2003; Langer et al. 2005).
Finally, an intriguing thing for clinicians and
researchers in this field is frequent confusion about
the ways to optimize existing standards. For example,
after Intergroup study (Turrisi et al. 1999) clearly
established hyperfractionation as the superior
approach in limited disease small cell lung cancer,
investigators have not embarked on further optimi-
zation of this, superior, approach, but rather on opti-
mization of inferior (currently once-daily radiation
therapy) through studies of RTOG/CALGB and EO-
RTC, respectively. This way, no matter how outcome
of the two ongoing studies may look like in the next
3–5 years, we have already lost precious time in: (1)
poorly practicing hyperfractionation in daily clinic
although it is de facto standard of treatment, (2)
designing trials that may perhaps (e.g. after some
15 years) show superiority of high-dose standard
fraction radiation therapy over Intergroup hyperfrac-
tionation schedule, and (3) lead us again to the issue
of more clinical research within the same loop,
e.g. hyperfractionation, to be tested in the next
10–15 years (from now) with e.g. 54 Gy in 36 frac-
tions in 18 treatment days and concurrent low-dose
chemotherapy, as this author successfully imple-
mented in both limited- and extensive-disease small
cell lung cancer (Jeremic et al. 1997, 1999). Suffice to
say, with this approach, we may end up in the e.g.
year 2030 knowing very little more than we do now,
continuously undermining once-existing standards of
care and seriously affecting treatment outcomes of
thousands of patients.
Clinical Research in Radiation Oncology of Lung Cancer: Why We Fail(ed)?
6 Possible Solutions
Possible solutions to overcome existing obstacles and
improve our ability to undertake meaningful clinical
research in radiation oncology of lung cancer could
include improvements in education (both residents
and staff radiation oncologists), identification of
existing weaknesses in research domain which may
present as obstruction to evidence-based oncology
principles, implementation of proven clinical trials
and meta analyses, especially those favoring radiation
therapy in lung cancer, necessary to produce more
clinical trials by radiation oncologists, especially
those which combine biology of the disease with the
technological capabilities of our profession, for which
(all of the above) we actually need more patients. So,
perhaps the very first step on our road towards
improvement would be to leave the departmental
premises and start both making our achievements
more public to both general public and also to other
medical professionals. One such successful case has
happened in Japan where radiation oncologists
prominent in stereotactic radiation therapy of early
lung cancer used various means to popularize suc-
cessful efforts to optimize treatments in this disease.
That led to more patients refusing surgery and
requesting stereotactic radiation therapy which,
importantly, came with excellent results and further
general popularization of this technique. By making
various (here, meaning both patient and medical
professionals!) target groups more aware of our
capabilities, we may be able to recruit more patients
for treatments and, hence, more of those suitable for
clinical trials. Such trials should preferably combine
biological and technological aspects of our profession
in the field of lung cancer. Biological aspects such as
irradiation-drug interactions could successfully be
explored through translational research using mech-
anistic studies to enlighten the problem of irradiation-
drug interactions, but only if translational research is
understood as ‘‘back and forth’’ from benchmark to
bedside and back, aiming to continuously enrich our
knowledge, performance capabilities and, ultimately,
treatment results. Such clinical studies should ask
simple questions, ask those questions important for
radiation oncologists, being biology of the disease-
driven and being at the same time, technology-adap-
ted. This is the only way we, as a profession, could
817
successfully integrate our capabilities and address
burning questions in the field of lung cancer, a
must for current and future generations of radiation
oncologists involved in care of patients with lung
cancer.
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Mori K, Tsukiyama I, Tamura T (2006) Docetaxel consol-
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 Pitfalls in the Design, Analysis,
Presentation, and Interpretation
of Randomized Clinical Trials
Richard Stephens
Contents
1 Introduction.............................................................. 819
2 Have all the Randomized Patients been
Accounted for? ......................................................... 820
3 What is the Control Treatment? ........................... 820
4 Is the Sample Size based on Information that is
Sensible and Feasible? ............................................ 821
5 Has the Trial been Designed to Answer a Clear,
Unconfounded Question?........................................ 822
6 Are the Number of Statistical Tests Limited,
and if not, Have the Significance Levels been
Adjusted Accordingly?............................................ 822
7 Are the Details of the Interim Analyses
and Stopping Rules Clearly Laid Out? ................ 823
8 Have the Hazard Ratio and Especially the 95%
Confidence Interval of the Time-to-Event
Analyses been given?............................................... 823
9 Are there Predefined Hypotheses for All Key
Endpoints? ................................................................ 824
10 How has Quality of Life been Assessed
and Reported?.......................................................... 825
R. Stephens (&)
Clinical Trials Unit, London, UK
e-mail: richardjamesstephens@gmail.com
B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_282, Ó Springer-Verlag Berlin Heidelberg 2011
11 Has the Result been put into the Context
of the Previous Work in this Area? ...................... 825
12 Conclusions ............................................................... 825
References.......................................................................... 825
Abstract
Randomised clinical trials are the gold standard
tool for testing new treatments, but need to confirm
to certain basic guidelines in order to be consid-
ered reliable. Good trial design, analysis, presen-
tation and interpretation and an awareness of the
common pitfalls are likely to maximise the rele-
vance and impact of the trial.
1 Introduction
We are in the era of evidence-based medicine, and the
foundation for this evidence is the randomized clini-
cal trial (RCT). In theory RCTs are very simple. Half
of the patients receive the standard treatment, the
other half receive the new treatment, and the out-
comes of the two groups are compared. What could
go wrong? Well, in practice, many things, as the
design, conduct, analysis, presentation, and interpre-
tation of RCTs can actually be very complex.
Therefore the importance of high-quality RCTs can-
not be understated. This chapter therefore aims to
alert both those involved with the running of RCTs,
and also those reading papers giving the results of
RCTs, to ten common pitfalls, which may prevent a
randomized trial from being a true and unbiased
comparison of the treatments.
819
820
2 Have all the Randomized Patients
been Accounted for?
Given a reasonable number of patients, the beauty of
randomization is that it separates them into perfectly
balanced groups (balanced not only on all their known
characteristics, such as age and sex, but also on every
unknown characteristic as well). Thus it sets up a
perfect scientific test where the only difference is
the treatment or management that the patients sub-
sequently receive. Retaining all randomized patients
in the trial and in the analysis (the ‘intent-to-treat’
principle), ensures this balance is maintained. Any
attempt to improve on this perfect balance between
the randomized groups is therefore, at best, ill
advised, and at worst raises concerns about the
motives of the researchers. Understanding and
applying the intent-to-treat principle is important, as
trials need to reflect the policy of choosing to treat a
group of patients in a certain way.
At the time of randomization all patients should
have been considered suitable for the treatments being
studied (and thus, once the trial has finished, should
reflect the population who are likely to be offered the
treatment). However, papers often list subgroups of
patients who are excluded from the trial and analyses,
such as those shown to be ineligible by post-
randomization investigations or independent review,
those who do not receive any or all of their protocol
treatment, or those not assessed for an endpoint. For
example, Georgoulias et al. (2001) excluded 35 of the
441 patients randomized and all analyses (which were
claimed to be ‘intent-to-treat’) were then performed
on the remaining 406 patients, and Schiller et al.
(2002) excluded 52 patients who were found to be
ineligible post-randomization in their trial of four
chemotherapy regimens. Removing patients from the
trial or analyses has the potential to upset the perfect
balance determined by randomization, especially
if there is an imbalance of exclusions across the
groups. In a recent clinical trial of prophylactic cra-
nial irradiation (PCI) versus observation for patients
with locally advanced non-small cell lung cancer
(Gore et al. 2011) 13 PCI and 3 Observation patients
were excluded from the analysis. Such an imbalance
inevitably makes one wonder if those in the PCI
group were seen more often and/or had more detailed
investigations that led to more ineligible patients
R. Stephens
being discovered and more patients deciding to
withdraw consent. Whilst it can be argued that an
imbalance of 13:3 can occur by chance, that removing
ineligible patients ensures the trial better reflects the
population defined by the protocol, and that including
or excluding this number of patients is unlikely to
have a major impact on the results, it is the principle
that is important, and it raises the question of where to
draw the line: how many patients need to be excluded,
or what difference in the number of patients excluded
in each trial arm needs to be seen, before a clinical
trial can no longer be considered a fair scientific test,
and the results can no longer be considered reliable.
Whilst some may think it completely illogical to
retain any ineligible patients in the analysis, as indi-
cated above, randomization will ensure that all pos-
sible patient characteristics are balanced between the
groups, including of course, the number of ineligible
patients, and the number of patients who will poten-
tially decide to drop out of the trial. Therefore, for the
sake of scientific credibility and complete transpar-
ency it is always preferable to retain all randomized
patients in the trial and report the number (not just the
proportion) of all patients in all analyses.
3 What is the Control Treatment?
In a randomized trial the choice of control treatment
is paramount. Logically, it should always be the
current best standard treatment for the condition,
although often knowing what is acknowledged as
‘best’ is difficult. Indeed, there may be situations
where the local, national, and international ‘best’ are
all different because of, for example, differences in
facilities, expertise, or access to drugs. The choice of
control treatment will depend on several factors,
including whether the trial result is aimed at affecting
local, national, or international practice, how prag-
matic the trial is (for example, if the question is ‘does
the addition of radiotherapy to chemotherapy improve
survival?’ the chemotherapy used may not need to be
stated) or how a non-local control treatment will
affect accrual. It is not difficult to see that the choice
of the control treatment can significantly influence the
way the trial result is interpreted, as unfortunately
much more attention is paid to trials with a ‘positive’
result. Thus in order to increase the chances of seeing
a ‘positive’ outcome, trials can be designed to
Pitfalls in the Design, Analysis, Presentation, and Interpretation
compare the new treatment with a poor or inappro-
priate control. A common trick is to compare the new
treatment alone with the new treatment in combina-
tion with a standard treatment. Thus in lung cancer
there are examples of trials comparing new drug
versus new drug plus cisplatin; for example Splinter
et al. (1996) compared teniposide with or without
cisplatin in advanced NSCLC. Not surprisingly, the
trial showed that the cisplatin combination resulted in
improved response, progression-free survival and
overall survival. Such results can be used to claim that
the new combination should be considered an
effective standard treatment, irrespective of whether
the new drug actually has any useful effect or not.
Because of the difficulty, due to the huge number of
patients required, of showing that a new treatment is
equivalent to a standard treatment, a course of action
sometimes taken is to show that the new treatment is
better than a previous standard to the same degree as the
current standard. Thus if new treatment B is 5% better
than standard treatment A, the options for another new
treatment C are either to try and show that C is equiv-
alent to B, or that C is also 5% better than A. However, it
could be argued that the latter is unethical, as patients
are not being offered treatment B, the new current
standard of care. Nevertheless, this is a commonly used
strategy. For example, given the NSCLC meta-analysis
(Non-Small Cell Lung Cancer Collaborative Group
1995) showed a highly significant (P \ 0.0001) sur-
vival benefit with cisplatin-based chemotherapy
over supportive care alone, it could be argued that
Roszkowski et al. (2000) should have compared
docetaxel against cisplatin-based chemotherapy rather
than supportive care. The fact that they did not, left
unanswered the question of the relative benefits of
docetaxel compared to cisplatin-based chemotherapy.
4 Is the Sample Size based
on Information that is Sensible
and Feasible?
If we had access to every patient with the disease
under scrutiny and could randomize them all, we could
obtain a fairly accurate measure of whether the new
treatment is better than the standard and if so by how
much. However, of course, we do not. We only have
access to a sample of these patients, and all that the
results of our randomized trial can do is to give an
821
estimation of the true difference. It stands to reason,
therefore, that the more patients we study, the better
the estimation. The ‘power’ of a trial relates to the
chances of identifying a difference if it exists.
Generally, trials are powered at about 90% (i.e. so that
a trial has a 90% chance of detecting a difference, if
one exists), but trials that are underpowered (i.e. do not
include enough patients to reliably detect the differ-
ence) are more likely to result in a false-negative result
(also referred to as a type II error). Unfortunately, of
course, we never know which ‘negative’ results are
false-negatives! However, all too often sample sizes
are based on what is feasible rather than what is
realistic. For instance, we know that, in lung cancer,
the addition of a new modality, be it radiotherapy or
chemotherapy, to surgery (or supportive care) will
probably improve survival by only about 5%
(Non-Small Cell Lung Cancer Collaborative Group
1995). Therefore it is unrealistic to consider that as a
result of tinkering with the drugs, dosages, or sche-
dule, we are suddenly going to see advantages of a
further 10 or 15%. Yet the vast majority of lung cancer
trials are based on seeing differences of about 15%,
which will generally require a sample size of around
400 patients. For example, Ranson et al. (2000)
powered their trial to look for a 100% improvement
(from 20% survival at 1 year with supportive care to
40% with paclitaxel), and Sculier et al. (2001), in a
three-arm trial considered that a 75% increase might be
possible with the addition of G-CSF or antibiotics to
standard chemotherapy. The rationale for such over-
optimistic expectations is that accrual is considered
feasible, whereas aiming for around 1,500 patients to
see a 10% difference or 4,000 patients to see a 5%
difference, which is probably the sort of target most
trials should now be aiming at, is simply considered an
impossible task. Maybe this explains why progress in
lung cancer has been so slow as we have had to wait for
meta-analyses to combine data from a number of trials
in order to accumulate the thousands of patients
required to confirm these small differences. A question
then arises as to whether it is ethical to run any trial of
less than perhaps 1,000 patients, given the high prob-
ability of an inconclusive result. An even greater
dilemma occurs with equivalence trials. Taking the
same example that the addition of a modality (chemo-
therapy) improves survival over surgery alone or sup-
portive care by about 5%, what happens when we want
to show that a new chemotherapy treatment is as
822
effective as the standard? If we compare the new che-
motherapy to standard chemotherapy with a trial of 400
patients the result may suggest no difference but actu-
ally all we are likely to be able to conclude is that the
new treatment is somewhere between 15% better and
15% worse than the standard, and thus could actually be
10% worse than no chemotherapy. Nevertheless, some
papers for example Gatzemeier et al. (2000), claim that
survival is comparable even though a 20% benefit or
detriment cannot be ruled out.
5 Has the Trial been Designed
to Answer a Clear, Unconfounded
Question?
Trials should also always aim to answer only one
clear question. Thus a logical trial design in che-
motherapy, where the standard is combination che-
motherapy would be to add or replace one drug. In
reality of course such simple designs are not always
possible or desirable, as often two widely used
treatments need to be compared, or entirely different
schedules or combinations of treatment investigated.
Nevertheless, results from trials that change two
drugs (or schedules or doses) do not allow one to
tease out the relative value of each changed factor.
For example, Kelly et al. (2001) compared paclitaxel
and carboplatin given in 3-weekly cycles with
vinorelbine and cisplatin given in 4-weekly cycles.
The trial reported equal efficacy, but if say, a benefit
had been seen with the paclitaxel/carboplatin sche-
dule would this have been because of the paclitaxel,
the carboplatin, or the 3-week cycles?
6 Are the Number of Statistical Tests
Limited, and if not, Have
the Significance Levels been
Adjusted Accordingly?
The P value indicates the probability that an observed
difference has not been found purely by chance. Thus
a P value of 0.05 indicates that this result would only
have occurred by chance five times in every 100. It is
generally considered that a difference with a P value
of B 0.05 is a ‘positive’ result. However, it is vital to
remember that this actually means that five out of
R. Stephens
every 100 ‘positive’ results will be false-positives
(also referred to as a type I error), found purely by
chance. Again, the trouble is we never know which!
Whilst we need to be aware that a proportion of
positive trial results may in fact be false-positives
(and a proportion of negatives false-negatives), the
problem of type I (and type II) errors also affect
analyses within a trial, as the more the tests per-
formed, the more likely it is that these will be
contaminated with false results. To reduce this risk,
the number of statistical tests performed in a trial
should be limited. A good way of doing this is to
consider that within a trial there is only a certain
amount of P value spending. So, if one test is per-
formed and the result is P B 0.05, then the result can
be considered significant. If two tests are performed
then perhaps they should only be considered signifi-
cant if P B 0.025, or as is often used to accommodate
interim analyses, the first is only considered signifi-
cant if P B 0.001 so that the second can be consid-
ered significant if P B 0.049. It is important to be
aware of how many statistical tests have been per-
formed and what is claimed to be significant, as there
can often be a tendency to trawl the data for inter-
esting results and significant P values. Consider, for
example, one table relating to the assessment of
quality of life (QL) in the paper by Sundstrom et al.
(2002) where 84 P values were calculated. Statistics
suggest that about four of these will be false-positives
and thus the authors indicated that only P \ 0.01
would be considered significant.
Sometimes it is not the number of tests that have
been performed but the data to which they have been
applied that raises concerns. It is, of course, logical
to list the pre-treatment characteristics and to high-
light the balance (or imbalance) between groups.
However, it is illogical to apply a statistical test to
show balance or imbalance in this situation. Statis-
tical tests are used to estimate the likelihood that an
observed difference has not occurred by chance.
However, differences in pre-treatment characteristics
can only have occurred by chance, and it is thus an
inappropriate use of a statistical test and a wasteful
use of P value spending. Recent examples of this
unnecessary testing can be found in papers by Tada
et al. (2004) and Langendijk et al. (2001). If
imbalances in pre-treatment characteristics are
observed, the analysis of the key endpoints should
be adjusted accordingly.
Pitfalls in the Design, Analysis, Presentation, and Interpretation
It is important to realize, however, that the P value
reflects statistical significance, and what is important
when assessing the results of trials, is clinical sig-
nificance. Given a large enough group of patients,
a tiny difference can be statistically significant, but it
is the scale of the improvement in outcomes and the
impact on patients that will determine whether clini-
cians and patients feel a new treatment is worthwhile.
The commentary by Lee (2011) argues that it is time
to move away from P values and towards a Bayesian
approach.
7 Are the Details of the Interim
Analyses and Stopping Rules
Clearly Laid Out?
To ensure patients’ safety it is imperative that the
accumulating data are reviewed at regular intervals
throughout the trial. Whether ‘regular’ means annu-
ally, when accrual reaches certain targets or when a
certain number of events have occurred, will depend
on the trial. This allows decisions to be made
regarding closing the trial for reasons such as a sig-
nificant difference being seen, or the likelihood that a
difference will never be seen. Rules for when the trial
should close early must also be agreed and there are a
number of options, from fixed P values to Bayesian
statements such as ‘the evidence must convince
sceptics’. It is important that among the Data Moni-
toring and Ethics Committee (DMEC) members there
is knowledge of the disease and treatments and pre-
vious DMEC experience, as often DMECs will be
called upon to make very difficult decisions. Clear
indications for the reasons for stopping trials early
need to be laid out and justified, as there are numerous
examples where trials have stopped early, but the
results have been unconvincing and new trials have
had to be set up to clarify the situation. For example,
two trials of neo-adjuvant chemotherapy for NSCLC
(Rosell et al. 1994; Roth et al. 1994) both stopped
early after accruing 60 patients, but subsequently
several large trials have been set up to clarify whether
any benefit exists. Few trial reports list stopping rules,
but guidelines on stopping suggest that P values of at
least \0.001 need to be seen at interim analyses to
avoid inappropriate closure. Certainly trials that stop
‘because a P value of \0.05 was observed at an
interim analysis’ need to be questioned.
823
8 Have the Hazard Ratio
and Especially the 95% Confidence
Interval of the Time-to-Event
Analyses been given?
Events such as death, progression, and second-line
treatment should be measured by time-to-event
analyses by constructing Kaplan–Meier curves and
comparing the groups using the log-rank test.
Time-to-event analyses should include all patients
randomized, and be calculated from the date of ran-
domization, since taking the start date as anything
other than randomization (which is the one common
time point for all patients) will have the potential to
bias the result. For example the date of diagnosis may
not be accurate for all patients, and the date of start of
treatment may include different delays for different
groups, and will not even exist for patients who do not
start treatment.
Treatments need to be compared on their overall
survival because choosing a landmark time point, be
it median or 1-year survival, may bias the results. For
instance in a trial of surgery versus a non-surgical
intervention, the expectation may well be that the
surgery group is likely to experience high early post-
operative mortality but better longer-term survival.
Thus quoting the survival at say 1 month or 5 years
might give an inaccurate picture of the true between-
treatment difference. For example, the shape of the
survival curves seen in the trials reported by Fossella
et al. (2000) and Takada et al. (2002) overlap for a
considerable time before splitting. Although the
expected median survival or proportion of patients
surviving at key time points is often quoted in pro-
tocols, these are simply snapshots of the likely sur-
vivals and the likely survival difference, and are also
used to calculate a sample size.
Therefore the hazard ratio (HR) is usually used to
indicate the overall survival difference, although in
certain situations, such as when survival curves
cross, the HR is not appropriate. Conventionally, an
HR of \1 indicates that the new treatment is better,
and [1 indicates that the new treatment is worse.
It is always vital that the 95% confidence interval
(95% CI) around the HR is quoted. This indicates
the range in which we are 95% sure that the true
value lies. Thus for example in a survival compari-
son, an HR of 0.85 with a 95% CI of 0.65–1.05
824
indicates that our best estimate of the survival dif-
ference is that the new treatment is 15% better, but
we are 95% confident that it is somewhere between
35% better and 5% worse. This surprisingly wide
range, however, is the sort of range commonly
obtained from randomized trials with a sample size
of about 250 patients. Thousands of patients are
required to obtain confidence intervals of only about
5% around the HR. Even in a trial of more than
1,000 patients, comparing surgery with or without
adjuvant chemotherapy, Scagliotti et al. (2003)
reported an HR of 0.96 with a 95% CI of 0.81–1.31
indicating that compared to the median survival of
48 months with surgery alone, adjuvant chemother-
apy could have resulted in a detriment of 5.5 months
or a benefit of 11 months.
One of the difficulties of time-to-event analyses is
what to do with patients who have not experienced the
event. In an analysis of overall survival this is
straightforward as patients who are still alive are cen-
sored at the time last seen, but analyses looking at a
specific cause of death, progression, or toxicity have
their own issues.
Although the cause of death may be of interest to
trialists, to indicate how the treatment is working,
survival analyses that only report deaths from cancer
may be interesting but very misleading. For exam-
ple, a treatment that causes many early treatment-
related deaths may, in a cancer-specific survival
analysis, appear to be the better treatment. Thus both
Sundstrom et al. (2002) reporting the disease-specific
survival rates in their trial of chemotherapy regimens
and Shepherd et al. (2002) in their analysis of pro-
gression-free survival, censored patients who died
from causes considered unrelated to disease or
treatment.
Many papers purport to show differences between
treatments in terms of time to progression with the
use of a Kaplan–Meier plot, taking progression as
the event and censoring those alive (or dead) without
progression. This sort of analysis can be very mis-
leading as patients who fail from a competing risk
(for example, an early treatment-related death) that
precludes the possibility of achieving the event are
treated the same as censored patients who still have
the potential for progression. Examples of this can
be found in papers by Sundstrom et al. (2002),
Ranson et al. (2000) and Pujol et al. (2001).
Progression-free survival, which takes into account
R. Stephens
deaths without progression, should always be the
preferred analysis.
Complications also arise when patients have
non-protocol or second-line treatment as effective
post-protocol treatments can compensate for poor first-
line treatments and give a false impression of their
effectiveness. In such situations, progression-free sur-
vival or time to treatment failure analyses need to be
considered.
9 Are there Predefined Hypotheses
for All Key Endpoints?
It is important that all the decisions regarding design
issues are clearly stated and justified in the protocol,
and also that a detailed analysis plan is written.
This particularly applies to subgroup analyses,
which are only reliable if they are predefined, which
will usually mean that they are hypothesis driven, and
take account of sample size and multiple statistical
testing. Unless the above rules are respected, subgroup
analyses should always be considered with caution and
treated as only hypothesis generating. All too often,
when clear overall results are not seen, the data are
trawled for interesting subgroup results and, when
found, hypotheses are built around them. Reporting
such findings as definitive results is irresponsible.
It is, of course, often interesting to explore whether
any overall survival difference observed is consistent
across all subgroups, and analyses stratified for pre-
treatment characteristics are therefore useful; whilst
Sause et al. (2000) did just that, the subgroup analyses
did not appear to have been predefined, accounted for
in the sample size, or considered only as exploratory or
hypothesis generating. Whilst exploratory analyses are
acceptable, analysis by post-randomization factors
(such as treatment received or response) are totally
unacceptable, as the groups being compared may be
defined by the outcome being tested. Thus, for exam-
ple, comparing the survival of responders versus non-
responders is flawed because the responders have to
survive long enough to respond. Therefore analyses
such as those presented by Fukuoka et al. (2003)
comparing survival by responders, and Socinski et al.
(2002) showing survival by number of cycles of che-
motherapy received, must be viewed with great cau-
tion. Prognostic factor analyses are sometimes run to
try and identify the factors most related to survival, but
Pitfalls in the Design, Analysis, Presentation, and Interpretation
usually there are far too few patients in a single trial to
draw any firm conclusions. For example, in a trial
reported by Pujol et al. (2001) multivariate analyses
were performed on only 226 patients. In addition, in
most trials, prognostic factor analyses are inappropri-
ate as treatment will be a confounding factor, and
predictive analyses, which look at the impact of treat-
ment on subgroups of patients, are needed.
10 How has Quality of Life been
Assessed and Reported?
Patient self-assessed QL data are especially difficult
to report reliably because the data are multi-
dimensional, longitudinal, and inevitably much is
missing. There are therefore few agreed methods of
presenting QL results, and care must be taken to be
conservative in making strong claims. Major prob-
lems can arise from starting with inadequate sample
sizes, multiple statistical testing, imputing missing
data, comparing the treatments at time points that
favor one group, and/or summarizing the data inap-
propriately. Non-standard analyses such as those used
by Ranson et al. (2000) estimating separate slopes for
dropouts and completers, or Sandler et al. (2000)
calculating the change in score from baseline to last
observation, should be avoided.
Many of these problems can be mitigated by pre-
defining QL hypotheses which have the effect of
guiding the choice of questionnaire, the choice of
administration time points, the sample size calcula-
tion and the analyses to be performed. However, there
are few examples of this actually being carried out in
practice, and consequently, the results from QL
aspects of trials are often disregarded and distrusted
by clinicians and patients.
11 Has the Result been put
into the Context of the Previous
Work in this Area?
Trials are rarely islands. Results need to be presented
and discussed in the context of the totality of previous
work. However, Clarke et al. (1998) reviewed the
discussion sections of reports of trials published in
five major journals during one month in 1997 and
found that only two (of 26) placed their results in the
825
context of an up-to-date systematic review. Repeating
this exercise in 2001, they reported no improvement,
with only three (of 30) trials being so reported
(Clarke et al. 2002). Such findings are disappointing
and suggest that there is a general lack of awareness
that individual trials are only part of the whole pic-
ture. We must never lose sight of the fact that lung
cancer is a global problem and without global col-
laboration progress will continue to be painfully slow.
12 Conclusions
All trials and all trial results are important as they
all in some way advance the progress of human
knowledge. Our ultimate aim as trialists is to improve
the treatment of future patients and it is therefore
important that we are as rigorous and honest in our
work as we can be.
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controlled trials published in general medical journals:
Islands in search of continents? JAMA 280:280–282
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journals. JAMA 287:2799–2801
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(2000) Randomized phase III trial of docetaxel versus
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(2003) Multi-institutional randomized phase II trial of
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Mattson K et al (2000) Phase III comparative study of high
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 New Directions in the Evaluation
and Presentation of Clinical Research
in Lung Cancer
Noelle O’Rourke, Fergus Macbeth, and Elinor Thompson

Contents Abstract
In this chapter we summarise the problems in
1 Introduction.............................................................. 827 accessing and summarising the vast body of
2 What the Evidence Tells and clinical research on lung cancer and outline how
Does Not Tell Us ...................................................... 828 research may be made more accessible, efficient
3 Defining the Gaps in Evidence: Formulating and relevant.
Our Questions .......................................................... 829
4 Harnessing the Information to Make It Work
for Us......................................................................... 829
1 Introduction
5 Controlled Clinical Trials as a Route
to Knowledge............................................................ 830
Every lung cancer publication opens with a depress-
6 Systematic Reviews and Meta-Analyses ............... 831 ing list of statistics. Globally lung cancer tops the
7 Cochrane Reviews.................................................... 832 incidence tables—1.61 million cases in 2008 (12.7%
8 Challenge of Novel Technologies ........................... 834 total cancer cases), and also tops mortality with a
consistently high fatality rate across the world—
9 Expanding Our Definition of Trial
Populations ............................................................... 834
1.38 million deaths in 2008, 18.2% of total cancer
mortality (Ferlay et al. 2010). Fifty-five percent of
10 Translating Evidence into Practice
new cases now occur in developing countries, a large
and the Elephant in the Room............................... 835
shift in the past decade, with anticipated continuation
11 What We Need to Do Next..................................... 835 of this trend as rates of cigarette smoking continue to
References.......................................................................... 836 rise in newly industrialised countries. Despite
important developments in surgery, radiotherapy and
chemotherapy over the last 20 years and many hun-
dreds of clinical trials, population-based 5-year sur-
vival rates for lung cancer still range from about 5%
to, at best, 15%. And importantly, all too little is
N. O’Rourke known and published about any changes (for either
Beatson West of Scotland Cancer Centre,
better or worse) in the quality of that survival.
Glasgow, UK
The challenges for lung cancer research in the
F. Macbeth (&)
decade ahead are to improve outcomes not just in
National Institute for Health and Clinical
Excellence (NICE), London, UK terms of added weeks or months of median survival
e-mail: Fergus.Macbeth@nice.org.uk but to increase long-term survival and also to dem-
E. Thompson onstrate improved quality of life by treatment inter-
Univeristy Pompeu Fabra, Barcelona, Spain ventions, especially in the palliative setting where

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 827
DOI: 10.1007/174_2011_299,  Springer-Verlag Berlin Heidelberg 2011
828
survival time is short. The emerging novel technolo-
gies in radiotherapy delivery for lung cancer present
specific research challenges, as these cannot be
evaluated easily by the conventional approach of
randomised controlled trials. The increasing lung
cancer burden of developing nations and indeed the
impact of global recession on health-care budgets
raise further challenges in terms of how to ensure that
newly introduced drugs and technologies are cost
effective for a population.
The massive and growing volume of biomedical
information needs to be harnessed so that we can
apply it effectively to our unanswered questions in
lung cancer management. In this chapter we will
reflect on what the evidence from research published
in conventional formats can tell us and what its lim-
itations are. We will then make some suggestions
about how we might improve the quality, reliability
and accessibility of that evidence. We will speculate
on the potential offered by evolving information
technologies and by new methodologies in clinical
research. Finally we will propose the need for struc-
tures to apply the evidence available to clinical
practice.
2 What the Evidence Tells and Does
Not Tell Us
Evidence-based medicine promotes effective use of
the literature to address areas of clinical uncertainty.
The critical consumer of the evidence first formulates
a clinical question, then searches the medical litera-
ture for relevant information, critically analyzes what
is available and finally applies the findings to clinical
practice. In 1996 David Sackett, one of the early
proponents of evidence-based medicine outlined the
notion of a hierarchy of evidence (Sackett et al. 1996).
This has since been refined to an established inter-
national standard (Atkins et al. 2004) in which the
robustness of the evidence is expressed as levels 1–5,
depending upon the quality of the supporting research
base. This ranges from systematic reviews (level 1)
through randomised controlled trials, cohort studies
and case controls to the variably biased ‘expert
opinion’ (level 5).
In this way we can list a number of accepted
‘truths’ in the treatment of lung cancer. But such is
the contestable nature of clinical science and clinical
N. O’Rourke et al.
practice that not everyone will agree with even these
few ‘truths’.
The following are, we believe, more or less firmly
accepted in the management of patients with non-
small-cell lung cancer (NSCLC):
• Radical surgery (lobectomy or pneumonectomy) is
an effective, potentially curative treatment for
early-stage disease. Adjuvant chemotherapy fol-
lowing surgery can improve by a few percent the 5-
year survival rates in selected patients.
• A combination of chemotherapy and radiotherapy
is effective for patients with unresectable stage III
disease, but there is uncertainty about which drugs
and radiotherapy regimens are the best.
• In patients receiving radical dose radiotherapy,
delivery of chemotherapy concurrent with radiation
improves survival relative to chemotherapy deliv-
ered sequentially, though with increased associated
toxicity.
• Cisplatin-based chemotherapy has a modest effect
on survival in patients with locally advanced and
metastatic disease but it is uncertain how much
overall benefit there is in terms of quality of life.
Second- and third-line chemotherapy in selected
patients may add further small-survival benefit.
And these are the more or less firmly accepted
‘truths’ in the management of patients with small-cell
lung cancer (SCLC):
• Combination chemotherapy improves survival in
all patients.
• A combination of chemotherapy and thoracic
radiotherapy in those with limited stage disease
improves survival and results in the cure of a small
minority of patients.
• Prophylactic cranial irradiation (PCI) for those in
complete remission is likely to be beneficial.
There is much however that the available evidence
cannot tell us. Data is accumulating on the effect of
tumour histology and patient genetic profile on the
response to targeted agents. More complete and more
precise information is needed on the effects of age,
sex and co-morbidities on the relative effectiveness
and toxicity of interventions. We also need to
understand better the effects of patient preferences,
perspectives and knowledge on both cure and pallia-
tion. And given that so few patients with lung cancer
are cured, we must increase our knowledge about
some important and difficult end-of-life issues such as
quality of life during second-line chemotherapy and
New Directions in the Evaluation and Presentation of Clinical Research in Lung Cancer
with palliative radiotherapy, when to stop active
treatment and how best to palliate important symp-
toms such as breathlessness.
3 Defining the Gaps in Evidence:
Formulating Our Questions
The first step in developing the evidence base for lung
cancer care is to formulate those questions to which
we do not currently have clear answers such as:
• Does screening with helical CT scanning reduce
mortality in high-risk populations?
• What is the optimal timing and regimen of che-
motherapy in patients with Stage-III NSCLC
undergoing radical dose radiation?
• How much more effective is hyperfractionated,
hypofractionated and/or accelerated radiotherapy
than conventional radical radiotherapy?
• What is the role of maintenance chemotherapy in
NSCLC?
• Is there a dose–response effect for radical radio-
therapy in both NSCLC and SCLC?
• What is the optimal management of early-stage
NSCLC in a medically unfit patient: limited surgery
or radical conventional radiotherapy or stereotactic
radiotherapy?
• Do the outcomes from radical radiotherapy
improve with use of new technologies: intensity
modulated radiotherapy IMRT, volumetric arc
therapy, particle therapy, image-guided radiother-
apy IGRT?
• Will co-registered-PET imaging enable more
accurate and effective radiotherapy planning and
improve outcomes?
And in formulating these questions, we need to
decide what outcomes we are interested in. Can the
evidence available answer these questions about sur-
vival but also take account of the patient-oriented
outcomes such as patient experience and quality of
life?
4 Harnessing the Information
to Make It Work for Us
There has been a huge and accelerating growth in
scientific publications on lung cancer over the last
30 years. Searching Medline for ‘Lung Neoplasms/dt,
829
rt, su, th’ (Drug Therapy, Radiotherapy, Surgery,
Therapy)’ gives over 68,000 hits. While MEDLINE is
a long established and widely used medical database,
its size and breadth may be an obstacle to extracting
relevant information in a filtered and organised
fashion. Moreover it indexes only about one-third of
all biomedical articles. Key to answering our ques-
tions we need a streamlined information retrieval
strategy that will search all possible resources and
integrate the diverse datasets obtained. This devel-
oping field of biomedical informatics has the potential
to combine the molecular advances in lung cancer
research with the ongoing clinical trials data and
individual patient data. This should enable and
accelerate the ‘bench to bedside’ promise of transla-
tional medicine.
The magnitude and diversity of data generated
from searching across the whole Life Sciences spec-
trum necessitates technology which can handle it all.
This is becoming a reality with the emergence of
Semantic Web technologies, the latest generation
(web 3.0) of web interface applications which permits
information retrieval based on the properties of the
data rather than their location within the search
environment.
There have been a number of specific initiatives
launched to promote this translational approach. In
the US the NCI has established the Cancer Biomed-
ical Informatics Grid (CaBIG) which is an open
source model network to connect the entire cancer
community for data sharing and with a variety of
software tools and systems available free to end users
(www.cabig.nci.nih.gov). In the UK there is the
Oncology Information Exchange (ONIX), a free
online resource which enables users to search across
diverse datasets from a single point of access.
Investigators can select the relevant resources for
their enquiry but tabulate multiple enquiries together
and re-use data gathered in this way for combined
meta-analyses.
Not only has advancing technology offered more
sophisticated means of data searching but the ease
with which this can be accessed and distributed con-
tinues to progress rapidly. With new hand-held tech-
nologies and internet-enabled mobile phones with
multimedia applications, it is now possible at the
bedside to tap into up-to-the-minute current trials,
synopses of evidence and clinical guidelines. With so
much information at our fingertips, it is therefore
830
surprising that the number of established ‘facts’ on
best treatment for lung cancer, as listed above, is
relatively short. It is clear that quantity of data alone
does not produce answers. We need to refine the
information according to its quality and relevance to
the questions we are asking.
5 Controlled Clinical Trials as a Route
to Knowledge
Within the hierarchy of clinical evidence, randomised
controlled trials rank as the gold standard for indi-
vidual studies. A current search of the Cochrane
Central Register of Controlled Clinical Trials identi-
fies 6,309 lung cancer trials and the published litera-
ture runs to many thousands of trial publications.
Faced with this vast literature and chasms of clinical
uncertainty, we need to ensure:
• an efficient search strategy
• a quality assurance process for what we find
• a mechanism for organizing the data in a way that
permits useful analysis.
An effective strategy to identify trials should
search through all the data quickly, finding everything
relevant and only the relevant—that is, both sensitive
and specific. Good search strategies will search all the
literature, published and unpublished, in all lan-
guages. They will also focus the search on identifying
trials which address specifically the clinical question
that is being asked.
Decisions as to study quality require the application
of criteria for assessing the design. The CONSORT
(Consolidated Standards of Reporting Trials) group of
scientists and editors established standards for report-
ing clinical trials in a statement first published in 1996
and most recently updated in 2010 with a revised and
elaborated document (www.consort-statement.org).
It should make clear in any publication whether the
methodology of analysis and reporting is robust, with a
checklist and flow diagram demonstrating adherence to
these principles. This will enable the reader to confirm
that the study was valid and the results were reported in
full. It may leave unanswered the question of whether a
small study can be generalised more widely and whe-
ther it can be applied to the individual patient or pop-
ulation that the reader is treating.
N. O’Rourke et al.
To achieve a comprehensive and objective analysis
of all the controlled trials relating to our clinical
question we can undertake a systematic review or
meta-analysis. These techniques combine data from
similar trials so that results (estimates of benefits and
harm) from a larger number of people can be evaluated
than have been obtained from individual trials alone.
Even so, a fool-proof search strategy, assessment
of trial quality and combined trials analysis do not
provide a lasting guarantee for the evidence base of
our practice. The whole process of data reporting,
sorting and collating requires continual updating. This
is facilitated by the existence of clinical trial registers.
In 2005 the International Committee of Medical
Journal Editors (ICJME) issued a joint statement that
clinical trials would only be considered for publication
if formally registered from the outset of the study on a
trials registry. The WHO facilitated international col-
laboration on this by defining the minimum dataset for
trial registration. There are now several internationally
recognised registers. Clinicaltrials.gov is sponsored by
the US National Library of Medicine and currently lists
over 100,000 trials across 174 countries with 3,544
lung cancer trials. It does limit trial registration with
emphasis on federal sponsors or new drug FDA
applications. Current Controlled Trials is a commercial
company that also owns the online publishing group
Biomed Central. Each trial on the register of which
there are 9,661 at present, has a unique identifier
number (International Standard Randomised Con-
trolled Trial Number register ISRCTN). This system
incorporates a metaRegister (mRCT) which divides the
whole set of registered trials into separate registers
such as UK National register of cancer trials
(UKCCCR) or NIH trials. Any investigator can access
this registry without subscription, can search for trials
and can register a new trial. Results of trials can be
published promptly online by BioMed Central to one
million users. Since 2008 Clinicaltrials.gov has offered
the option of reporting summary results online also.
Similarly the Global Trial Bank, a partnership between
the Public Library of Science and the American Med-
ical Informatics Association, offers a freely accessible
repository for clinical trial results which has indepen-
dent peer-review. (The lack of peer review in some of
the sites offering rapid access trial results limits their
value).
New Directions in the Evaluation and Presentation of Clinical Research in Lung Cancer
A specialised trials register is a database of ran-
domised controlled trials (RCTs) in a particular area
of health care. The aim of a specialised register is to
collate the references of all RCTs published, by
means of specially designed, exhaustive searches
repeated at regular intervals. In addition to searches
of the world’s major electronic databases
(e.g., MEDLINE, EMBASE, CINAHL, LILACS,
Current Contents, Biosis and Index to UK Theses) a
specialised register also includes references to
reports of trials (both on-going and completed) that
have not been indexed, or that have been published
in non-indexed journals, as well as trials found by
hand searching of conference proceedings and
unpublished trials.
In its simplest form a specialised register is a ref-
erence-based database of citations of RCTs in which
any one trial may have several references, one for
each article published. A reference-based register is
the easiest and least resource intensive register to
assemble. To construct the register, electronic sear-
ches are undertaken using specially developed search
strategies, and citations and/or abstracts of all refer-
ences identified are then downloaded and reviewed by
an information specialist to ensure that they meet the
criteria of the register. A study-based register is more
sophisticated, though more resource intensive to
assemble and update. It uses each individual trial as
the basic record, rather than every reference pub-
lished. If a trial has 100 identified publications, these
will be linked to the one record relating to the main
trial report. Depending on the level of sophistication
of the register, there may be more detailed data for
each study on disease stage, number, age and sex of
participants, interventions used (including agents in
each arm) and outcome measures assessed. In this
way an investigator consulting the register would be
able to undertake very precise searches—examples of
which might include:
• trials of chemotherapy in extensive small-cell lung
cancer in which cisplatin was included in one arm
• trials in people over 75 in whom quality of life was
measured.
Importantly a register of lung cancer trials aside
from its research potential on the data offered, would
inform the research strategy on gaps in the evidence
and target future trial design appropriately.
831
6 Systematic Reviews and
Meta-Analyses
The pitfalls of traditional ‘expert’ reviews have been
clearly identified and well described. They are subject
to a variety of biases which are usually not explicit and
the status of the authors may confer a spurious
authority and validity to the conclusions. These nar-
rative reviews, which may falsely advertise themselves
as ‘systematic’, are characterized by their lack of the
essential components of a systematic review: a focus-
sed research question, comprehensive search strategy
with explicit methodology, and a rigorous method of
analysis. The science of systematic reviews, so-called
‘secondary’ research (research on the research litera-
ture), and meta-analysis is now well defined with
standards in place in regard to their structure and
reporting (Preferred Reporting Items for Systematic
Reviews and Meta-Analyses: www.prisma-statement.
org). As with clinical trials the PRISMA statement
advocates registration of all protocols for systematic
reviews (Booth et al. 2011).
A meta-analysis refers to the statistical combination
(or pooling) of quantitative data from more than one
original study, in order to amalgamate results from a
larger sample of patients than was available in any of
the individual original studies. A meta-analysis should,
therefore have greater statistical power to assess the
relative risks and benefits of interventions than the
individual studies. There are drawbacks associated
with pooling data from different studies, which include
differences in the populations of patients in the studies,
differences in the interventions given and other dif-
ferences in the studies’ designs. Meta-analyses may be
undertaken in one of two ways: either by combining the
data as presented in the published reports, or by com-
bining the original data on the individual patients
included in each of the original trials—an individual
patient data analysis. Most published meta-analyses
are reports of pooled data from published reports as
these are much quicker and easier to do, although their
findings are less robust.
An individual patient data meta-analysis (IPD) is a
long and time-consuming process which requires
contact with the authors of all the original studies to
gain access to the original dataset. The data must then
832
be cleaned and re-analysed on all the patients in the
included trials—a process, which often involves many
hundreds if not thousands of patient records. Indi-
vidual patient data analyses are therefore more reli-
able than meta-analyses of published data and these
reviews have been influential in shaping clinical
practice. A recent example in lung cancer is the
comparison of concomitant with sequential radio-
chemotherapy in locally-advanced NSCLC (Auperin
et al. 2010).
A systematic review does not always contain a
meta-analysis because the pooling of quantitative data
from studies included in the review would not be
feasible—as a result of differences in either the data
itself or the way that data was collected. Systematic
reviews may be either independent/‘ad-hoc’ reviews
or Cochrane Reviews.
7 Cochrane Reviews
The Cochrane Collaboration was founded in 1993 to
promote informed decisions about health care by
dissemination of available scientific evidence. An
international, not-for-profit organisation, the Collab-
oration consists of a network of researchers, health
professionals, consumers and others around the world
who work together to prepare, maintain and ensure
accessibility of systematic reviews of health-care
interventions. Working together in collaborative
topic-focused Review Groups, of which there are
currently 53, Cochrane reviewers use a rigorous
methodology for undertaking extensive searches of
published and unpublished research, critically
appraising abstracts and articles found, and conduct-
ing qualitative and quantitative analyses of the find-
ings. Cochrane reviews are published in electronic
format (online and on a CD Rom issued quarterly) as
part of the Cochrane Library and versions of reviews
may also be published in a peer-reviewed journal
(Clarke and Horton 2001). The main focus of the
Collaboration is on conducting reviews of random-
ised, controlled trials as the ‘gold-standard’ of sci-
entific investigation (Cochrane 1972).
Cochrane reviews are based on pre-defined rigor-
ous and explicit methodology as set out in the
Cochrane handbook. A title is registered followed by
a peer reviewed protocol, and the final article is
N. O’Rourke et al.
Collaborative
Review Centres
Groups
Steering
Group Methods
Fields
Groups
The
Consumer
Network
Fig. 1 Cochrane collaboration entities
subject to peer reviewing by experts in both the rel-
evant clinical field and in the methodology of sys-
tematic reviews. There is a formal mechanism for
assessing risk of potential bias in all studies included.
The reviews, all written in a standardised format, each
provide recommendations on both research and
practice that can be accessed by anyone interested in
the topic, be they clinician, health-care consumer,
manager, health policy maker or researcher.
In addition to the topic-focused Cochrane Review
Groups (CRGs) of which the Lung Cancer Review
Group is one, there are also Methods Working Groups
which develop methodology, Fields Groups which
focus on the dimensions of health care such as setting
or type of consumer, the Consumer Network and
Cochrane Centres which support people in their
geographic location. The whole is co-ordinated by a
steering group (Fig. 1).
Within the Collaboration, all review groups are
expected to develop and maintain their specialised
trials register and to download their contents at reg-
ular intervals into the Cochrane Central Register of
Controlled Clinical Trials (CENTRAL). The specia-
lised register is used by Cochrane review groups as a
fundamental resource to support reviewers in the
preparation and maintenance of reviews.
The Cochrane Lung Cancer Collaborative
Review Group (LCG) was formed in 1997. The
organisational structure includes an international,
coordinating editorial team supported by reviewers,
translators and consumers. The LCG editorial team
keeps a list that it has developed in consultation
New Directions in the Evaluation and Presentation of Clinical Research in Lung Cancer
Table 1 Cochrane lung cancer review group
Systematic reviews and protocols published in Cochrane
Library April 2011
Published reviews
Non-small-cell lung cancer
1. Post-operative radiotherapy (PORT) for NSCLC
2. Radical radiotherapy for stage I/II medically inoperable
NSCLC
3. Chemotherapy for NSCLC
4. Chemo and supportive care versus supportive care alone in
advanced NSCLC
5. Palliative radiotherapy for NSCLC
6. Second-line chemotherapy for NSCLC
7. Concurrent chemoradiotherapy in NSCLC
8. Surgery for local and locally-advanced NSCLC
9. Prophylactic cranial irradiation for preventing brain
metastases in patients undergoing radical treatment for
NSCLC
10. Surgery versus radiosurgery for patients with a solitary
brain metastasis
11. Chemotherapy and surgery versus surgery alone in
NSCLC
12. Second or third additional chemo drug for advanced
NSCLC
13. Palliative endobronchial brachytherapy for NSCLC
Small-cell lung cancer
14. Cranial irradiation for preventing brain metastases in
SCLC
15. Chemotherapy versus best supportive care for extensive
SCLC
16. Early versus late chest radiotherapy for limited-stage
SCLC
17. Platinum agents versus non-platinum agents for SCLC
General
18. Screening for lung cancer
19. Steroids, radiotherapy, chemotherapy and stents for SVC
obstruction
20. Surgical sealant for air leak prevention after pulmonary
resection
21. Drugs for preventing lung cancer
22. Pleurodesis for malignant pleural effusion
23. Non-invasive interventions for improving well-being and
quality of life
24. Elemene for the treatment of lung cancer
Mesothelioma
25. Radiotherapy for malignant pleural mesothelioma
(continued)
833
Table 1 (continued)
26. Pemetrexed disodium for malignant pleural mesothelioma
Published protocols
Non-small-cell lung cancer
1. Gemcitabine for NSCLC
2. Optimal duration of chemotherapy for advanced NSCLC
3. Erlotinib for advanced NSCLC
4. Gefitinib for NSCLC
5. Taxane schedules for NSCLC
Small-cell lung cancer
6. First-line chemotherapy for synchronous brain mets SCLC
7. Second-line chemo for SCLC
General
8. Anti-angiogenic therapy for lung cancer
9. Particle therapy versus conventional treatment for lung
cancer
New titles
1. Pharmacotherapy for the prevention of radiation-induced
pneumonitis
2. Cisplatin-based versus carboplatin-based chemo in NSCLC
3. Topotecan for advanced NSCLC
4. Topotecan for SCLC
5. PET-CT for assessing mediastinal lymph nodes
involvement NSCLC
with members of the review group in which are
detailed the titles registered for future systematic
reviews, published review protocols and completed
reviews. A list of the 26 completed systematic
reviews and nine published protocols are shown in
Table 1. A further five titles have also been regis-
tered (see www.cochrane.es/lcg).
The scope of the LCG covers all aspects of pri-
mary and secondary prevention, therapy, supportive
care, psychological interventions, biological therapy,
and complementary therapy for lung cancer, other
intra-thoracic tumours (if not addressed by other
review groups) and metastatic lung disease. Although
the remit of the group covers prevention, smoking is
not covered because there is a separate Cochrane
Review Group addressing tobacco addiction.
The Cochrane Lung Cancer Group has laid the
foundation stones and made significant progress in the
development of an evidence-based, global informa-
tion resource in lung cancer care.
834
8 Challenge of Novel Technologies
Systematic reviews, meta-analyses and access to
specialised trials registers offer us the means of
evaluating clinical trial data, but the rapidly evolving
new technologies in lung cancer radiotherapy cannot
easily be assessed by these means. In recent years we
have had expanding options for radiation treatment
with IMRT, IGRT, stereotactic radiation, volumetric
arc therapy (VMAT), particle beam options with
protons or heavy ions and a variety of enhanced
imaging alternatives for radiotherapy planning using
4D-CT or functional imaging with PET. These new
technologies may have superior biological or physical
characteristics relative to conventional treatment.
They may demonstrate improved, more conformal
dose distribution but we cannot make the uncritical
assumption that these features guarantee improved
outcomes clinically, in the absence of effectiveness
data.
There are major theoretical and practical obstacles,
however to conducting randomised controlled trials in
the application of new technology. Society has been
unable to resist the technological imperative over the
years so that if a more sophisticated technology
comes along with theoretical advantages, then it
should be adopted at the first opportunity. Certainly
the improved dose distribution of new radiotherapy
techniques promises the possibility of dose escalation
with improved tumour control, without sacrificing
normal tissue complication rates. The small incre-
ments of clinical benefit which might derive from
such new techniques would not be possible to test in
an adequately powered clinical trial. Moreover the
test of how effective the new treatment is might
depend upon the late toxicity associated with radio-
therapy or the second malignancy rate, which both
require substantially prolonged follow-up. And the
whole issue of cost of new technology makes evalu-
ation even more problematic, as the major capital and
development cost of introducing a new technique
would need to precede a clinical trial and so the
cancer centre has to make the commitment in advance
of being in a position to judge its effectiveness. Fac-
toring cost into an assessment of effectiveness of new
technology is further complicated by continuous
change as cost decreases over time for new technol-
ogies, and the user learning curve means that there is
N. O’Rourke et al.
increased efficiency with time with cost per unit
activity falling further.
If it is not feasible to conduct a randomised trial,
then we must examine other means of appraising the
new technologies. The most robust method is likely to
be a prospective comparative cohort study, which has
less risk of bias than uncontrolled or retrospective
case series. Indeed this may prove to have better
external validity than an RCT in that all patients eli-
gible for treatment can be included without the
exclusions often required for RCTs. More useful still
than a single centre cohort study would be a national
or international prospective register of patients treated
with this technique, gathering anonymised patient
data. This would also help to define the geographical
needs for this technique in terms of capacity and
location. With central collection and analysis of data
across countries there would need to be processes in
place for quality assurance of radiotherapy at con-
tributing centres and for gathering patient demo-
graphics and data on cost. The output from this would
be to assess effectiveness and quality issues of the
new technique on a large-scale prospective database.
9 Expanding Our Definition of Trial
Populations
Only a tiny percentage of lung cancer patients
worldwide are entered into randomised controlled
trials. Not only does this contribute to the gaps in our
evidence base for clinical practice but it raises the
question of external validity of published studies if
many patients, especially the elderly and those with
co-morbidity, are excluded from trials. Can we then
generalise research findings to the patient in front of
us if our patient is frail and elderly?
We have further difficulty in applying our ‘gold-
standard’ of RCT evidence to the evaluation of new
technologies, as described above. There is potential
for developing the methodology of systematic
reviews to incorporate the types of research that are
likely to address new research questions, rather than
limiting our reviews to RCTs. Prospective cohort
studies may provide the most efficient means of
gathering data and measuring outcomes with new
treatment techniques. But the largest wealth of
clinical data worldwide, as yet untapped, are the
thousands of ‘‘N of 1’’ experiments conducted daily
New Directions in the Evaluation and Presentation of Clinical Research in Lung Cancer
by health-care professionals on lung cancer patients
around the world.
The philosophy of ‘knowledge commons’ has
emerged in recent years in the drive to share knowl-
edge freely and rapidly on the internet. Cancer
Commons is an open science initiative for physicians,
scientists and patients engaged in personalised
oncology (www.cancercommons.org). The aim is to
individualize treatment based on tumour genomics, to
then learn as much as possible from each individual
patient’s response to treatment and to rapidly dis-
seminate these findings to enable other professionals
and patients to use this information in their own
treatment decisions. The vision is to co-ordinate the
thousands of ‘‘N of 1’’ trials into a giant adaptive
search for better, individualized cancer treatments.
10 Translating Evidence into Practice
and the Elephant in the Room
Our purpose in evaluating clinical research is to guide
management of individual patients. We strive to offer
each patient the best treatment available for their
individual characteristics and stage of disease, but
also to make consistent management decisions across
groups of patients. On a national and international
level this consistency of approach and application of
evidence is achieved by clinical practice guidelines.
Over recent years a variety of lung cancer guidelines
have been developed by national groups (SIGN
(2005) and NICE (2011) in UK, ACCP in US,
Australian National Health and Medical Research
Council Guidelines) and by professional associations
(IASLC).
As with assessing clinical trials, there are now
formal evaluation systems for judging the methodol-
ogy and robustness of recommendations within
treatment guidelines. Those rigorously developed
guidelines will grade the levels of evidence for each
topic 1–5 as described above, with one being highest
level of evidence from systematic reviews. The
guideline will then propose treatment recommenda-
tions graded A–D, depending on the level of evidence
available to support the recommendation, with grade
A requiring consistent level 1 evidence to support it.
The quality of the guideline can be checked using
systems such as the AGREE criteria (www.
agreetrust.org), which identify a number of key
835
domains for assessment. These include whether a
clear statement is made as to scope and purpose of the
guideline, whether there has been stakeholder
involvement, applicability of the guideline to the
population, editorial independence and overall rigor
of development. ‘Consensus’ guidelines derived from
collected ‘expert’ opinion, like the ad-hoc expert
reviews, should be objectively assessed for their
reliability.
The majority of clinical guidelines focus exclu-
sively on the effectiveness of treatment but with rising
lung cancer incidence in the developing countries and
ever increasing financial demands in health-care
worldwide, we can no longer ignore the ‘elephant in
the room’. The issue of cost effectiveness of treatment
is likely to become a more dominant factor in treat-
ment choices in the years ahead. Funding for new
drugs is already subject to thorough cost-effectiveness
evaluations by governments and health providers in a
number of countries. The same scrutiny can be
expected to be applied to all aspects of lung cancer
care. The onus therefore is on researchers to not just
demonstrate which treatments are most effective but
to investigate their cost effectiveness.
The UK Department for Health has recently
completed a consultation process on value-based
pricing for drugs, a new concept in health-care
funding which attempts to correlate the cost of the
drug with the actual magnitude of benefit it offers. A
similar proposal is being developed by a worldwide
non-profit organisation Incentives for Global Health,
in its Health impact Fund. This type of cost/benefit
analysis presents particular challenges in lung cancer
when the median survival for many patients may be a
small number of months. Some organisations now
take account of this in weighting the added value of
extra months of life when life expectancy is short.
11 What We Need to Do Next
In conclusion both health-care professionals and
clinical researchers in the field need access to the
reliable and up-to-date information on clinical effec-
tiveness that can be provided by systematic reviews
and meta-analyses. A specialised trials register has
much to offer in accessing trial information. Sys-
tematic reviews of the type promoted and published
by the Cochrane Collaboration should be an essential
836
tool for clinicians, researchers, research funders,
health policy makers and anyone with an interest in
lung cancer prevention, treatment and care. They are
tools to improve the quality of clinical practice and
clinical research, to inform a strategic research
agenda and to help streamline a more effective and
efficient use of research funding. But systematic
reviews are only as good as the original research from
which they are derived and they can never substitute
for poor quality research, absent research or a disor-
ganised research direction and agenda.
One important conclusion which comes from the
reviews already published in the Cochrane Library is
the need to improve not only the quality of individual
trials (their design and reporting) but also the world-
wide co-ordination of research in lung cancer.
Resources are increasingly scarce and the advent
of new drug treatments as well as evolving radiation
technology will place substantial financial demands
on health-care providers in the years ahead.
The challenge ahead is to answer the important
questions in lung cancer by planning research in a
more systematic way. This will enable us to deliver
individualised optimal treatment for each and every
patient. We have the opportunity with innovations in
information technology to facilitate a much more
organised, strategic and global approach to wider
recruitment to soundly designed trials and to
N. O’Rourke et al.
gathering and analysing data on all our clinical
activity. If we really want to increase our under-
standing of the biggest cancer killer of our time, the
means are already at our disposal.
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guidelines/fulltext/80/index.html
 Index

(TD0/5), 744 Angiogenic squamous dysplasia (ASD), 47

(TD5/5), 744 Angiopoietin-2, 22
(TD50/5), 744 Angiotensin-converting enzyme (ACE), 235
‘beam’s eye view, 145 Aortopulmonary window, 95
11
C-choline, 182 ARDS, 390
11
C-methionine, 182 Argon plasma coagulation (APC) catheters, 584
18
F-fluoro-deoxyglucose(FDG), 76 Argon plasma coagulation (APC), 50
18
F-fluoro-thymidine (FLT), 76 Arterial oxygen pressure on room air (PO2), 352
201
Tl, 182 Arterioplasty, 109
3D conformal RT (3DCRT), 160 Ataxia, 649
3D planning, 145 Autofluorescence bronchoscopy (AFB), 46
4D computed tomography (4DCT), 148, 347, 728 Avalanche photodiodes (APDs), 78
4-D imaging, 72 Axitinib, 259, 779
4D-cone beam CT (4DCBCT), 160
4D-imaging, 188
a-difluoromethylornithine (DMFO), 654 B
Balloon Dilatation, 584
Basic fibroblast growth factor (b-FGF), 233
A Basic fibroblast growth factor (bFGF/FGF-2), 19
Abraxane, 768 Basic fibroblast growth factor (FGF-2), 654
Accelerated fractionation, 132 Batho and equivalent-tissue-air ratio
Accelerated hyperfractionated radiation therapy, 507 (ETAR) methods, 154
Accelerated hyperfractionation, 498 Bcl-2 Inhibitors, 219, 237, 260
Accelerated repopulation, 144 Bcl-2, 9
Acidic fibroblast growth factor (aFGF/FGF-1), 19 Bevacizumab, 254, 778
Active breathing control (ABC), 148, 347 Bilobectomy, 109
Acute esophagitis, 638 Biological markers, 676, 677
Acute fatigue, 450 Biologically effective dose (BED), 516, 566
Acute myocardial infarction (AMI), 618 Bioreductive drugs, 217
Acute pneumonitis, 611 Blood–brain barrier, 649
Adaptive radiotherapy, 730 Bone marrow, 598
Adenocarcinoma (ADC), 54 Bone metastases, 561
Adenocarcinoma, 446, 812 Bone scans, 71
Adjuvant chemotherapy, 439, 250 Boron neutron capture therapy (BNCT), 649
Age, 446 Bortezomib, 780
AKT Pathway Inhibition, 217 Brachytherapy, 477
ALK targeted inhibitors, 271, 784 Bragg peak, 745, 754
Altered fractionation regimens, 411 Brain metastases, 445, 514, 566, 647
Amifostine (Ethyol), 226 Brain neurotoxicity, 517
Amifostine (WR-2721), 616 Breath-hold techniques, 347
Amifostine, 425, 630, 643 Bronchial artery embolization, 589
Anemia, 600 Bronchial stenosis, 485
Angiogenesis, growth factors, 678 Bronchioloalveolar carcinoma, 55
Angiogenesis, 18 Bronchoplasty, 109

B. Jeremić (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, 837
DOI: 10.1007/978-3-642-19925-7, Ó Springer-Verlag Berlin Heidelberg 2011
838 Index

B (cont.) CT staging, 446

Bronchoscopic balloon dilatation, 51 CT-based planning, 174
Brown–Sequard syndrome, 628 CTV/PTV, 455
CyberKnife image-guided robotic radiosurgery, 715
Cyclooxygenase COX-2-Inhibitors, 219
C Cyclooxygenase-2 (COX2), 12
Carbogen, 215 Cyclooxygenase-2 Inhibitors, 783
Carbon ion radiation therapy, 754 Cyclopamine, 785
Carbon monoxide (CO), 612 Cytokinesis-block micronucleus (MN) test, 124
Carbon-11 (11C), 76
Carboplatin, 276, 292, 776
Carboplatin/paclitaxel, 249 D
Case controls, 828 Dampening, 347
Cediranib, 259, 779 Data Monitoring and Ethics Committee (DMEC), 823
Celecoxib, 783 Decreased sexual interest, 518
Central airway stenosis (CAO), 46 Deep inspiration breath-hold, 347
Cervical Mediastinoscopy, 94 Dementia, 649
Cetuximab, panitumimab, 775 Demyelination, 629, 650
Cetuximab, 256 Density-correction algorithms, 154
Chart, 411 Depression, 450
Chartwel, 411 Diffusewhite matter changes, 651
Chasing, 347 Diffusing capacity for carbon monoxide (DLCO), 352
Chemical pleurodesis, 586 Diffusion capacity (DLCO), 612
Chemotherapy, 201, 248, 267, 364, 409, 454, 492, Digitally reconstructed radiographs (DRRs), 151
514, 518, 809 Direct machine parameter optimization (DMPO), 702
Chest pain, 454 DNA Repair Inhibitors, 217
Chest radiographs, 64 Docetaxel, 251, 302
Chromogranin A, 801 Dose escalation, 400
Chronic lung fibrosis, 611 Dose intensification, 495
Chronic obstructive pulmonary disease (COPD), 576, 611 Dose-functional histograms (DFHs), 617
Chronic pulmonary dysfunction, 610 Dose-response, 319
Cisplatin, 249, 276 Dose-volume histogram (DVH), 350, 368, 614
Cisplatin/etoposide, 492 Dose-volume relationship, 144
Clinical target volume (CTV), 146, 188, 202, 348, 749, 755 Dynamic and diffusion-weighted
Clinical trials, 524 (DWI) MRI, 72
Clumsiness, 628 Dysphagia, 454, 638
c-MET, 10 Dysphoria, 649
CMR (complete metabolic response), 180 Dyspnea, 575
c-MYC proto-oncogene, 7 Dyspnoea, 450, 454, 551
Cognitive dysfunction, 517
Cognitive functioning, 518
Cohort studies, 828 E
Colony formation method, 120 Early Stage Non-Small-Cell Lung Cancer, 525
Combined modality treatment, 434 Echinoderm microtubule-associated protein-like 4
Computed tomography (CT), 64, 90, 173, 202 (EML4)-anaplastic lymphoma kinase (ALK)
Computer aided detection (CAD), 67 fusion oncogene (EML4-ALK), 6
Concurrent Radiochemotherapy, 415 Echinoderm Microtubule-Associated Protein-Like 4-Anaplastic
Cone beam CT (CBCT) , 736, 346 Lymphom Kinase Translocation, 800
Consolidation chemotherapy, 420, 810 Edema, 650
CONSORT (Consolidated Standards of ReportingTrials), 830 Efaproxaril, 237
Continuous hyperfractionated accelerated radiation therapy Efaproxiral (RSR-13), 215
(CHART), 132 Elderly, 524, 812
Control treatment, 820 Elective nodal irradiation, 203
Conventional radiation therapy, 316 Elective nodal irradiation (ENI), 192
Convolution-superposition (CS) method, 154 Electrocautery (EC), 49
Cough, 454, 518, 551, 575 Electromagnetic navigation (EMN) bronchoscopy, 46, 48
COX-2 inhibitors, 231, 271 Electronic portal imaging device (EPID), 694
Crizotinib, 259, 784 Electronic portal imaging devices (EPIDs), 738
Cryotherapy, 52, 483, 583 Emotional functioning, 518
Cryptogenic organizing pneumonia (COP), 122 En bloc chest wall resection, 109
CT on rails, 346 Endobronchial brachytherapy (EBBT), 52, 556
Index 839

Endobronchial Prosthesis, 580 Granulocyte colony stimulating factor, 19

Endobronchial ultrasonography (EBUS), 71 Granulocyte-colony stimulating factors (G-CSFs), 603
Endobronchial ultrasound (EBUS), 46, 94 Gross tumor volume (GTV), 145, 188, 202, 348, 455,
Endoluminal brachytherapy, 477 748, 755, 813
Endoscopic (esophageal) ultrasound (EUS), 90 GyE (Gray equivalents), 754
Endoscopic ultrasound, 71
Enhancement of tumour response, 268
Epidermal growth factor recepto proto-oncogenes: H
c-erb-B1, 796 Hazard ratio (HR), 823
Epidermal growth factor receptor (EGFR), 22, 57, 234, 775 HDAC inhibitors, 271, 781
Epidermal growth factor receptor (EGFR; ErbB-1), 11 Heavy particle beams, 754
Equivalent uniform dose (EUD), 699 Heavy-charged particle, 746
Equivalent-pathlength (EPL) model, 154 Hedgehog inhibitors, 260
Erlotinib, 252, 775, 777 Hedgehog Pathway Inhibitors, 260, 271, 785
Erythropoiesis-stimulating agent (ESA), 605 Hematopoietic growth factors, 589
Erythropoietin (EPO), 216 Hematopoietic stem cells, 589
Esophageal Endoscopic Ultrasound (EUS), 94 Hemiparesis, 628
Esophageal ultrasonography (EUS), 71 Hemoglobin (Hb), 604
Esophagitis index, 639 Hemoptysis, 454, 485, 551, 575
Etoposid, 260, 276, 773 Hemorrhage, 390
Everolimus, 782 Hepatocyte growth factor, 22
Evidence-based medicine, 819, 828 Hepatocyte growth factor/scatter factor (HGF/SF), 19
Extended cervical mediastinoscopy, 95 High linear energy transfer (LET), 754
Extensive disease small cell lung cancer, 505, 537, 813 High-dose chemotherapy, 494
Extremity weakness, 628 High-dose rate brachytherapy, 477
High-dose rate endobronchial brachytherapy (HDR-EBRT), 52
High-molecular-weight mucin-like antigen KL-6, 120
F Histology, 812
FACT-L, 664 Histone deacetylase inhibitors, 781
FACT-TOI, 664 Histone deacetylases (HDAC), 218
FDG-PET, 189 Horners syndrome, 454
Febrile neutropenia (FN), 599 Human manganese superoxide dismutase transgene, 644
Fibroblast growth factor-3 (FGF-3/ int-2), 19 Human MutS Homologue and Human MutL
Fibroblast growth factor-4 (FGF-4/hst/K-FGF), 19 Homologue 1, 800
Fiducial markers, 344, 739 Human recombinant keratinocyte growth factor, 644
Figitumumab, 782 Hybrid Stents, 582
Fine motor coordination, 517 Hyperbaric oxygen (HBO), 633, 655
Flavopiridol (alvocidib), 236 Hyperbaric Oxygen, 214
Flexible intraoperative template (FIT), 472 Hyperfractionation, 132, 498
FLT, 182 Hypoxia, 184, 214, 576
Fluorescence, 374 Hypoxic Cell Radiosensitizers, 216
Forced expiratory volume in one second (FEV1), 352, 612
Forced vital capacity (FVC), 352, 612
Four dimensional computed tomography (4D-CT), 692 I
Four-dimensional (4D)-CT scanning approach, 196 Idiopathic interstitial pneumonitis, 120
Four-dimensional radiotherapy (4DRT), 157 Ifosfamide, 277
Frontal lobe dysfunction, 517 IGF-1R pathway inhibitors, 260
Functional Assessment of Cancer Therapy-General IGF-IR targeting therapies, 271
(FACT-G), 664 Interleukin [IL]-1b, 231
Interleukin 1 (IL-1), 120, 613, 629, 649
IL-6, 615
G Interleukin-8, 19
Gamma linolenic [omega-6] acid, 653 Image guided radiotherapy (IGRT), 725, 736
Gating, 347 Imaging, 148
Gefitinib, 255, 777 Increased vascular permeability, 650
Gemcitabine, 251, 297 Independent cell kill, 268
Gender, Age and Ethnicity, 679 Individual patient data meta-analysis (IPD), 831
Gene expression profiles, 796 Induction chemotherapy, 413, 414, 439, 440, 810
Genetic tumor factors, 677 Inhibitors to poly(ADP-ribose) polymerase (PARP), 237
Geographic miss, 144 Insulin-like growth factor (IGF), 630
Geriatric assessment, 524 Insulinlike growth factor-1 (IGF-1), 654
840 Index

I (cont.) Location, 812

Intellectual decline, 649 Locoregional post-surgical recurrences, 545
Intensity modulated (IMRT), 367 Locoregional recurrence of small-cell lung cancer, 556
Intensity-modulated radiation therapy (IMRT), 133, 401, 424, Low-dose CT screening, 65
528, 692 Low-dose daily chemotherapy, 507
Intensity-modulated arc therapy (IMAT), 692 Lung Cancer Symptom Scale (LCSS), 664
Intensity-modulated proton therapy, 747 Lung metastases, 568
Intercellular adhesion molecule-1 (ICAM-1), 649 Lung tumors, 119
Internal margin (IM), 755 Lymph node dissection, 92
Internal target volume (ITV), 188, 203
International Commission on Radiation Units
(ICRU), 188, 202 M
International Commission on Radiation Units Magnetic resonance imaging(MRI), 90
and Measurements (ICRU), 145 Malacia, 629
Inter-observer variability, 188 Manganese superoxide dismutase (MnSOD), 238
Interstitial brachytherapy, 477 Markers of cellular adhesion, 677
Interventional pulmonology, 45 Markers of DNA Repair, 798
Intracranial stereotactic radiosurgery (SRS), 716 Markers of tumor proliferation, 677
Intraoperative brachytherapy, 470 Matrix metalloproteinases, 22
Intraoperative interstitial brachytherapy, 477 Maximal intensity projection (MIP) approach, 702
Intraoperative nodal staging, 92 Maximum intensity projection (MIP), 165, 197
Intraoperative radiation (IORT), 462 Maximum tolerated dose (MTD), 402
Intrapulmonary recurrence, 545 Mean lung dose, 121
Intratumoral microvessel density (MVD), 20 Mediastinal lymph node recurrences, 545
Invasive mediastinal staging, 92 Mediastinal lymph node sampling, 92
Irinotecan, 251, 303 Mediastinotomy, 95
Irradiation volume, 499 Medical Outcomes Study (MOS), 663
Irritability, 518 Medical Outcomes Study 36 item Short Form Health Survey
ITV, 348 (MOS SF-36), 664
Megavoltage EPIDs, 738
Memory loss, 649
K Meta-Analyses, 515, 831
Keratinocyte growth factor (KGF), 233 Metallic Stents, 581
Kilovoltage EPIDs, 738 Metastasis, 516
Metastatic Non-Small-Cell Lung Cancer, 532
Metastatic spinal cord compression, 561
L Misonidazole, 216
Lack of energy, 518 Mitogen-activated protein (MAP) kinase, 218
Large cell carcinoma, 54, 446, 812 Mitomycin, 277
Late esophageal damage, 639 Mobile linear accelerator, 464
Late toxicity, 611 Molecular markers, 794
Lethargy, 649 MRI (Magnetic Resonance Imaging), 64
Leukopenia, 599 M-Staging, 81
Lhermitte sign, 628 mTOR inhibitors, 260, 271, 782
Light Emitting Diodes (LED), 373 Multileaf collimator (MLC), 149
Light initiation interval (DLI), 374 Multi-leaf collimators (MLCs), 692
Light source, 372 MVCT, 728
Limited disease small-cell lung cancer, 533, 492, 815 Myelosuppression, 589
Limited stage disease, 201
Linear analogue self-assessment [LASA] scales, 667
Linear-quadratic (LQ) formula, 350 N
Line-of-response (LOR), 76 Nanotechnology, 272
Linifanib, 259 Narrow band imaging bronchoscopy, 46
Liver metastases, 568 Nd: YAG laser, 483
Lobectomy, 109, 249, 367, 439 Nd:YAG Laser Photoresection, 48
Local control, 144 Neo-adjuvant chemotherapy, 250, 447
Locally advanced non-small cell lung cancer Neurocognitive Function, 450
(LA-NSCLC), 445 Neuron-Specific Enolase, 801
Locally Advanced Nonsmall-Cell Lung Cancer, 409, 529 Nimorazole, 216
Locally recurrent lung cancer, 546 Nitrogen-13 (13N), 76
Locally recurrent non-small-cell lung cancer, 544 Non small-cell lung cancer (NSCLC), 54, 515
Index 841

Non-coplanar beams, 344 Potential doubling time (Tpot), 124

Non-small cell carcinoma (NSCLC), 54, 524, 812 Pre-chemotherapy volume, 190, 499
Normal lung tissue, 119 Pro-Gastrin-Releasing Peptide, 801
Normal tissue complication probability (NTCP), 144, 403 Prognostic factors, 327, 676
N-stage, 81, 90 Proliferative activity, 124
Numbness, 628 Prophylactic cranial irradiation (PCI), 446, 492,
506, 514, 647
Prostaglandin E2 (PGE2), 231
O Protease inhibitors, 271
Odynophagia, 638 Proteasome Inhibitors, 780
Once-daily thoracic radiation, 498 Protection of normal tissues, 268
Organs at risk (OARs), 692 Proton-beam dosimetry, 746
Overall treatment time, 498 Protons, 744
Oxygen, 214 Proto-oncogene KRAS, 8
Oxygen-enhancement ratio (OER), 214 Pulmonary bronchitis, 485
Pulmonary function tests(PFTs), 612

P
p53 Tumor Suppressor Gene, 795 Q
p53, 12 QLQ-LC13, 664
Paclitaxel, 292 Quality of Life Questionnaire Core 30 (QLQ-C30), 664
Palifermin, 644 Quality of life (QOL), 661, 332, 450
Palliative radiation therapy, 533 Quality-adjusted life expectancy (QALE), 518
Palliative radiotherapy, 454 Quality-adjusted survival (QAS), 295
Paraneoplastic syndromes, 492
Paresthesias, 628
PARP inhibitors, 271, 780, 218 R
Pathological fractures, 561 Radiation induced brain toxicity, 648
Patient immobilization, 344 Radiation myelopathy, 627
Patient-reported outcomes (PROs), 662 Radiation pneumonitis, 121, 754
Patient-Reported Outcomes Measurement Information System Radiation response, 119
(PROMIS), 670 Radiation Sensitizers, 213
Pemetrexed, 251, 304, 766 Radiation therapy, 267, 249, 410, 492, 525, 809
Pentoxifylline (Trental), 234 Radiation-induced liver disease (RILD), 569
Performance Status, 680 Radiation-induced lung toxicity, 609
Perfusion and ventilation scans, 612 Radiochemotherapy, 410, 529
Perioperative high-dose-rate brachytherapy (PHDRB), 471 Radiofrequency ablation, 382
Permanent interstitial transbronchial implantation, 478 Radiopharmaceuticals, 271, 785
Personalized medicine, 794 Radioprotectors, 424
PET (Positron Emission Tomography), 64 Radiosensitivity, 124
PET- CT, 64 Radiosensitizer, 214
PET/MR imaging, 77 Radiosurgery, 568
Photodynamic reaction (PDR), 372 Radiotherapy planning, 177
Photodynamic Therapy (PDT), 52, 371, 483, 583 Radiotherapy, 439, 454, 514, 518
Photomultipliers (PMTs), 77 Radivnecrosis, 651
Photosensitizing agent (PS), 372 Randomised controlled trials, 828
Planning target volume (PTV), 146, 188, 203, 348, Randomized clinical trial (RCT), 819
748, 755 Ras Oncogenes p21, 794
Platelet-derived growth factor (PDGF), 19, 120, 654 Recombinant human erythropoietin
Pleuropneumonectomy, 109 (r-HuEPO epoietin-alfa), 604
PMD (progressive metabolic disease), 180 Recombinant interleukin-11 (rIL-11), 234
PMR (partial metabolic response), 180 Recurrence, 544
Pneumonectomy, 109, 249, 367, 390, 439 Reirradiation of Small-Cell
Polo-like kinase inhibitors, 271, 784 Lung Cancer, 556
Poly(ADP-Ribose) Polymerase Inhibitors, 236 Reirradiation, 549
Porphyrins, 372 Relative mean lung dose (rMLD), 404
Positron emission tomography (PET), 75, 92, 147, Reoperation, 545
173, 202 Residual volume(RV), 612
Post-chemotherapy volumes, 190, 499 Respiratory correlated PET-CT, 347
Postoperative radiation therapy (PORT), 364 Respiratory gated therapy, 148
Postoperative Radiotherapy, 194 Respiratory Gating, 183
842 Index

R (cont.) TGF-b, 613, 615

rh-MnSOD (manganese superoxide dismutase), 654 Therapeutic ratio, 268
Ribonucleotide-Diphosphate Thoracentesis, 585
Reductase M1, 799 Thoracic radiation therapy, 506
Thoracic radiotherapy, 201, 364
Thoracoscopy, 585
S Thoracotomy, 90
Search strategy, 830 Three-dimensional conformal radiation therapy, 188, 317, 403,
Segmentectomy, 109 424, 455, 692
Sequential radiochemotherapy, 412 Thrombocytopenia, 599
Serine/threonine kinase 11 (STK 11), 7 Thrombopoietin (TPO), 605
Serological Tumor Markers, 678 Thymidine phosphorylase, 22
Serum Proteomic Profiling, 801 Thyroid transcription factor 1 (TTF-1), 5
Set-up error, 197 Time-to-event analyses, 823
Set-up uncertainty, 146 Tirapazamine, 217
Shortness of breath, 518, 610 Tiredness, 518
Sickness Impact Profile (SIP), 663, 664 TNF-a PDGF, 613
Silastic Stents, 580 TNFa, 629
Simultaneous integrated boost(SIB), 699 Tomotherapy, 725
Single nucleotide polymorphism (SNP) arrays, 4 Topotecan, 260
Single-photon-emission computed Total lung capacity (TLC), 612
tomography(SPECT), 612 Toxicity, 328, 450, 532
Sleeve resection, 109 Tracheobronchial stents, 51
Slow CT scanning, 196 Tracheoesophageal Fistula, 587
Slow CT, 347 Transbronchial Needle Biopsy (TBNBx), 93
Small molecule drugs, 32 Transesophageal ultrasound, 64
Small-cell carcinoma (SCLC), 54, 201, 492, 514, 533 Transforming growth factor-a(TGF-a), 19
SMD (stable metabolic disease), 180 Transforming growth factor-b(TGF-b), 19
Sorafenib, 259, 779 Translational research, 794
Spatial cooperation, 268 Transthoracic Needle Biopsy (TTNBx), 93
SPECT, 182 Treated volume, 455
Squamous carcinoma, 446 Treatment planning, 144
Squamous cell carcinomas, 812 Treatment Volume, 323
Stage, 454, 812 Trial outcome index, 664
Standard radiation therapy, 411 Tri-modality approach, 436
Standardized uptake (SUV), 180, 190 T-stage, 90
Stereotactic ablative radiotherapy (SABR), 715, 344 T-staging, 80, 90
Stereotactic body radiation therapy (SBRT), 344, 569, 692, Tumor angiogenesis, 19
715, 728 Tumor histology, 677
Stereotactic fractionated radiation therapy, 424 Tumor motion, 148
Stereotactic radiation therapy, 528 Tumor necrosis factor a (TNF-a), 19, 231, 649
Stereotactic radiosurgery (SRS), 647 Tumor size, 322
Subjective significance questionnaire (SSQ), 666 Tumor stage, 322
Sucralfate, 644 Tumorcontrol probability, 144
Sunitinib, 259, 779 Tumour size, 454
Superior sulcus tumors, 434 Twice-daily tho racic radiation, 498
Superior vena cava syndrome, 454 Two-dimensional radiotherapy (2DRT), 454
Surgery, 315, 364, 545, 809 Type I error, 821
Surgical resection, 647 Type II error, 822
Surgical staging, 89 Type II pneumocyte, 120
Symptomatic relief, 549 Tyrosine kinase inhibitors (TKIs), 775
Syncope, 450
Systematic error, 188
Systematic reviews, 828, 831 V
V/Q (Ventilation and Perfusion)
Scans, 71
T V20, 121
Target volume, 202 V20, 350
Targeted gene therapy, 32 V5, 121
Temozolamide, 780 Vandetanib, 259, 779
Temporary implants, 480 Vascular disrupting agents, 32
Index 843

Vascular endothelial growth factor (VEGF), 18, 257, 629 W

Vatalanib, 259 Weakness, 450
Verbal memory, 517 Wedge resection, 109
Video-assisted thoracic surgery Weight loss, 454, 680
(VATS), 90, 95, 112, 249 White matter necrosis, 629
Vinblastin, 277 Whole-brain radiotherapy (WBRT), 566, 647
Vinorelbine, 249, 297
Vital capacity (VC), 612
Volumetric-modulated arc therapy (VMAT), 692 Z
Vorinostat, 781 Zileuton, 783