Advances in Radiation Oncology in Lung Cancer, 2nd Edition

Medical Radiology Radiation Oncology Series Editors Luther W. Brady Hans-Peter Heilmann Michael Molls Carsten Nieder ...

Author: Branislav Jeremic

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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 Jeremic´ 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 Jeremic´ Institute of Lung Diseases Institutski put 4 21204 Sremska Kamenica Serbia e-mail: [email protected]

ISSN 0942-5373 ISBN 978-3-642-19924-0 DOI 10.1007/978-3-642-19925-7

e-ISBN 978-3-642-19925-7

Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2011936026 Ó Springer-Verlag Berlin Heidelberg 2011 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: eStudio Calamar, Berlin/Figueres Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

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 innovative 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 investigations, 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 bronchoscopy, 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.

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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.

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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 professional, 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 Jeremic´

Contents

Part I

Basic Science of Lung Cancer

Molecular Biology and Genetics of Lung Cancer . . . . . . . . . . . . . . . . . Dusan Milanovic

3

Angiogenesis and Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wenyin Shi and Dietmar W. Siemann

17

Part II

Clinical Investigations

Interventional Pulmonology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Branislav Perin, Bojan Zaric´, and Heinrich D. Becker

45

Pathology of Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mary Beth Beasley

53

Radiologic Imaging of Lung Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . Palmi Shah and James L. Mulshine

63

PET/CT for Staging and Diagnosis of Lung Cancer . . . . . . . . . . . . . . . Sigrid Stroobants

75

Surgical Staging of Lung Cancer for Advances in Radiation Oncology of Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Farhood Farjah and Valerie W. Rusch

Part III

89

Basic Treatment Considerations

Lung Cancer Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sidhu P. Gangadharan, Walter J. Lech, and David J. Sugarbaker

103

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

119

xi

xii

Contents

Radiation Time, Dose, and Fractionation in the Treatment of Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Daniel Gomez, Melenda D. Jeter, Ritsuko Komaki, and James D. Cox 3D Radiation Treatment Planning and Execution . . . . . . . . . . . . . . . . . Mary K. Martel Four-dimensional Radiation Therapy for Non-Small Cell Lung Cancer: A Clinical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Max Dahele, Johan Cuijpers, and Suresh Senan

129

143

157

PET and PET/CT in Treatment Planning. . . . . . . . . . . . . . . . . . . . . . . Michael P. Mac Manus and Rodney J. Hicks

173

Target Volume Definition in Non-Small Cell Lung Cancer . . . . . . . . . . Lucyna Kepka and Milena Kolodziejczyk

187

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

201

Radiation Sensitizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anthony M. Brade and Zishan Allibhai

213

Radioprotectors and Chemoprotectors in the Management of Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ritsuko Komaki, Zhongxing Liao, James D. Cox, Kathy A. Mason, and Luka Milas Systemic Therapy for Lung Cancer for the Radiation Oncologist . . . . . Chandra P. Belani Combined Radiotherapy and Chemotherapy: Theoretical Considerations and Biological Premises . . . . . . . . . . . . . . . . . . . . . . . . Branislav Jeremic, Dusan Milanovic, and Nenad Filipovic Radiotherapy and Second Generation Drugs . . . . . . . . . . . . . . . . . . . . Michael Geier and Nicolaus Andratschke Radiotherapy and Third Generation Concurrent Chemotherapy Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ross Bland, Puneeth Iyengar, and Hak Choy

Part IV

223

247

267

275

291

Current Treatment Strategies in Early-Stage Non-Small Cell Lung Cancer

Conventional Radiation Therapy in Early Stage Non-small-cell Lung Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Branislav Jeremic´, Sinisa Stanic, and Slobodan Milisavljevic

315

Contents

xiii

Stereotactic Ablative Radiotherapy for Early Stage Lung Cancer . . . . . John H. Heinzerling and Robert D. Timmerman

343

Postoperative Radiotherapy for Non-Small Cell Carcinoma . . . . . . . . . Ellen Kim and Mitchell Machtay

363

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

371

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

Part V

381

Current Treatment Strategies in Locally Advanced Non-Small Cell Lung Cancer

Lung Dose Escalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bradford S. Hoppe and Kenneth E. Rosenzweig

399

Radiochemotherapy in Locally Advanced Non-small-Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Branislav Jeremic´, Francesc Casas, and Asuncion Hervas-Moron

409

Tri-Modality Therapy in Locally Advanced Non-Small-Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jan P. van Meerbeeck and Elke Vandenbroucke

433

Prophylactic Cranial Irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jason Francis Lester

445

Palliative External Beam Thoracic Radiation Therapy of Non-Small Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stein Sundstrøm

453

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

461

Brachytherapy for Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Polo, M. Castro, A. Montero, and P. Navío

Part VI

477

Current Treatment Strategies in Small Cell Lung Cancer

Limited-Disease Small-Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . Branislav Jeremic´, Zˇeljko Dobric´, and Francesc Casas

491

xiv

Contents

Radiation Therapy in Extensive Disease Small Cell Lung Cancer . . . . . Branislav Jeremic´ and Luhua Wang

505

Prophylactic Cranial Irradiation in Small-Cell Lung Cancer . . . . . . . . Michael C. Stauder and Yolanda I. Garces

513

Part VII

Treatment in Specific Patient Groups and Other Settings

Radiation Therapy for Lung Cancer in Elderly . . . . . . . . . . . . . . . . . . Branislav Jeremic´ and Zˇeljko Dobric´

523

Radiation Therapy for Recurrent Disease. . . . . . . . . . . . . . . . . . . . . . . Branislav Jeremic´, Jai Prakash Agarwal, and Sherif Abdel-Wahab

543

Radiation Therapy for Metastatic Disease . . . . . . . . . . . . . . . . . . . . . . Dirk Rades

561

Advances in Supportive and Palliative Care for Lung Cancer Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michael J. Simoff

Part VIII

575

Treatment-Related Toxicity

Hematological Toxicity in Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . Francesc Casas, Ferran Ferrer, and Núria Viñolas

597

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

609

Spinal Cord Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Timothy E. Schultheiss

627

Radiation Therapy-Related Toxicity: Esophagus. . . . . . . . . . . . . . . . . . Voichita Bar Ad and Maria Werner-Wasik

637

Brain Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Nieder

647

Part IX

Quality of Life Studies and Prognostic Factors

Quality of Life Outcomes in Radiotherapy of Lung Cancer . . . . . . . . . M. Salim Siddiqui, Farzan Siddiqui, and Benjamin Movsas

661

Prognostic Factors in Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . Frank B. Zimmermann

675

Contents

xv

Part X

Technological Advances in Lung Cancer

Intensity-Modulated Radiation Therapy and Volumetric-Modulated Arc Therapy for Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inga S. Grills and Victor S. Mangona

691

Image-Guided Robotic Stereotactic Ablative Radiotherapy for Lung Tumors: The CyberKnife . . . . . . . . . . . . . . . . . . . . . . . . . . . Billy W. Loo Jr. and Iris C. Gibbs

715

Advances in Radiation Oncology of Lung Cancer . . . . . . . . . . . . . . . . . Deepak Khuntia and Minesh P. Mehta

725

Image-Guided Radiotherapy in Lung Cancer . . . . . . . . . . . . . . . . . . . . Percy Lee and Patrick Kupelian

735

Proton Therapy for Lung Cancer: State of the Science . . . . . . . . . . . . . David A. Bush

743

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

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] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Corey J. Langer Novel Targeted Agents and Radiopharmaceuticals in Lung Cancer. . . . Martin J. Edelman and Nadia Ijaz

Part XII

753

765

773

Clinical Research in Lung Cancer

Translational Research in Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . Deepinder Singh, Kevin Bylund, and Yuhchyau Chen

793

Clinical Research in Radiation Oncology of Lung Cancer: Why We Fail(ed)? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Branislav Jeremic´

809

Pitfalls in the Design, Analysis, Presentation, and Interpretation of Randomized Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Richard Stephens

819

xvi

Contents

New Directions in the Evaluation and Presentation of Clinical Research in Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . Noelle O’Rourke, Fergus Macbeth, and Elinor Thompson

827

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

837

Contributors

Ron R. Allison Greenville, NC, USA; e-mail: [email protected] Nicolaus Andraschke Munich, Germany; e-mail: [email protected] Mary Beth Beasley New York, NY, USA; e-mail: [email protected] Chandra P. Belani Hershey, PA, USA; e-mail: [email protected] William Blackstock Winston Salem, NC, USA; e-mail: [email protected] Anthony Brade Toronto, Canada; e-mail: [email protected] David Bush Loma Linda, CA, USA; e-mail: [email protected] Felipe Calvo Madrid, Spain; e-mail: [email protected] Francesc Casas Barcelona, Spain; e-mail: [email protected] Y. Chen e-mail: [email protected] Hak Choy Dallas, TX, USA; e-mail: [email protected] James D. Cox Houston, TX, USA; e-mail: [email protected] Martin Edelman Baltimore, MD, USA; e-mail: [email protected] Yolande Garces Rochester, MN, USA; e-mail: [email protected] Inga Grills Royal Oak, MI, USA; e-mail: [email protected] Lucyna Kepka Warsaw, Poland; e-mail: [email protected] Ritsuko Komaki Houston, TX, USA; e-mail: [email protected] Patrick Kupelian Los Angeles, LA, USA; e-mail: [email protected] Corey Langer Philadelphia, PA, USA; e-mail: [email protected] Percy Lee Los Angeles, LA, USA; e-mail: [email protected] Jason Lester Cardiff, Wales, UK; e-mail: [email protected] Bill Loo Stanford, CA, USA; e-mail: [email protected] Fergus R. Macbeth Cardiff, Wales, UK; e-mail: [email protected] Mitchell Machtay uhhospitals.org

Cleveland,

OH,

USA;

e-mail:

mitchell.machtay@

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Contributors

M. McManus e-mail: [email protected] Lawrence B. Marks Chapel Hill, NC, USA; e-mail: [email protected] Mary K. Martel Houston, TX, USA; e-mail: [email protected] Minesh P. Mehta Chicago, IL, USA; e-mail: [email protected] Tadaaki Miyamoto Chiba, Japan; e-mail: [email protected] Benjamin Movsas Detroit, MI, USA; e-mail: [email protected] James L. Mulshine Chicago, IL, USA; e-mail: [email protected] Carsten Nieder Bodo, Norway; e-mail: [email protected] Branislav Perin Sremska Kamenica, Serbia; e-mail: [email protected] Alfredo Pol Madrid, Spain, e-mail: [email protected] Dirk Rades Luebeck, Germany; e-mail: [email protected] Kenneth Rosenzweig New York, NY, USA; e-mail: ken.rosenzweig@ mountsinai.org Valerie Rusch New York, NY, USA; e-mail: [email protected] Dietmar W. Siemann Gainsville, FL, USA; e-mail: siemadw@ufl.edu Michael Simoff Detroit, MI, USA; e-mail: [email protected] Richard Stephens London, UK; e-mail: [email protected] Timothy E. Schultheiss Duarte, CA, USA; e-mail: [email protected] Suresh Senan Amsterdam, The Netherlands; e-mail: [email protected] Yuta Shibamoto Nagoya , Japan; e-mail: [email protected] Stein Sundstrom Trondheim, Norway; e-mail: [email protected] Sigrid Stroobants Antwerp, Belgium; e-mail: [email protected] David J. Sugarbaker Boston, MA, USA; e-mail: [email protected] Robert Timmerman utsouthwestern.edu

Dallas,

TX,

USA;

e-mail:

robert.timmerman@

Jan Van Meerbeeck Ghent, Belgium; e-mail: [email protected] John Varlotto Hershey, PA, USA; e-mail: [email protected] Gregory Videtic Cleveland, OH, USA; e-mail: [email protected] Maria Werner-Wasik Philadelphia, PA, USA; e-mail: maria.werner-wasik@ mail.tju.edu Frank B. Zimmermann Basel, Switzerland; e-mail: [email protected]

Molecular Biology and Genetics of Lung Cancer Dusan Milanovic

Contents

12

Other Factors ...........................................................

12

13

Conclusion ................................................................

13

References..........................................................................

13

1

Introduction..............................................................

3

2

Genetical Changes Detected with Microarray.....

4

3

Nkx2.1 .......................................................................

5

Abstract

4

EML4-ALK ..............................................................

6

5

LKB 1........................................................................

7

6

c-MYC .......................................................................

7

7

KRAS ........................................................................

8

8

Bcl-2...........................................................................

9

9

MET ..........................................................................

10

10

EGFR ........................................................................

11

11

p53 .............................................................................

12

DNA Microarray technology allowed analysis of gene expression profile of lung cancer (NSCLC and SCLC). Better understanding of the molecular and biological basis of this disease has led to the identification of a number of druggable targets. In the last years, targeted therapies with small molecule kinase inhibitors showed promising clinical activity in lung carcinoma but after some period of time development of resistance was common event observed in patients treated with these drugs. There is an urgent need not only to clarify important molecular-biological mechanism 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 progression of this disease.

1

D. Milanovic (&) Department of Radiation Oncology, University Hospital Freiburg, Robert Koch Strasse 3, 79106 Freiburg, Germany e-mail: [email protected]

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.

B. Jeremic´ (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, DOI: 10.1007/174_2011_310, Ó Springer-Verlag Berlin Heidelberg 2011

3

4

2

D. Milanovic

Genetical Changes Detected with Microarray

To detect genetic changes in lung carcinoma single nucleotide polymorphism (SNP) arrays was performed 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 frequently 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 recurrent events. The most frequent genomic alteration in lung adenocarcinoma was a copy-number gain of chromosome 5p, which is found in 60% of total samples. The most significant focal deletions, detected in 3% of all samples, involve CDKN2A/CDKN2B, wellknown tumor suppressor genes localized on chromosome 9p21 which protein products inhibit Cdk4 and Cdk6 cyclin dependet kinases. Three additional deletions were also detected—deletions of the 50 untranslated 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) single-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 predicted inactivating changes in the tyrosine phosphatase domain indicating that PTPRD is one probable cancerassociated gene. The TP53 locus which is normaly mutated in *50% of lung adenocarcinomas in this data series shows no homozygous deletions. The amplification 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 amplification events) in chromosome 5p15 delineate a region containing ten genes including TERT. These results indicate that TERT may be the target of the amplification 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 adenocarcinoma. 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 protein is one NK2-related homeobox transcription factor. 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 terminal respiratory unit (TUR), which contain peripheral 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 characterized by cellular lineage. Nkx2.1 may be a candidate for ‘‘lineage-survival oncogene’’, which could explain ‘‘lineage-specific dependency’’ mechanism in carcinogenesis (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 interference (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 copies 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 survival in subgroup of patients with lung ADC (Berghmans et al. 2006). Eight studies were metaanalyzed and it has been observed that Nkx2.1 positivity 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 additional 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 identified Nkx2.1 as a candidate suppressor of malignant progression. In this mice model, low Nkx2.1 expression was characterized with high malignant and poorly-differentiated primary tumors. In non-metastatic 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-histopathological grades. In gain- and loss-of-function experiments in cells derived from metastatic to nonmetastatic 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 manipulation 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 activation 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, developed 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 disappearance 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 shrinkage 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 development 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


crizotinib pretreated and resistant cells, with other two structurally different ALK inhibitors, NVPTAE684 and AP26113, were highly active. Interestingly, 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, combination of EML4-ALK inhibitors with Hsp90 inhibitors, 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 adenosine 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 characterized 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 minimaldeleted 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) singlecopy 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 carcinoma, 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 experiments 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 disruption 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

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D. Milanovic

Fig. 1 Signaling pathways involved in the pathogenesis of lung carcinoma

Activation/Production Inhibition Mechanism unknown

DNA Damage HDM2

p21(ARF)

p16(INK4A)

p14(ARF)

Cell Cycle

p53

Cdk4/6:cyclin D RB:E2F

E2F

Telomerase

Gene Expression

MAPK

RTK

IGF

RTK

Growth Factors

PTEN Akt

PI3K

MEK

Raf

Rho

Rac

Ras

Myc:Mad Receptor

Neuropeptides

Myc:Max Cells

CAM ECM

Apoptosis 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 disease, 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

Bax Bcl-2

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 regenerating 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 prognosis. These authors conclude that MYC amplification 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 experiments should be performed specially concering its safety profile.

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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 proteins that translocate to the nucleus resulting in the transcription and cell proliferation (Vakiani and Solit 2011).


RAS can be activated by mutations in different tumor types. Approximately 20% of human tumors have activating point mutations in RAS (usually in codons 12, 13 and 61). About 85% of all RAS mutations are found in KRAS, 15% in NRAS and less than 1% in HRAS (Downward 2003). KRAS mutation is detected in 10–30% of lung adenocarcinomas, is very rarely found in other NSCLC form and is not present in SCLC. It has been found that TBK1, non-canonical IjB kinase, which activate antiapoptotic signals involving cREL and BCL-XL is essential for development of KRAS-driven lung tumors (Barbie et al. 2009). KRAS can induce IL-8 overexpression, one chemokine which plays important role in cell growth, tumor cells migration and angiogenesis (Sunaga et al. 2011). In 89 NSCLC surgical specimens IL-8 expression was significantly higher in male patients, smokers, elderly patients, in patients with pleural involvement and KRAS mutated adenocarcinomas. In one study, the relationship between KRAS amplification, detected by Fluorescence in situ hybridization and mutation was investigated in two cohorts of patients. In one cohort (538 Swiss patients) the prevalence of KRAS amplification was 13.7%; in other cohort (402 patients from New York) the prevalence of KRAS amplification was 15.1%. Patient with KRAS amplification had a larger, less-differentiated and aggressive tumors, with characteristic angiolymphatic invasion. Especially in adenocarcinoma subset harboring activating KRAS mutations, KRAS amplification was observed, suggesting a synergistic relationship 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 investigated in various clinical studies. Despite of conflicting results, a meta-analysis has revealed that RAS mutations may have some prognostic value for determination of a poor prognosis (Mascaux et al. 2005). On the other hand, one review data strongly suggests that KRAS mutations cannot be used as a factor which can predict response to conventional chemotherapy (Loriot et al. 2009). Because of its interaction with different crucial pathways involved in carcinogenesis, KRAS inhibition could represent an attractive therapeutic approach Table 1.

9 Table 1 Molecular abnormalities in lung cancer Frequency of Abnormality (%)a NSCLC

SCLC

Ras

25

\1

Akt

70–90

65

Myc

20–60

20–30

Growth Signals

EGFR

50

0–50

HER2/neu

30

30

c-Kit

30–40

50

Neuropeptides

*50

*50

IGF

*90

*90

RB

15–30

[90

p16(INK4A) inactivation

50–70

0–20

Tumor Suppressor Genes

3p deletions

70

90

FHIT inactivation

40–70

70

RASSF1A silencing

50

90

p53

40–50

60–75

Bcl-2

20–35

71

80–100

80–100

VEGF

75

75

COX-2

[70

Not reported

N-CAM, non-adhesive

not reported

90

Laminin-5 inactivation

20–60

65–85

Apoptosis

Replicative Potential Telomerase Angiogenesis

Metastasis

a

See text for selected references

8

Bcl-2

Bcl-2 is a member of Bcl-2 genes family which plays an important role in the regulation of apoptosis. Bcl-2 is encoded by BCL-2 gene which has been implicated in a different neoplastic disease including lung carcinoma. So far, 15 mammalian family members divided in three subfamilies were identified—Bcl-2, BAX and BH 3. Some of them act as proapoptotic (BAX and BH3 family members) some as antiapoptotic factors (Bcl-2 family members). The product of bcl-2 is a 26 kDa protein which is mainly located in

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D. Milanovic

the inner mitochondrial membrane. The most important 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.

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MET

c-MET is a proto-oncogene which encodes the tyrosine kinase receptor for HGF/SF1 (hepatocyte growth factor/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 vasculature. HGF/SF consists of six domains: an aminoterminal 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

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 responsible 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 embryological 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 fundamental 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; Matsumoto 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 overexpression (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 treatment. By approximately 50% of patients reason to


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 protooncogene. In this cell-line increased MET amplification (5–10 times) was observed and sequencing analysis 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 significantly effects ERBB3 and Akt phosphorylation. In contrast, gefitinib in combination with PHA-665752 completely suppressed ERBB3 and Akt phosphorylation in these cells, suggesting that observed resistance 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/erlotinibresistant tumor specimens. Notably, dual inhibition of Met/EGFR was investigated in an globally randomized, 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 promising strategy to treat lung cancer. This new therapeutic approach already reveals promising response in patients with lung carcinoma.

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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 transduction of malignant cell. Phosphorylated tyrosine residues play important role as a docking site for proteins SH2, Grb2 and Shc and enzymes such as phospholipase C, phosphatidylinositol-3 kinase (PI-3K) and the Src family kinases. These proteins are important for initiation of multiple intracellular signal transduction cascades that cause activation of many downstream pathways of EGFR such as ras/mitogenactivated protein kinase (MAPK), PI-3K/Akt and signal 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 respiratory bronchioles and alveoli and increased amounts of cells in the alveolar septae (Sibilia and Wagner 1995).

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EGFR is overexpressed in 50% of NSCLC; the highest rate (80%) is detected in squamous cell carcinoma (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 molecule 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 harboring 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 mutations in PIK3CA (Kawano et al. 2006), crosstalk between EGFR and insulin-like growth factor receptor 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 gefitinib resistance in NSCLC with wild-type EGFR. For some patients with EGFR mutations, treatment with small tyrosin kinase inhibitors represents a valuable 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 (Olivier 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 upregulated 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


frequently overexpressed in NSCLC (*70%) while in SCLC overexpression is not detected. Elevated COX2 protein levels and increased mRNA levels were associated with poor prognosis of patients with NSCLC (Wolff et al. 1998). Preclinical data showed that treatment 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 demonstrate 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 transcription, migration, angiogenesis, cell growth, proliferation, 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 extracellular 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 constitutively 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 cyclindependent kinases which are responsible for initiation of phosphorylation of the retinoblastoma tumor suppressor protein, RB, which is encoded by the RB1 gene located on chromosome 13q14.1–q14.2. RB1 expression 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 common 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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Molecular Biology and Genetics of Lung Cancer Michalopoulos GK, DeFrances MC (1997) Liver regeneration. Science 276:60–66 Millau JF, Bastien N, Drouin R (2008) P53 transcriptional activities: a general overview and some thoughts. Mutat Res 681:118–133 Mok TS, Wu YL, Thongprasert S et al (2009) Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361(10):947–957 Mulloy R, Ferrand A, Kim Y et al (2007) Epidermal growth factor receptor mutants from human lung cancers exhibit enhanced catalytic activity and increased sensitivity to gefitinib. Cancer Res 67(5):2325–2330 Nakamura T, Mizuno S, Matsumoto K et al (2000) Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF. J Clin Invest 106:1511–1519 Olivier M, Eeles R, Hollstein M et al (2002) The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat 19:607–614 Pao W, Miller V, Zakowski M, Doherty J et al (2004) EGF receptor gene mutations are common in lung cancers from ‘‘never smokers’’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101(36):13306–13311 Pelengaris S, Khan M, Evan G (2002) c-MYC: more than just a matter of life and death. Nat Rev Cancer 2:764–776 Pezzella F, Turley H, Kuzu I et al (1993) bcl-2 protein in nonsmall-cell lung carcinoma. N Engl J Med 329:690–694 Pratilas CA, Hanrahan AJ, Halilovic E et al (2008) Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res 68:9375–9383 Salgia R, Skarin AT (1998) Molecular abnormalities in lung cancer. J Clin Oncol 16:1207–1217 Sanchez-Cespedes M, Parrella P, Esteller M et al (2002) Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res 62:3659–3662 Schmidt C, Bladt F, Goedecke S et al (1995) Scatter factor/ hepatocyte growth factor is essential for liver development. Nature 373:699–702 Shaik MS, Chatterjee A, Jackson T et al (2006) Enhancement of antitumor activity of docetaxel by celecoxib in lung tumors. Int J Cancer 118:396–404 Sharma SV, Lee DY, Li B et al (2010) A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141:69–80 Shimizu E, Coxon A, Otterson GA et al (1994) RB protein status and clinical correlation from 171 cell lines representing lung cancer, extrapulmonary small cell carcinoma, and mesothelioma. Oncogene 9:2441–2448 Sibilia M, Wagner EF (1995) Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269:234–238 Soda M, Choi YL, Enomoto M, Takada S et al (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–566 Soda M, Takada S, Takeuchi K et al (2008) A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A 105:19893–19897 Sos ML, Koker M, Weir BA et al (2009) PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 69:3256–3261

15 Soucek L, Whitfield J, Martins CP et al (2008) Modelling Myc inhibition as a cancer therapy. Nature 455:679–683 Spigel DR, Ervin TJ, Ramlau R et al (2011) Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. J Clin Oncol 29:(suppl; abstr 7505) Sunaga N, Imai H, Shimizu K et al (2011) Oncogenic KRASinduced interleukin-8 overexpression promotes cell growth and migration and contributes to aggressive phenotypes of non-small cell lung cancer. Int J Cancer (Epub ahead of print: 4 May, 2011) Talbot SG, Estilo C, Maghami E et al (2005) Gene expression profiling allows distinction between primary and metastatic squamous cell carcinomas in the lung. Cancer Res 65: 3063–3071 Tanaka H, Yanagisawa K, Shinjo K et al (2007) Lineagespecific dependency of lung adenocarcinomas on the lung development regulator TTF-1. Cancer Res 67:6007–6011 Vakiani E, Solit DB (2011) KRAS and BRAF: drug targets and predictive biomarkers. J Pathol 223:219–229 Vennstrom B, Sheiness D, Zabielski J et al (1982) Isolation and characterization of c-myc, a cellular homolog of the oncogene (v-myc) of avian myelocytomatosis virus strain 29. J Virol 42:773–779 Voortman J, Lee JH, Killian JK et al (2010) Array comparative genomic hybridization-based characterization of genetic alterations in pulmonary neuroendocrine tumors. Proc Natl Acad Sci U S A 107(29):13040–13045 Wagner PL, Stiedl AC, Wilbertz T et al (2011) Frequency and clinicopathologic correlates of KRAS amplification in nonsmall cell lung carcinoma. Lung Cancer (Epub ahead of print: 7 Apr, 2011) Weir BA, Woo MS, Getz G et al (2007) Characterizing the cancer genome in lung adenocarcinoma. Nature 450: 893–398 Winslow MM, Dayton TL, Verhaak RG et al (2011) Suppression of lung adenocarcinoma progression by Nkx2-1. Nature 473:101–104 Wistuba I, Behrens C, Virmani AK et al (2000) High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res 60:1949–1960 Wolff H, Saukkonen K, Anttila S et al (1998) Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 58:4997–5001 Wong DW, Leung EL, So KK et al (2009) The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 115(8):1723–1733 Wu JY, Wu SG, Yang CH et al (2008) Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin Cancer Res 14:4877–4882 Yatabe Y, Mitsudomi T, Takahashi T (2002) TTF-1 expression in pulmonary adenocarcinomas. Am J Surg Pathol 26:767–773 Zhao X, Weir BA, LaFramboise T et al (2005) Homozygous deletions and chromosome amplifications in human lung carcinomas revealed by single nucleotide polymorphism array analysis. Cancer Res 65:5561–5570

Angiogenesis and Lung Cancer Wenyin Shi and Dietmar W. Siemann

Contents

Abstract

1

Introduction..............................................................

17

2

Angiogenesis .............................................................

18

3

Angiogenesis in Lung Cancer ................................

19

Anti-Angiogenic Therapy........................................ Drugs that Block Angiogenic Factors ...................... Drugs that Inhibit Endothelial Cell Function ........... Drugs that Block Breakdown of Extracellular Matrix.............................................. 4.4 Drugs that Target Survival Factors of Neovessels...

23 24 30 31 31

5

Vascular Disrupting Therapies ..............................

32

6

Conclusions ...............................................................

33

References..........................................................................

33

4 4.1 4.2 4.3

Lung cancer is one of the most frequent causes of cancer deaths worldwide. Current treatment regimens with conventional anticancer therapies offer only a limited survival benefit. There clearly exists a need for the development of new therapeutic strategies. Recent evidence suggests that angiogenesis is critical to lung cancer progression and related to poor prognosis. Consequently tumor angiogenesis, a process that features an imbalance between pro and antiangiogenic mediators, is being targeted by novel therapies in the treatment of lung cancer. A variety of therapeutic approaches and agents have been developed to compromise the growth and/or function of tumor vasculature. In October 2006, bevacizumab was the first antiangiogenic agent approved by the US Food and Drug Administration for the treatment of advanced, nonsquamous, nonsmall cell lung cancer in combination with platinum-based chemotherapy. Other antiangiogenic agents are actively being evaluated in pre-clinical and clinical settings.

1 W. Shi (&) Department of Radiation Oncology, Thomas Jefferson University, 111 S 11 ST Suite G301, Philadelphia, PA 19107, USA e-mail: [email protected] D. W. Siemann Department of Radiation Oncology, Shands Cancer Center, University of Florida, Gainesville, FL 32610, USA

Introduction

Lung cancer is a significant public health problem in the United States and the world. In the United States, lung cancer ranks as the second most common cancer among both men and women. In 2010, an estimated 222,520 new cases of lung cancer were diagnosed in the United States; a number representing approximately 14.6% of all new cancers diagnosed. Lung cancer is the most common cause of cancer-related deaths in both female and male, accounting for


17

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 histologic classification schemes (WHO 1979), there are four primary pathological types of lung cancer: smallcell carcinoma, squamous-cell carcinoma, adenocarcinoma and large-cell carcinoma. However, for therapeutic purposes, lung cancer is generally divided into small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC) with the latter representing approximately 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 Hermes 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 presence 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 development of novel therapeutic strategies for this disease. In October 2006, the anti-angiogenic agent bevacizumab 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 development and formation of new blood vessels from a preexisting 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 reproduction 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 compromises or halts the expansion of a tumor cell population. 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 endothelial cells. While tightly controlled under normal physiological conditions, this rigid control is absent in angiogenesis associated with tumors. Indeed alterations of the expression and/or function of pro-angiogenic 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 quiescence and stability while Ang-2/Tie-2 association allows for vessel plasticity and destabilization (Papapetropoulos 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 endothelial cells. These include platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF/ FGF-2), acidic fibroblast growth factor (aFGF/FGF1), 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 factorb (TGF-b), tumor necrosis factor-a (TNF-a), granulocyte 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 Benjamin 2003). Tumor angiogenesis is a complex, wellorchestrated, 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 endothelial cells (Holash et al. 1999). The vascular basement membrane and extracellular matrix surround existing capillaries are then degraded by proteases produced by tumor cells (Werb et al. 1999). Subsequently, endothelial cells proliferate, invade the surround 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 distant metastases (Folkman 1971, 1990b). Unlike blood vessels in normal tissue, tumor-associated vasculature is irregular and unstable, likely due to the over-production 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 dependent 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 angiogenic 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

Anti-angiogenic Factors

Vascular endothelial growth factor (VEGF-A, B, C, D, E)

Angiostatin

Placental growth factor

Endostatin

Platelet-derived growth factor (PDGF)

Vasostatin

Basic fibroblast growth factor (bFGF/FGF-2)

Thrombospondin-1 and internal fragment

Acidic fibroblast growth factor (aFGF/FGF-1)

Vascular endothelial growth factor inhibitor

Fibroblast growth factor-3 (FGF-3/int-2)

Fragment of platelet factor-4

Fibroblast growth factor-4 (FGF-4/hst/K-FGF)

Derivative of prolactin

Hepatocyte growth factor/Scatter factor (HGF/SF)

Restin

Transforming growth factor-a (TGF-a)

Proliferin-related protein

Transforming growth factor-b (TGF-b)

SPARC cleavage product

Tumor necrosis factor-a (TNF-a)

Osteopontin cleavage product

Granulocyte colony stimulating factor

Interferon-a, Interferon-b

Interleukin-8

METH-1, METH-2

Pleiotropin

Angiopoietin-2

Angiogenin

Antithrombin III fragment

Proliferin

Interferon-inducible protein-10

Matrix metalloproteinases (MMPs)

Tissue inhibitors of metalloproteinases (TIMPs)

Angiopoietin-2

Prolactin

Prostaglandin E1 and E2

Interleukin 1, 6, 12

Thymidine phosphorylase (TP)

VEGF soluble receptor

Platelet-derived endothelial cell growth factor (PD-ECGF)

Dll4

Intergrin Ephrin

Typically, angiogenesis in tumors has been assessed indirectly by determining intratumoral microvessel 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 criteria 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 concentration of blood vessels, referred to as ‘hot spots’. While there is evidence, accumulated over the past 10 years, that correlates this parameter with angiogenic growth factor expression, tumor growth and the occurrence of distant metastases (Weidner et al. 1993;

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 gastric 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


(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 radiotherapy 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; Macluskey 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. Interestingly, 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 circumstance MVD is unlikely to be of prognostic utility. 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 particularly 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 expression, it is also possible to measure VEGF concentrations 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 handled, 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 utilizing VEGF associated measurements as markers of tumor growth and/or response to therapy remains an area of intense interest, particularly for those therapies that target the VEGF pathway (Drevs 2003; Mihaylova et al. 2007; Dalaveris et al. 2009; Carrillode Santa Pau et al. 2010). Basic FGF is another potent stimulator of angiogenesis 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 conflicting 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 (Abdelrahim et al. 2010; Dudek et al. 2010; Gordon et al. 2010). Finally, a range of non-invasive imaging technologies 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 vasculature, 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


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 measurements 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 changes 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 treatment (Batchelor et al. 2007; Jain et al. 2009). However, high molecular weight contrast agents are not yet readily available clinically, and the BOLD contrast method is dependent on the field gradient used, making both comparisons between measurements made on different MR machines and serial measurements difficult. DCE-MRI using Gd-DTPA is becoming increasingly widespread in microcirculation 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 characteristics 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


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 assessment of tumor vasculature include 15O labeled water for measurement of blood flow, and 11C labeled carbon monoxide for measurement of blood volume (Hoekstra et al. 2002). Although the resolution obtained with PET is poorer compared with DCEMRI 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 feasible 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 capillaries mean that flow in these vessels is not measured 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 biological activities, these strategies can be categorized into several broad classes. One class of agents specifically 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 receptors. A second class of agents includes those designed to inhibit endothelial cell function, such as thalidomide 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 supply, 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 circulating 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 combined 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

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 compared 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. Bevacizumab 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 respectively, 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 bevacizumab group and 9.7% for the high-dose bevacizumab 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 chemotherapy 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 combination 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


(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 bevacizumab 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), neutropenia, and febrile neutropenia were more common among the patients who received bevacizumab. The study concluded that the combination of chemotherapy plus bevacizumab increased the response rate and progression-free survival of patients with NSCLC. With respect to overall survival the benefits of bevacizumab 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 maintenance setting in the management of NSCLC. The ATLAS phase III trial compared bevacizumab with or without erlotinib after completion of a first-line chemotherapy 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. Secondline patients received either bevacizumab with singleagent chemotherapy or erlotinib at physician’s discretion as well. For 106 patients, no grade C2 central nervous system hemorrhages were reported; two

25

grade 5 events were observed but both were pulmonary 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 chemotherapy 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 accompanying 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). Hypertension, 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 survival and progression-free survival in only one study (Hurwitz et al. 2010). The predictive value of bevacizumab-induced hypertension might not extend to all cancers or all treatment regimens. The measurement 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 treatment (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 maintenance for up to 1 year in patients with extensivestage 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 etopside-cisplatin alone. In another multicenter phase II trial, patients with extensive SCLC received irinotecan, carboplatin, and bevacizumab. Patients who had no progression also received maintenance bevacizumab (Spigel et al. 2009). The objective responsive 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 chemotherapy alone. Another recent trial from the Hoosier 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 bevacizumab 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


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 tracheoesophageal fistula, decreased cardiac ejection fraction, cerebral ischemia, and reversible posterior leukoencephalopathy. 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 extracellular 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 secondline 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 inhibiting the activation of the receptor and subsequent


27

Table 2 Tyrosine kinase inhibitors and their targets TKI

VEGFR1

Vandetanib

VEGFR2

VEGFR3

+

+

PDGFR

EGFR

KIT

+

Other RET

Cediranib

+

+

+

+

+

Sorafenib

+

+

+

+

+

RAF, FLT3

Sunitinib

+

+

+

+

+

FLT3, RET

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 anilinoquinazoline that inhibits VEGFR1, VEGFR2, VEGFR3, 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 vandetanib were tested with docetaxel compared with docetaxel alone in NSCLC patients previously treated with platinum-based chemotherapy. The progressionfree 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

+

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 pemetrexed also increased the incidence of some adverse events, including rash, diarrhea, and hypertension, while showing a reduced incidence of nausea, vomiting, 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 placebo 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 randomized 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 vandetanib 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 analysis. The trial concluded that in patients with previously 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 Pharmaceuticals Corporation, West Haven, CT) is a raf and VEGFR inhibitor with activity against PDGFR and KIT. It has proven activities in renal cell carcinoma and hepatocellular carcinoma (Escudier et al. 2007; Rimassa and Santoro 2009). In the phase III ESCAPE trial, which randomize patients to carboplatin 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 carcinoma patients (Scagliotti et al. 2010). A large phase II trial, E2501, enrolled more than 300 patients and compared sorafenib with placebo in patients with


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 placebo. 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 Kollmannsberger 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). Treatment 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 VEGFR, 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


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 (Polverino 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 bevacizumab plus carboplatin and paclitaxel was estimated 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, Philadephia) 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 pazopanib monotherapy in patients with operable stage I/ II NSCLC. Patients scheduled for resection received oral pazopanib 800 mg/d for 2–6 weeks preoperatively. 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, validating target-specific response and indicating a persistent pazopanib effect on lung cancer tissue. Further clinical evaluation of pazopanib in NSCLC is planned (Altorki et al. 2010). BIBF1120 (Vargatef, Boehringer-Ingelheim, Ingelheim, 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 difference between treatment arms. Median overall survival (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 VEGFreceptor mRNA are also under development. Preclinical studies with these constructs induced inhibition 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, thalidomide 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 survival was 3.6 years (Dudek et al. 2009). Unfortunately, in a large randomized double-blind placebocontrolled 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 extensive-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 (Kalmadi 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 extensivestage SCLC (NCT00537511). Cyclooxygenase 2 (COX2), an enzyme that is involved in prostaglandin synthesis, is frequently upregulated in NSCLC, and may be a marker of worse prognosis (Dannenberg et al. 2001). It also may promote 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 demonstration of the potential benefit of such combinations awaits randomized trials. Another phase II trial evaluated celecoxib in combination with paclitaxel, carboplatin, 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 predetermined goal of 80% overall response rate. In unselected patients, the addition of celecoxib to concurrent chemoradiotherapy with inoperable stage IIIA/B NSCLC


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 compared 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 apricoxib 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 markedly suppressed by systemic endostatin therapy. At a dose of 20 mg/kg once daily, there was almost complete regression of established primary tumors (O’Reilly et al. 1997). However, in patients, no clinical responses were observed (Thomas et al. 2003). A few patients did demonstrate changes in their dynamic CT scans suggestive of a decline in microvessel 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 antitumor 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 inhibitor that blocks the growth of new blood vessels by inhibiting methionine aminopeptidase, 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, particularly 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 endopeptideases 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). Unfortunately, clinical outcomes with these agents have been large and very disappointing. Marimastat was the first orally administrated synthetic 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 appearance 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 completing the cytotoxic therapy, patients were randomized to receive placebo or marimastat. The results

31

showed no significant difference in survival (Shepherd 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 randomized study of induction platinum-based chemotherapy 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 survival in patients with unresectable stage III NSCLC. This study does not support the use of shark cartilage-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 NCICanada-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 survival with VEGF being perhaps the most notable. Indeed it is now recognized that anti-VEGF therapeutic 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 endothelial 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, differentiation, 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 extracellular 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 considered 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 apoptosis of activated endothelial cells. Consequently, these agents block endothelial tube formation and angiogenesis in tumors (Brooks et al. 1994). Cilengitide (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 compromise 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 disrupting agents and their therapeutic application may be broadly divided into two categories: biological agents and small molecule drugs. Biological approaches include targeted gene therapy, antibodies to neovascular antigens, and fusion proteins targeting specific endothelial cell receptors. Although investigations utilizing these approaches have, to date, been confined to preclinical investigations, encouraging results have been reported. For

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 tumorassociated vasculature to toxins or pro-coagulant/proapoptotic effector molecules that can induce endothelial 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 therapeutic 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 TNFa (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 evaluated 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 firstline therapy and the second (ATTRACT-2) as secondline therapy (McKeage et al. 2009). Both combinations 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


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 tubulinbinding 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 ischemic 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. Doselimiting 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, MN029, and BNC105 are in early clinical trial development (Siemann 2011). Optimal treatment strategies with agents that damage the existing tumor vessel network will ultimately likely combine such therapeutics with conventional therapies including radiotherapy and chemotherapy for maximum treatment effect (Siemann 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 antiangiogenic strategies. Evidence suggests that antiangiogenic agents may be especially well suited for micrometastatic disease or early-stage cancer (Lozonschi 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 antiangiogenic therapy, providing hope that similar benefits may be seen in other tumor types including lung cancer. Ultimately, such endeavors are likely to incorporate both anti-angiogenic and vascular disrupting strategies in combination with conventional anti-cancer measurements.

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Interventional Pulmonology Branislav Perin, Bojan Zaric´, and Heinrich D. Becker

Contents

Abstract 46

1 Introduction.............................................................. 1.1 Diagnostic Interventional Pulmonology Techniques ................................................................. 1.2 Therapeutic Interventional Pulmonology Techniques .................................................................

48

References..........................................................................

52

B. Perin (&) B. Zaric´ Institute for Pulmonary Diseases of Vojvodina, Clinic for Pulmonary Oncology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia e-mail: [email protected] H. D. Becker Department for Interdisciplinary Endoscopy, Thoraxklinik, Heidelberg, Germany

46

Interventional pulmonology is relatively new field within pulmonary medicine focused on use of advanced bronchoscopy methods and interventional techniques in diagnosis and therapy of respiratory diseases. Various respiratory disorders may result in central airway obstruction (CAO), and central airway obstruction can cause significant 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 composed of interventional pulmonologists, thoracic surgeons, pulmonologists, oncologists, anesthesiologists and radiologists. Evaluation of procedures and their efficacy is extremely difficult; randomization 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 hand all of the patients are critically ill and randomization in this case is unethical. That is the reason why the majority of studies are retrospective analyses. One thing is for certain—the use of novel technology and interventional procedures leads to improvement in survival and quality of life of patients with CAO.


45

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B. Perin et al.

The primary question is no more ‘‘Is therapy helpful?’’ but ‘‘Which therapy is best for particular patient?’’.

1

Introduction

In recent years interventional pulmonology techniques have found their place in the palliative treatment of lung cancer invading central airways (trachea and principal bronchi). The curative effect of interventional 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 diagnostic and therapeutical. Diagnostic interventional techniques, among others are: autofluorescence bronchoscopy (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. Therapeutical 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, electrocautery (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 emission tomography, endobronchial ultrasound and autofluorescence 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,

electrocautery, argon plasma coagulation and placement of tracheobronchial stents. Other therapeutic interventions can proceed, after the initial treatment and re-opening of the airway. Interventional pulmonology 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 considered as a potentially fatal one. Adequate bronchoscopic evaluation can offer appropriate indication for imminent interventional technique for rapid airway desobstruction. Interventional pulmonology techniques are extremely expensive and they should be available only to the top respiratory institutions. Deployment of these techniques requires a multidisciplinary team of interventional pulmonologists, anesthesiologists, thoracic surgeons, radiologists and oncologists. Institutions where interventional techniques 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 bronchoscopy designed for thorough examination of bronchial mucosa. The integration of autofluorescence and videobronchoscopy provides clear images of normal and pathologically altered bronchial mucosa. Major indications 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 follow-up after surgical resection, this tool might be more often used by bronchoscopists. Sharp learning curve and clear designation between healthy and pathologically 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

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overcome with the appearance of new and improved technologies in autofluorescence such as: addition of backscattered light analysis, ultraviolet spectra, fluorescence-reflectance or dual digital systems. Quantitative 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), SAFE3,000 (Pentax Co, Japan), D-Light AF system (Karl Storz, Tuttlingen, Germany) or Onco-LIFE (Xillix Technologies Corp. Richmond, Canada), produce clear, high-quality images of bronchial mucosa. Images generated by the new systems are easy to interpret and characteristic. In the mentioned systems autofluorescence 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).

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 magnifying 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 nonmalignant 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 inexperienced bronchoscopist. It is believed that the combination of NBI with autofluorescence videobronchoscopy will give even better results in lung cancer detection.

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 videobronchoscopy 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 bronchial 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

1.1.3 Endobronchial Ultrasound There are currently two major types of endobronchial 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 bronchoscopist 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 necessary 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 irreplaceable for the assessment of bronchial wall in early-stage lung cancer.

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Fig. 1 White light videobronchoscopy image of the tumor in the distal part of intermediary bronchus

Fig. 2 Autofluorescence imaging (AFI) videobronchoscopy image of the tumor in the distal part of intermediary bronchus

Comparative images of white light videobronchoscopy, AFI, NBI and radial EBUS on the same lesion are presented in Figs. 1, 2, 3, 4.

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 (neodymium: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 obstruction due to intraluminal growth of malignant or benign tissue. Lesions most suitable for laser resections 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

1.1.4

Novel Diagnostic Techniques in Interventional Pulmonology There are several newly developed techniques that entered the arena of diagnostic interventional pulmonology in the last years. Electromagnetic navigation (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 fluorescence 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


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

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lesion is advisable. Laser re-section is usually performed 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-operatively, 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 current leaves the body through a grounding plate, usually 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 penetration and spray—for surface haemostasis. Indications 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

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common indication for its use. Absolute contraindications 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 performed 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 tracheobronchial 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 correlates with histologic tissue damage effect on the targeted tissue. Possible complications of EC include airway perforation, 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 noncontact 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.

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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 recommendable. 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 hemoptysis 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 posttransplantation benign tracheobronchial stenosis. There are no absolute contraindications for APC use, except for extraluminal disease. Relative contraindications 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 avoided. 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


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 settings 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 compression from tumors or enlarged lymphnodes, (2) stabilizing airway patency after removal of endobronchial malignancy, (3) sealing of tracheo-oesophageal fistulas and (4) treatment of benign central airway obstruction. Tracheobronchial stents are divided 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

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of the airway, serious bleeding and trauma. Confirmation 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 biologically 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 successfully used for the treatment of post-intubation or posttransplantation stenoses or as an introductory technique in the treatment of malignant obstruction before stenting. 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 endoscopically 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.

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1.2.2.2 Endobronchial Brachytherapy Endobronchial brachytherapy (EBBT) allows application 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 interventional 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 bronchial obstruction is urgent, EBBT can safely follow laser resection, electrocautery or argon plasma coagulation. Palliative effect of EBBT is recognized in majority of the studies that investigated its effect on dyspnea, cough, post obstructive pneumonia, hemoptysis and other symptoms of lung cancer. In recent studies HDR EBBT was used for treatment of earlystage lung cancer and benign central airway obstruction. 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

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late complications of HDR EBBT. While early studies showed small percentage of complications, latter studies revealed more frequent complications, especially hemoptysis. Usually reported complication rate is less than 5%, however, in some studies complications 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 extremely 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

Abstract

Introduction..............................................................

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2 Adenocarcinoma ...................................................... 2.1 Background ................................................................ 2.2 Bronchioloalveolar Carcinoma, Adenocarcinoma in situ and Minimally Invasive Adenocarcinoma .... 2.3 ‘‘Mixed Subtype’’ Adenocarcinoma ......................... 2.4 Mucinous Adenocarcinomas ..................................... 2.5 Adenocarcinoma Conclusions and Areas in Need of Further Study ........................................................

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3

Squamous Cell Carcinoma .....................................

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4

Molecular Testing in Lung Cancer .......................

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5

Pathology of Lung Carcinomas Treated With Radiation and/or Neo-adjuvant Therapy .............

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References..........................................................................

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1

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 classification 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.

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1 M. B. Beasley (&) Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10128, USA e-mail: [email protected]

Introduction

Multiple subtypes of lung carcinoma have always existed from a pathologic standpoint, and the current World Health Organization (WHO) classification is


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Table 1 2004 World Health Organization classification of pulmonary malignant epithelial tumors (Travis et al. 2004) Pre-invasive lesions Squamous cell carcinoma in situ Atypical adenomatous hyperplasia Diffuse idiopathic neuroendocrine cell hyperplasia Squamous cell carcinoma Variants-papillary, clear cell, small cell, basaloid Adenocarcinoma Adenocarcinoma, mixed type Acinar adenocarcinoma Papillary adenocarcinoma Bronchioloalveolar carcinoma Non-mucinous Mucinous Mixed Solid adenocarcinoma with mucin production Variants Fetal adenocarcinoma Mucinous ‘‘colloid’’ carcinoma Mucinous cystadenocarcinoma Signet ring cell adenocarcinoma Clear cell adenocarcinoma Small-cell carcinoma

carcinoma, with clinicians primarily being concerned with whether a carcinoma was small-cell carcinoma (SCLC) or non-small-cell carcinoma (NSCLC), the later typically comprising squamous cell carcinoma (SCC), adenocarcinoma (ADC) and large cell carcinoma. This clinical grouping has traditionally existed as treatment for SCLC differed from that of NSCLC, but did not differ significantly among the subtypes of NSCLC (Travis et al. 2004; Beasley et al. 2005; Lim et al. 2008). The advent of expanded chemotherapeutic options and targeted therapies has shifted this paradigm and placed a greater role on the pathologist in regard to accurate subtyping of tumors as well as molecular testing (Pirker et al. 2010; Travis et al. 2011). Clearly, the variety of malignant lung tumors is myriad; however, the scope of this article will focus on the evolving issues involving the most commonly encountered tumors, namely adenocarcinoma and squamous cell carcinoma, with particular focus on adenocarcinoma. Practical issues regarding tumor diagnosis and molecular testing as they pertain to specimens obtained from interventional radiologists will also be discussed. The chapter will end with a brief discussion of the histologic features encountered in tumors which have undergone pre-operative or neo-adjuvant therapy.

Combined small-cell carcinoma Large-cell carcinoma

2

Adenocarcinoma

2.1

Background

Large-cell neuroendocrine carcinoma Combined large-cell neuroendocrine carcinoma Other variants-basaloid carcinoma, lymphoepithelioma-like carcinoma, clear cell carcinoma, large-cell carcinoma with rhabdoid phenotype Adenosquamous carcinoma Sarcomatoid carcinoma Variants-pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and pulmonary blastoma Carcinoid tumor Typical carcinoid Atypical carcinoid Salivary gland tumors—mucoepidermoid carcinoma, adenoid cystic carcinoma, epithelial-myoepithelial carcinoma

presented in Table 1 (Travis et al. 2004). In spite of this, the role of the pathologist has traditionally been relatively limited in the management of lung

Adenocarcinoma now represents the most common subtype of lung carcinoma. The current WHO classification divides adenocarcinoma into acinar, papillary, bronchioloalveolar and solid types, along with several other variants including mucinous carcinomas. The WHO classification also includes a category of ‘‘mixed type adenocarcinoma’’ which, given the known histologic heterogeneity of lung carcinomas, encompasses up to 90% of all lung adenocarcinomas and thus provides minimal information of clinical relevance (Travis et al. 2004). As such, a new classification of adenocarcinoma was recently proposed jointly by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS) and the European Respiratory Society (ERS). This new classification scheme, which will be referred to as the ‘‘IASLC classification’’ in this text,

Pathology of Lung Cancer Table 2 IASLC/ATS/ERS (Travis et al. 2011)

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classification

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 Invasive adenocarcinoma Lepidic predominant (formerly non-mucinous BAC pattern with [5 mm of invasion)

Fig. 1 Adenocarcinoma with non-mucinous lepidic growth (H and E 2009). Non-mucinous tumor cells grow along preexisting alveolar septa. Tumors consisting purely of this growth pattern are classified as adenocarcinoma in situ in the IASLC classification system

Acinar predominant Papillary predominant Micropapillary predominant Solid predominant with mucin production Variants Invasive mucinous adenocarcinoma (formerly mucinous bronchioloalveolar carcinoma) Colloid carcinoma Fetal (low and high grade) Enteric

is presented in Table 2 (Travis et al. 2011). The primary issues addressed by the new classification which differ significantly from the WHO classification are the issue of bronchioloalveolar carcinoma (BAC) and the heterogeneous nature of the ‘‘mixed subtype’’ of adenocarcinoma, and the issue of mucinous carcinomas of the lung. The classification also emphasizes the need to accurately discriminate between ADC and SCC and the importance of appropriate tissue management for molecular testing.

2.2

Bronchioloalveolar Carcinoma, Adenocarcinoma in situ and Minimally Invasive Adenocarcinoma

In the WHO classification, BAC is defined as an adenocarcinoma with pure lepidic growth without stromal, pleural or vascular invasion, and is divided

into non-mucinous and mucinous subtypes (Travis et al. 2004). The term ‘‘lepidic’’ refers to growth along pre-existing alveolar walls and derives from the greek word ‘‘lepis’’ meaning ‘‘scales’’. As strictly defined, isolated non-mucinous BAC generally appears as a ground glass lesion radiographically and is associated with a nearly 100% 5-year survival, as first noted by Noguchi et al. (1995) and subsequently supported by other studies (Suzuki et al. 2002, Sakurai et al. 2004a; Borczuk et al. 2009). The BAC terminology has unfortunately been inappropriately applied by pathologists and clinicians alike, which has led to much confusion in the literature. In an attempt to emphasize the strict definition and prognostic implications, the IASLC classification has proposed that the term ‘‘adenocarcinoma in situ (AIS)’’ be used for solitary lesions with pure lepidic growth (Fig. 1). The IASLC classification retains the current WHO definition for BAC but additionally emphasizes that papillary and micropapillary growth patterns, as well as significant intra-alveolar tumor cells should be absent (Travis et al. 2011). A second significant change in the IASLC classification is the addition of a category of ‘‘minimally invasive adenocarcinoma (MIA)’’. Several studies have evaluated the impact on survival of the amount of stromal invasion present in a tumor otherwise showing non-mucinous lepidic growth (Suzuki et al. 2002; Sakurai et al. 2004a, b; Yim et al. 2007;

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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 present, 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 because the majority of the research on these tumors 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 subtype 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 significant foci of invasion (Travis et al. 2004, 2011).

Fig. 2 Pulmonary adenocarcinoma with papillary morphology. Note the branching papillary structures with fibrovascular cores (H and E 2009)

2.3

Fig. 3 Pulmonary adenocarcinoma with micropapillary morphology, characterized by small free-floating tufts of tumor surrounding a fibrotic core (H and E 4009)

‘‘Mixed Subtype’’ Adenocarcinoma

Using the current WHO classification, up to 90% of all lung ADC fall into the category of ‘‘mixed subtype’’ (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 recommends that tumors with multiple growth patterns should be classified by the predominant growth pattern, 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.

The IASLC classification emphasizes that papillary and micropapillary growth are forms of invasive carcinoma, which is not always intuitive from a histologic 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

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(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 morphologically, but also on immunohistochemical and molecular 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 carcinoma (which would encompass most tumors previously 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 cystadenocarcinoma 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 correlated 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).

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M. B. Beasley

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 therapeutic 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 classification post-dates the 7th edition of the AJCC staging guidelines and this will need to be rectified. In particular, 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 poorlydifferentiated tumors, and it has become more critical to accurately separate SCC from ADC for optimal patient management. This is primarily due to treatment management in regard to chemotherapy. Patients with SCC should not receive the vascular endothelial growth factor (VEGF) inhibitor bevacizumab due to the increased risk of life-threatening hemorrhage (Cohen et al. 2007). Conversely, EGFR tyrosine kinase inhibitors such as erlotinib and gefitinib are primarily recommended for patients with advanced ADC harboring EGFR mutations, particularly those in exons 19 or 21 (Mitsudomi et al. 2005; Mok et al. 2009; Maemondo et al. 2010). Additionally, pemetrexed is recommended for patients with

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’’ histology (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 immunohistochemical 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 factor1 (TTF-1) and a mucin stain such as mucicarmine will resolve the majority of cases, although ultimately a small percentage will remain unclassifiable. A staining pattern of p63 positive, CK5/6 positive, TTF-1 negative and mucin negative supports a diagnosis 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 differentiation 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 treatment 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 mutations are generally unresponsive to these agents (Dacic 2008; Dacic et al. 2010). EML4-ALK translocations are also of particular interest as their presence is associated with response to crizotinib (Soda et al. 2007). Other mutations which are not frequently found in lung carcinomas but are of increasing clinical interest include BRAF and PIK3CA HER2, and MET, among others. While there has been some correlation with clinical features and certain histologic 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 cytology 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 radiologists 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, communication is particularly critical for fine needle aspirations. For needle aspiration cytology specimens, adequate material must be present in a cell block

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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 pathologist 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 requirements 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).

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(Fig. 6a, b). Typically a region of necrosis is surrounded by a rim of foamy macrophages and inflammatory 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 pretreatment 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).

References

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 macrophages (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 exhibiting 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

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Pathology of Lung Cancer Douillard JY, Shepherd FA et al (2010) Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 28(5):744–752 Finberg KE, Sequist LV et al (2007) Mucinous differentiation correlates with absence of EGFR mutation and presence of KRAS mutation in lung adenocarcinomas with bronchioloalveolar features. J Mol Diagn 9(3):320–326 Gillespie JW, Best CJ et al (2002) Evaluation of non-formalin tissue fixation for molecular profiling studies. Am J Pathol 160(2):449–457 Hata A, Katakami N et al (2010) Frequency of EGFR and KRAS mutations in Japanese patients with lung adenocarcinoma with features of the mucinous subtype of bronchioloalveolar carcinoma. J Thorac Oncol 5(8):1197–1200 Hoshi R, Tsuzuku M et al (2004) Micropapillary clusters in early-stage lung adenocarcinomas: a distinct cytologic sign of significantly poor prognosis. Cancer 102(2):81–86 Inamura K, Satoh Y et al (2005) Pulmonary adenocarcinomas with enteric differentiation: histologic and immunohistochemical characteristics compared with metastatic colorectal cancers and usual pulmonary adenocarcinomas. Am J Surg Pathol 29(5):660–665 Junker K, Thomas M et al (1997a) Tumour regression in nonsmall-cell lung cancer following neoadjuvant therapy. Histological assessment. J Cancer Res Clin Oncol 123(9):469–477 Junker K, Thomas M et al (1997b) [Regression grading of neoadjuvant non-small-cell lung carcinoma treatment]. Pathologe 18(2):131–140 Junker K, Langner K et al (2001) Grading of tumor regression in non-small cell lung cancer : morphology and prognosis. Chest 120(5):1584–1591 Kamiya K, Hayashi Y et al (2008) Histopathological features and prognostic significance of the micropapillary pattern in lung adenocarcinoma. Mod Pathol 21(8):992–1001 Kargi A, Gurel D et al (2007) The diagnostic value of TTF-1, CK 5/6, and p63 immunostaining in classification of lung carcinomas. Appl Immunohistochem Mol Morphol 15(4):415–420 Kawakami T, Nabeshima K et al (2007) Micropapillary pattern and grade of stromal invasion in pT1 adenocarcinoma of the lung: usefulness as prognostic factors. Mod Pathol 20(5):514–521 Kuroda N, Hamaguchi N et al (2006) Lung adenocarcinoma with a micropapillary pattern: a clinicopathological study of 25 cases. APMIS 114(5):381–385 Lim E, Goldstraw P et al (2008) Proceedings of the IASLC International Workshop on Advances in Pulmonary Neuroendocrine Tumors 2007. J Thorac Oncol 3(10):1194–1201 Liu-Jarin X, Stoopler MB et al (2003) Histologic assessment of non-small cell lung carcinoma after neoadjuvant therapy. Mod Pathol 16(11):1102–1108 Loo PS, Thomas SC et al (2010) Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens. J Thorac Oncol 5(4):442–447 Maemondo M, Inoue A et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362(25):2380–2388 Makimoto Y, Nabeshima K et al (2005) Micropapillary pattern: a distinct pathological marker to subclassify tumours with a significantly poor prognosis within small peripheral lung

61 adenocarcinoma (\/=20 mm) with mixed bronchioloalveolar and invasive subtypes (Noguchi’s type C tumours). Histopathology 46(6):677–684 Mitsudomi T, Kosaka T et al (2005) Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 23(11): 2513–2520 Mitsudomi T, Morita S et al (2010) Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11(2):121–128 Miyoshi T, Satoh Y et al (2003) Early-stage lung adenocarcinomas with a micropapillary pattern, a distinct pathologic marker for a significantly poor prognosis. Am J Surg Pathol 27(1):101–109 Mok TS, Wu YL et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361(10):947–957 Nicholson AG, Gonzalez D et al (2010) Refining the diagnosis and EGFR status of non-small cell lung carcinoma in biopsy and cytologic material, using a panel of mucin staining, TTF-1, cytokeratin 5/6, and P63, and EGFR mutation analysis. J Thorac Oncol 5(4):436–441 Noguchi M, Morikawa A et al (1995) Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer 75(12):2844–2852 Pirker R, Herth FJ et al (2010) Consensus for EGFR mutation testing in non-small cell lung cancer: results from a European workshop. J Thorac Oncol 5(10):1706–1713 Rekhtman N, Brandt SM et al (2011) Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung carcinoma: high accuracy of tumor subtyping and feasibility of EGFR and KRAS molecular testing. J Thorac Oncol 6(3):451–458 Rodig SJ, Mino-Kenudson M et al (2009) Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 15(16):5216–5223 Rossi G, Murer B et al (2004) Primary mucinous (so-called colloid) carcinomas of the lung: a clinicopathologic and immunohistochemical study with special reference to CDX-2 homeobox gene and MUC2 expression. Am J Surg Pathol 28(4):442–452 Sakurai H, Dobashi Y et al (2004a) Bronchioloalveolar carcinoma of the lung 3 centimeters or less in diameter: a prognostic assessment. Ann Thorac Surg 78(5):1728–1733 Sakurai H, Maeshima A et al (2004b) Grade of stromal invasion in small adenocarcinoma of the lung: histopathological minimal invasion and prognosis. Am J Surg Pathol 28(2):198–206 Sartori G, Cavazza A et al (2009) EGFR and K-ras mutations along the spectrum of pulmonary epithelial tumors of the lung and elaboration of a combined clinicopathologic and molecular scoring system to predict clinical responsiveness to EGFR inhibitors. Am J Clin Pathol 131(4):478–489 Scagliotti GV, Parikh P et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage nonsmall-cell lung cancer. J Clin Oncol 26(21):3543–3551 Scagliotti G, Hanna N et al (2009a) The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist 14(3):253–263

62 Scagliotti GV, Park K et al (2009b) Survival without toxicity for cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemonaive patients with advanced non-small cell lung cancer: a risk-benefit analysis of a large phase III study. Eur J Cancer 45(13):2298–2303 Soda M, Choi YL et al (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448(7153):561–566 Srinivasan M, Sedmak D et al (2002) Effect of fixatives and tissue processing on the content and integrity of nucleic acids. Am J Pathol 161(6):1961–1971 Suzuki K, Asamura H et al (2002) ‘‘Early’’ peripheral lung cancer: prognostic significance of ground glass opacity on thin-section computed tomographic scan. Ann Thorac Surg 74(5):1635–1639 Terry J, Leung S et al (2010) Optimal immunohistochemical markers for distinguishing lung adenocarcinomas from

M. B. Beasley squamous cell carcinomas in small tumor samples. Am J Surg Pathol 34(12):1805–1811 Travis WD, Brambilla E et al (2004) Pathology and genetics: tumours of the lung, pleura, thymus and heart. IARC, Lyon Travis WD, Brambilla E et al (2011) International association for the study of lung cancer/american thoracic society/ european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 6(2):244–285 Wu M, Wang B et al (2003) p63 and TTF-1 immunostaining. A useful marker panel for distinguishing small cell carcinoma of lung from poorly differentiated squamous cell carcinoma of lung. Am J Clin Pathol 119(5):696–702 Yim J, Zhu LC et al (2007) Histologic features are important prognostic indicators in early stages lung adenocarcinomas. Mod Pathol 20(2):233–241

Radiologic Imaging of Lung Cancer Palmi Shah and James L. Mulshine

Contents

Abstract

1

Introduction..............................................................

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2

Overview ...................................................................

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3 3.1 3.2 3.3

Radiologic Imaging.................................................. Detection .................................................................... Staging ....................................................................... PostTherapy Imaging.................................................

64 64 68 72

4

Conclusions ...............................................................

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5

Future........................................................................

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References..........................................................................

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Recent advances in technology like faster, high resolution CT scanners, new data in lung cancer screening combined with many changes in the classification, staging and novel therapies for lung cancer are redefining the role imaging plays in detection, staging and management of the disease. This chapter describes the utility and limitations of the different radiological modalities in various stages of the disease. Since it is the mainstay in lung cancer management emphasis is placed on the application of CT imaging. PET-CT has been discussed separately in this volume.

1

P. Shah Department of Radiology, Rush University, Chicago, IL, USA J. L. Mulshine (&) Department of Internal Medicine, Rush University, Chicago, IL, USA e-mail: [email protected]

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 incidence 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 most commonly diagnosed cancer and the second leading cause of cancer death globally. It accounted for 13% (1.6 million) of the total cases and 18% (1.4 million) of the deaths in 2008 globally (Jemal et al. 2011). Lung cancer remains the leading cause of cancerrelated death in the United States.


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P. Shah and J. L. Mulshine

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 integrated 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.

these cancers and to introduce more immunohistochemical 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, appropriate 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.

2

3

Overview

The 2004 World health organization (WHO) (Travis et al. 2004) classification of primary lung tumors divided them by their light microscopy features intosmall-cell cancer and non-small-cell cancer (NSCLC). NSCLC includes adenocarcinoma including bronchioloalveolar cell carcinoma (BAC), squamous cell carcinoma and large cell carcinoma. A new pathological classification for adenocarcinomas 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 histologic subtyping to recognize the heterogeneity of

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 tissue. In this location detected cancers are more commonly adenocarcinomas. On radiographs the nodule may display a range of features including ill defined/spiculated margins or a thick-walled cavity. Squamous cancers more frequently are found centrally and often present as cavitating lesions. Eccentric or stippled calcification may be present, and this presentation is more common with adenocarcinomas. All other forms of calcification 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 processes 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, convexity of the mediastinum and splaying of the carina have been described. More advanced disease can present with rib/osseous 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

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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 comparative approaches (Henschke et al. 2010). Given the legacy of lung cancer screening, research into defining 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 mortality 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 proposed 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 sensitivity of CT scanners make them the primary modality for the initial evaluation of solitary pulmonary nodules, mediastinal or hilar masses. Sometimes lung cancers are detected on the incidental 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

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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 nodules 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


differentiation between benign and malignant nodules. 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 specificity 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 lobulated 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 additional 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, invasion 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 adenocarcinomas with bronchioloalveolar cell component or bronchioloalveolar carcinomas. These nodules may be purely groundglass in density (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).


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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).

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 component 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 followup (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 second 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

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 mediastinal 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/pneumonias 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 benefits 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 consolidation for greater 2 weeks may also be suggestive of the presence of neoplastic disease (Fig. 2). Endobronchial tumors may present as nondependant 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.

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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 important 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 consolidation in whom iodinated contrast is contraindicated. 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 brachial 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

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 comprehensive reevaluation effort and were revised to more accurately reflect survival in the different disease 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, smallcell 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 diaphragm, 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 multislice 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 Quantitative Imaging Biomarker Alliance. CT scans also play a big role in disease quantification and helps in the initial radiological staging of the tumor. Usually they are performed prior to bronchoscopy as detection of extensive disease may preclude the need for the same. They are also helpful in determining therapy options and help in treatment planning.


Accurate staging of the tumor is essential as therapeutic options depends on stage of the disease, in addition to the cell type and the clinical and functional 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 chemotherapy 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 combinations of radiotherapy and chemotherapy depending 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 noncontrast 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 detection 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 accurate 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.

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CECT or MRI may be necessary to accurately evaluate 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 erosions, 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

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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 carcinomatosis, 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


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 disease, 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 abdomen 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 iodinated 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 overwhelmingly 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).


Fig. 4 CECT showing left apical pancoast tumor with chest wall invasion, rib and vertebral body destruction

Although postcontrast head CT can detect intracranial 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 mediastinoscopy (Vansteenkiste et al. 2010). Esophageal ultrasonography (EUS) helps in visualization 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 guided tissue diagnosis, reported a pooled sensitivity of 90% and 94%, respectively, for CT-enlarged or PETpositive mediastinal lymph nodes with a prevalence of malignant N2/3 disease of 68% (Gu et al. 2009).

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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 brachial 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 progressively 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 alkaline 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

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with the residual postoperative lung function. Ventilation 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 frontrunner for more accurate radiologic staging in bulky primary lung cancer. This imaging tool can be frequently 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 suboptimal 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 examination 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 chemotherapy 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. Followup imaging after therapy, which may or may not include chemotherapy, radiation therapy and surgery,

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 acquisition 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, determine 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 rapidly advancing tailored therapy, while we slowly unlock the secrets of lung cancer development.


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PET/CT for Staging and Diagnosis of Lung Cancer Sigrid Stroobants

Contents

Abstract

Basic Principles and Technical Improvement ..... Tracers........................................................................ Conventional Versus Time-of-Flight (TOF)-PET .... Technical Advances in Hybrid Systems...................

75 76 76 76

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 .....................................................

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80

3 3.1 3.2 3.3

Staging of Non-Small Cell Lung Cancer .............. T-Staging.................................................................... N-Staging ................................................................... M-Staging ..................................................................

80 80 81 81

4

Small-Cell Lung Cancer .........................................

83

5

Implementation in Clinical Practice .....................

85

References..........................................................................

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1 1.1 1.2 1.3

Positron emission tomography (PET) is an imaging technique, which allows for accurate non-invasive measurements of metabolic pathways in tissues of man in vivo. The most frequently used tracer in PET oncology is the glucose analog 18F-fluoro-2deoxy-glucose (FDG). The preferential accumulation of FDG in neoplastic cells permits differentiation between benign and malignant tissue. The ability to perform whole-body imaging within one examination without increasing the radiation burden makes it an ideal technique to ‘‘screen’’ patients for cancer deposits. Also in thoracic oncology, FDG-PET has proven its superiority over other imaging techniques in staging nodal and metastatic disease. However, the poor anatomic detail of PET can lead to errors in 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.

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1

S. Stroobants (&) Department of Nuclear Medicine, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium e-mail: [email protected]

Basic Principles and Technical Improvement

Positron emission tomography (PET) is a functional imaging modality which uses small amounts of pharmaceuticals labeled with positron-emitting radioisotopes for metabolic imaging. Because of their similarity


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to naturally occurring atoms in the human body, positron emittors as carbon-11 (11C), nitrogen-13 (13N), and fluor-18 (18F) can be incorporated in biological molecules, without significantly influencing their physiological and biochemical interactions. This allows in vivo imaging of metabolic pathways and receptor– ligand interactions at pico-to-nanomolar sensitivities.

1.1

Tracers

Although, there are numerous PET tracers described in the literature, evidence of PET in oncology mainly rests upon the glucose analog 18F-fluoro-deoxyglucose (FDG), capitalizing that cancer has higher glucose metabolism than most tissues (Pauwels et al. 1998). Since PET relies on the detection of metabolic alterations observed in cancer cells, this examination yields data independently of associated structural characteristics. However, since FDG accumulation is not tumor specific but can also be present in inflammation, clinically relevant positive findings often require confirmation. While FDG has made the way for PET in oncology, clinical practice with other tracers is limited. In order to reduce tracer uptake in inflammatory tissue, more cancer-specific tracers were developed. The most promising one is probably 18F-fluoro-thymidine (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. (2010), FLT and FDG-PET were compared for primary staging of non-small cell lung cancer (NSCLC) in 31 patients. FDG proved to be more sensitive for detection of the primary tumor compared to FLT (94 vs. 74%) due to more intense trapping of the tracer (mean FDG-SUV = 7.7 vs. mean FLT-SUV = 4.2, p = 0.002). For nodal staging, FLT proved to be more specific (98 vs. 84%) but less sensitive (65 vs. 85%). Therefore, the role of FLT-PET for staging will be limited. More promising is its use for treatment response evaluation, especially after targeted therapy.

1.2

Conventional Versus Time-of-Flight (TOF)-PET

The biodistribution of the positron-emitting tracers is measured using a PET camera. Positron-emitting isotopes have an excess of protons and are, therefore,

unstable. They decay by emission of a positron, which is the subatomic, positively charged, antiparticle of the negatively charged electron. A positron transverses a short distance through the tissue (0.6 mm for 18F) until it combines with an electron in the surrounding media (annihilation). This generates a pair of photons which 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 pattern in the PET camera. Photons that simultaneously interact with these detectors are registered as decay events along a line-of-response (LOR). Based on these records, tomographic images of the regional radioactivity distribution are reconstructed (emission images). In conventional PET, the actual location where the annihilation occurred along the LOR is not measured, which inherently generates blurring in the reconstructed image. The availability of faster detectors and electronics allows to measure the time difference between detection of each photon pair. In TOF-PET this additional timing information is used to better localize the event within a small range along each LOR. The better localization of each event using TOF combined with more powerful reconstruction algorithms improves the image quality especially in larger patients (Kadrmas et al. 2009) (Fig. 1) . This leads to better lesion detection and results in faster acquisition times which makes a typically whole-body PET/CT feasible in 10–15 min.

1.3

Technical Advances in Hybrid Systems

Interpretation of PET scans is hampered by the lack of anatomical detail which makes it sometimes difficult to correctly localize hot spots or differentiate tumor tissue from benign structures with physiological highFDG uptake as seen in muscle, brown fat, gut or inflammation. These challenges are largely resolved by the introduction of the combined PET/CT scanner. Current designs comprise a CT scanner in tandem with a PET scanner with a common patient bed for both systems. Although the scanner appears externally as a single device, internally there is little or no mechanical integration. CT and PET images are acquired consecutively for the same axial extent with a simple horizontal translation of the bed. Upon completion of the scans, CT and PET images are co-registered with fusion software and can be viewed

PET/CT for Staging and Diagnosis of Lung Cancer

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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

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)

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

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 challenging since conventional PET detectors are based on relatively bulky photomultipliers (PMTs). PMTs are very sensitive even to weak-magnetic fields and are

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Fig. 2 Patient with extensive disease SCLC with multiple liver and bone metastasis on PET (a, b). A liver metastasis in the liver dome is erroneously regarded as a lung metastasis of fusion images (c) due to a breathing artifact resulting in

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misalignment between PET and CT. Therefore, when no anatomical correlate is seen on CT (d), adjacent slices should also be viewed to localize the lesion (e)

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/ PET scanner. In addition, its size would steal too much space from the open magnet bore if integrated

within an MRI scanner. Therefore alternative, new semiconductor-based light detectors, such as avalanche photodiodes (APDs) are replacing PMTs in


integrated MR/PET. In spring 2011, the first integrated 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-equipment costs and lower-throughput capabilities compared 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 cancer. 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. Characterization 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

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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 granulomatous 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

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(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 necessary 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 attenuation correction utilized (Boellaard 2009).

(Ashraf et al. 2011). Twenty of the 54 nodules proved to be malignant (mean diameter 13 mm). In a multivariable 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 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 findings 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 bronchoalveolar 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 positive 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-centimetric 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 negative 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

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 edition) 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 literature 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 complemented 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 assessment 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 surrounding 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).


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 specificity 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 dissemination. Since this is often caused by multiple very small pleural nodules beyond the resolution of a PET system, 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 negatives) 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

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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-centimeter 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 consecutive cohort of 159 patients. Factors associated with unforsceen N2 were central tumors, adenocarcinoma histology, PET/CT hilar N1 disease and CT mediastinal 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 mandatory 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 inflammatory 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 distant 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 scintigraphy) are far from perfect. A systemic relapse develops

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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

underwent thoracotomy. Final stage was pT2aN1M0. This case underlines the importance to always confirm PET positives nodes with histology

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 significantly 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 solitary extrathoracic PET findings that determine the

chances for radical therapy. In these patients, a confirmatory 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


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 performance characteristics in assessing bone metastases, with specificity, sensitivity, NPV, PPV and accuracy all exceeding 90%, though false-positive and falsenegative 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 fieldof-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 metastasis, 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

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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 procedures commonly used to stage the disease include chest and abdomen CT, brain CT or MRI, radionuclide 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 mediastinal 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 extensive versus limited-stage disease ranged between 89–100 and 78–95%, respectively. More recent studies confirm these data with change in stage classification 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

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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

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

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%).

While the results of PET staging are promising, we need larger prospective trials before definite conclusions 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 frequency of correct and incorrect staging changes when PET is added to conventional tests and link diagnostic


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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

limited to extensive disease was confirmed by biopsy of the hot spot of lesion in the left sacrum (d)

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).

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).

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 cancerspecific imaging of the entire patient in one single non-invasive test with a better accuracy than conventional imaging, thus with a potential impact on stage designation and therapeutic decision. Diagnosis and staging of lung cancer has become a truly multidisciplinary process involving imaging, endoscopic

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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 definite 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 inflammation. Therefore, clinically relevant FDG-avid mediastinal LNs should always be examined with the most appropriate tissue sampling technique.

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87 Niho S, Fujii H, Murakami K et al (2007) Detection of unsuspected distant metastases and/or regional nodes by FDG-PET in LD-SCLC scan in apparent limited-disease small-cell lung cancer. Lung Cancer 57:328–333 Nomori H, Watanabe K, Ohtsuka T et al (2004) Valuation of F-18 fluorodeoxyglucose (FDG) PET scanning for pulmonary nodules less than 3 cm in diameter, with special reference to the CT images. Lung Cancer 45:19–27 Pantel K, Izbicki J, Passlick B et al (1996) Frequency and prognostic significance of isolated tumour cells in bone marrow of patients with non-small cell lung cancer without overt metastases. Lancet 347:649–653 Pastorino U, Bellomi M, Landoni C et al (2003) Early lung cancer detection with spiral CT and positron emission tomography in heavy smokers: 2-year results. Lancet 362: 593–597 Pauwels EK, McCready VR, Stoot JH, van Deurzen DF (1998) The mechanism of accumulation of tumour-localising radiopharmaceuticals. Eur J Nucl Med 25:277–305 Pfannenberg AC, Aschoff P, Brechtel K et al (2007) Low dose non-enhanced CT versus standard dose contrast-enhanced CT in combined PET/CT protocols for staging and therapy planning in non-small cell lung cancer. Eur J Nucl Med Mol Imaging 34:36–44 Quint LE, Tummala S, Brisson LJ et al (1996) Distribution of distant metastases from newly diagnosed non- small cell lung cancer. Ann Thorac Surg 62:246–250 Rodriguez E, Lilenbaum RC (2010) Small cell lung cancer: past, present and future. Curr Oncol Rep 12:327–334 Sathekge MM, Maes A, Pottel H et al (2010) Dual time-point FDG PET-CT for differentiating benign from malignant solitary pulmonary nodules in a TB endemic area. S Afr Med J 100:598–601 Schaffler GJ, Wolf G, Schoellnast H et al (2004) Non-small cell lung cancer: evaluation of pleural abnormalities on CT scans with 18F FDG PET. Radiology 231:858–865 Schirrmeister H, Arslandemir C, Glatting G et al (2004) Omission of bone scanning according to staging guidelines leads to futile therapy in non-small cell lung cancer. Eur J Nucl Med Mol Imaging 31:964–968 Schlemmer HP, Pichler BJ, Krieg R et al (2009) An integrated MR/PET system: prospective applications. Abdom Imaging 34:668–674 Schrevens L, Lorent N, Dooms C et al (2004) The role of PET scan in diagnosis, staging, and management of non-small cell lung cancer. Oncologist 9:633–643 Shields AF, Grierson JR, Dohmen BM et al (1998) Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med 4:1334–1336 Shim SS, Lee KS, Kim BT et al (2005) Non-small cell lung cancer: prospective comparison of integrated FDG PET-CT and CT alone for preoperative staging. Radiology 236: 1011–1019 Shim SS, Lee KS, Kim BT et al (2006a) Focal parenchymal lung lesions showing a potential of false-positive and falsenegative interpretations on integrated PET/CT. AJR Am J Roentgenol 186(2):639–648 Shim SS, Lee KS, Kim BT et al (2006b) Integrated PET/CT and the dry pleural dissemination of peripheral adenocarcinoma of the lung: diagnostic implications. J Comput Assist Tomogr 30:70–76

88 Siegelman SS, Khouri N, Leo FP, Fishman EK et al (1986) Solitary pulmonary nodules: CT assessment. Radiology 160:307–312 Silvestri GA, Gould MK, Margolis ML et al (2007) Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines 132(Suppl 3): 178S–201S (2nd ed) Swensen SJ, Viggiano RW, Midthum DE et al (2000) Lung nodule enhancement at CT: multicenter study. Radiology 214:73–80 Swensen SJ, Jett JR, Hartman TE et al (2003) Lung cancer screening with CT: Mayo clinic experience. Radiology 226:756–761 Tan BB, Flaherty KR, Kazerooni EA et al (2003) The solitary pulmonary nodule. Chest 123(Suppl 1):89S–96S Ung YC, Maziak DE, Vanderveen JA et al (2007) 18Ffluorodeoxyglucose positron emission tomography in the diagnosis and staging of lung cancer: a systematic review. J Natl Cancer Inst 99:1753–1767

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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

1

Introduction..............................................................

89

2 2.1 2.2 2.3

Stage Classification and Determination ................ T-Stage....................................................................... N-Stage ...................................................................... M-Stage......................................................................

90 90 90 92

3 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9

Invasive Mediastinal Staging Modalities .............. Transthoracic Needle Biopsy .................................... Transbronchial Needle Biopsy .................................. Endobronchial Ultrasound......................................... Esophageal Endoscopic Ultrasound .......................... Cervical Mediastinoscopy ......................................... Mediastinotomy ......................................................... Extended Cervical Mediastinoscopy......................... Video-Assisted Thoracic Surgery ............................. Limitations of the Literature on Individual Mediastinal Staging Modalities.................................

93 93 93 94 94 94 95 95 95 95

4

Randomized Trials of Staging Algorithms ...........

96

5

Staging in the Community at Large .....................

97

6

General Recommendations .....................................

97

References..........................................................................

97

This chapter reviews surgical approaches to determining T, N, and M status for lung cancer; an expanded description of individual mediastinal staging modalities; the evidence for invasive mediastinal staging procedures and multi-modality staging strategies; and staging practices in the community at large.

Abbreviations

AJCC CT EBUS EUS IASLC UICC MRI NSCLC PET SCLC TBNBx TTNBx VATS

1 F. Farjah V. W. Rusch (&) Thoracic Surgery Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA e-mail: [email protected]

American Joint Committee on Cancer Computed tomography Endobronchial ultrasound Esophageal endoscopic ultrasound International Association for the Study of Lung Cancer International Union Against Cancer Magnetic resonance imaging Non-small cell lung cancer Positron emission tomography Small cell lung cancer Transbronchial needle biopsy Transthoracic needle biopsy Video-assisted thoracic surgery

Introduction

The purpose of lung cancer staging is to aid therapeutic decision-making and provide the patient with a prognosis. ‘‘Surgical staging’’ often refers to the combined information obtained from the clinical


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F. Farjah and V. W. Rusch

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 multimodality 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 predicting a unique prognosis (survival rate).

2.1

T-Stage

Determinants of T-stage include tumor size, location, sequelae of airway obstruction (atelectasis, pneumonitis, 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.

Methods for determining T-stage include computed 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 uncertainty over T-status. Endoscopic (esophageal) ultrasound (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 thoracoscopic (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 needle 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 treatment. 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 abnormal nodes on PET (Silvestri et al. 2007; Gould et al. 2003; Ettinger et al. 2010). The significance of understaging 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). Nevertheless, since practice guidelines recommend neoadjuvant 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 standardized 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 mediastinal 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


resources, such as a cytotechnologist who can be present to evaluate specimen quality during the procedure. 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 staging 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 evolving. 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 recommendation 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 pericardial 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 metastatic disease include a CT-guided biopsy, excisional/ incisional soft tissue biopsy, thoracentesis, VATS,


93

Table 1 Mediastinal lymph nodes accessible by individual staging modalities 2R

2L

Transthoracic needle biopsy

4R

4L

5

6

X

X

X

X

7

Transbronchial needle biopsy

X

X

X

Endobronchial ultrasound guided biopsy

X

X

X

Esophageal endoscopic ultrasound guided biopsy Cervical mediastinoscopy

X

X

X

X

X

X

Extended cervical mediastinoscopy

X

X

X

X

Video-assisted thoracoscopic node biopsy (right)

X

Mediastinotomy

Video-assisted thoracoscopic node biopsy (left)

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 evacuation of an effusion. A patient may require a thoracentesis 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). Performing 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 discovered 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 performed procedure where a portion of the pericardium is removed in addition to evacuation of fluid. This procedure may be performed either through a subxiphoid 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.

X

X

9R

X

X

9L

X X

X

X

X

X

X

X X

X

8

X X X

X X

3

Invasive Mediastinal Staging Modalities

3.1

Transthoracic Needle Biopsy

X

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 targeting. This outpatient procedure is performed in either an endoscopy suite or operating room. Challenges associated with sampling paratracheal nodes include knowing precisely where the nodes are with bronchoscopic 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 identified 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 populations. 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 performed using a special endoscope with either a radial

(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 prevalence 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 general 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 performed immediately prior to resection. Risks associated with mediastinoscopy among a series of 2,145 cases included bleeding (0.33%), vocal cord dysfunction (0.55%), tracheal injury (0.09%), pneumothorax (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 videoendoscope, 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


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 operator 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 procedure 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 mediastinoscope is passed into the mediastinum. The second 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 sensitivity 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 sensitivity 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 (Detterbeck 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 pretreatment 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 performance characteristics of individual staging modalities across studies. There are also significant differences in patient characteristics across investigations that make it difficult to compare results across studies, particularly with regard to the proportion of

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NSCLC and SCLC patients and prevalence of mediastinal nodes (Detterbeck et al. 2007). Another problem with the existing body of literature is the lack of a uniform reference standard. Surgery is often times regarded as the ‘‘gold standard’’ 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 intraoperative 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 important 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 competing 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 incorporating 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;

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 significantly higher in the mediastinoscopy group. Preliminary results from a different trial found that incorporating routine EUS into a conventional algorithm consisting of CT and selective TTNBx, TBNBx, and mediastinoscopy led to fewer unnecessary 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 ‘‘conventional’’ or ‘‘standard’’ staging algorithm based on local or national guidelines. Yet, the control algorithms varied significantly across studies suggesting


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, Epidemiology, 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 trimodality 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%).

6

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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 metastatic disease should have tissue confirmation of a cancer diagnosis and a referral to medical and radiation oncology. For cases where there is a plausible alternative explanation for what appears to be metastatic disease on CT/PET, invasive staging is indicated 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 mediastinal nodes when the primary tumor is an adenocarcinoma, 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. Mediastinoscopy, 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 determine resectability.

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98 lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 81:1013–1020 Al-Sarraf N, Aziz R, Gately K, Lucey J, Wilson L, McGovern E, Young V (2008) Pattern and predictors of occult mediastinal lymph node involvement in non-small cell lung cancer patients with negative mediastinal uptake on positron emission tomography. Eur J Cardiothorac Surg 33(1):104–109 American Joint Committee on Cancer (2010) AJCC Cancer Staging Manual, 7th edn. Springer, New York Annema JT, Van Meerbeeck JP, Rintoul RC, Dooms C, Deschepper E, Dekkers OM, De Leyn P, Braun J, Carroll NR, Praet M, de Ryck F, Vansteenkiste J, Vermassen F, Versteegh MI, Veseliç M, Nicholson AG, Rabe KF, Tournoy KG (2010) Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. J Am Med Assoc 304(20):2245–2252 Cangemi V, Volpino P, Drudi FM, D’Andrea N, Cangemi R, Piat G (1996) Assessment of the accuracy of diagnostic chest CT scanning. impact on lung cancer management. Int Surg 81(1):77–82 Cerfolio RJ, Bryant AS, Eloubeidi MA (2006) Routine mediastinoscopy and esophageal ultrasound fine-needle aspiration in patients with non-small cell lung cancer who are clinically N2 negative. a prospective study. Chest 130:1791–1795 CTCAE and National Cancer Institute (2006) Common terminology criteria for adverse events v.3.0. http://ctep.cancer. gov/forms/CTCAEv3.pdf. Accessed 2006 Cybulsky IJ, Bennett WF (1994) Mediastinoscopy as a routine outpatient procedure. Ann Thorac Surg 58:176–178 Darling GE, Allen MS, Decker PA, Ballman K, Malthaner RA, Inculet RI, Jones DR, McKenna RJ, Landreneau RJ, Putnam JB Jr (2010) Number of lymph nodes harvested from a mediastinal lymphadenectomy: results of the randomized, prospective ACOSOG Z0030 trial. doi: 10.1378/chest. 10-0859 De Giacomo T, Rendina EA, Venuta F, Della Rocca G, Ricci C (1997) Thoracoscopic staging of IIIB non-small cell lung cancer before neoadjuvant therapy. Ann Thorac Surg 64:1409–1411 Defranchi SA, Cassivi SD, Nichols FC, Allen MS, Shen KR, Deschamps C, Wigle DA (2009) N2 disease in T1 nonsmall cell lung cancer. Ann Thorac Surg 88(3):924–928 Detterbeck FC, Jantz MA, Wallace M, Vansteenkiste J, Silvestri GA, The American College of Chest Physicians (2007) Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132(3 Suppl):202S–220S Eggeling S, Martin T, Böttger J, Beinert T, Gellert K (2002) Invasive staging of non-small cell lung cancer—a prospective study. Eur J Cardiothorac Surg 22(5):679–684 Ettinger DS, Akerley W, Bepler G, Blum MG, Chang A, Cheney RT, Chirieac LR, D’Amico TA, Demmy TL, Ganti AK, Govindan R, Grannis FW Jr, Jahan T, Jahnanzeb M, Johnson DH, Kessinger A, Komaki R, Kong FM, Kris MG, Krug LM, Le Q-T, Lennes IT, Martins R, O’Malley J, Osarogiagbon RU, Otterson GA, Patel JD, Pisters KM, Reckamp K, Riely GJ, Rohren E, Simon GR, Swanson SJ, Wood DE, Yang SC, NCCN Non-Small Cell Lung Cancer Panel Members (2010) Non-small cell lung cancer. J Natl Compr Canc Netw 8(7):740–801

F. Farjah and V. W. Rusch Farjah F, Flum DR, Ramsey SD, Heagerty PJ, Symons RG, Wood DE (2009) Multi-modality mediastinal staging for lung cancer among medicare beneficiaries. J Thorac Oncol 4(3):355–363 Felip E, Rosell R, Maestre JA, Rodriguez-Paniagua JM, Morán T, Astudillo J, Alonso G, Borro JM, González-Larriba JL, Torres A, Camps C, Guijarro R, Isla D, Aguiló R, Alberola V, Sánchez-Palencia A, Sánchez JJ, Hermosilla E, Massuti B, The Spanish Lung Cancer Group (2010) Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small cell lung cancer. J Clin Oncol 28(19):3138– 3145 Fischer B, Lassen U, Mortensen J, Larsen S, Loft A, Bertelsen A, Ravn J, Clementsen P, Hogholm A, Larsen K, Rasmussen T, Keiding S, Dirksen A, Gerke O, Skov B, Steffensen I, Hansen H, Vilmann P, Jacobsen G, Backer V, Maltbaek N, Pedersen J, Madsen H, Nielsen H, Hojgaard L (2009) Preoperative staging of lung cancer with combined PETCT. N Engl J Med 361:32–39 Gilligan D, Nicolson M, Smith I, Groen H, Dalesio O, Goldstraw P, Hatton M, Hopwood P, Manegold C, Schramel F, Smit H, van Meerbeeck J, Nankivell M, Parmar M, Pugh C, Stephens R (2007) Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet 369:1929–1937 Gould MK, Kuschner WG, Rydzak CE, Maclean CC, Demas AN, Shigemitsu H, Chan JK, Owens DK (2003) Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with nonsmall cell lung cancer. a meta-analysis. Ann Int Med 139:879–892 Herder GJM, Kramer H, Hoekstra OS, Smit EF, Pruim J, van Tinteren H, Comans EF, Verboom P, Uyl-de-Groot CA, Welling A, Paul MA, Boers M, Postmus PE, Teule GJ, Groen HJM (2006) Traditional versus up-front [18F] fluorodeoxyglucose-positron emission tomography staging of non-small cell lung cancer: a Dutch cooperative randomized study. J Clin Oncol 24:1800–1806 Holty JE, Kuschner WG, Gould MK (2005) Accuracy of transbronchial needle aspiration for mediastinal staging of non-small cell lung cancer: a meta-analysis. Thorax 60(11):949–955 International Union Against Cancer (2009) TNM classification of malignant tumours, 7th edn. Wiley-Blackwell, Oxford Kanzaki R, Higashiyama M, Fujiwara A, Tokunaga T, Maeda J, Okami J, Kozuka T, Hosoki T, Hasegawa Y, Takami M, Tomita Y, Kodama K (2011) Occult mediastinal lymph node metastasis in NSCLC patients diagnosed as clinical N0–1 by preoperative integrated FDG-PET/CT and CT: risk factors, pattern, and histopathological study. Lung Cancer 71(3):333–337 Larsen SS, Vilmann P, Krasnik M, Dirksen A, Clementsen P, Maltbaek N, Lassen U, Skov BG, Jacobsen GK (2005) Endoscopic ultrasound guided biopsy performed routinely in lung cancer staging spares futile thoracotomies: prelminary results form a randomised clinical trial. Lung Cancer 49(3):377–385

Surgical Staging of Lung Cancer for Advances in Radiation Oncology LeBlanc JK, Espada R, Ergun G (2003) Non-small cell lung cancer staging techniques and endoscopic ultrasound: tissue is still the issue. Chest 123:1718–1725 Lee PC, Port JL, Korst RJ, Liss Y, Meherally DN, Altorki NK (2007) Risk factors for occult mediastinal metastases in clinical stage I non-small cell lung cancer. Ann Thorac Surg 84:177–181 Lemaire A, Nikolic I, Petersen T, Haney JC, Toloza EM, Harpole DH Jr, D’Amico TA, Burfeind WR (2006) Nineyear single center experience with cervical mediastinoscopy: complications and false negative rate. Ann Thorac Surg 82(4):1185–1189 Little AG, Rusch VW, Bonner JA, Gaspar LE, Green MR, Webb WR, Stewart AK (2005) Patterns of surgical care of lung cancer patients. Ann Thorac Surg 80:2051–2056 Little AG, Gay EG, Gaspar LE, Stewart AK (2007) National survey of non-small cell lung cancer in the United States: epidemiology, pathology and patterns of care. Lung Cancer 57(3):253–260 Ludwig MS, Goodman M, Miller DL, Johnstone PA (2005) Postoperative survival and the number of lymph nodes sampled during resection of node-negative non-small cell lung cancer. Chest 128(3):1545–1550 Manfredi R, Pirronti T, Bonomo L, Marano P (1996) Accuracy of computed tomography and magnetic resonance imaging in staging bronchogenic carcinoma. MAGMA 4(3–4):257– 262 Maziak DE, Darling GE, Inculet RI, Gulenchyn KY, Driedger AA, Ung YC, Miller JD, Gu C-S, Cline KJ, Evans WK, Levine MN (2009) Positron emission tomography in staging early lung cancer. Ann Intern Med 151:221–228 Micames CG, McCrory DC, Pavey DA, Jowell PS, Gress FG (2007) Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: a systematic review and metaanalysis. Chest 131(2):539–548 Rivera MP, Mehta AC, The American College of Chest Physicians (2007) Initial diagnosis of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132(Suppl 3):131S–148S Robinson LA, Ruckdeschel JC, Wagner H Jr, Stevens CW, The American College of Chest Physicians (2007) Treatment of non-small cell lung cancer - stage IIIA: ACCP evidence-

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based clinical practice guidelines (2nd edition). Chest 132(Suppl 3):243S–265S Sebastián-Quetglás F, Molins L, Baldó X, Buitrago J, Vidal G, The Spanish Video-Assisted Thoracic Surgery Group (2003) Clinical value of video-assisted thoracoscopy for preoperative staging of non-small cell lung cancer. a prospective study of 105 patients. Lung Cancer 42:297–301 Silvestri GA, Gould MK, Margolis ML, Tanoue LT, McCrory D, Toloza E, Detterbeck F, The American College of Chest Physicians (2007) Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 132(3 Suppl):178S–201S Song WA, Zhou NK, Wang W, Chu XY, Liang CY, Tian XD, Guo JT, Liu X, Liu Y, Dai WM (2010) Survival benefit of neodjuvant chemotherapy in non-small cell lung cancer: an updated meta-analysis of 13 randomized control trials. J Thorac Oncol 5(4):510–516 Tournoy KG, de Ryck F, Vanwalleghem LR, Vermassen F, Praet M, Aerts JG, Van Maele G, Van Meerbeeck JP (2008) Endoscopic ultrasound reduces surgical mediastinal staging in lung cancer: a randomized trial. Am J Respir Crit Care Med 177(5):531–535 Vallières E, Pagé A, Verdant A (1991) Ambulatory mediastinoscopy and anterior mediastinotomy. Ann Thorac Surg 52:1122–1126 van Tinteren H, Hoekstra OS, Smit EF, van den Bergh HJAM, Schreurs AJM, Stallaert RALM, van Velthoven PCM, Comans EFI, Diepenhorst FW, Verboom P, van Mourik JC, Postmus PE, Boers M, Teule GJJ, The PLUS Study Group (2002) Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected nonsmall cell lung cancer: the PLUS multicentre randomised trial. Lancet 359:1388–1392 Varadarajulu S, Schmulewitz N, Wildi SF, Roberts S, Ravenel J, Reed CE, Block M, Hoffman BJ, Hawes RH, Wallace MB (2004) Accuracy of EUS in staging of T4 lung cancer. Gastrointest Endosc 59:345–348 Viney RC, Boyer MJ, King MT, Kenny PM, Pollicino CA, McLean JM, McCaughan BC, Fulham MJ (2004) Randomized controlled trial of the role of positron emission tomography in the management of Stage I and II non-small cell lung cancer. J Clin Oncol 22:2357–2362

Lung Cancer Surgery Sidhu P. Gangadharan, Walter J. Lech, and David J. Sugarbaker

Contents 1

Abstract

Lung cancer is the most common cancer worldwide. Current estimates project over 222,000 new cases of lung cancer in the US alone in 2010, amounting to over 157,000 deaths. Despite a modest improvement in 5-year survival over the past three decades, deaths from lung cancer continue to exceed cancer deaths from all other sites. This chapter updates the role of surgical resection in the management of lung cancer. Among the topics reviewed are the diagnostic work-up and preoperative assessment of suitability for resection, open and video-assisted thoracoscopic operative strategies, and recent changes in both the lung cancer staging and histological classification systems. Indications for radiation therapy in selected patients with T3 tumors are also discussed.

Introduction.............................................................. 103

2 Preoperative Assessment......................................... 104 2.1 Diagnosis.................................................................... 104 2.2 Preoperative Fitness................................................... 108 3 3.1 3.2 3.3 3.4 3.5 3.6

Operative Strategy................................................... Nomenclature and Anatomy ..................................... Extent of Resection ................................................... Technique of Resection............................................. Postoperative Course ................................................. Video-Assisted Thoracoscopic Surgery .................... Radiation Therapy for Patients Undergoing Lung Resection: T3 Tumors ...............................................

109 109 109 110 111 112 113

References.......................................................................... 113

S. P. Gangadharan Division of Thoracic Surgery, Beth Israel Deaconess Medical Center, 185 Pilgrim Road, W/DC 201, Boston, MA 02115, USA S. P. Gangadharan Assistant Professor of Surgery, Harvard Medical School, Boston, MA, USA W. J. Lech D. J. Sugarbaker (&) Division of Thoracic Surgery, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA e-mail: [email protected]; [email protected] W. J. Lech Instructor in Surgery, Harvard Medical School, Boston, MA, USA D. J. Sugarbaker The Richard E. Wilson Professor of Surgical Oncology, Harvard Medical School, Boston, MA, USA

1

Introduction

Lung cancer is the most common cancer in the world, with an incidence of 1.52 million cases and 1.31 million deaths in the year 2008 (Boyle and Levin 2008). It has been estimated that over 222,000 new cases of lung cancer occurred in the US in 2010, accounting for 15% of all cancer diagnoses (American Cancer Society 2010). More than 157,000 Americans are expected to die in 2010 as a result, comprising nearly 28% of all non-melanoma cancerrelated deaths. Over the past three decades the US has experienced a modest, yet statistically significant improvement in 5-year survival, increasing from

B. Jeremic´ (ed.), Advances in Radiation Oncology in Lung Cancer, Medical Radiology. Radiation Oncology, DOI: 10.1007/174_2011_318, Springer-Verlag Berlin Heidelberg 2011

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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 adenocarcinoma 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 presence 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

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 likelihood 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 brushings, 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 noninvasive (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 infiltration into the chest wall or carina versus involvement 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 bronchoscopic debridement of tumor, photodynamic therapy, airway stenting, or brachytherapy. The staging system for NSCLC is based on TNM classification. The 7th edition of the

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TMN

N0

N1

N2

N3

T1a

IA

IIA

IIIA

IIIB

T1b

IA

IIA

IIIA

IIIB

T2a

IB

IIA

IIIA

IIIB

T2b

IIA

IIB

IIIA

IIIB

T3

IIB

IIIA

IIIA

IIIB

T4

IIIA

IIIA

IIIB

IIIB

M1a

IV

IV

IV

IV

M1b

IV

IV

IV

IV

Fig. 1 Non-small cell lung cancer staging. 7th edition of IALSC Staging System

International Lung Cancer Staging System was published in 2009 (Fig. 1) (Detterbeck et al. 2009), and subsequently adopted by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC) in 2010 (Edge et al. 2010). While the N descriptor remained unaltered, the T (Rami-Porta et al. 2007) and M (Postmus et al. 2007) descriptor classifications have been revised extensively to provide greater prognostic specificity: • T1 (B3 cm) has been subclassified into T1a (B2 cm) and T1b ([2 but B3 cm). • T2 ([3 cm) has been subclassified into T2a ([3 but B5 cm) and T2b ([5 but B7 cm). • T2 ([7 cm) has been upstaged to T3. • Separate nodule in the same lobe (T4) has been downstaged to T3.

• Separate nodule in an ipsilateral lobe (M1) has been downstaged to T4. • M1 has been subdivided into M1a and M1b. • Malignant pericardial or pleural effusion (T4) has been upstaged to M1a. • Separate nodule in a contralateral lobe (M1) is subclassified as M1a. • Distant metastasis is now designated as M1b. 2.1.1.1 T Stage T1 tumors are \3 cm in diameter, surrounded completely 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 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. 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 invasive behavior, involving the parietal pleura, chest wall (including the superior sulcus), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium or a 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 nodules within the same lobe. T4 tumors invade the carina, trachea, mediastinum, vertebral body, recurrent laryngeal nerve, great vessels, heart, or esophagus. If a 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 despite historical data that demonstrate an inability to distinguish between T1/T2 and T3/T4 tumors up to one-quarter of the time, (Antoch et al. 2003; Lardinois et al. 2003) a limitation that may affect the extent of surgical resection (Webb et al. 1991). Integrated PET-CT scan may prove more accurate, yielding 98% correct clinical staging when compared to pathological staging (Lardinois et al. 2003). Radiologic reconstruction of the tracheobronchial tree is insufficient to exclude airway invasion, therefore, our policy is to perform bronchoscopy to assess the airway before surgical resection. Determination of the proximal extent of endobronchial tumor invasion (i.e., distance from carina) may be accomplished, in addition to assessment for anatomic abnormalities, which might influence the surgical resection. Intraoperatively, frozen section analysis may be useful to

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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

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 ipsilateral mediastinal or subcarinal lymph nodes (singledigit 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 performed 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 mediastinum, 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 involvement of the neural foramina or tumors abutting the mediastinum, structures of the chest wall, or diaphragm. 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 comparison of CT versus CT/PET, the sensitivity, specificity, and accuracy of CT were 70, 69, and 69%,

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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 sensitivity may be accomplished with the addition of extended cervical or anterior mediastinotomy techniques (Ginsberg et al. 1987; McNeill and Chamberlain 1966). EBUS-TBNA has expanded the options for staging NSCLC, extending the ability to sample stations 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%) (Eberhardt 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 randomized 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 mediastinoscopy sampling. With the development of video-assisted mediastinoscopy (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

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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 confirmation 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 permanent section analysis by pathology instead of relying on frozen section analysis. Thus, the planned pulmonary resection is deferred to a second operative setting. The surgical approach to cervical mediastinoscopy and lymph node sampling commences with a small incision above the sternal notch, followed by dissection between the strap muscles until the pre-tracheal 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). Determination 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 progression of disease, we recommend pulmonary resection 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


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 recurrence 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 cervical 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 insufficiency, or other co-morbidities, all patients considered for surgical resection at our institution undergo pulmonary 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 commensurately 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 = preoperative 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 ppoFEV1 [ 40% of predicted and DLCO [ 40% of predicted 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 thoracic surgeon skilled in these techniques. Exercise testing 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 complications following lung surgery (Datta and Lahiri 2003; Beckles et al. 2003). In patients who are scheduled to undergo pneumonectomy 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. Occasionally, 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

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bronchopulmonary structures—pulmonary vein, pulmonary artery or bronchus—or the attendant draining lymphatics or lymph nodes. Segmentectomy describes an anatomic resection of the bronchopulmonary segment. 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 apicoposterior 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. Bilobectomy is similar resection of two lobes from the same lung. Sleeve resection denotes the removal of a circumferential 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 resection 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 performed by Davies in 1912 (Davies 1913). Churchill refined lung resection with the introduction of the technique of individual ligation of the bronchopulmonary structures (Churchill and Belsey 1939). Graham

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reported the first successful pneumonectomy for lung cancer in 1933 (Graham and Singer 1933). Pneumonectomy 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 nonanatomic 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 lymphadenectomy 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 significant 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 resection 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 lobectomy, 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 sublobar resection compared to lobectomy. Importantly, however, they also found that survival after segmentectomy 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 segmentectomy with complete lobar and mediastinal dissection (i.e., extended segmentectomy), Yoshikawa


et al. (2002) found that for T1 tumors \2 cm in diameter, 5-year survival (87.1%) was nearly equivalent 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 survival (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 randomized 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 diseasefree 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 pneumonectomy, 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 accomplished using a double-lumen endotracheal tube or single-lumen tube with a bronchial blocker. The patient is positioned in thoracotomy position—a lateral 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 latissimus 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 thoracotomy, usually in the fourth intercostal space, is another alternative. Sufficient analgesia for these incisions 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 divided using a stapling device. Lymphadenectomy is performed. The margins are inspected by a pathologist upon removal of the specimen to assure a negative bronchial margin. The integrity of the bronchial stump is checked by testing the stump with ventilatory pressure up to 30 cm of H2O. When the patient has received neoadjuvant radiation or may receive postoperative radiation, it is our preference to buttress 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

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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 conferring a higher risk (5.7%) than lobectomy (0.6%). The rate of major complication (defined as postoperative bleeding leading to exploration, respiratory 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 common (Tschernko et al. 1996; Kirby et al. 1995). At our institution all patients are transferred to a specialized thoracic surgery intermediate care unit after lobectomy or lesser resection. After 1-to-3 days in this setting, to permit invasive hemodynamic monitoring, continuous oxygen monitoring, and frequent pulmonary 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).

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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 conditions (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 interspace is used to place a port for a 5- or 10-mm videoscope. 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

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 morbidity (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 thoracotomy, 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 significant difference in length of stay (Kirby et al. 1995). A subsequent randomized trial and several nonrandomized trials, however, were able to show a reduction in length of stay with the minimally invasive 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 outcomes 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 difference 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. Several 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 associated with a 5-year survival of \10% (Detterbeck 1997; Deslauriers et al. 1994). Treatment of Pancoast tumors begins with neoadjuvant therapy. These tumors

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were initially approached with preoperative radiotherapy alone (Shaw et al. 1961). Recently, however, retrospective 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 chemotherapy 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

Abstract

We reviewed recent investigations on radiation response of normal lung tissue and lung tumors and also introduced our own investigations. The mechanisms for response of normal lung tissues to radiation are not yet fully understood. Recent researches have revealed that various cytokines and lung parenchymal cells are involved in the pathogenesis of radiation response of normal lung tissues. Prediction of tumor and/or normal tissue sensitivity to treatment is being investigated for tailor-made cancer treatment based on the biological characteristics. In the near future, it is hoped that the relationship among clonogenic death of target cells, cytokine induction, gene expression and radiation pneumonitis, and that among radiosensitivity, 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.

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 .......................

120 120 121 122 122 122 124 125 126

References.......................................................................... 127

1

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: [email protected]

Introduction

Radiation response of the normal lung tissue and lung tumors has been studied for nearly 90 years. Pulmonary 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 reported in the 1930–1950s (Engelstad 1940; Bergmann and Graham 1951). Radiotherapy for lung tumors moved into full swing in the early 1950s. Since then,


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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 cellular levels. Most of the important biological phenomena 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 possibly 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 development 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 investigations 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 various lung parenchymal cells contribute to the pathogenesis 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

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 interleukin 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 factor 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 Fasligand 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 Fasligand, 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

KL-6 (U/ml)

p

Hazard ratio, 95% CI

p

Hazard ratio, 95% CI

0.04

6.1 (1.1–34.7)

0.02

6.8 (1.5–31.5)

0.10

6.1 (0.7–50.8)

0.10

6.0 (0.7–50.9)

0.15

2.6 (0.7–9.1)

0.22

2.2 (0.6–7.5)

0.56

2.0 (0.2–22.6)

0.64

0.7 (0.1–3.8)

0.38

2.1 (0.4–11.6)

(C500, \500) Sex (M, F) PTV volume (cm3) (C43, \43)a Presence of IP (+, -) V20

b Lung

(%)

(C6, \6)a Mean lung dose (Gy) (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 of Radiation Pneumonitis

Factors such as age, gender, smoking status, location of tumor, and lung dosimetric factors can also contribute to the lung damage caused by radiation. Previous reports have shown a correlation between severe radiation pneumonitis and dose-volume parameters such as the mean lung dose, V20 (percentage 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 radiotherapy cases, recent researchers have revealed that appropriate inhibition of key cytokines at an early stage might provide new tools for the effective treatment of radiation pneumonitis (Anscher et al. 2003; Goto et al. 2001). However, in patients undergoing SBRT for lung tumors, only a few reports have suggested that the early response of blood markers mentioned above is a good indicator of severe radiation 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 measurement for predicting the occurrence and

management of severe radiation pneumonitis after 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 epithelial cells (Stahel et al. 1994; Hilkens et al. 1992). The serum levels of KL-6 have been shown to correlate 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 pneumonitis 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

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).

2500

KL–6 (U/ml)

2000

1500

2.3

1000 * 500

* *

0 –3

–2

–1

0

1 Months

2

3

4

5

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 developed. 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 (pretreatment serum KL-6 level, gender, and PTV volume) that showed a p value of \0.05 were analyzed, and again, only the KL-6 level proved to be significant. In our study, KL-6 levels increased almost in accordance with the occurrence of C Grade 2 radiation 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

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 pneumonitis usually occurs within several months 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 previous symptomatic radiation pneumonitis before COP-like pneumonitis. Figure 2 shows the example of unusual pneumonitis like COP after SBRT for primary 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


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, Chisquare test)

Fig. 2 Chest CT, radiograph and dose distribution of stereotactic 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 predictive 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 prediction did not become a commonly used tool in clinics.

124

Adenocarcinoma

Squamous cell carcinoma

p = 0.02

p < 0.001

400

300 Volume increase rate (%)

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. Modified from Murai et al. (2011)

H. Iwata et al.

200

100

0

8

16

24

32 0

8

16

24

32

Waiting time (weeks)

The reasons for this may include labor intensiveness and a long waiting time before obtaining assay results. Shibamoto et al. (1994, 1998) tried to establish a more rapid assay of radiosensitivity using the cytokinesis-block micronucleus (MN) test. MN formation represents chromosomal damage and the MN frequency increases with radiation dose. Using this assay, a method of simultaneously estimating radiosensitivity and proliferative activity of human tumors was devised (Shibamoto et al. 1994, 1998). Estimation of tumor proliferative activity is also important in radiotherapy, since rapidly-growing tumors are considered 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 characteristics 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

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 radiotherapy 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 headand-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 carcinoma (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 Adenocarcinoma (n=32) Squamous cell carcinoma (n=23)

100

Overall survival(%)

(23%) did not show volume increase during WTs [ 25 days. In 41 patients waiting for B4 weeks, no patient showed T-stage progression, whereas in 25 of 120 (21%) patients waiting for [4 weeks, T stage 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 progressed (p = 0.002). The risk of T-stage progression in T1 lung cancer was significantly higher in the group waiting for longer than 4 weeks. Therefore, this study supports the recommendation of the British Thoracic Society (1998) that the WT should be less than 4 weeks in patients undergoing curative surgery. In addition, 4 weeks may be appropriate for acceptable WT before SBRT, although the WT should be as short as possible.

125

80 60 40 20 0 0

12

24

36

48

0

12

24

36

48

0

12

24

36

48

60

72

100

Radiation sensitivity is known to differ with tumor histology. In primary lung cancer, small cell carcinomas are generally considered to be more radiosensitive than adenocarcinomas and squamous cell carciniomas, but this impression may be largely due to the rapid response of small cell carcinomas to radiation. Ultimate local control rates might not be so different among the three histological subtypes of lung cancer (Ruckdeschel 1998; Brodin et al. 1991). During carbon-ion radiotherapy performed at the National Institute of Radiological Sciences, Chiba, squamous cell carcinomas tended to show lower local control rates than melanomas and adenoid cystic carcinomas (Mizoe et al. 2004). During proton therapy and carbon-ion radiotherapy performed for headand-neck cancer at Hyogo Ion Beam Medical Center, a similar trend was also experienced (Murakami et al. 2009). A similar trend was also observed for particle therapy of primary lung cancer. We evaluated the clinical outcome of particle therapy for stage I nonsmall-cell lung cancer (Iwata et al. 2010). Figure 4 shows overall survival, local control and disease-free survival curves according to histology in patients treated with proton therapy. The local control rates were higher for adenocarcinoma than for squamous cell carcinoma (p = 0.02). This is in contrast to the laboratory and clinical observations for

80

Local control (%)

Radiation Response by Tumor Histology

60 40 20 0 60

72

100

Disease-free survival (%)

3.3

80 60 40 20 0 60

72

Time (months)

Fig. 4 Overall survival, local control, and disease-free survival curves for patients treated with proton therapy according to histology. Patients with adenocarcinoma had a higher local control rate than those with squamous cell carcinoma (p = 0.022), although the overall and disease-free survival rates were not different (p = 0.19 and 0.061, respectively). Modified from Iwata et al. (2010)

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 radiotherapy 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 metastases with other histology (45 vs. 91%, respectively, at 18 months). There were many reports with radiotherapy for brain metastasis according to histology. Brain metastases of renal cell carcinoma, colorectal cancer, and melanoma etc. were reported as radioresistant (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 pneumonitis, and that among radiosensitivity for each tumor histology, tumor gene expression and patient characteristics 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 AURKA 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


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 collaboration. 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...................................

Abstract 130 130 131 132 132 133 133 134 134 135 135 136 136 138

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: [email protected]

Radiation therapy has been an important component of potentially curative treatment of lung cancer for more than 40 years. The radiosensitivity of normal tissues in the thorax, especially the normal lung and esophagus, has led to efforts to enhance the antitumor effects of radiation while reducing its acute and late adverse effects on normal tissues. Improving local control of medically inoperable or locally advanced unresectable disease (stage III non-small cell lung cancer or limited-stage small cell lung cancer, defined as disease confined to one hemithorax and the ipsilateral supraclavicular lymph nodes) can favorably influence overall survival rates. The therapeutic ratio of radiation for the treatment of lung cancer can 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 radiation 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


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Table 1 Fractionation definitions for lung cancer Schedule

Dose per fraction (Gy)

No. fractions per week

Intervals between fractions (h)

Total no. fractions

Duration of treatment (weeks)

Total dose (Gy)

Standard

1.8–2.75

4–6

24

25–40

5–8

55–75

Hypo

[3.0

1–4

48–168a

;

NC or ;

NC or ;

Hyper

0.7–1.3

10–25

2–12

:

(;) NC

NC (:)

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 setting 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 tomography (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 control 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 therapeutic ratio.

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 satisfactory, and hence several attempts have been made to manipulate fractionation dose and schedule to escalate the biologically effective dose to the tumor and thus improve the outcome. Table 1 gives some definitions 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 constraint was approximately 20 Gy at 1.5 Gy/fraction. With regard to the volume of lung subjected to radiation, Graham et al. 1995 used dose–volume histogram 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 treatments 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 largedose 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 oncologists 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 threedimensional 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 standardfractionation 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 radiation 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 localregionally advanced NSCLC.

1.2

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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 fractionation published 2 years later by Cox (1985) confirmed 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 fractionation, 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 subsequent 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

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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 recommendations that lower fractionation regimens be used for tumors in this location. A recent report of 59 patients with solely peripheral 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 toxicity, 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 comparing SBRT schedules for patients with stage I peripheral NSCLC who are not candidates for surgery. Patients are randomly assigned to one of two fractionation regimens, either 48 Gy in four once-daily fractions or 34 Gy in one fraction. The primary endpoint 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 fractions 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

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 fractionation 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 accelerated course of radiation therapy was conducted at Mount Vernon Hospital in the UK by Saunders et al. (Saunders et al. 1997; Saunders 2000). Their investigation 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 metastasis 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).


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 hyperfractionated radiation, and they found that a hyperfractionated 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 examining 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 radiation 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, especially symptomatic toxicity, and the volume of irradiated 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

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with disease rather than broadly applying nodal irradiation. 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 involvedfield 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).

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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 standard practice for locally advanced NSCLC.

1.7

Accounting for Tumor Motion

That intrathoracic tumors move in concert with respiratory 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 significantly 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

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 direction, 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 delivered while the patient holds their breath at full inspiration (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 category of conformal therapy. The advantage of proton beam therapy lies in the dose distribution characteristics 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 comparisons 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) compared 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,


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 inoperable T1N0 or T2-T3N0 NSCLC. All patients received a dose of 87.5 Gy in 2-Gy fractions. At a median followup 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 evidence exists to suggest the feasibility of modulating proton fluence, akin to the modulation of photons in IMRT. A dose–volume histogram analysis of treatment 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

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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 fractions were given daily for 10 days, followed by an interruption of 4 weeks and then daily 2.5-Gy fractions 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 clonogens, 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, longterm 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

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chemotherapy alone have shown that use of combination therapy improves survival rates; other trials have shown that concurrent chemotherapy and thoracic 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 controlled. 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 chemotherapy alone versus chemotherapy plus thoracic radiation 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 doseintensity), which prevents the proliferation of clonogens. Potential disadvantages of concurrent therapy are enhanced toxicity to normal tissues, which could necessitate dose modification or treatment breaks; the

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 cyclophosphamide 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 twicedaily 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 chemotherapy, 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 chemotherapy in the sequential group. The radiation therapy consisted of 45 Gy delivered to the thorax in twicedaily 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 twicedaily 1.5-Gy fractions given 5 days a week. The incidence 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


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, cyclophosphamide, 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 cyclophosphamide, doxorubicin, and vincristine alternating with etoposide and cisplatin (CAV/PE). Patients were randomly assigned to receive thoracic radiation therapy (40 Gy to the primary tumor site in 15 fractions over 3 weeks given concurrently with etoposide and cisplatin) beginning either at week 3 (the early group) or at week 15 (the late group). Those who showed a complete 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 lateradiation 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 eliminating the clonogens in the primary tumor. However, this study was essentially repeated by investigators in the UK with conflicting results. In that

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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 regimen 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 platinum-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 regimens 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

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chemotherapy cycle. Patients who achieved a complete 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 induction 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 survival rate in this study was 48%, and the progressionfree 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 primary endpoint is overall survival, and secondary endpoints are complete response rates, progressionfree 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;

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 limitedstage SCLC. The maximum tolerated dose of hyperfractionated radiation therapy was 45 Gy given in 30 fractions over 19 days. However, in daily fractionation, 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 pneumonitis) that could be given in combination with


139

Table 2 Intergroup Study 0096 versus RTOG 9712 Intergroup

Thoracic radiation dose

RTOG 9712

Group 1

Group 2

45 Gy

45 Gy

61.2 Gy

Duration of radiation

5 weeks

3 weeks

5 weeks

Median survival time

19 months

23 months

–

1-year

63%

67%

–

2-years

44%

47%

–

5-years

16%

26%*

–

Local failure rate

52%

36%

–

Incidence of grade 3 esophagitis

11%

27%

\40%

Survival rates

*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 concomitant 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, twicedaily 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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D. Gomez et al. carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 48(1):7–16 Goto K, Nishiwaki Y, Takada M et al (1999) Final results of a phase III study of concurrent versus sequential thoracic radiotherapy (TRT) in combination with cisplatin (P) and etoposide (E) for limited-stage small cell lung cancer (LDSCLC): the Japan Clinical Oncology Group (JCOG) study (abstract). Proc ASCO 18:A1805 Graham MV, Purdy JA, Emami B, Matthews JW, Harms WB (1995) Preliminary results of a prospective trial using three dimensional radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys 33:993–1000 Grills IS, Yan D, Martinez AA, Vicini FA, Wong JW, Kestin LL (2003) Potential for reduced toxicity and dose escalation in the treatment of inoperable non-small-cell lung cancer: a comparison of intensity-modulated radiation therapy (IMRT), 3D conformal radiation, and elective nodal irradiation. Int J Radiat Oncol Biol Phys 57(3):875–890 Grutters JP, Joore MA, Wiegman EM, Langendijk JA, de Ruysscher D, Hochstenbag M et al (2010) Health-related quality of life in patients surviving non-small cell lung cancer. Thorax 65(10):903–907 Janaki L, Rector D, Turrisi A et al (1994) Patterns of failure and second malignancies from SWOG-8629: concurrent cisplatin, etoposide, vincristine, and once daily radiotherapy for the treatment of limited small cell lung cancer (abstract). Proc ASCO 13:331 Jeremic B, Milicic B (2008) From conventionally fractionated radiation therapy to hyperfractionated radiation therapy alone and with concurrent chemotherapy in patients with earlystage nonsmall cell lung cancer. Cancer 112(4):876–884 Komaki R, Swann RS, Ettinger D (2003) Phase I study of thoracic radiation dose-escalation with concurrent chemotherapy for patients with limited small cell lung cancer (LSCLC): Radiation Therapy Oncology Group (RTOG) Protocol 9712. Proc ASCO 22:631 Komaki R, Scott C, Ettinger D, Lee JS, Fossella FV, Curran W et al (9204) Randomized study of chemotherapy/radiation therapy combinations for favorable patients with locally advanced inoperable nonsmall cell lung cancer: Radiation Therapy Oncology Group (RTOG). Int J Radiat Oncol Biol Phys 38:149–155 Lee JS, Scott CB, Komaki R, Ettinger DS, Sause WT (2002) Impact of institutional experience on survival outcome of patients undergoing combined chemoradiation therapy for inoperable non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 52(2):362–370 Liao Z, Komaki R, Stevens C (2002) Twice daily irradiation increases locoregional control in patients with medically inoperable or surgically unresectable stage II–IIIB non-smallcell lung cancer. Int J Radiat Oncol Biol Phys 53(3):558–565 Liao ZX, Komaki RR, Thames HD Jr, Liu HH, Tucker SL, Mohan R et al (2010) Influence of technologic advances on outcomes in patients with unresectable, locally advanced non-small-cell lung cancer receiving concomitant chemoradiotherapy. Int J Radiat Oncol Biol Phys 76(3):775–781 Liu HH, Balter P, Tutt T, Choi B, Zhang J, Wang C et al (2007) Assessing respiration-induced tumor motion and internal target volume using four-dimensional computed tomography for radiotherapy of lung cancer. Int J Radiat Oncol Biol Phys 68(2):531–540

Radiation Time, Dose, and Fractionation in the Treatment of Lung Cancer McCracken JD, Janaki LM, Crowley JJ (1990) Concurrent chemotherapy/radiotherapy for limited small-cell lung carcinoma: a Southwest Oncology Group Study. J Clin Oncol 8:892–898 Michalski D, Sontag M, Li F, de Andrade RS, Uslene I, Brandner ED et al (2008) Four-dimensional computed tomography-based interfractional reproducibility study of lung tumor intrafractional motion. Int J Radiat Oncol Biol Phys 71(3):714–724 Murray N, Coy P, Pater JL, Hodson I, Arnold A, Zee BC et al (1993) Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11(2):336–344 Perez CA, Stanley K, Rubin P, Kramer S, Brady L, PerezTamayo R et al (1988) A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-small cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer 45:2744–2753 Pignon JP, Arriagada R, Ihde DC, Johnson DH, Perry MC, Souhami RL et al (1992) A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327(23):1618–1624 Pijls-Johannesma M, De Ruysscher D, Vansteenkiste J, Kester A, Rutten I, Lambin P (2007) Timing of chest radiotherapy in patients with limited stage small cell lung cancer: a systematic review and meta-analysis of randomised controlled trials. Cancer Treat Rev 33(5):461–473 Qiao X, Tullgren O, Ingmar L, Sirzen F, Lewensohn R (2003) The role of radiotherapy in treatment of stage I non-small cell lung cancer. Lung Cancer 41:1–11 Rosenzweig KE, Sim SE, Mychalczak B, Braban LE, Schindelheim R, Leibel SA (2001) Elective nodal irradiation in the treatment of non-small-cell lung cancer with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys 50(3):681–685 Rosenzweig KE, Sura S, Jackson A, Yorke E (2007) Involvedfield radiation therapy for inoperable non small-cell lung cancer. J Clin Oncol 25(35):5557–5561 Saunders MI (2000) The implications of the CHART trial for the treatment of non-small cell lung cancer. Lung Cancer 2:177–178 Saunders MI, Dische S, Barret S, Harvey A, Gibson D, Parmar M (1997) Continuous hyperfractionated accelerated radiotherapy versus conventional radiotherapy in small-cell lung cancer: a randomized multicentre trial. Lancet 350:161–165 Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R et al (1995) Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary results of a phase III trial in regionally advanced, unresectable non-small cell lung cancer. J Natl Cancer Inst 87(3):198–205 Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhourt J, van Houtte P et al (1992) Effects of

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concomitant cisplatin and radiotherapy on inoperable nonsmall cell lung cancer. N Engl J Med 326:524–530 Sejpal S, Komaki R, Tsao A, Chang JY, Liao Z, Wei X et al (2011) Early findings on toxicity of proton beam therapy with concurrent chemotherapy for nonsmall cell lung cancer. Cancer Spiro SG, James LE, Rudd RM, Trask CW, Tobias JS, Snee M et al (2006) Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis. J Clin Oncol 24(24):3823–3830 Thames HD, Peters LJ, Withers HR, Fletcher GH (1983) Accelerated fractionation versus hyperfractionation: rationales for several treatments per day. Int J Radiat Oncol Biol Phys 9:127–138 Timmerman R, Papiez L, McGarry R, Likes L, DesRosiers C, Frost S et al (2003) Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 124(5):1946–1955 Timmerman R, McGarry R, Yiannoutsos C, Papiez L, Tudor K, DeLuca J et al (2006) Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 24(30):4833–4839 Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J et al (2010) Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303(11): 1070–1076 Turrisi AT III, Kim K, Blum R, Sause WT, Livingston RB, Komaki R et al (1999) Twice-daily compared with oncedaily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340(4):265–271 Uematsu M, Shioda A, Suda A et al (2001) Computed tomography-guided frameless stereotactic radiotherapy for stage I non-small-cell lung cancer: a 5-year experience. Int J Radiat Oncol Biol Phys 51(3):666–670 Warde P, Payne D (1992) Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10: 890–895 Yuan S, Sun X, Li M, Yu J, Ren R, Yu Y et al (2007) A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III nonsmall cell lung cancer. Am J Clin Oncol 30(3):239–244 Zhang X, Li Y, Pan X, Xiaoqiang L, Mohan R, Komaki R et al (2010) Intensity-modulated proton therapy reduces the dose to normal tissue compared with intensitymodulated radiation therapy or passive scattering proton therapy and enables individualized radical radiotherapy for extensive stage IIIB non-small-cell lung cancer: a virtual clinical study. Int J Radiat Oncol Biol Phys 77(2): 357–366

3D Radiation Treatment Planning and Execution Mary K. Martel

Contents

Abstract

1

Introduction.............................................................. 143

2 2.1 2.2 2.3

Treatment Planning Process .................................. Introduction................................................................ Immobilization and Simulation................................. Planning Target Volume ...........................................

Technological advances have become commercially available and widely implemented. In particular, 3D conformal therapy has become the first step in improving the targeting of dose to the tumor while sparing dose to normal tissue. The 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.

144 144 145 145

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: [email protected]

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 tolerated 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 dosevolume 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 problematic, 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). Accordingly, 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 underway (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 technological 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, normal 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 noncoplanar, non-axial beam angles with 3D visualization tools (McShan et al. 1990). This allows dose to ‘‘conform’’ to the tumor/target volume while maximizing 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 planning process for both standard and conformal radiotherapy techniques for lung cancer will be reviewed here. In addition, Senan et al. (2004) have an excellent 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, optimally 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 immobilization 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 geometrical 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

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approximate the location of soft tissue target volumes. Computed tomography (CT) scan information supplements, 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 structures, 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 coronal) 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 approximate 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

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M. K. Martel

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 considerations. 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 chapters 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 delineation of the 3D gross tumor volumes of NSCLC among oncologists. The authors propose standardization of the approach and give guidelines, which

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 contrast-enhanced. If the planning image does not have contrast, a recent (within 2 weeks of planning) diagnostic 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 microscopic spread. Opacities thought unlikely to represent tumor, but that a prudent radiation oncologist might include in the CTV because of lack of absolute certainty, 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


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 interface between the tumor/node and fat or contrastenhanced 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 settings, 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 cavitating, 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 atelectatic 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) information 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

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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 transformation (Pelizzari 1998). For example, one of the simplest 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 alignment 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

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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 treatment, 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 workstations. The contouring process segments the image data into separate structures, each uniquely identified. Semi-automated and automated algorithms are

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 parallelopposed 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


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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 contours) with the anterior field (left), the head of the machine must be rotated until the virtual simulation software shows

‘‘separation’’ of the cord from the tumor volume (outlined in blue) (middle). Blocks to shield normal tissue are then drawn (outside blue line) (right)

surrounding normal tissue. The block shape is represented 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

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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 characterize 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 distributions 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

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 treatment 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 contoured on CT, and are displayed as solid surfaces in 3D in a variety of BEV displays. The PTV, in red, is targeted by beams directed from five different machine gantry angles, and several different couch angles.


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 tissue avoidance. A set of criteria for normal tissue tolerances (discussed in the next section) must be given to guide the treatment planner. Dose distributions 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,

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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 changes 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 pattern. 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 distribution. 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 carried 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 collimators, 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 balance of achieving high dose delivery to the tumor with a low rate of normal tissue toxicity. A set of criteria

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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 occurring in 5 years was also given for each organ. These 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 early efforts towards the use of objective criteria in evaluating treatment plans. However, the tolerance

Fig. 7 Dose-volume histograms for treatment plan shown in Fig. 6

doses given were based on limited volumetric dose data publications and on ‘‘guesstimates’’ based on clinical experience. As 3D dose distributions for


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 radiation pneumonitis and the mean lung dose in an analysis 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 pneumonitis 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;

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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 Institute (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 conformal 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 corrections 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 ranging 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 performed (Klein et al. 1997), dose delivered to the PTV

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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%;

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)

with 6 MV was within 5% of predicted, but low by 11% with use of 18 MV.

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 algorithm 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 distributions with the CS model shows that the 95% isodose 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

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 buildup 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.


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 planning. 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 conformal 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 levels. 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

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decades is to determine the impact of new technology on treatment outcome.

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156 treatment for non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 45:323–329 Grills IS, Yan D, Martinez AA et al (2003) Potential for reduced toxicity and dose escalation in the treatment of inoperable non-small-cell lung cancer: a comparison of intensity-modulated radiation therapy (IMRT), 3D conformal radiation, and elective nodal irradiation. Int J Radiat Oncol Biol Phys 57:875–890 Harris KM, Adams H, Lloyd DCF et al (1993) The effect of apparent size of simulated pulmonary nodules of using three standard CT window settings. Clin Radiol 47:241–244 Hayman JA, Martel MK, Ten Haken RK et al (2001) Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial. J Clin Oncol 19:127–136 Hazuka MB, Turrisi AT 3rd, Lutz ST et al (1993) Results of high-dose thoracic irradiation incorporating beam’s eye view display in non-small cell lung cancer: a retrospective multivariate analysis. Int J Radiat Oncol Biol Phys 27:273–284 ICRU (1993) Prescribing, recording and reporting photon beam therapy, Report 50, ICRU Press, Bethesda ICRU (1999) Prescribing, recording and reporting photon beam therapy (Su lement to ICRU Report 50) ICRU Press, Bethesda Klein EE, Morrison A, Purdy JA et al (1997) A volumetric study of measurements and calculations of lung density corrections for 6 and 18 MV photons. Int J Radiat Oncol Biol Phys 37:1163–1170 Kong FM, Hayman JA, Griffith KA et al (2006) Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (NSCLC): predictors for radiation pneumonitis and fibrosis. Int J Radiat Oncol Biol Phys 65:1075–1086 Kubo HD, Len PM, Minohara S et al (2000) Breathingsynchronized radiotherapy program at the University of California Davis Cancer Center. Med Phys 27:346–353 Kwa SL, Lebesque JV, Theuws JC et al (1998) Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients. Int J Radiat Oncol Biol Phys 42:1–9 Mackie TR, el-Khatib E, Battista J et al (1985) Lung dose corrections for 6 and 15 MV X rays. Med Phys 12:327–332 Marks LB, Munley MT, Bentel GC et al (1997) Physical and biological predictors of changes in whole-lung function following thoracic irradiation. Int J Radiat Oncol Biol Phys 39:563–570 Martel MK, Ten Haken RK, Hazuka MB et al (1994) Dosevolume histogram and 3-D treatment planning evaluation of patients with pneumonitis. Int J Radiat Oncol Biol Phys 28:575–581 Martel MK, Ten Haken RK, Hazuka MB et al (1999) Estimation of tumor control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients. Lung Cancer 24:31–37 McShan DL, Fraass BA, Lichter AS (1990) Full integration of the beam’s eye view concept into computerized treatment planning. Int J Radiat Oncol Biol Phys 18:1485–1494

M. K. Martel Mehta M, Scrimger R, Mackie R et al (2001) A new approach to dose escalation in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 49:23–33 Narayan S, Henning GT, Ten Haken RK et al (2004) Results following treatment to dose of 92.4 or 102.9 Gy on a phase I dose escalation study for non-small cell lung cancer. Lung Cancer 44:79–88 Oetzel D, Schraube P, Hensley F et al (1995) Estimation of pneumonitis risk in three-dimensional treatment planning using dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 33:455–460 Pelizzari CA (1998) Image processing in stereotactic planning: volume visualization and image registration. Med Dosim 23:137–145 Radiation Therapy Oncology Group RTOG 93-11 (1993) A phase I/II dose escalation study using three dimensional conformal radiation therapy in patients with inoperable nonsmall cell lung cancer web page: www.rtog.org Rice RK, Mijnheer BJ, Chin LM (1988) Benchmark measurements for lung dose corrections for X-ray beams. Int J Radiat Oncol Biol Phys 15:399–409 Robertson JM, Ten Haken RK, Hazuka MB et al (1997) Dose escalation for non-small cell lung cancer using conformal radiation therapy. Int J Radiat Oncol Biol Phys 37:1079–1085 Rosenzweig KE, Mychalczak B, Fuks Z et al (2000) Final report of the 70.2 and 75.6 Gy dose levels of a phase I dose escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable non-small cell lung cancer. Cancer J 6:82–87 Senan S, de Koste J, Samson M et al (1999) Evaluation of a target contouring protocol for 3D conformal radiotherapy in non-small cell lung cancer. Radiother Oncol 53:247–255 Senan S, De Ruysscher D, Giraud P et al (2004) Literaturebased recommendations for treatment planning and execution in high dose radiotherapy for lung cancer. Radiother Oncol 71:139–146 Sepenwoolde Y, Lebesque JV, de Jaeger K et al (2003) Comparing different NTCP models that predict the incidence of radiation pneumonitis. Normal tissue complication probability. Int J Radiat Oncol Biol 55:724–735 Sibley GS, Mundt AJ, Shapiro C et al (1995) The treatment of stage III nonsmall cell lung cancer using high dose conformal radiotherapy. Int J Radiat Oncol Biol Phys 33:1001–1007 Ten Haken RK, Martel MK, Kessler ML et al (1993) Use of Veff and iso-NTCP in the implementation of dose escalation protocols. Int J Radiat Oncol Biol Phys 27:689–695 Timmerman R, Papiez L, McGarry R et al (2003) Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 124:1946–1955 Wang L, Yorke E, Chui CS (2002) Monte Carlo evaluation of 6 MV intensity modulated radiotherapy plans for head and neck and lung treatments. Med Phys 29:2705–2717 Wong JW, Sharpe MB, Jaffray DA et al (1999) The use of active breathing control (ABC) to reduce margin for breathing motion. Int J Radiat Oncol Biol Phys 44:911–919

Four-dimensional Radiation Therapy for Non-Small Cell Lung Cancer: A Clinical Perspective Max Dahele, Johan Cuijpers, and Suresh Senan

Contents 1

Abstract

The purpose of this chapter is to review 4-dimensional 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.

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

1

7

Conclusion ................................................................ 168

Translating existing knowledge and techniques into routine clinical use can present significant challenges, but is essential for improving the effectiveness 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 reason 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

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: [email protected]

Introduction


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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

Comments

Three-dimensional conformal radiotherapy (3DCRT)

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)

Stereotactic lung RT

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%

Intensity modulated RT (IMRT)

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)

Respiratory gated RT (RGRT)

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)

Cone beam CT (CBCT)

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

Use of external markers to track lung tumor motion

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)

Computed tomography (CT) for imaging tumor motion

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

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Table 1 (continued) Advances

Comments

Positron emission tomography

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)

Heterogeneity corrected treatment planning systems

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)

Multi-modal image fusion for treatment planning

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

Uncertainty margins

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 dosefractionation 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 implementation 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 planning and delivery. This concept is not new as the movement of lung tumors and surrounding structures was also appreciated during treatment simulation 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 (retrospective) respiratory- correlated computed tomography (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 encompassing internal target volume (ITV) with isotropic

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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 conventional 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). However, conventional CT scans may contain substantial motion artifact and they provide no information about tumor displacement which risks both a geographic 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 appreciated that the availability of 4DCT, a radiation treatment 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 configuration that provides all the physical building blocks for a fully-fledged 4D-adaptive lung RT program. Figure 1 puts 4D lung RT into the wider context of a comprehensive conventional and stereotactic lung RT program.


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 Underberg et al. (2004) who compared a single ten-phase 4DCT with six fast multi-slice CT scans, Guckenberger 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 information 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

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Table 3 Lung tumor motion evaluated with four-dimensional computed tomography (4DCT) Author (Refs.)

Institutions

Comments

Liu (2007)

MD Anderson

166 tumors, 152 patients (57.2% stage III/IV) 4DCT normal respiration 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 (2009)

Johns Hopkins

20 patients 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 stereotactic 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 systematically 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 assessing 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 consequences of such changes.


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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 mediolateral plane

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 calculation 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

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. Furthermore, 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 priorities and other major barriers to implementing effective 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 equipment is not possible, less sophisticated variants of 4DRT may still be possible.

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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.)

Years

Radiation arm of interest

Outcomes

RTOG 9410 (three-arm phase III study) (Curran et al. 2003)

1994–1998

63 Gy/34fr (1.8 Gy 9 25, then 2 Gy 9 9)

Median survival (MS) 17 m with 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 three arms

Two-phase (boost) technique CT-based treatment planning whenever possible SWOG 9504 (single arm phase II study) (Gandara et al. 2003)

1996–1998

61 Gy/33fr (1.8 Gy 9 25, then 2 Gy 9 8)

MS of 26 m for 83 eligible patients with median FU 32 m

Two phase RT using postinduction volume for phase two)

1, 2, and 3 year survival rates 76, 54 and 37%

Concurrent chemo-RT Proven stage IIIB 2 dimensional planning Sura et al. (2008) (retrospective institutional review)

2001–2005

Stages I–IIIB inoperable Patients CT-planned and treated with IMRT using 1.8–2 Gy/fr

MS 25 m for stage III, with median FU 26 m among survivors

Minimum dose 60 Gy, mean 69.5 Gy

2 year overall survival 58% for stage III

23/39 stage III pts had sequential chemo-RT and 13/39 concurrent chemoRT Liao et al. (2010) (retrospective institutional review comparing CT ? 3DCRT with 4DCT ? IMRT)

1999–2006, 4DCT ? IMRT introduced 2004

Concurrent chemo-RT

Mean FU 3DCRT = 2.1 years, mean FU 4DCT/IMRT = 1.3 years

3DCRT = 318pts, 4DCT/ IMRT = 91pts

Median survival 0.85 years (10.2 m) for 3DCRT and 1.4 years (16.8 m) for 4DCT/IMRT

Both groups median dose 63 Gy

Reduced grade C3 radiation 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 chemoradiation, a more recent cohort whose radiotherapy


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 survival is supported, or whether they were one factor associated with it. So where does this leave things? Our own department, which operates within the constraints of a public healthcare system, aims to create an environment 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, earlystage 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 localization 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 stereotactic RT: 3 9 18, 5 9 11 and 8 9 7.5 Gy using

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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 procedure. 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 reconstructed 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 maximum 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

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Fig. 5 Flowchart illustrating the approach to fourdimensional 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 implanted fiducials are not currently used for stereotactic lung RT at our center. Patients are treated under free


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 necessary. 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 volumetric modulated RT, routinely consisting of two arcs (Verbakel et al. 2009). Initial work has not demonstrated 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 Evolution ± 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 mediastinal 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

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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 features. 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 random errors and allow a reduction in setup margins (Higgins et al. 2010; Yeung et al. 2010). After treatment 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 significant 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 planning. Whilst the slow CT strategy can be used for stereotactic lung RT it is not suited to locally advanced tumors, however, expiratory/inspiratory

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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 planar image-guidance [e.g., orthogonal kilovoltage (kV) or megavoltage (MV) images] with patient setup on the spine. Note that prior to commencing CBCTbased tumor matching in 2008 for stereotactic RT of peripheral lung tumors, we used stereoscopic kilovoltage 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 expansion 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 presents 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

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 programs 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 performed without patient-specific motion information. The essential components of 4D lung RT can be implemented into routine clinical workflows and performed using standard linear accelerators with a minimum 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 treatment 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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Four-dimensional Radiation Therapy radiotherapy for elderly patients with stage I non-small-cell lung cancer: a population-based time-trend analysis. J Clin Oncol 28(35):5153–5159 Pantarotto JR, Piet AH, Vincent A, de Koste JR, Senan S (2009) Motion analysis of 100 mediastinal lymph nodes: potential pitfalls in treatment planning and adaptive strategies. Int J Radiat Oncol Biol Phys 74(4):1092–1099 Phernambucq EC, Spoelstra FO, Verbakel WF, Postmus PE, Melissant CF, Maassen van den Brink KI, Frings V, van de Ven PM, Smit EF, Senan S (2011) Outcomes of concurrent chemoradiotherapy in patients with stage III non-small-cell lung cancer and significant comorbidity. Ann Oncol 22(1):132–138 Ragan DP, Perez CA (1978) Efficacy of CT-assisted two dimensional treatment planning: analysis of 45 patients. AJR Am J Roentgenol 131(1):75–79 Redmond KJ, Song DY, Fox JL, Zhou J, Rosenzweig CN, Ford E (2009) Respiratory motion changes of lung tumors over the course of radiation therapy based on respirationcorrelated four-dimensional computed tomography scans. Int J Radiat Oncol Biol Phys 75(5):1605–1612 Riegel AC, Chang JY, Vedam SS, Johnson V, Chi PC, Pan T (2009) Cine computed tomography without respiratory surrogate in planning stereotactic radiotherapy for nonsmall-cell lung cancer. Int J Radiat Oncol Biol Phys 73(2):433–441 Ritchie CJ, Hsieh J, Gard MF, Godwin JD, Kim Y, Crawford CR (1994) Predictive respiratory gating: a new method to reduce motion artifacts on CT scans. Radiology 190(3):847–852 Rosenzweig KE, Hanley J, Mah D, Mageras G, Hunt M, Toner S, Burman C, Ling CC, Mychalczak B, Fuks Z, Leibel SA (2000) The deep inspiration breath-hold technique in the treatment of inoperable non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 48(1):81–87 Routsis D, Staffurth J, Beardmore C, Mackay R (2010) Radiotherapy Development Board Education and training for intensity-modulated radiotherapy in the UK. Clin Oncol (R Coll Radiol) 22(8):675–680 Sher DJ, Wolfgang JA, Niemierko A, Choi NC (2007) Quantification of mediastinal and hilar lymph node movement using four-dimensional computed tomography scan: implications for radiation treatment planning. Int J Radiat Oncol Biol Phys 69(5):1402–1408 Shih HA, Jiang SB, Aljarrah KM, Doppke KP, Choi NC (2004) Internal target volume determined with expansion margins beyond composite gross tumor volume in three-dimensional conformal radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys 60(2):613–622 Simpson DR, Lawson JD, Nath SK, Rose BS, Mundt AJ, Mell LK (2009) Utilization of advanced imaging technologies for target delineation in radiation oncology. J Am Coll Radiol 6(12):876–883 Sirkin HL, Keenan P, Jackson A (2005) The hard side of change management. Harv Bus Rev 83(10):108–118 158 Slotman BJ, Lagerwaard FJ, Senan S (2006) 4D imaging for target definition in stereotactic radiotherapy for lung cancer. Acta Oncol 45(7):966–972 Sonke JJ, Belderbos J (2010) Adaptive radiotherapy for lung cancer. Semin Radiat Oncol 20(2):94–106 Sonke JJ, Zijp L, Remeijer P, van Herk M (2005) Respiratory correlated cone beam CT. Med Phys 32(4):1176–1186

171 Spear SJ (2004) Learning to lead at Toyota. Harv Bus Rev 82(5):78–86 151 Sura S, Gupta V, Yorke E, Jackson A, Amols H, Rosenzweig KE (2008) Intensity-modulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Radiother Oncol 87(1):17–23 Taremi M, Hope A, Dahele M, Pearson S, Fung S, Purdie T, Brade A, Cho J, Sun A, Bissonnette JP, Bezjak A (2011) Stereotactic body radiotherapy for medically inoperable lung cancer: prospective, single-center study of 108 consecutive patients. Int J Radiat Oncol Biol Phys [Epub ahead of print] Underberg RW, Lagerwaard FJ, Cuijpers JP, Slotman BJ, de Koste JR, Senan S (2004) Four-dimensional CT scans for treatment planning in stereotactic radiotherapy for stage I lung cancer. Int J Radiat Oncol Biol Phys 60(4):1283–1290 Underberg RW, Lagerwaard FJ, Slotman BJ, Cuijpers JP, Senan S (2005) Use of maximum intensity projections (MIP) for target volume generation in 4DCT scans for lung cancer. Int J Radiat Oncol Biol Phys 63(1):253–260 van Dam IE, de Koste JR, Hanna GG, Muirhead R, Slotman BJ, Senan S (2010) Improving target delineation on 4 dimensional CT scans in stage I NSCLC using a deformable registration tool. Radiother Oncol 96(1):67–72 van Elmpt W, Hamill J, Jones J, De Ruysscher D, Lambin P, Ollers M (2011) Optimal gating compared to 3D and 4D PET reconstruction for characterization of lung tumours. Eur J Nucl Med Mol Imaging 38(5):843–855 Verbakel WF, Senan S, Cuijpers JP, Slotman BJ, Lagerwaard FJ (2009) Rapid delivery of stereotactic radiotherapy for peripheral lung tumors using volumetric intensity-modulated arcs. Radiother Oncol 93(1):122–124 Verbakel W, Ladenius-Lischer I, Slotman BJ, Senan S (2010) A hybrid IMRT technique for high-dose radiotherapy in large-volume stage III lung tumors: planning comparison with 3 other techniques. Int J Radiat Oncol Biol Phys 78(3):S811 (A3357) Verellen D, Depuydt T, Gevaert T, Linthout N, Tournel K, Duchateau M, Reynders T, Storme G, De Ridder M (2010) Gating and tracking, 4D in thoracic tumours. Cancer Radiother 14(6-7):446–454 Wanet M, Lee JA, Weynand B, De Bast M, Poncelet A, Lacroix V, Coche E, Grégoire V, Geets X (2011) Gradient-based delineation of the primary GTV on FDG-PET in non-small cell lung cancer: a comparison with threshold-based approaches, CT and surgical specimens. Radiother Oncol 98(1):117–125 Weiss E, Wijesooriya K, Dill SV, Keall PJ (2007) Tumor and normal tissue motion in the thorax during respiration: analysis of volumetric and positional variations using 4D CT. Int J Radiat Oncol Biol Phys 67(1):296–307 Whitton A, Warde P, Sharpe M, Oliver TK, Bak K, Leszczynski K, Etheridge S, Fleming K, Gutierrez E, Favell L, Green E (2009) Organisational standards for the delivery of intensity-modulated radiation therapy in Ontario. Clin Oncol (R Coll Radiol) 21(3):192–203 Williams MV, Cooper T, Mackay R, Staffurth J, Routsis D, Burnet N (2010) The implementation of intensity-modulated radiotherapy in the UK. Clin Oncol (R Coll Radiol) 22(8):623–628

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PET and PET/CT in Treatment Planning Michael P. Mac Manus and Rodney J. Hicks

Contents 1

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 radiotherapy. PET imaging, using 18F-flurodeoxyglucose as the tracer, and more recently in the form of FDGPET/CT is now the most important single imaging modality for staging, patient selection and radiotherapy 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 selection and radiotherapy planning are discussed. Additionally, the use of FDG-PET for response assessment is described and finally the potential value of PET tracers other than FDG is considered.

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

181

181 183 183

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: [email protected] R. J. Hicks Centre for Molecular Imaging, Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, VIC 3002, Australia

1

Introduction

The advent of positron emission tomography (PET) has been the most significant advance in cancer imaging since the introduction of computed tomography (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


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M. P. Mac Manus and R. J. Hicks

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 disease 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 considered 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 discussed in this chapter. A single PET/CT scan can perform dual roles for the radiation oncologist; (1) staging for patient selection for radiotherapy and (2) determination 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 considered, commonly using a short axis diameter of 1 cm to indicate malignancy. Accordingly CT has poor

sensitivity and specificity for the detection of lymph node involvement by tumor (Toloza et al. 2003). Numerous clinicopathological studies and metaanalyses 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 contrast, 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 approximately 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 techniques can miss small volume nodal deposits that can only be identified by pathological examination. Survival in NSCLC is powerfully correlated with lymph node staging and drops precipitously when mediastinal 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 radionuclide 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)/chemoradiotherapy (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 correlated 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 comorbidity may also be treated with radical radiotherapy. The factors that make these patients unsuitable for surgery (advanced disease or significant comorbidities), militate against confirmation of their intrathoracic lymph node status at thoracotomy. These factors consequently necessitate accurate non-invasive methods 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 indicated 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 disease, despite the relative paucity of studies in which rigorous pathological confirmation has been performed in this setting. Because it is generally neither ethical or feasible to subject such patients to comprehensive biopsy of all PET and CT detected lesions simply to assess diagnostic accuracy, the only practical means to compare diagnostic performance is to perform detailed follow-up using serial imaging and survival 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 radiotherapy, in most cases given with concurrent chemotherapy, 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 irradiation. 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 considered 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 radical 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 radiotherapy, 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 significantly higher in stage III (p = 0.039) than I–II.

176


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 metabolicallyactive 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 carboplatin from 1989 to 1995. Eligible patients had Stages I–III, Eastern Cooperative Oncology Group


status 0 or 1, \10% weight loss, and had not undergone 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 planning. 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 staging 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’’ radiotherapy in NSCLC is cure but with acceptable toxicity. 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 unattainable, 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 surrounding 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 oncologist to do anything other than guess where the boundary between tumor and lung lies. However, when CT information is supplemented by FDG PET information, 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


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 RT field

100% 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 suspected 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 suspicious 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 impossible 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 consequence of the use of PET and PET/CT for radiotherapy 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 standardized contouring process is used. One cause of difficulty is the relative low resolution of PET compared 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


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 subsequent editing and thereby reduce variation between observers. Some centers have used simple SUV cutoffs 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 imaging are plagued by inevitable distortions and contractions that occur when tissues are processed for pathological examination (Dahele et al. 2008). Analysis 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 salvage 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 progressive 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 pneumonitis 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 treatment 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 correlated 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. PETresponse categories were defined as follows; (1) CMR (complete metabolic response)—no abnormal tumor FDG uptake; activity in the tumor absent or similar to mediastinum. (2) PMR (partial metabolic response)—any appreciable 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)—appreciable increase in tumor FDG uptake or volume of known tumor sites or evidence of disease progression at other intrathoracic or distant metastatic sites. Responses were correlated with subsequent survival. 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.


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). Changes in SUV have been shown to have prognostic significance after neoadjuvant chemotherapy prior to surgery and after palliative chemotherapy for incurable NSCLC. Use of SUV-based assessment following radiotherapy may be compromised by a number of factors, including the commonly observed and sometimes intense inflammatory reaction to radiotherapy in normal tissues. These changes may have a measured SUV in the ‘‘malignant’’ range but can usually be identified as such on qualitative assessment. Post-radiotherapy changes conform to the volume 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 previously 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 scanning for predicting survival after radical radiation therapy. The powerful prognostic information available 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 radiotherapy could provide early prognostic information and provide a basis for modifying therapy during the treatment course.


181

Fig. 2 Coronal images at baseline FDG PET/CT before (left upper panel) and after chemoradiotherapy (postCRT, 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 craniocaudal 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

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

false positives related to inflammatory conditions. The excellent clinical performance of FDG PET suggests that this is not a major practical limitation in countries with a relatively low prevalence of granulomatous 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 probability 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 comparison between FDG PET and 201Tl, a tumor imaging 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 nonenlarged 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 histopathological 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 primary 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 significance (Sasaki et al. 2001). A more recent, but relatively 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 relatively low FDG-avidity and more specific with lack of significant uptake into inflammatory lesions, such as tuberculosis. In the restaging setting, where inflammatory changes may pose difficulties in determining nature of increased FDG activity, the MD Anderson Cancer Center group found that 11C-methionine and


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 phosphatidylcholine. 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-methionine. 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 prognosis 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 proliferation, 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 suggested that both were predictive of progression-free


survival but only early (day 14) FDG response predicted 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 pretreated 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).

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 7.2

Respiratory Gating of PET Data

The acquisition of the emission data used to reconstruct PET images occurs over several minutes and therefore integrates the effects of respiratory movement. 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 movement 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 holding 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

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 densities 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 monoclonal 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, further 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

Abstract

Proper target volume delineation is a crucial stage of treatment planning, so any error introduced in this process is a systematic error and cannot be quantified and/or detected by modern treatment technologies, unlike other sources of geometrical uncertainties. All steps of target definition should be standardized. In non-small cell lung cancer radiotherapy, there are specific problems related to the definition of all three consecutive target volumes recommended by ICRU: gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV). In GTV delineation, 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. Additionally, 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.

Introduction.............................................................. 187

Gross Tumor Volume Definition ........................... GTV for Tumor ......................................................... GTV for Nodes.......................................................... Problems Related to the Use of PET-CT for GTV Definition ................................ 2.4 Definition of GTV After Chemotherapy .................. 2 2.1 2.2 2.3

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.............

188 188 189 189 190 191 191 192 193 194

4 Planning Target Volume Definition ...................... 196 4.1 Internal Target Volume: Respiratory Motion Management............................................................... 196 4.2 Margins for Set-up .................................................... 197 References.......................................................................... 197

1 L. Kepka (&) M. Kolodziejczyk M. Sklodowska-Curie Memorial Cancer and Institute of Oncology, Warsaw, Poland e-mail: [email protected]

Introduction

Target volume delineation is the most important step in the radiation therapy planning. While set-up and respiratory motion displacements can be quantified


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188

L. Kepka and M. Kolodziejczyk

Table 1 The International Commission on Radiation Units and Measurements (ICRU 1993, 1999) definitions of target volumes Gross tumor volume (GTV)

Macroscopic extent of the malignant growth, e.g., clinically palpable and/or visualized by the imaging

Clinical target volume (CTV)

Anatomical-clinical concept that needs to be defined before delineation. It contains GTV and/or subclinical microscopic disease which should be eliminated

Planning target volume (PTV)

Geometrical concept. A 3D-expansion 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 volume (ITV)

A component of PTV specified by 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 discussed. Those three stages of target volume definition follow the recommendation of the International Commission on Radiation Units (ICRU) and Measurements Report 50 (ICRU 1993) and Report 62 (ICRU 1999). The ICRU recommends the consecutive 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.

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 differences 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 radiotherapy (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 consideration of the respiratory motion is crucial for radiotherapy 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 inconvenience. 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 delineation 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 sensitivity and specificity is estimated at 73 and 85%, respectively (Pasic et al. 2005). The special clinical case for such setting represents a roentgenographically occult carcinoma, a rare entity treated usually with combination of external-beam and endobronchial 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 routinely 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 involvement is 21% (de Langen et al. 2006). So the formulation of the guidelines may indicate that we should include all FDG-PET positive lymph nodes (unless

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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 published (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

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based images. The methods for outlining were used: (1) the qualitative visual method, (2) the GTV 2.5 standardized uptake value (SUV) units, (3) the linear adaptive SUV threshold function method, and (4) the use of any threshold of local maximal uptake value in which the threshold of 41–42% established in the phantoms studies (Boellard et al. 2010; Black et al. 2004) is commonly used. Despite the fact that thresholds of 42 (van Loon et al. 2010) and 50% (Wu et al. 2010) were seen as fitting the best for the diameter of the tumor reported on the pathology examination, the use of predefined thresholds is a source of potential errors. It was proven that due to the heterogeneity of the FDG uptake in the lung tumor and poor spatial resolution of the PET leading to the partial volume effect, the automatic delineation with any predefined threshold cannot provide the reliable GTV definition (Devic et al. 2010). The recommended approach of contouring of the FDG-PET images is the qualitative visual method (de Ruysscher et al. 2010). It is also not a perfect solution, as it is related to the risk of inter-observer variability. To overcome this problem, the contouring should be held in close cooperation of the radiation oncologist and the nuclear medicine physician in experienced centers.

2.4

Definition of GTV After Chemotherapy

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 radiotherapy delivered after induction chemotherapy recommended the use of pre-chemotherapy volumes for target definition. Thus we should use a prechemotherapy volume for GTV definition except in cases where such approach would lead to an unacceptable 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 radiotherapists used post-chemotherapy target volumes and the differences in this regard were seen even among

Table 2 Phase III clinical studies which had in one of arms radiotherapy delivered after induction chemotherapy and recommended the use of pre-chemotherapy volumes for target definition Trial, year

Design of the study

Le Chevalier et al. 1991

Radiotherapy alone versus sequential radiochemotherapy

Dillman et al. 1996


Furuse et al. 1999

Sequential radiochemotherapy versus concurrent radiochemotherapy

Sause et al. 2000


Curran et al. 2003


Zatloukal et al. 2004


Fournel et al. 2005


Huber et al. 2006

Induction chemotherapy followed by radiotherapy or concurrent radiochemotherapy

Vokes et al. 2007

Concurrent radiochemotherapy versus induction chemotherapy followed by concurrent radiochemotherapy

van Meerbeeck et al. 2007

Induction chemotherapy followed by surgery or definitive radiotherapy

Belderbos et al. 2007


Thomas et al. 2008

Induction chemotherapy followed by radiochemotherapy and surgery versus surgery and postoperative radiotherapy

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 prechemotherapy volumes may be an additional source of uncertainty and errors in radiotherapy planning, especially, if only the visual inspection for comparison of images is used. The co-registration and fusion of pre- and post-chemotherapy imaging is a recommended 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).


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, margin for endobronchial spread, and margin for extracapsular 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-operative 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 pathologic 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 underestimation 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 oncology. For this reason, it is crucial to identify the factors

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related to the presence of the microscopic spread around pulmonary mass. Giraud et al. (2000) indicated 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 adenocarcinoma 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 prediction 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 techniques 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 elimination) 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 intramucosal, 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 additionally incorporate the bronchoscopy findings into a target definition. Clinical target volume around involved lymph nodes was not as extensively studied as the extent of

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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 extracapsular microscopic extension might have reached up to 12 mm. Mediastinal lymph nodes larger than 30 mm were not included in the study. So this indicates 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 contains 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 supraclavicular region, in view of eradication of probable micrometastases within this field. The ENI volume, as a part of the CTV, remains an anatomic-clinical concept. The mediastinal ENI volume could appear as a result of clinical compromise between the need of eradication of subclinical disease and acceptable toxicity. The diagnostic possibilities and technical facilities 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

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 retrospective 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 retrospective 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 radiotherapy in NSCLC which changed the clinical practice. The toxicity of ENI has not been documented convincingly enough up to now. PET-CT is more


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 mediastinoscopy 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) geographical misses on the CT-alone based plans. Thirteen patients from this group had ENI initially planned on CT-alone. For seven patients judged as less advanced, the ENI was abandoned. It was demonstrated 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 PETCT. 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 meaningful 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 postoperative radiotherapy (PORT), the issue of proper

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delineation of lymph node stations (LNS) appears. In the era of 3D-CRT, the recommendations for delineation 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 abandonment. However, there was a need for such guidelines, for many purposes, out of which postoperative radiotherapy was one of the most pertinent. Those recommendations, 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 mediastinal 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 (MDATS) 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 variations of delineation of LNS according to those guidelines 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 guidelines 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 constraints 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 recommendations leads to the creation of the elective fields larger than traditionally defined in the 2D

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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 mediastinal 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 comparison 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 radiation oncology planning. The guidelines used for LNS delineation should be specified and reported in all treatment protocols involving the LNS delineation.

3.4

Postoperative Radiotherapy Target Volume

Clinical target volume definition for postoperative radiotherapy (PORT) represents another source of controversies, as no clear consensus and evidence exist in this field. It is related to the controversies with

Fig. 1 Difference in delineation of lymph node stations for guidelines of Atlas of Michigan (Chapet et al. 2005) and International Association of the Study for Lung Cancer (IASLC) staging committee of a new lymph node map for 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 according to the Atlas of Michigan (2R in red and 2L in orange). b Delineation according to the IASLC map (2R in blue and 2L in green). c Difference in left hilar lymph node station— 10L. In the IASLC map, 10L is delineated around main bronchus (marked red in the picture), while in the Atlas of Michigan, the medial border of 10L is the arbitrary imaginary line drawn between a lateral border of the pulmonary trunk and aorta descendens (marked light green in the picture)


the use of PORT itself. The value of PORT for NSCLC was questioned by the results of the PORT meta-analysis (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 disclosed 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 Radiotherapy Trial (Lung ART) Investigators Group that prepared the randomized trial of PORT for pN2 NSCLC patients demonstrated a large variability of CTV definition 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 (stations 2R and 2L according to Mountain and Dressler (1997) nomenclature) were still subject to large variations of the contouring. This was related to the unclear definition of the upper border of those LNS. Recommended 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 prospectively the quality of life and cardiopulmonary morbidity 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

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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 ipsilateral 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 demonstrated before. However, if one is using PORT, possibly 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).

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The use of PORT after incomplete resection (R1 or R2) in subject to fewer controversies, as it is a common belief, that additional local treatment may prevent 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 evidence-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 dissemination of cancer to the visceral cavities. However, all other indications may be divided in cases of non-radical (R1) tumor and non-radical (R1) lymph node resections; and PORT represents the conceivable 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 margin. 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 performed. 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 irradiation 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 planning 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)

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 estimated 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 generated at maximal inspiration and expiration, and recently one approach that superseded all former methods—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. Approaches 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 represents an increase in the workload at the radiation oncology department. One solution is to only use of two extreme phases of the respiratory cycle, i.e., the endexpiration 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 underestimation of the changes of the shape of the tumor between delineated phases (possible ignorance of the hysteresis


effect) and introduction of artifacts by interpolation (Persson et al. 2010). Another help in contouring on the 4D-CT dataset is using the post-processing tool of maximum intensity projection-MIP (the use of the maximum density in Hounsfield units on all CT scans for automatic generation of the target) for rapid computation of the ITV. However, this method is far from being perfect and is only suitable for tumors surrounded by pulmonary parenchyma, and even in those cases, the careful visual inspection of the GTV on all datasets of respiratory cycle should be done (Rietzel et al. 2008). The ITV computed from 4D-CT including all tumor motion leads to the inclusion of the large volume of lung tissue in the PTV. Thus—in case of the major tumor mobility—the gated radiotherapy techniques are in use, as, for example, the irradiation at the end of expiration. In such scenario, GTV is delineated in the dataset corresponding to the needed respiratory phase. It was shown that the impact of the respiratory induced motion on the accumulated GTV dose is relatively small, providing that the time-averaged mean position of the GTV is correctly positioned. Wolthaus et al. (2006) have developed a concept of mid-ventilation scan, which is extracted from 4D-CT dataset and represents an average position of the tumor during a respiratory cycle. On such chosen 3D CT frame, the GTV and subsequent CTV are delineated. The appropriate margins for tumor motion and other uncertainties margins are calculated. Such constructed final PTV is smaller than ITV computed from a whole the 4D-CT dataset and it still adequately accounts for motion. Those considerations of the tumor mobility require the use of complex equipment which, even if it is commercially available, may be too expensive and/or too time consuming for use in all cases. When such equipment is not available, at least an estimation of the tumor mobility for tumors located in the lower lobes and/or for patients with restricted pulmonary reserves is needed. The recognized mobility of lymph nodes of about 0.5 cm (for most) and about 1.0 cm for subcarinal nodes should be considered (van Sornsen de Koste et al. 2002).

4.2

Margins for Set-up

Set-up error defined as a difference of bony anatomy between plan and treatment represents an immanent part of the geometrical uncertainty for any treatment with radiation. For lung cancer it should be considered

197

together with tumor/lymph nodes mobility and (at lesser extent) anatomical changes during treatment. To account for those uncertainities, the populationbased recipes for margins between CTV and PTV were formulatd, from which the Van Herk et al. (2000) formula has become the standard for margins definition (Sonke and Beldernos 2010). In order to deliver at least 95% of dose to the CTV for 90% of patients the margin should be calculated according to the formula: X p 2 M ¼ 2:5 þb r þ r2p brp P where M is the CTV to PTV margin; the total standard deviation (SD) of the systematic errors; r the total SD of the random errors; rp the width of the penumbra modeled by a cumulative Gaussian, and b is the value of the inverse cumulative standard normal distribution at the prescribed PTV minimum dose level (van Herk et al. 2000). It shows that systemtic error (that occurs at the planning stage) impacts much more than random errors occurring at the treatment delivery. For lung cancer, the one SD for systematic and random set-up error is up to 4–5 mm (Hurkmans et al. 2001 and Borst et al. 2007); the one SD for systematic and random respiratory motion displacement is up to 7 mm (Sonke and Beldernos 2010). For calculation of the margin, the all components of the inaccuracies should be considered. However, the set-up and motion errors are generally uncorrelated, and a linear addition of these two components is not correct (van Herk et al. 2000). Thus the different sources of geometrical uncertainities should be added in quadrature not in a linear fashion. It is common to add the margin directly to the CTV without separating two components (for ITV and set-up). In most clinical scenarios of lung cancer, the margin for PTV does not exceed 1 cm. At the planning stage, the populationbased margins should be established. The repetitive imaging during treatment, using multiple available technologies of image-guided radiotherapy, may lead to the individualization of the margins by individual quantification of the inter- and intrafractional errors which has now become a new emerging standard.

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Target Volume Definition in Non-Small Cell Lung Cancer Kara M, Dizbay Sak S, Orhan D, Kavukcu S (2001) Proximal bronchial extension with special reference to tumor localization in non-small cell lung cancer. Eur J Cardiothorac Surg 20:350–355 Kara M, Dikmen E, Kilic D et al (2002) Prognostic implication of microscopic proximal bronchial extension in non-small cell lung cancer. Ann Thorac Surg 74:348–354 Kelsey CR, Marks LB, Glatstein E (2009) Elective nodal irradiation for locally advanced non-small-cell lung cancer: it’s called cancer for a reason. Int J Radiat Oncol Biol Phys 73:1291–1292 Kepka L, Bujko K, Garmol D et al (2007) Delineation variation of lymph node stations for treatment planning in lung cancer radiotherapy. Radiother Oncol 85:450–455 Kepka L, Bujko K, Zolciak-Siwinska A (2008) Risk of isolated nodal failure for non-small cell lung cancer (NSCLC) treated with the elective nodal irradiation (ENI) using 3D-conformal radiotherapy (3D-CRT) techniques. Acta Oncol 47:95–103 Kepka L, Tatro D, Moran JM et al (2009a) Designing targets for elective nodal irradiation in lung cancer radiotherapy: a planning study. Int J Radiat Oncol Biol Phys 73:1397–1403 Kepka L, Tyc-Szczepaniak D, Bujko K (2009b) Dose per fraction escalation of accelerated hypofractionated threedimensional conformal radiotherapy in locally advanced non-small cell lung cancer. J Thorac Oncol 4:853–861 Kepka L, Bujko K, Orlowski T et al (2011) Cardiopulmonary morbidity and quality of life in non-small cell lung cancer patients treated with or without postoperative radiotherapy. Radiother Oncol 98:238–243 Kołodziejczyk M, Kepka L, Dziuk M et al (2010) Impact of [18F]fluorodeoxyglucose PET-CT staging on treatment planning in radiotherapy incorporating elective nodal irradiation for non-small cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys (in press) Lagerwaard FJ, van de Vaart PJ, Voet PW et al (2002) Can errors in reconstructing pre-chemotherapy target volumes contribute to the inferiority of sequential chemoradiation in stage III non-small cell lung cancer (NSCLC)? Lung Cancer 38:297–301 Le Chevalier T, Arriagada R, Quoix E et al (1991) Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non–small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 83:417–423 Macmanus M, Nestle U, Rosenzweig KE et al (2009) Use of PET and PET-CT for radiation therapy planning: IAEA expert report 2006–2007. Radiother Oncol 91:85–94 Mountain CF, Dresler CM (1997) Regional lymph node classification for lung cancer staging. Chest 111:1718–1723 Naruke T, Suemasu K, Ishikawa S (1978) Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 76:833–839 Nestle U, Kremp S, Grosu A (2006) Practical integration of [18F]-FDG-PET and PET-CT in the planning of radiotherapy for non-small cell lung cancer (NSCLC): the technical basis, ICRU-target volumes, problems, perspectives. Radiother Oncol 81:209–225 Pasic A, Brokx HA, Comans EF (2005) Detection and staging of preinvasive lesions and occult lung cancer in the central airways with 18F-fluorodeoxyglucose positron emission tomography: a pilot study. Clin Cancer Res 11:6186–6189

199 Persson GF, Nygaard DE, Brink C et al (2010) Deviations in delineated GTV caused by artefacts in 4DCT. Radiother Oncol 96:61–66 PORT Meta-analysis Trialists Group (1998) Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomized controlled trials. Lancet 352:257–263 Rami-Porta R, Wittekind C, Goldstraw P, International Association for the Study of Lung Cancer (IASLC) Staging Committee (2005) Complete resection in lung cancer surgery: proposed definition. Lung Cancer 49:25–33 Rietzel E, Liu AK, Doppke KP et al (2006) Design of 4D treatment planning target volumes. Int J Radiat Oncol Biol Phys 66:287–295 Rietzel E, Liu AK, Chen GTY, Choi N (2008) Maximum intensity volumes for fast contouring of lung tumors including respiratory motion in 4DCT planning. Int J Radiat Oncol Biol Phys 71:1245–1252 Rocmans P, Emami B, Cox JD et al (1991) Quality control in NSCLC treatment: a consensus report. Lung Cancer 7: S19–S20 Rowell NP, Williams CJ et al (2001) Radical radiotherapy for stage I/II non-small cell lung cancer in patients not sufficiently fit or declining surgery (medically inoperable). Cochrane Database Syst Rev 2:CD002935 Rusch VW, Asamura H, Watanabe H et al Members of IASLC Staging Committee (2009) . The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 4:568–577 Saito M, Yokoyama A, Kurita Y et al (2000) Treatment of roentgenographically occult endobronchial carcinoma with external beam radiotherapy and intraluminal low-dose rate brachytherapy: a second report. Int J Radiat Oncol Biol Phys 47:673–680 Sause W, Kolesar P, Taylor SI et al (2000) Final results of phase III trial in regionally advanced unresectable non– small-cell lung cancer: radiation therapy oncology group, eastern cooperative oncology group, and southwest oncology group. Chest 117:358–364 Silvestri GA, Gould MK, Margolis ML et al (2007) Noninvasive staging of non-small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132:178–201 Slotman BJ, Lagerwaard FJ, Senan S (2006) 4D imaging for target definition in stereotactic radiotherapy for lung cancer. Acta Oncol 45:966–972 Sonke JJ, Beldernos J (2010) Adaptive radiotherapy for lung cancer. Sem Radiat Oncol 20:94–106 Sornsen van, de Koste JR, Lagerwaard FJ, Nijssen-Visser MRJ et al (2002) What margins are necessary for incorporating mediastinal nodal mobility into involved-field radiotherapy for lung cancer? Int J Radiat Oncol Biol Phys 53:1211–1215 Sornsen van, de Koste JR, Lagerwaard FJ, Nijssen-Visser MRJ et al (2003) Tumor location cannot predict the mobility of lung tumors: a 3D analysis of data generated from multiple CT scans. Int J Radiat Oncol Biol Phys 56:348–354 Spoelstra FOB, Senan S, Le Pechoux C et al (2010) Variations in target volume definition for postoperative radiotherapy in stage III non-small cell lung cancer: analysis of an international contouring study. Int J Radiat Oncol Biol Phys 76:1106–1113

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L. Kepka and M. Kolodziejczyk Cancer Group et al (2007) Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 99:442–450 Videtic GM, Rice TW, Murthy S et al (2008) Utility of positron emission tomography compared with mediastinoscopy for delineating involved lymph nodes in stage III lung cancer: insights for radiotherapy planning from a surgical cohort. Int J Radiat Oncol Biol Phys 72:702–706 Vokes EE, Herndon JE 2nd, Kelley MJ, Cancer, Leukemia Group B et al (2007) Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Nonsmall-cell lung cancer: cancer and leukemia group B. J Clin Oncol 25:1698–1704 Wolthaus JWH, Schneider C, Sonke JJ et al (2006) Midventilation CT scan construction from four dimensional respiration-correlated CT scans for radiotherapy planning of lung cancer patients. Int J Radiat Oncol Biol Phys 65:1560–1571 Wu K, Ung YC, Hornby J et al (2010) PET CT thresholds for radiotherapy target definition in non-small cell lung cancer: how close are we to the pathologic findings? Int J Radiat Oncol Biol Phys 77:699–706 Yuan S, Meng X, Yu J et al (2007a) Determining optimal clinical target volume margins on the basis of microscopic extracapsular extension of metastatic nodes in patients with non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 67:727–734 Yuan S, Sun X, Li M et al (2007b) A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III non-small cell lung cancer. Am J Clin Oncol 30:239–244 Zatloukal P, Petruzelka L, Zemanova M et al (2004) Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small-cell lung cancer: A randomized study. Lung Cancer 46:87–98

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

Contents 1

Introduction to the Role of Radiotherapy in SCLC .................................................................... 201

2

Historic Trends in Lung Cancer Target Definition...................................................... 202

3

SCLC Target Definition and the Impact of CHT ...................................................................... 203

4

SCLC Target Definition and ENI.......................... 206

5

SCLC Target Definition and FDG-PET ............... 208

6

SCLC Target Definition in Extensive Disease ..... 208

7

SCLC Target Definition in Current Trials .......... 209

8

Conclusions ............................................................... 209

Abstract

What constitutes the appropriate target in the treatment of small-cell lung cancer is an area of active investigation. Advances in the last 30 years in radiologic and nuclear imaging as well as in radiotherapy delivery have prompted revision of the classically defined target which was designed to be ‘‘tolerable’’ and encompass visible tumor and potential areas of microscopic disease. Current trends are to minimize normal tissue irradiation and more precisely define the extent of potential microscopic spread in order to optimize target volume. This chapter will review historic trials and ongoing studies to provide a comprehensive understanding on the evolution of the radiotherapy target in small-cell lung cancer.

References.......................................................................... 209

1

G. M. M. Videtic (&) Department of Radiation Oncology/T28, Taussig Cancer Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected]

Introduction to the Role of Radiotherapy in SCLC

Thoracic radiotherapy (TRT) is an integral component 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; FaivreFinn et al. 2005a, b; Socinski and Bogart 2007; Curran 2001; de Ruysscher and Vansteenkiste 2000). These reports have shown that the addition of TRT to combination chemotherapy (CHT) significantly reduces the risk of loco-regional failure


201

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(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 chemotherapy (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 prevention 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 radiotherapy (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 initiation 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 radiographs and also included all the regional nodes considered at risk, which were generally those in the mediastinum and the bilateral hilar and supraclavicular (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, ‘‘formulaic’’ 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 clinically 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 Radiation 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-motionassociated geometric uncertainties and daily set-up errors have become more sophisticated. An internal target volume (ITV) reflecting potential tumor displacements 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 sophisticated means of image-guided RT (IGRT) systems. IGRT may permit real time adjustment of RT as needed on the basis of and according to therapyinduced 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 contemporary clinical trials and routine treatment (Senan and de Ruysscher 2005), despite the fact that there are only very limited prospective data outcomes to support 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 expectation 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 clinically oriented questions with respect to target definition since they have been the common ones addressed in prospective studies of TRT. As reference, Table 1 provides a comprehensive list of completed or ongoing clinical trials over the last 30 years and their respective definitions of the target. Notwithstanding the range of technological innovations in imaging and RT delivery and their rapid implementation 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 benefits 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 significant 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 volume. 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 randomization schema based on response; in short, patients with a partial response or stable disease after four cycles of CHT (non-platinum based) were randomized to RT fields based either on the pre- or the postCHT volume of disease. No statistical differences in survival or recurrence patterns were noted as a function of volume treated: for complete responders, with local recurrence rates of 50% with RT, and 72%

Author (ref.)

CALGB30610/ RTOG0538

EORTCCONVERT

van Loon et al. (2010)

Schild et al. (2007)

Spiro et al. (2006)

Baas et al. (2006)

de Ruysscher et al. (2006)

Bogart et al. (2004)

Publication year

Ongoing

Ongoing

2010

2007

2006

2006

2006

2004

Phase II

Phase II

Phase II

Phase III

Phase II

Phase II

Phase III

Phase III

Study type

2D or 3D

3D

3D

2D

2D

3D

3D

3D

Planning (2D, 3D)

After cycle 2 CHT

CT during the first cycle of CHT

After cycle 1 CHT

Pre-CHT

Post-CHT cycle 4/5 of 6

Post-CHT (median of 18 days)

With cycle 2

With cycle 1 or 2

Pre- or postCHT primary target

CTV2 [to 70 Gy] = GTV ? ispilateral hilum

CTV1 [to 44 Gy] = GTV ? ipsilateral non-involved MLNs ? margin (continued)

GTV = post induction lung tumor and involved MLN (pre- AND post-CHT)

PTV = GTV ? margin

GTV = primary tumor and MLNs with a short-axis diameter of [1 cm

Primary tumor ? all clinical and radiological involved lymph nodes with a shortaxis diameter of [1 cm

Tumor with margin ? entire mdstnm; SCF if involved

Arms 1, 2: primary

Split course: cycle 4-primary tumor with ipsilateral hilar, mediastinal, and SCF nodes; cycle 5-cone-down to ‘‘reduced’’ mdstnm and only involved SCF

No. ENI

Margin from GTV to CTV = 5 mm, from CTV to PTV = 5 mm for MLNs and 10 mm for primary

If PET negative in mdtsnm and CT positive, mdstnm not included in GTV.

If induction CHT, post-CHT volume considered GTV of primary tumor but for MLNs, pre-CHT used

GTV and PTV defined by PET and CT

No ENI

PTV = 10 mm sup/inf; 8 mm lat

CTV = GTV ? 5 mm

GTV by CT, and PET if available

PTV 1 and 2- non-ITV or ITV based margins, between 15 and 5 mm, respectively

CTV1-GTV ? ipsilateral hilum; CTV2-revised; GTV after CHT; otherwise no ENI

ITV for motion

GTV by CT, and PET if available

Overall target definition

Table 1 Target volume definitions from completed and ongoing prospective studies in limited stage SCLC

204 G. M. M. Videtic

Takada et al. (2002)

Skarlos et al. (2001)

Turrisi et al. (1999)

Jeremic et al. (1997)

Work et al. (1997)

Murray et al. (1993)

Perry et al. (1987)

Kies et al. (1987)

Perez et al. (1981)

2002

2001

1999

1997

1997

1993

1987

1987

1981

Phase III

Phase III

Phase III

Phase III

Phase III

Phase III

Phase III

Randomized phase II

Phase III

Study type

2D

2D

2D

2D (‘‘CTplanning not mandatory’’)

2D (rare 3D)

2D

2D

2D

Not specified

Planning (2D, 3D)

Pre-CHT

Arm ‘‘reduced field’’: postCHT

Arm ‘‘widefield’’: pre-CHT

Pre-CHT

Pre-CHT

Pre-CHT

Pre-CHT

Pre-CHT

Pre-CHT

Pre-CHT

Pre- or postCHT primary target

Arms 1, 2: primary tumor with margin ? entire mdstnm, bilateral hila, bilateral SCF

Primary tumor, ‘‘abnormal appearing lung’’, mdstnm, ‘‘low’’ SCF

Boost to 50 Gy-residual disease on a mid-course CXR

Arms 1, 2: to 40 Gy-primary tumor with margin ? entire mdstnm, bilateral hila, bilateral SCF

Arms 1, 2: Primary tumor with margin ? entire mdstm, SCF if involved

Primary tumor, ipsilateral hilum, entire mdstnm, SCF only if involved

Arm 2: initial tumor volume

Arm 1: primary tumor, ipsilateral hilum, entire mdstnm, SCF only if involved

Primary tumor, bilateral mediastinal and ipsilateral hilar lymph nodes, SCF only if involved, specifically: ‘‘inferior border … 5 cm below the carina or to a level including ipsilateral hilar structures, whichever was lower’’.

Arm 2: ‘‘initial tumor volume’’

To 45 Gy-primary tumor

Arm 1: to 30 Gy-primary tumor ? entire mdtsnm ? bilateral hila; SCF if involved

Arm 2: RT after 4 cycles CHT-‘‘pretreatment tumor volume’’

Arm 1: RT with CHT cycle 1-primary disease with margin, ipsilateral hilum, entire mdstnm, SCF if involved

Overall target definition

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

Author (ref.)

Publication year

Table 1 (continued)

The Radiation Target in Small-Cell Lung Cancer 205

206

without RT, and for partial responders or those with stable disease, local recurrences were 32% for preCHT 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 preversus 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 malignant pleural effusion but not nodal structures, suggesting 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 encompassed post-CHT tumor volumes, suggesting no difference 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 definition may have on TRT fields have included retrospective 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 techniques became commonplace, especially CT-based planning, Arriagada et al. (1991) and Brodin et al. (1990) each found that tumor recurrences predominated 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 conducted 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


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 anteroposteriorposteroanterior 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 published 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 preCHT and post-CHT) (Bogart et al. 2004). A 2007 report by Schild et al. on the results of a Phase II study of highdose 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 twicedaily) 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 isolated 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 supraclavicular 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 concurrent 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

G. M. M. Videtic

CT-based selective nodal irradiation, which resulted in a higher percentage of isolated nodal failures (11%) (de Ruysscher et al. 2006). A recent (2010) retrospective 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 reporting 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

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 validate clinical results with pathologic sampling, nor did they discuss implications for therapy. In summary, PET imaging contributes substantially to better identification of tumor burden, and can definitely influence RT treatment plans. A major weakness of all these studies is the absence of histologic 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 accurately 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 survival. These data recall a not-yet-replicated phase III study on the role of thoracic RT in favorable ESSCLC patients by Jeremic et al. (1999). In that study, accelerated hyperfractionated RT and concurrent lowdose 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 target delineation.


7

SCLC Target Definition in Current Trials

The European Organization for Research and Treatment 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 (Concurrent once-daily VErsus twice-daily RadioTherapy) is a Phase III trial in which patients with LS-SCLC are randomized to either twice-daily thoracic radiotherapy (45 Gy in 30 fractions starting with the second 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 staging, 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 randomized. CTV-1 will include the GTV and the ipsilateral 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

Abstract

1

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

2 2.1 2.2 2.3 2.4 2.5

Oxygen ...................................................................... Hyperbaric Oxygen.................................................... Carbogen .................................................................... Efaproxiral ................................................................. Red Blood Cell Transfusion ..................................... Erythropoietin ............................................................

Discovery of effective radiosensitization strategies that improve the therapeutic ratio for patients with lung cancer has been a goal of researchers and an area of vigorous investigation for the past several decades. 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. In this chapter we outline the previous and ongoing attempts to radiosensitize lung cancers through improved tumor oxygenation, augmentation of the effectiveness of radiotherapy in hypoxic tumor cells, and use of drugs that modulate with DNA repair and apoptosis. To date, 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.

214 214 215 215 215 216

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 5.1 5.2 5.3

DNA Repair Inhibitors ........................................... AKT Pathway Inhibition ........................................... Mitogen-Activated Protein Kinase Inhibition .......... HDAC-Inhibitors .......................................................

217 217 218 218

6 Apoptosis Modulating Agents ................................ 219 6.1 Bcl-2 Inhibitors.......................................................... 219 6.2 Cyclooxygenase COX-2-Inhibitors ........................... 219 References.......................................................................... 219

1

A. M. Brade (&) Z. Allibhai Department of Radiation Oncology, Princess Margaret Hospital, 5-912 610 University Avenue, Toronto, ON M5G 2M9, Canada e-mail: [email protected] A. M. Brade University of Toronto, Toronto, Canada

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


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A. M. Brade and Z. Allibhai

selectively increase the radiosensitivity of the target tumor. The advantages of this approach are potentially significant given that the presumed radioresistance 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 radiosensitizers. 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), inhibitors 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

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 demonstrated 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 neoadjuvant 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 incidence 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 discovering 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,


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 accelerated 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.

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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 encouraging median survival of 20.6 months, while the rates of severe toxicity were relatively low (Choy et al. 2005). These encouraging results prompted the proposal 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 demonstrated that it increases oxygen tension within tumor tissue and that this positively affects the tumor’s response to radiation (Yamamoto et al. 2009).

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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 erythropoietin (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 metaanalysis 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 etanidazole and pimonidazole were subsequently developed to improve the pharmacokinetic profile of this class of drugs and reduce toxicity. Unfortunately,

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 fractionated 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 outside 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 nitroimidazole compound called doranidazole (PR-350) has shown promise in both NSCLC and SCLC. Preclinical and early clinical trials have demonstrated a relatively 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


of large fractions of radiation over a very short period of time may not allow for sufficient tumor re-oxygenation. 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 completed phase III TROG 02.02/HeadSTART trial adding tirapazamine to chemoradiation in locally advanced head and neck carcinoma did not demonstrate 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 chemoradiotherapy 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 irradiation 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

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gliomas and head and neck cancers, where the ability to avoid immediately adjacent critical structures is of particular importance. Although its use in the treatment 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. Important DNA repair pathways including homologous recombination repair (HRR), non-homologous endjoining (NHEJ), base-excision repair (BER), nucleotide-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 amplification of EGFR (Ohsaki et al. 2000) which stimulates the phosphatidylinositol 3-kinase (PI3K)/AKT pathway as well as the Ras-Raf-Mek-ERK signaling cascade, 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

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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 demonstrated the ability to enhance radiosensitivity in cervical cancer and more recently NSCLC. These agents drive apoptosis following exposure to ionizing radiation 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 DNAPKcs 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 upregulated 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 DNADSB 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 cetuximab functioning through MAPK in human NSCLC cell lines (Kriegs et al. 2010). This confirmed a similar finding reported previously by Tanaka using

gefitinib, again in human NSCLC lines (Tanaka et al. 2008).

5.3

HDAC-Inhibitors

Histone deacetylases (HDAC) modulate the acetylation status of histones, thus affecting the gene transcription. 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 conjunction with HDAC to regulate transcription. Interestingly, recent studies have shown that HATinhibitors 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 PARPinhibitors 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). Preclinical studies of PARP inhibitors in lung cancer models have been encouraging (Albert et al. 2007).


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 signaling and others functioning as anti-apoptotic modulators. 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, nimesulide (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 component 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 randomized 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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Radiation Sensitizers human non-small cell lung cancer via antiangiogenesis in vivo. Strahlenther Onkol 187(1):45–51 Epub 2010 Dec 23 Komaki R, Liao Z, Milas L (2004) Improvement strategies for molecular targeting: cyclooxygenase-2 inhibitors as radiosensitizers for non-small cell lung cancer. Semin Oncol 31(1 Suppl 1):47–53 Kriegs M, Kasten-Pisula U, Rieckmann T et al (2010) The epidermal growth factor receptor modulates DNA doublestrand break repair by regulating non-homologous endjoining. DNA Repair 9(8):889–897 Laurie SA, Jeyabalan N, Nicholas G et al (2006) Association between anemia arising during therapy and outcomes of chemoradiation for limited small-cell lung cancer. J Thorac Oncol 1(2):146–151 Le Q, Erler JT, Giaccia A (2007) Tumor hypoxia and metastasis in non-small-cell lung cancers. JTO 2(8):S154– S155 Le QT, Moon J, Redman M, Williamson SK, Lara PN Jr, Goldberg Z, Gaspar LE, Crowley JJ, Moore DF Jr, Gandara DR (2009) Phase II study of tirapazamine, cisplatin, and etoposide and concurrent thoracic radiotherapy for limitedstage small-cell lung cancer: SWOG 0222. J Clin Oncol 27(18):3014–3019 Lee DJ, Cosmatos D, Marcial VA et al (1995) Results of an RTOG phase III trial (RTOG 85-27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head- and neck-carcinomas. Int J Radiat Oncol Biol Phys 32(3):567–576 Leyland-Jones B (2003) BEST Investigators and Study Group, Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 4:459–460 Liu W, Chen Y, Wang W et al (2003) Combination of radiation and celebrex (celecoxib) reducemammary and lung tumor growth. Am J Clin Oncol 26(4):S103–S109 Liu SK, Coackley C, Krause M et al (2008) A novel poly(ADPribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia. Radiother Oncol 88(2):258–268 Loriot Y, Mordant P, Brown BD et al (2010) Inhibition of BCL2 in small cell lung cancer cell lines with oblimersen, an antisense BCL-2 oligodeoxynucleotide (ODN): in vitro and in vivo enhancement of radiation response. Anticancer Res 30(10):3869–3878 MacRae R, Shyr Y, Johnson D (2002) Declining hemoglobin during chemoradiotherapy for locally advanced non-small cell lung cancer is significant. Radiother Oncol 64(1):37–4 Manegold C, von Pawel J, Zaitloukal P et al (2008) B017704: a phase III randomized study of first-line bevacizumab combined with cisplatin/gemcitabine (CG) in patients (pts) with advanced or recurrent non-squamous, non-small cell lung cancer (NSCLC). Ann Oncol 19:viii1 Marks PA, Richon VM, Rifkind RA et al (2000) Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. JNCI J Natl Cancer Inst 92(15):1210–1216 Moretti L, Li B, Kim KW et al (2010) AT-101, a pan-Bcl-2 inhibitor, leads to radiosensitization of non-small cell lung cancer. J Thorac Oncol 5(5):680–687 Mok TS, Wu YL, Thongprasert S et al (2009) Gefitinib or carboplatin paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957

221 Nagata Y, Takahashi A, Ohnishi K et al (2010) Effect of rapamycin, an mTOR inhibitor, on radiation sensitivity of lung cancer cells having different p53 gene status. Int J Oncol 37(4):1001–1010 Nishimura Y, Nakagawa K, Takeda K et al (2007) Phase I/II Trial of sequential chemoradiotherapy using a novel hypoxic cell radiosensitizer, Doranidazole (PR-350), in patients with locally advanced non–small-cell lung cancer (WJTOG0002). IJROBP 69(3):786–792 Ohsaki Y, Tanno S, Fujita Y et al (2000) Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression. Oncol Rep 7:603–607 Overgaard J (1994) Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors. Oncol Res 6:509–518 Overgaard J, Hansen HS, Overgaard M et al (1998) A randomized double-blind Phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish head and neck cancer study (DAHANCA) protocol 5–85. Radiother Oncol 46:135–146 Park SY, Kim YM, Pyo H (2010) Gefitinib radiosensitizes nonsmall cell lung cancer cells through inhibition of ataxia telangiectasia mutated. Mol Cancer 9:222 Rischin D, Peters LJ, O’Sullivan B et al (2010) Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the TransTasman Radiation Oncology Group. J Clin Oncol 28(18):2989–2995 Roa W, Chen H, Alexander A et al (2005) Enhancement of radiation sensitivity with BH3I-1 in non-small cell lung cancer. Clin Invest Med 28(2):55–63 Robnett TJ, Machtay M, Hahn SM et al (2002) Pathological response to preoperative chemoradiation worsens with anemia in non-small cell lung cancer patients. Cancer J 8:263–267 Rubin P, Hanley J, Keys HM et al (1979) Carbogen breathing during radiation therapy. The RTOG study. IJROBP 5:1963–1970 Sanli T, Liu C, Rashid A et al (2011) Lovastatin sensitizes lung cancer cells to ionizing radiation: modulation of molecular pathways of radioresistance and tumor suppression. J Thorac Oncol 6(3):439–450 Scott C, Suh J, Stea B et al (2007) Improved survival, quality of life, and quality-adjusted survival in breast cancer patients treated with efaproxiral (Efaproxyn) plus whole-brain radiation therapy for brain metastases. AJCO 30(6):580–587 Shannon AM, Telfer BA, Smith PD et al (2009) The mitogenactivated protein/extracellular signal-regulated kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) enhances the radiation responsiveness of lung and colorectal tumor xenografts. Clin Cancer Res 15:6619–6629 Sobolewski C, Cerella C, Dicato M et al (2010) The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies. Int J Cell Biol 2010:215158 Suh JH, Stea B, Nabid A et al (2006) Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. JCO 24(1):106–114 Tanaka T, Munshi A, Brooks C et al (2008) Gefitinib radiosensitizes non-small cell lung cancer cells by

222 suppressing cellular DNA repair capacity. Clin Cancer Res 14(4):1266–1273 Toulany M, Kehlbach R, Florczak U et al (2008a) Targeting of AKT1 enhances radiation toxicity of human tumor cells by inhibiting DNA-PKcs-dependent DNA double-strand break repair. Mol Cancer Ther 7(7):1772–1781 Toulany M, Dittmann K, Fehrenbacher B et al (2008b) PI3KAkt signaling regulates basal, but MAP-kinase signaling regulates radiation-induced XRCC1 expression in human tumor cells in vitro. DNA Repair 7(10):1746–1756 Tsao MS, Sakurada A, Cutz JC et al (2005) Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 353(2):133–144 Turrisi AT, Kim K, Blum R et al (1999) Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340(4):265–271 Vansteenkiste J, Pirker R, Massuti B et al (2002) Double-blind, placebo-controlled, ran-domized phase III trial of darbepoetin-alfa in lung cancer patients receiving chemotherapy. JNCI 94:1211–1220 Vansteenkiste J, Van Cutsem E, Dumez H et al (2008) Early phase II trial of oral vorinostat in relapsed or refractory breast, colorectal, or non-small cell lung cancer. Invest New Drugs 26(5):483–488

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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

12

Contents

Concluding Remarks ............................................... 238

References.......................................................................... 239 1

Introduction.............................................................. 224

2 2.1 2.2 2.3 2.4 2.5

Thiols as Radioprotective Agents .......................... Amifostine: Preclinical Findings............................... Amifostine: Clinical Studies ..................................... Amifostine: Meta-Analyses of Clinical Studies ....... Amifostine: Route of Administration ....................... Amifostine: Quality of Life Studies .........................

225 226 227 229 230 231

3 Prostanoids, COX-2 and COX-2 Inhibitors ......... 231 3.1 Clinical Trials of COX-2 Inhibitors for Lung Cancer ........................................................ 232 4 4.1 4.2 4.3 4.4

Growth Factors and Cytokines.............................. Basic Fibroblast Growth Factor ................................ Keratinocyte Growth Factor...................................... Interleukin-11............................................................. Epidermal Growth Factor Receptor..........................

233 233 233 234 234

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: [email protected] K. A. Mason L. Milas Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Abstract

Lung cancer is the leading cause of cancer death in most developed countries. The prognosis remains poor with an overall survival rate at 5 years of only about 15%. Between 70 and 85% of all cases are histologically classified as non-small cell lung carcinoma (NSCLC). Radiation therapy has traditionally been the treatment of choice for locally advanced disease and medically inoperable early stage NSCLC. However radiation therapy alone was not effective treatment for patients with locally advanced NSCLC. The addition of cytotoxic drugs to radiotherapy considerably improves treatment outcome, and the combination of chemotherapy with radiotherapy has become common 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 radiation 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 cisplatin-based drug combinations. However, concurrent chemoradiotherapy has increased significant


223

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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 mechanism 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, Pentoxifylline, Angiotensin-Converting Enzyme Flavopiridol Poly(ADP-Ribose) Polymerase, Bcl-2 , and Efaproxaril, 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 nonsmall cell lung carcinoma (NSCLC), which comprises squamous cell, adenocarcinoma, large cell, or undifferentiated 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 dissemination. 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 considerably 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

achieved by reducing cell burden in tumors undergoing 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) chemotherapy 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 treatment (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 survival 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 chemoradiotherapy and clearly demonstrated the therapeutic superiority of the latter approach (Schaake-Konig et al. 1992; Curran et al. 2003), concurrent chemoradiotherapy 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 therapeutic 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

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

Phosphorothioates

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 concurrent (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 biological 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 radioprotective effects of amifostine. Additional information 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 chemical 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-mediated 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-

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dependent (Travis 1984). Another mode of protection occurs via H-atom donation (the fixation–repair model). Thiols compete with oxygen for radiationinduced DNA radicals. DNA radicals are ‘‘fixed’’ (not repaired) by reacting with oxygen and potentially harmful hydroxyperoxides may be generated. However, DNA radicals can be chemically repaired when they react with thiols by donation of hydrogen (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 ionizing 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 radioprotective 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 administration, 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 amifostine 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

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 biochemical 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 bloodbrain 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 therapeutic gain of radiotherapy. The mechanism of amifostine’s selective or preferential protection of normal tissues is related to


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 phosphatase necessary for uptake and conversion of amifostine 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, amifostine 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-damaging agents such as radiation. In addition to interacting 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 amifostine 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

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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 carboplatin) and radiation treatment plus/minus daily amifostine given iv at 300 mg/m2 15 to 20 min before each fraction of radiotherapy and before chemotherapy in patients with locally advanced lung cancer. The results showed that amifostine significantly reduced the incidence of severe (grade C3) radiationinduced 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 whether 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 conversely 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 chemoradiotherapy alone but in no patients that received amifostine in addition to chemoradiotherapy. Consistent with findings from other studies, hypotension

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Table 2 Randomized trials of amifostine for lung cancer Reference

No. of patients

Radiation dose

Chemotherapy

Amifostine dose

Comments

Movsas et al. (2005)

242

69.6 Gy at 1.2 Gy twice daily, days 43–78

Induction P ? C 9 2; concurrent weekly C

500 mg iv 4 9 per week between twicedaily RT fractions

No difference in esophagitis but improved self-reported swallowing and weight loss Median survival, 15.6 months with versus 17.9 months without amifostine

Antonadou et al. (2001)

146

55–60 Gy at 2.0 Gy once daily

340 mg/m2 daily before RT

None

; pneumonitis ; esophagitis (no survival data)

300 mg/m daily before chemoRT and RT

; esophagitis (P \ 0.001)

Concurrent P ? C q week 9 7; gemcitabine and cisplatin 9 3 after chemoradiation

500 mg iv before weekly chemo; 200 mg iv daily before RT

No difference in toxicity, no survival data (ongoing trial)

Concurrent iv cisplatin day 1, 8, 29, 36

500 mg iv day 1 and 2 each week before chemo and first RT fraction

; degree of esophagitis

55–60 Gy at 2.0 Gy once daily

Concurrent weekly P or C

63

64.8 Gy at 1.8 Gy once daily, beginning on day 1

62

69.6 Gy at 1.2 Gy twice daily, beginning on day 1

Antonadou et al. (2003)

73

Senzer (2002)

Komaki et al. (2004a)

2

; pneumonitis (P = 0.009) (no survival data)

Etoposide po days 1–5 8–12, 29–33, 36–40

Leong et al. (2003)

60

60–66 Gy at 2.0 Gy once daily, beginning on day 43

Induction P ? C 9 2; concurrent weekly P

; pneumonitis ; neutropenic fever Median survival, 19 months with versus 20 months without amifostine)

740 mg/m2 with each chemo (day 1, 22, 43, 50, 57, 64, 71, 78)

Esophagitis grade 2–3 43% in amifostine group, 70% in control group (not 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 demonstrated 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 radiotherapy (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 neutropenia, but interestingly patient self-assessments indicated that amifostine was associated with clinically meaningful improvements in swallowing and pain. Amifostine did not reduce the rates of severe


Percent Experiencing Toxicity

50

40

30 Control Amifostine 20

10

0

Mild

Moderate

Severe

Degree of Esophageal Toxicity

Percent Experiencing Toxicity

Fig. 1 Effect of amifostine on the severity of esophageal toxicity induced by chemoradiotherapy in patients with nonsmall cell lung cancer (modified from Komaki et al. 2004a, with permission)

100 80 60

Control Amifostine

40 20 0

Constipation

Pneumonitis

Neutropenic fever

Fig. 2 Effect of amifostine on the incidence of constipation, pneumonitis, and neutropenic fever caused by chemoradiotherapy 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 amifostine are intriguing, the median follow-up times have been relatively short and none of the randomized controlled trials conducted to date has been powered to address the question of whether amifostine, in addition

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to having protective effects on normal tissues, would also have protective effects on tumors, thereby affecting the efficacy of therapy. To date, three meta-analyses have been conducted to address this question. In the first of these analyses (Sasse et al. 2006), the investigators reviewed 14 randomized trials (1451 patients) that compared radiation with or without amifostine for treatment of a variety of types of cancer. They found that the use of amifostine significantly reduced the risk of developing mucositis, esophagitis, acute xerostomia, late xerostomia, dysphagia, acute pneumonitis, and cystitis. Although no difference in the overall response rate was noted between the amifostine and no-amifostine groups, the complete response rate was thought to be superior for patients using amifostine. The next meta-analysis focused specifically on patients with locally advanced NSCLC who had been treated with radiation or chemoradiation with or without amifostine or a placebo (Mell et al. 2007). This analysis of six studies (552 patients) revealed that amifostine was associated with slightly improved 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 response in locally advanced NSCLC. 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 metaanalysis, 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 progressionfree survival in patients treated with radiation or chemoradiation therapy—in other words, that amifostine had no tumor-protective effect. They did note that any benefit in terms of reduced radiationinduced toxicity from amifostine must be weighed against the costs and side effects of this agent, particularly given the ongoing improvements in technologies that allow better sparing of normal tissues (Brizel 2007).

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R. Komaki et al. A. % Survival

100 P=0.99

75

Amifostine

50 25

Control

0

0

B.

1

2

3

100

% LR Control

Fig. 3 Kaplan–Meier survival curves showing the effect of amifostine on a overall survival rate, b local-regional (LR) tumor control, and c distantmetastasis (DM)-free survival among patients with nonsmall cell lung cancer after chemoradiotherapy (modified from Komaki et al. 2004a, with permission)

P=0.39

75 Control

50 25

Amifostine

0

2.4

% DM-Free Survival

0

C.

1

2

3

100 P=0.77

75 Control

50 25

Amifostine

0

0

Amifostine: Route of Administration

Although most of the larger clinical trials of amifostine 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 amifostine 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, tolerance, 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 tolerated, effectively reduced the early toxicity of radiotherapy, and prevented treatment-induced delays. Patients reported a reduction in hypotension and nausea as compared with intravenous administration.

1

2

3

Another study by the same group showed that subcutaneous 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 subcutaneous 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 chemoradiation 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 subcutaneous 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.


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 treatment 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 prostaglandin 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 immunosuppressive substance, is the major prostaglandin involved. PGE2 is produced in abundance by pro-inflammatory

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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 proinflammatory 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 antiinflammatory 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. Interestingly, 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 prostaglandin 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 suggestive evidence that giving the inhibitor during the development phase of acute pneumonitis may reduce either the latency or severity of lung injury. It should

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be emphasized that even in the absence of lung radioprotection by COX-2 inhibitors, their administration 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 associated 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 celecoxib 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 carboplatin for previously untreated stage III NSCLC

(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 combining 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 combining 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 combination 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 evaluable for tumor response, 14 had complete response, 13 had partial responses, and 10 had stable or progressive 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-inflammatory drugs used for symptomatic treatment of radiation-induced pneumonitis. They inhibit production of all prostanoids because, in addition to their ability to


inhibit COX enzymes, they prevent release of arachidonic acid from membrane phospholipids by stimulating the generation and secretion of lipocortins. (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 development 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.

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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 endothelial cells against radiation-induced apoptosis. Histologic 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 radiation-induced pneumonitis were absent in mice treated 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 proliferation 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 bleomycin-induced fibrosis and in improving the survival of treated animals. Significant protection was also rendered against the damage inflicted by the combination of bleomycin plus radiation treatment. A more recent

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study (Terry et al. 2004) showed that a single intratracheal 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 chemotherapy 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 antiEGFR 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 cetuximab 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 cetuximab 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).

That study, which involved 93 patients (87 evaluable) with unresectable NSCLC and good performance status receiving 63 Gy in combination with weekly carboplatin 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 radiation and chemotherapy have also produced encouraging 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., bevacizumab) 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 twodrug 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, regulation of tissue-damaging cytokines such as TNFa, and enhancement of blood flow in injured microvasculature. 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 pentoxifylline was modestly effective, increasing the median time to relapse by 2 months and the median survival time from 7 to 18 months. Although pentoxifylline


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 prophylactic 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 radiation 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 vitamin 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

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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 hypoperfusion 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 fractionated 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 progressive functional deterioration of the heart after irradiation. Mechanisms of captopril-mediated radioprotection 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 irradiation and cyclophosphamide as a model of bone marrow transplantation has implicated the inflammatory 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 inhibitors 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 hypertension 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

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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 (Camphausen 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 fractionated 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 therapeutic gain was achieved when flavopiridol was initiated either before or after the start of irradiation and that this compound showed promising clinical potential administered 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 adenocarcinoma cells (2006) and ovarian cancer cells (2003) in vitro and sharply enhanced the radioresponse of SEG-1 tumor xenografts (2006). Their findings further 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 radiosensitizing 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

agents. In a preclinical study (Kim et al. 2004), treating mice bearing H460 lung carcinoma xenografts with docetaxel and flavopiridol significantly enhanced the effects of radiation, with the effects being greatest when docetaxel was given first, followed 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 endometrial 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 lymphomas, 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, fluorouracil, 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 responsiveness of tumor-cells to chemotherapy and radiation is determined by a combination of genetic factors, particularly those that modify cell cycle arrest, repair of DNA damage, or cell death, and microenvironmental factors such as hypoxia. Experimental evidence from


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 radiosensitization 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 combinations have been associated with severe, doselimiting 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 radiosensitization 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 radioresponsive. 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 radioresponsive 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

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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 tumorcell proliferation and vascular density to a greater extent than radiation alone. These investigators concluded 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 synthetic molecule that noncovalently binds to hemoglobin, 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 partitioning 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 efaproxaril to whole-brain irradiation for patients with brain metastases from breast cancer was also associated with improvements in quality of life and qualityadjusted survival (Scott et al. 2007).

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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 superoxide 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 overwhelm 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 administration of SOD can prevent radiation injury (Petkau 1987) and can even reduce preexisting radiationinduced 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 elevation 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. Intraesophageal 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

organizing alveolitis (Epperly et al. 1999). Intratracheal MnSOD-PL gene therapy also reduced radiationinduced inflammatory cytokines without rendering protection to orthotopic Lewis lung cancer models (Guo et al. 2003). Preclinical animal studies suggested that radioprotective gene therapy reduces radiationinduced toxicity and may facilitate dose-escalation protocols to improve the therapeutic ratio of lung cancer radiotherapy. However, the efficacy and specificity 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 treatmentrelated 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 radioprotective 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 reductions in the incidence and severity of esophagitis and pneumonitis. The agents discussed have complex mechanisms of action and affect a variety of radiation-induced tissue reactions both directly and indirectly. 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


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 radiation 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 tissues with radioprotectors.

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R. Komaki et al. Thienelt CD, Bunn PA Jr, Hanna N et al (2005) Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small-cell lung cancer. J Clin Oncol 23:8786–8793 Travis E (1984) The oxygen dependence of protection by aminothiols: implications for normal tissues and solid tumors. Int J Radiat Oncol Biol Phys 10:1495–1501 Travis EL, Thames HD Jr, Tucker SL et al (1985) Late functional and biochemical changes in mouse lung after irradiation: differential effects of WR-2721. Rad Res 103: 219–231 Turrisi AT, Kim K, Blum R et al (1999) Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:265–271 Ulich TR, Yi ES, Longmuir K et al (1994) Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo. J Clin Invest 93:1298–1306 Utley JF, Seaver N, Newton GL et al (1984) Pharmacokinetics of WR-1065 in mouse tissue following treatment with WR2721. Int J Radiat Oncol Biol Phys 10:1525–1528 Viani GA, Manta GB, Fonseca EC et al (2009) Whole brain radiotherapy with radiosensitizer for brain metastases. J Exp Clin Cancer Res 28:1 Vujaskovic Z, Feng Q, Rabbani ZN et al (2002a) Assessment of the protective effect of amifostine on radiation-induced pulmonary toxicity. Exp Lung Res 28:577–590 Vujaskovic Z, Feng Q, Rabbani ZN et al (2002b) Radioprotection of lungs by amifostine is associated with reduction in profibrogenic cytokine activity. Radiat Res 157: 656–660 Wang LW, Fu XL, Clough R et al (2000) Can angiotensionconverting enzyme inhibitors protect against symptomatic radiation pneumonitis? Radiat Res 153:405–410 Wang R, Kagan R, Tome M (2004) Subcutaneous amifostine during radiation or chemoradiation for the treatment of head and neck cancers. ASCO Annual Meeting Proceedings. J Clin Oncol 22(14S):8154 Ward HE, Kemsley L, Davies L et al (1992a) The effect of steroids on radiation-induced lung disease in the rat. Radiat Res 136:22–28 Ward WF, Kim YT, Molteni A et al (1988) Radiation-induced pulmonary endothelial dysfunction in rats: modification by an inhibitor of angiotensin converting enzyme. Int J Radiat Oncol Biol Phys 15:135–140 Ward WF, Kim YT, Molteni A et al (1992b) Pentoxifylline does not spare acute radiation reactions in rat lung and skin. Radiat Res 129:107–111 Ward WF, Lin PP, Wong PS et al (1993) Radiation pneumonitis in rats and its modification by the angiotension-converting enzyme inhibitor captopril evaluated by high resolution computer tomography. Radiat Res 135: 81–87 Ward WF, Molteni A, Ts’ao C et al (1990a) Captopril reduces collagen and mast cell accumulation in irradiated rat lung. Int J Radiat Oncol Biol Phys 19:1405–1409 Ward WF, Molteni A, Ts’ao C et al (1990b) The effect of captopril on benign and malignant reactions in irradiated rat skin. Br J Radiol 63:349–354 Ward WF, Molteni A, Ts’ao C et al (1992c) Radiation pneumotoxicity in rats: modification by inhibitors of

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

Contents

Abstract

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 ................................. Histology-based treatment of advanced Non-Small Cell Lung Cancer ...................................................... Maintenance therapy ................................................. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors .................................................................... Mechanisms of Resistance to Epidermal Growth Factor Receptor ........................................................

6.1 6.2 6.3 6.4

251 252 252 254 256

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: [email protected]

Worldwide, approximately 1.6 million new cases of lung cancer are diagnosed each year. It continues 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 types, nonsquamous carcinoma and squamous cell carcinoma, the former including adenocarcinoma, large cell carcinoma, bronchioloalveolar carcinoma, and poorly differentiated histological subtypes. Most patients present after NSCLC have spread to regional or distant sites. Patients presenting 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 regimens 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 maintenance therapy in patients with advanced disease


247

248

following four cycles of combination chemotherapy 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 regulatory 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 hypertension. It remains to be seen whether the combination of VEGF TKI and chemotherapy will surpass the efficacy seen with bevacizumab-chemotherapy 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 associated 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 wildtype 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 adenocarcinoma, bronchioloalveolar carcinoma, squamous 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 treatment 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 failure. 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 Metaanalysis 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.

4

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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 micrometastatic 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) demonstrated 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 limited 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 usually recommended (Pignon et al. 2008). Cisplatin-based combination therapy is the ‘standard of care’ in the adjuvant setting. Whether carboplatin 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,

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C. P. Belani

Table 1 Adjuvant chemotherapy for early stage resected NSCLC Adjuvant lung project Italy(ALPI) (Scagliotti 2005)

Big lung trial(BLT) (Stephens et al. 2002)

International adjuvant lung trial(IALT) (Arriagada et al. 2004)

JBR 10 National Cancer Institute of Canada (Winton et al. 2005)

Adjuvant navelbine international trialist association (ANITA) (Douillard et al. 2006)

Design

MVPa vs. observation

Cisplatin doublet vs. observation

Cisplatin doublet vs. observation

Cisplatin vinorelbine vs. observation

Cisplatin vinorelbine vs. observation

Median PFS

36.5 vs. 28.9 months HR 0.89; P = 0.128

27 vs. 24.7 months HR 0.97; P = 0.81

–

-

36.3 vs. 20.7 months HR 0.8; P = 0.017

Median survival

55.2 vs. 68 months HR 0.96; P = 0.589

33.9 vs. 32.6 months HR 1.02; P = 0.9

–

94 vs. 73 months HR 0.69; P = 0.04

65.7 vs. 43.7 months HR 0.8; P = 0.017

5-year Survival

–

–

44.5 vs. 40.4% HR 0.86; P \ 0.03

–

–

Comment

No benefit

No benefit

Overall 4.1% absolute benefit in survival

Benefit limited to stage II patients

Degree of benefit higher with stage

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 induction 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 versus 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 preoperative 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 evaluated by immunohistochemistry for ERCC1 expression (Olaussen et al. 2006). Patients with high ERCC1 expression did not appear to derive benefit from cisplatin-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 evaluate treatment selection based on ERCC1 expression for patients with early stage NSCLC.


In the adjuvant setting, epidermal growth factor receptor (EGFR) inhibitors have also been investigated for patients with resected early stage NSCLC. Though gefitinib as adjuvant therapy failed to demonstrate 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 completed accrual and the results are eagerly awaited. A combination of bevacizumab with standard chemotherapy 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 chemotherapy 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 controversies 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 symptoms, 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 recognized 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 performance status (ECOG 2, 3 or 4) have short median survival duration of approximately 4 months (Ruckdeschel et al. 1986). Systemic therapy remains the mainstay or treatment of advanced stage NSCLC. Combination chemotherapy 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 regimens 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, vinorelbine, 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

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efficacy of four commonly used combination regimens in the treatment of advanced NSCLC (Schiller et al. 2002). Cisplatin–docetaxel, cisplatin–gemcitabine, and carboplatin–paclitaxel were all associated with comparable efficacy parameters to that of the control arm of cisplatin–paclitaxel. These observations, supported by findings of other contemporaneous 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 platinumbased 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-histology of NSCLC is a new paradigm. Scagliotti et al. (2008b) showed that cisplatin-pemetrexed combination 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 cisplatin–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

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 adenocarcinoma compared to squamous or small cell carcinoma (Scagliotti et al. 2009). Another novel chemotherapeutic agent, albuminbound 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 accumulation 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 chemotherapy 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 treatment 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 chemotherapy 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


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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. (2006)

Park et al. (2007)

Belani et al. (2010)

Design

MVP 9 3 cycles vs. MVP 9 6 cycles

PC 9 4 cycles vs. PC until progression

GC vs. GC followed by G

PC 9 4 cycles vs. PC 9 6 cycles

GC followed by BSC vs. GC followed by G

PFS

5 vs. 5 months

–

5 vs. 6.6 months P = 0.0001

6.2 vs. 4.3 months P = 0.001

7.4 vs. 7.7 months P = 0.575

OS

6 vs. 7 months

8.5 vs. 6.6 P = 0.63

11 vs. 13 months P = 0.469

15 vs. 16 months P = 0.469

8 vs. 9.3 months P = 0.838

Table 3 Clinical trials of switch maintenance in advanced NSCLC Westeel et al. (2005)

Fidias et al. (2009)

SATURN trial (Cappuzzo et al. 2010)

ATLAS trial (Miller et al. 2009)

IFCT-GFPC0502 (Perol et al. 2010)

Design

MIC vs. MIC followed by V

GC followed immediately by D vs. GC followed by D at progression

Platinum doublet followed by placebo vs. Erlotinib

Platinum doublet ? Bevacizumab followed by: Bevacizumab vs. Erlotinib ? Bev

GC followed by BSC vs. G vs. Erlotinib

PFS

5 vs. 3 months P = 0.32

5.7 vs. 2.7 months P = 0.001

11.1 vs. 12.3 weeks P = 0.001

4.76 vs. 3.75 P = 0.0012

2.9 vs. 1.9 months erlotinib (P = 0.002) 3.8 vs. 1.9–G (P = 0.001)

OS

10.4 vs. 11 months

12.3 vs. 9.7 months P = 0.853

12 vs. 11 months P = 0.088

15.9 vs. 13.9 months 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 maintenance 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 setting in responding and stable patients [progressionfree 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 activating mutations in the EGFR TK domain although it is modest at best in the overall populations. Both Pemetrexed and erlotinib have established the foundation 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 improvement 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 evaluating maintenance are the paramount trial and the POINTBREAK STUDIES (Figs. 1, 2). These will provide further insights into this new treatment paradigm. 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

C. P. Belani

Fig. 1

Fig. 2

has not been established (Sandler et al. 2006; Pirker et al. 2009). Prolonged use of the targeted agent following 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 carboplatin, 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

it to second-line therapy and lack of crossover to the ‘‘agent’’ is the placebo arm at progression will continue 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


255

Table 4 First-line therapy with EGFR TKIs for advanced NSCLC: Randomized studies in enriched patient populations Trial

Selection method

Design

PFS

OS

(WJTOG3405a Trial) (Mitsudomi et al. 2010)

EGFR mutation

Gefitinib vs. cisplatin/ docetaxel

9.2 vs. 6.3 months P \ 0.0001

Not reported

Rosell et al. (2009)

EGFR mutation

Erlotinib

14.0 months (95% CI, 11.3-16.7)

27.0 months (95% CI, 22.7–31.3)

Maemondo et al. (2010)

EGFR mutation

Gefitinib vs. carboplatin/ paclitaxel

10.8 vs. 5.4 months P \ 0.001

30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P = 0.31)

Mok et al. (2009)

Clinical characteristics

Gefitinib vs. carboplatin/ paclitaxel

5.7 m vs. 5.8, HR 0.74, months P \ 0.001

18.6 vs. 17.3 months HR 0.91

First Signal Trial (Lee et al. 2009)

Clinical characteristics

Gefitinib vs. cisplatin/ gemcitabine

6.6 vs. 6.1 months P = 0.044

21.3 vs. 23.3 P = 0.420

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 evaluation (ISEL) study as they had more aggressive/progressive disease but the subsets of never-smokers/ Asian ethnicity demonstrated a benefit. Clinical characteristics for response to EGFR TKIs in the early trials included female sex adenocarcinoma histology, neversmokers, 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 population 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 TKIs

C. P. Belani Drug

Class

Targets

Status

BIBW 2992

EGFR/HRE2

EGFR and HER2

Phase III

HKI-272

EGFR/HER2

EGFR and HER2

Phase II

EKB-569

EGFR/HER2

EGFR and HER2

Phase II

CI-1033

Pan-ErbB

EGFR, HER2, and HER4

Phase II

PF00299804

Pan-ErbB

EGFR, HER2, and HER4

Phase II

AV-412/MP-412 EGFR/HER2 EGFR and HER2 EGFR epidermal growth factor receptor, TKIs tyrosine kinase inhibitors

addition, thin trials have also established the necessity 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 beneficial 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.

6.4

Phase I

Mechanisms of Resistance to Epidermal Growth Factor Receptor

The efficacy of EGFR inhibitors is limited by primary and acquired resistance. Primary resistance to erlotinib and gefitinib has been associated with inframe 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. Secondary 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 resistance (Balak et al. 2006). Also, as a result of genetic heterogeneity the clones with activating mutation may decrease or disappear during treatment 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 inhibitors 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).


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 ARQ197, a small molecular C-MET (Schiller et al. 2010) demonstrated a significant improvement in progression-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 antiangiogenic agents for the treatment of NSCLC. Continuing the common trend in clinical investigations, 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 anticancer 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 evaluated 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 progressionfree survival and OS were all improved with the

257

addition of 15 mg/kg dose of bevacizumab to chemotherapy. 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 regimen 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 randomized study to document an improvement in OS with the addition of a targeted agent to chemotherapy 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 gemcitabine 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

C. P. Belani

Table 6 Bevacizumab in combination with chemotherapy for advanced NSCLC Author

Regimen

Phase

Response rate (%)

Median PFS (m)

Median survival (m)

Sandler et al. (2006)

Carboplatin, paclitaxel ? Bevacizumab

III

35

6.2

12.3

15

4.5

10.3

III

34

6.7

13.6

Cisplatin, gemcitabine ? Bevacizumab (15 mg/kg)

30

6.5

13.4

Cisplatin, gemcitabine

20

6.1

13.1

Carboplatin, paclitaxel Reck et al. (2009)

Cisplatin, gemcitabine ? Bevacizumab (7.5 mg/kg)

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 bevacizumab 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, subsequent 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 therapy. The safety of bevacizumab has also been documented 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 associated 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

a trend towards higher treatment-related deaths in patients C70 years of age (Ramalingam et al. 2008). This calls for careful evaluation of patient performance 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 bevacizumab with thoracic radiotherapy, since trachealesophageal 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 cisplatin-based chemotherapy with or without concurrent 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.


259

vandetanib is an active agent in the treatment of

9

Other Vascular Endothelial Growth advanced NSCLC. However, given the relatively modest efficacy, it is unlikely to be useful for routine Factor Receptor Inhibitors

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 improvement 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 heavily 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

clinical care in any of the settings mentioned here. An ongoing phase III study compares vandetanib to placebo 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 cediranib, 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 combination 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 randomized phase II study (Blumenschein et al. 2009b). The two treatment arms were associated with comparable efficacy though there was some distinct additional toxicity with the oral agent. All of these agents have varying inhibitory concentrations, bioavailability, 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

C. P. Belani

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 adenocarcinoma 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 deacetylase) 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 prevailing 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 decades. 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.

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 chemotherapy-sensitive disease (von Pawel et al. 1999). Higher response rate than that with topotecan has been noted with amrubicin, an anthracycline derivative, in phase II studies for refractory SCLC. This is now being evaluated in a phase III study for secondline 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 limitedstage 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 consideration 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 chemotherapy 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 personalized approaches to treatment. Deciphering of the dominant oncogenic drivers in the tumors from patients with lung cancer and increase in the knowledge of lung cancer biology will be of utmost importance in guiding various treatment methods and strategies.


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Combined Radiotherapy and Chemotherapy: Theoretical Considerations and Biological Premises Branislav Jeremic, Dusan Milanovic, and Nenad Filipovic

Contents 1

Introduction.............................................................. 267

2

Exploitable Mechanisms ......................................... 268

3

Implications from Clinical Evidence..................... 269

4

Future Consideration .............................................. 271

Abstract

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 radiobiological premises of combined radiation and chemotherapy. Both are 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 radiation therapy and chemotherapy can interact were established including spatial cooperation, independent cell kill, protection of normal tissues and enhancement of tumor response, the latter frequently replaced by terms such as radiosensitization 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.

References.......................................................................... 272

B. Jeremic (&) Institute of Lung Diseases, Sremska Kamenica, Serbia e-mail: [email protected] D. Milanovic Department of Radiation Oncology, University of Freiburg, Freiburg, Germany N. Filipovic Bioengineering Research Centre, Kragujevac, Serbia

1

Introduction

Over the past several decades combined radiation therapy and chemotherapy have been increasingly used in many human cancers. Increasing evidence had been mounting in various tumour sites such as head


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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 radiation and chemotherapy have also been intensively investigated, particularly in locally advanced stage III nonsmall cell lung cancer (NSCLC) and limiteddisease small cell lung cancer. The rationale for combining radiation and chemotherapy in clinic is to achieve improved treatment outcome. This designation 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 radiobiological premises of combined radiation and chemotherapy. Both are 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.

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 treatment 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 Independent cell kill (simple addition of anti-tumour effects) described. With it, an improvement in therapeutic result is sought. Provided that two anticancer agents

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 chemotherapy 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 otherwise has been described as Protection of normal tissues 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 radiation therapy and chemotherapy. Finally, the mechanism 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 radiation 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 (perturbation 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 (synergistic). 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, supraadditive (synergistic) effect is the effect of two independent 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 examples of ‘‘sensitization’’ or ‘‘potentiation’’ include attempts to overcome tumour hypoxia by using hypoxic 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 considerations 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 chemotherapy (following concurrent radiochemotherapy) in

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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 nonsmall 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) starting 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 rationale 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 therapy 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 (intrathoracic) tumour control. Although concurrent chemotherapy 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 significant improvement in survival owing to significant improvement in locoregional tumour control. If one now wants to put these data into the perspective of exploitable mechanisms of combined radiation therapy and chemotherapy, spatial cooperation was the only mechanism enabling the therapeutic

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benefit of induction regimens. No independent cell kill can be noted in any of the induction chemotherapy 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 reason, 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 regimens, 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 chemotherapy 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 accumulation 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 processes, 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 concurrent radiochemotherapy alone and the same concurrent 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 prospective randomized clinical trials show that exploitable mechanisms of combined radiotherapy and chemotherapy in locally advanced NSCLC may be seen as appropriately identified. From the discussion above, one may assume that concurrent radiochemotherapy 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 prospective 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 concurrent 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 consolidation 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 chemotherapy). 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 morbidity (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 magnitude 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 contemporary studies, using paclitaxel and carboplatin (LUN-56 and LUN-63) (Choy et al. 1998, 2000) it

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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 chemotherapy as the major factor contributing to much lower toxicity in contemporary concurrent radiochemotherapy regimens. Concurrent low-dose chemotherapy 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 performed at the same time, and using higher doses of concurrent chemotherapy, especially when late bronchopulmonary 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 bronchopulmonary 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-thanoptimal 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 inhibitors, HDAC inhibitors, m-TOR inhibitors, IGF-IR targeting therapies, COX-2 inhibitors, ALK targeted inhibitors, Aurora kinase and Polo-like kinase inhibitors 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 proven 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

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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 therapies, 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 sideeffects. 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 optimizing drug/compound delivery using nanotechnology offers substantial advantage over current means of transportation and drug/compound delivery. If so, this may shed a new light on possible drugrelated issues (e.g. metabolism, excretion, time to achieve certain plasma level as a surrogate for therapeutic efficiency) or time to achieve certain tumor concentration (deemed as necessary for certain level of radio enhancement) as well as various radiobiological 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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B. Jeremic et al. Brown JM (2001) Therapeutic targets in radiotherapy. Int J Radiat Oncol Biol Phys 49:319–326 Byhardt RW, Scott CB, Ettinger DS (1995) Concurrent hyperfractionated irradiation and chemotherapy for unresectable nonsmall cell lung cancer. Results of Radiation Therapy Oncology Group 90-15. Cancer 75:2337–2344 Byhardt RW, Scott C, Sause WT (1998) Response, toxicity, failure patterns, and survival in five Radiation Therapy Oncology Group (RTOG) trials of sequential and/or concurrent chemotherapy and radiotherapy for locally advanced non-small-cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 42:469–478 Chen Y, Pandya K, Keng PC, Johnstone D, Li J, Lee Y-J (2003) Phase I/II clinical study of pulsed paclitaxel radiosensitization for thoracic malignancy: a therapeutic approach on the basis of preclinical research of human cancer cell lines. Clin Cancer Res 9:969–975 Choy H, Akerley W, Safran H et al (1998) Multiinstitutional phase II trial of paclitaxel, carboplatin and concurrent radiation therapy for locally advanced nonsmall cell lung cancer. J Clin Oncol 16:3316–3322 Choy H, Devore RW 3rd, Hande KR et al (2000) A phase II study of paclitaxel, carboplatin and hyperfractionated radiation therapy for locally advanced inoperable nonsmall-cell lung cancer (a Vanderbilt Cancer Center Affiliate Network study). Int J Radiat Oncol Biol Phys 47:931–937 Clamon G, Herndon J, Cooper R (1999) Radiosensitization with carboplatin for patients with unresectable stage III nonsmall-cell lung cancer: a phase III trial of the Cancer and Leukemia group B and the Eastern Cooperative Oncology Group. J Clin Oncol 17:4–11 Curran WJ Jr, Scott C, Langer C, Komaki R, Lee JS, Hauser S (2000) Phase III comparison of sequential Vs cancer (NSCLC): initial report of Radiation Therapy Oncology Group concurrent chemoradiation for patients with unresected stage III non-small cell lung (RTOG). Proc Am Soc Clin Oncol 19:484a (Abstract 1891) Dillman RO, Seagren SL, Propert KJ, Guerra J, Eaton WL, Perry MC (1990) A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 323:940–945 Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y, Kudoh S (1999) Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine and cisplatin in unresectable stage III nonsmall-cell lung cancer. J Clin Oncol 17:2692–2699 Furuse K, Hosoe S, Masuda N, Sugiura S, Yokota K, Ohbayashi M (2000) Impact of tumor control on survival in unresectable stage III non-small cell lung cancer (NSCLC) treated with concurrent thoracic radiotherapy (TRT) and chemotherapy (CT). Proc Am Soc Clin Oncol 19:484a (Abstract 1893) Gandara DR, Chansky K, Albain KS et al (2006) Long-term survival with concurrent chemoradiation therapy followed by consolidation docetaxel in stage IIIB non-small-cell lung cancer: a phase II Southwest Oncology Group study (S9504). Clin Lung Cancer 8:116–121 Hanna N, Neubauer M, Yiannoutsos C, McGarry R, Arseneau J, Ansari R, Reynolds C, Govindan R, Melnyk A, Fisher W, Richards D, Bruetman D, Anderson T, Chowhan N, Nattam S,

Combined Radiotherapy and Chemotherapy: Theoretical Considerations and Biological Premises Mantravadi P, Johnson C, Breen T, White A, Einhorn L, Hoosier Oncology Group; US Oncology (2008) Phase III study of cisplatin, etoposide and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol 26:5755– 5760 Huang SM, Harari PM (1999) Epidermal growth factor receptor inhibition in cancer therapy: biology, rationale and preliminary clinical results. Invest New Drugs 17:259–269 Jeremic B, Shibamoto Y, Acimovic L, Djuric L (1995) Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III nonsmall-cell lung cancer. J Clin Oncol 13:452–458 Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S (1996) Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non small cell lung cancer: a randomized study. J Clin Oncol 14:1065–1070 Kishi K, Petersen S, Petersen C, Hunter N, Mason K, Masferrer JL (2000) Preferential enhancement of tumor radioresponse by a cyclooxygenase-2 inhibitor. Cancer Res 60:1326–1331 Komaki R, Scott C, Ettinger D et al (1997) Randomized study of chemotherapy/radiation therapy combinations for favorable patients with locally advanced inoperable nonsmall cell lung cancer: Radiation Therapy Oncology Group (RTOG) 92–04. Int J Radiat Oncol Biol Phys 38:149–155 Lau D, Leigh B, Gandara D, Edelman M, Morgan R, Israel V (2001) Twice-weekly paclitaxel and weekly carboplatin with concurrent thoracic radiation followed by carboplatin/ paclitaxel consolidation for stage III non-small-cell lung cancer: a California Cancer Consortium phase II trial. J Clin Oncol 19:42–447 Le Chevalier T, Arriagada R, Tarayre M, Lacombe-Terrier MJ, Laplanche A, Quoix W (1992) Significant effect of adjuvant chemotherapy on survival in locally advanced non small cell lung carcinoma. J Natl Cancer Inst 84:58 (letter) Lee JS, Scott C, Komaki R et al (1996) Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small-cell lung cancer Radiation Therapy Oncology Group protocol 91–06. J Clin Oncol 14:1055–1064 Milas L (2001) Cyclooxygenase-2 (COX-2) enzyme inhibitors as potential enhancers of tumor radioresponse. Semin Radiat Oncol 11:290–299

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Qiao WB, Zhao YB, Zhao YH, Wang RZ (2005) Clinical and dosimetric factors of radiation induced esophageal injury: radiation-induced esophageal toxicity. World J Gastroenterol 11:2626–2629 Raju U, Nakata E, Yang P, Newman RA, Ang KK, Milas L (2002) In vitro enhancement of tumor cell radiosensitivity by a selective inhibitor of cyclooxygenase-2 enzyme: mechanistic considerations. Int J Radiat Oncol Biol Phys 54:886–894 Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R (1995) Radiation Therapy Oncology Group 88– 08 and Eastern Cooperative Oncology Group 4588: preliminary results of a phase III trial in regionally advanced, unresectable nonsmall cell lung cancer. J Natl Cancer Inst 87:198–205 Schaake-Koning C, van der Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P (1992) Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med 326:524–530 Sekine I, Nokihara H, Sumi M, Saijo N, Nishiwaki Y, Ishikura S, Mori K, Tsukiyama I, Tamura T (2006) Docetaxel consolidation therapy following cisplatin, vinorelbine, and concurrent thoracic radiotherapy in patients with unresectable stage III non-small cell lung cancer. J Thorac Oncol 1:810–815 Socinski MA, Blackstock AW, Bogart JA, Wang X, Munley M, Rosenman J, Gu L, Masters GA, Ungaro P, Sleeper A, Green M, Miller AA, Vokes EE (2008) Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol 26:2457–2463 Steel GG, Peckham MJ (1979) Exploitable mechanisms in combined radiotherapy and chemotherapy: the concept of additivity. Int J Radiat Oncol Biol Phys 5:85–91 Vokes EE, Herndon JE 2nd, Crawford J, Leopold KA, Perry MC, Miller AA, Green MR (2002) Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non small-cell lung cancer: Cancer and Leukemia Group B study 9431. J Clin Oncol 20:4191–4198

Radiotherapy and Second Generation Drugs Michael Geier and Nicolaus Andratschke

Contents

Abstract

1

Introduction.............................................................. 275

2

Mechanism of Action of Second Generation Chemotherapeutic Agents and Their Interaction with Radiotherapy ................................................... Platinum Compounds (Cisplatin and Carboplatin) ............................................................... Etoposide.................................................................... Vincaalkaloide (Vinblastin, Vindesine) .................... Ifosfamide .................................................................. Mitomycin..................................................................

2.1 2.2 2.3 2.4 2.5

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 clinical investigation of combinded radiochemotherapy protocols with second generation chemotherapeutic drugs as a definitive treatment in inoperable NSCLC. Not for all substances used unequivocal experimental evidence for a true radiosensitizing effect could be demonstrated. Instead, the effects may result from independent additive cytotoxicity crucial for sterilizing clonogenic tumor cells surviving radiotherapy and a different non-overlapping toxicity profile. This chapter summarizes the preclinical data and early clinical evidence for the rational of combining second generation drugs with radiotherapy in advanced stage NSCLC.

276 276 276 277 277 277

3 Early Clinical Evaluation ....................................... 277 3.1 Sequential Radiochemotherapy ................................. 278 3.2 Concurrent Radiochemotherapy................................ 279 4

Summary................................................................... 287

References.......................................................................... 288

1

M. Geier N. Andratschke (&) Department of Radiation Oncology, Technical University of Munich, Munich, Germany e-mail: [email protected]

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 lung cancer (NSCLC) in curative intent is combined radiochemotherapy with platinum-based regimens. Effective protocols have emerged, though outcomes still remain unsatisfactory.


275

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M. Geier and N. Andratschke

Radiotherapy by itself is highly effective in eradicating 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 radioresistance such as sub-lethal damage repair, repopulation or intrinsic radiosensitivity. Furthermore chemotherapy has the potential to control an early stage of systemic cancer disease by sterilizing microscopic metastases. This is an important aspect in the treatment 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

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 platinum 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 transcription, 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 toposimerase 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 Catharanthus roseus/vinca rose—are a class of drugs that interfere with the formation and function of microtubuli 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 metaphase is induced. At higher concentrations microtubule 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 radiotherapy with the Vinblastine or Vindesine, i.e. supraadditive 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

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 radiationinduced 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 lavendulae, 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 preclinical studies administering Mitomycin C before radiation. The enhancement seemed to be related both to direct radiosensitization and independent cytotoxicity against radio-resistant hypoxic cells (Grau and Overgaard 1991).

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, including 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

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 chemotherapy. 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 aforementioned 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 employing low-dose platinum-based regimens were designed to exploit synergistic effects by close temporal cooperation as a results of daily or weekly administration 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 chemoradiation 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 normofractionated radiotherapy to a total dose of 60 Gy. Only 61% of the 61 enrolled patients completed the intended chemoradiation regimen. The results regarding 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 thrombocytopenia 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 chemoradiation arm and 30 in the radiotherapy arm. The addition

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 hyperfractionated 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).


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 chemotherapy 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 chemotherapy (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 combining two extra fractions of radiotherapy and four extra fractions at Level IV respectively with concurrent 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 granulocyte colony stimulating factor was used for hematopoietic 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 chemotherapy with high therapy-related toxicity and split-course radiotherapy did yield a disappointing outcome regarding locoregional progression and overall survival (Pujol et al. 1999). Another low-dose Cisplatin-based chemoradiotherapy 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 radiotherapy 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 disappointing 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 evaluating Carboplatin as radiosensitizer after Cisplatinbased induction chemotherapy in NSCLC patients with locally advanced disease. Induction of triple


chemotherapy consisting of Cisplatin, Mitomycin and a vinca alkaloid was followed by a standard fractionated 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 chemotherapy (350 mg/m2) was assessed in an phase I study of Kelly et al. including 30 patients with inoperable NSCLC. Chemotherapy consisted of daily Carboplatin 25 mg/m2 or 30 mg/m2 concurrent to radiotherapy. 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 thrombocytopenia 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 radiotherapy to a total dose of 66 Gy and concurrent daily Carboplatin chemotherapy with 15 mg/m2 administered 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 percent 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).

Number of patients

80

19

44

40

40

65

36

15

32

Author

Komaki et al. (1997)

Van den Brande et al. (1998)

Pujol et al. (1999)

van Harskamp et al. (1987)

Boven et al. (1988)

Hazuka et al. (1994)

Palazzi et al. (1996)

Sarihan et al. (1998)

Ardizzoni et al. (1999)

Standard fractionated

Concomittant boost

Hyperfractionated accelerated


Hypofractionated split-course



Hypofractionated


RTx

Cisplatin l.d. daily








Cisplatin

CTx

12.5

16

8

14

10.5

10.5

12

10.6

15.5

Overall survival, median (months)

52

37

56

49

47

65

1 year (%)

26

24

19

16

2 years (%)

Table 1 Summary of phase I/II studies with second generation chemotherapy concurrent to radiotherapy

19 (3 years)

5 (3 years)

5 years (%)

21 (RCTx), 31 (Induction CTx)

–

–

14

–

Thrombopenia 2

Neutropenia 66 (grade 4), leukopenia 34 (grade 4), thrombopenia 25 (grade 4)

Leukopenia 22

62 (grade 4)

Hematological toxicity C3 (%)

Esophageal 6

Nausea 60

Esophageal 14, late pulmonary 3 (grade 5)

Esophageal 16, nausea 8 (grade 3), nausea 6 (grade 4)

–

(continued)

Induction: Cisplatin, Vinblastine

Continuous concomittant: Cisplatin

Consolidation: Cispaltin;

Induction: Cisplatin, Ifosfamide, Etoposide Late pulmonary 23, esopahgeal 9

–

Induction: Cisplatin, Ifosfamide, Vindesine

Induction: Cisplatin, Vinblastine

Remarks

Neurotoxicity 18; pneumonitis 11

Esophageal 3

Nonhematological toxicity C3 (%)

Radiotherapy and Second Generation Drugs 281

Number of patients

40

29

40

30

19

76

82

30

21

Author

Uitterhoeve et al. (2000)

Thomas et al. (1997)

Bardet et al. (1997)

Kelly et al. (1998)

Kalemkerian et al. (1999)

Lee et al. (1996, 1998)

Komaki et al. (2002)

Pottgen et al. (2002)

Blanke et al. (1997)

Table 1 (continued)


Hyperfractionated accelerated, standard fractionated boost







Hypofractionated

RTx

Cisplatin, Etoposide




Cisplatin l.d. daily, Etoposide l.d. daily

Carboplatin l.d. daily




CTx

50.2 (weeks)

13

14.4

18.9

18

18.3

9

12


45

58

67

63

38

53

1 year (%)

31

35

42

49

15

40

2 years (%)

11

5 years (%)

Leukopenia 55, thrombopenia 40 (grade 4)

Leukopenia 63, Thrombopenia 23

33 (grade 4)

57 (grade 4)

47 (RCTx), 38 (consolidation CTx)

4 (consolidation CTx)

38 (induction CTx), 13 (RCTx)

–

10


Pulmonary 25, esophageal 40

Esophageal 33, Pneumonitis 3 (grade 4)

Esophageal 38

(continued)

Early closure due to pulmonary toxicity

Induction: Cisplatin, Etoposide

Phase I; consolidation: Cisplatin, Etoposide

Esophageal 42

6.6 (grade 4/5), esophageal 53, pulmonary 25

Consolidation: Carboplatin

Induction: Carbopaltin, Etoposide;

21

Esophageal 43 (grade 4)

Phase I induction: Cisplatin, Mitomycin, Vinca Alkaloid

Phase I/II;

Remarks

Esophageal 10 (at highest Carboplatin level of dose escalation)

Nausea/ vomiting 8, late esophageal 5


282 M. Geier and N. Andratschke

61

22

161

Furuse et al. (1995)

Atagi et al. (2002)

Lee et al. (2003)

l.d. low-dose

42

Byhardt et al. (1995)

10

34

11

Tsuchyia et al. (2001)

Le Pechoux et al. (1996)

41


70


58


Kubota et al. (2000)


63

Lau et al. (1998)



Standard fractionated split-course



Standard fractionated split-course





50

Albain et al. (2002)

RTx

Number of patients

Author

Table 1 (continued)

Cisplatin, Mitomycin, Vinblastine

Cisplatin, Mitomycin, Vindesine

Cisplatin, Mitomycin, Vindesine

Cisplatin, Vinblastine

Low-dose Cisplatin, Vindesine

Cisplatin, Vindesine



Carboplatin, Etoposide

Carboplatin, Etoposide (oral)

Carboplatin, Etoposide


CTx

15

51.2

25.1

34.5

84.8

19

28

34(3 years)

24

21

17(3 year)

2 years (%)

36.7

54

53

70

64

42

1 year (%)

16

12.2

14.8

25

10

13

15


14.8

12

14.8

29

9.1

15

5 years (%)

–

Leukopenia 82, thrombopenia 27

Leukopenia 95, Thrombopenia 45

45 (grade 4)

6 (grade 4)

Leukopenia 93

Leukopenia 90

Leukopenia 91

30

22

Leukopenia 50, tthrombopenia 23

Neutropenia 32 (grade 4)


–

Esophageal 5, pulmonary 5 (grade 4)

Nausea 16, Esophageal 6

Esophageal 24

Esophageal 9

Nausea/ vomiting 27

Pneumonitis 20 (grade5)

Esophageal 27

Esophageal 15, Pulmonary 12

Consolidation: Cisplatin, Vindesine;

Phase I

Elderly patients

Poor risk patients

Esophageal 15

Esophageal 7, Pulmonary 4

Consolidation: Cisplatin, Etoposide

Remarks

Esophageal 12 (grade 3), esophageal 8 (grade 3)


Radiotherapy and Second Generation Drugs 283

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 1and 2-year overall survival was 67 and 35%, respectively 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 reported. One treatment-related death due to severe radiation 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 induction 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 hyperfractionated accelerated radiotherapy had a favorable effect regarding time to in-field progression compared to the standard fractionation arm (26 versus 45% at

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 predominantly 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 chemoradiotherapy 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 radiotherapy 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 normofractionated boost of 20 Gy to a total cumulative dose of 65 Gy. Acceptable toxicity with no treatment-related 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


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 intravenous 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 weekend. 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 concurrent 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 hematological 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 accelerated 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 hyperfractionated 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 hematological 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 unresectable 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 hemoptysis (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 chemotherapy 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 chemotherapy 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 survival 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 hematological, 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


regimens in nonelderly patients with a 1-, 2- and 5-year overall survival of 45, 24 and 9.1%, respectively 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 cardiovascular, 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 leucopenia, 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 chemoradiation 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 chemotherapy 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 normofractionated 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 toxicity was quite low, though two treatment-related deaths were reported due to interstitial pneumonitis and pulmonary infection after esophagobronchial fistula (Furuse et al. 1995).


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 chemotherapy 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 hematologic ([= 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 radiotherapy 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 simultaneously with radiotherapy to a total dose of 64.8 Gy to 70 Gy in 1.2 Gy per fraction b.i.d.. After a minimum 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 significantly 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 treatmentrelated 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 properties 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 nonoverlapping 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 radiotherapy as well as the sequencing and dosage of chemotherapy (sequential vs. simultaneous) and the combination of agents used. In addition, patient inclusion 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 toxicity and appeared—depending on the chemotherapy protocol—to be superior to radiotherapy alone, especially when combined with concurrent chemotherapy. As the platinum compounds Cisplatin and Carboplatin proved to be most potent in combination with radiotherapy they formed the basis of all protocols with concurrent radiotherapy either as single agent or as part of multiple agent protocols. Concurrent 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 disappointing results both with regards to outcome and toxicity and therefore failed to hold to the hypothetical 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 protocols 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 chemotherapy 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, radiochemotherapy 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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289 conformal radiotherapy and concurrent mitomycin-C, vinblastine, and cisplatin chemotherapy for Stage III locally advanced, unresectable, non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 56:996–1004. doi:S03603016 03001275 Mirimanoff RO, Moro D, Bolla M, Michel G, Brambilla C, Mermillod B, Miralbell R, Alberto P (1998) Alternating radiotherapy and chemotherapy for inoperable Stage III non-small-cell lung cancer: long-term results of two Phase II GOTHA trials. Groupe d’Oncologie Thoracique Alpine. Int J Radiat Oncol Biol Phys 42:487–494. doi:S036030 1698002466 Palazzi M, Morrica B, Montanaro P, Cerizza L, Leoni M (1996) Hyperfractionated radiotherapy and concomitant cisplatin in stage III non-small cell lung cancer: a phase II study by the AIRO-Lombardia Cooperative Group. Lung Cancer 15: 85–91. doi:0169500296005739 Planting A, Helle P, Drings P, Dalesio O, Kirkpatrick A, McVie G, Giaccone G (1996) A randomized study of high-dose split course radiotherapy preceded by high-dose chemotherapy versus high-dose radiotherapy only in locally advanced non-small-cell lung cancer. An EORTC Lung Cancer Cooperative Group trial. Ann Oncol 7:139–144 Pottgen C, Eberhardt W, Bildat S, Stuben G, Stamatis G, Hillejan L, Sohrab S, Teschler H, Seeber S, Sack H, Stuschke M (2002) Induction chemotherapy followed by concurrent chemotherapy and definitive high-dose radiotherapy for patients with locally advanced non-small-cell lung cancer (stages IIIa/IIIb): a pilot phase I/II trial. Ann Oncol 13:403–411 Pujol JL, Lafontaine T, Quantin X, Reme-Saumon M, Cupissol D, Khial F, Michel FB (1999) Neoadjuvant etoposide, ifosfamide, and cisplatin followed by concomitant thoracic radiotherapy and continuous cisplatin infusion in stage IIIb non-small cell lung cancer. Chest 115:144–150 Sarihan S, Darendeliler E, Kizir A, Tuncel N, Oral EN, Karadeniz A, Bilge N (1998) A phase II trial, feasibility of combination of daily cisplatinum and accelerated radiotherapy via concomitant boost in stage III non-small cell lung cancer. Lung Cancer 20:37–46. doi:S0169500298000038 Scagliotti GV, Ricardi U, Crino L, Maranzano E, De Marinis F, Morandi MG, Meacci L, Marangolo M, Emiliani E, Rosti G, Figoli F, Bolzicco G, Masiero P, Gentile A, Tonato M (1996) Phase II study of intensive chemotherapy with carboplatin, ifosfamide and etoposide plus recombinant human granulocyte colony-stimulating factor and sequential radiotherapy in locally advanced, unresectable non-smallcell lung cancer. Cancer Chemother Pharmacol 38:561–565 Sekine I, Nishiwaki Y, Ogino T, Yokoyama A, Saito M, Mori K, Tsukiyama I, Tsuchiya S, Hayakawa K, Yoshimura K, Ishizuka N, Saijo N (2002) Phase II study of twice-daily high-dose thoracic radiotherapy alternating with cisplatin and vindesine for unresectable stage III non-small-cell lung cancer: Japan Clinical Oncology Group Study 9306. J Clin Oncol 20:797–803 Sui M, Fan W (2005) Combination of gamma-radiation antagonizes the cytotoxic effects of vincristine and vinblastine on both mitotic arrest and apoptosis. Int J Radiat Oncol Biol Phys 61:1151–1158. doi:S0360-3016(04)03144-X [pii] Thomas P, Kleisbauer JP, Robinet G, Clavier J, Poirier R, Vernenegre A, Bonnaud F, Taytard A, Paillotin D, Pommier

290 De Santi P, Barriere JR, Pignon T (1997) Carboplatin as radiosensitizer in non-small cell lung cancer after cisplatin containing chemotherapy. A phase I study of a groupe francais de pneumo-cancerologie (G.F.P.C.). Lung Cancer 18:71–81. doi:S0169-5002(97)00047-0 Tsuchiya S, Ohe Y, Sugiura T, Fuwa N, Kitamoto Y, Mori K, Kobayashi H, Nakata K, Sawa T, Hirai K, Etoh T, Saka H, Saito A, Fukuda H, Ishizuka N, Saijo N (2001) Randomized phase I study of standard-fractionated or acceleratedhyperfractionated radiotherapy with concurrent cisplatin and vindesine for unresectable non-small cell lung cancer: a report of Japan Clinical Oncology Group Study (JCOG 9601). Jpn J Clin Oncol 31:488–494 Uitterhoeve AL, Belderbos JS, Koolen MG, van der Vaart PJ, Rodrigus PT, Benraadt J, Koning CC, Gonzalez Gonzalez D, Bartelink H (2000) Toxicity of high-dose radiotherapy combined with daily cisplatin in non-small cell lung cancer: results of the EORTC 08912 phase I/II study. European Organization for Research and Treatment of Cancer. Eur J Cancer 36:592–600. doi: S0959804999003159

M. Geier and N. Andratschke Van Belle S, Fortan L, De Smet M, De Neve W, Van der Elst J, Storme G (1994) Interaction between vinblastine and ionizing radiation in the mouse MO4 fibrosarcoma in vivo. Anticancer Res 14:1043–1048 Van den Brande P, De Ruysscher D, Vansteenkiste J, Spaas P, Specenier P, Demedts M (1998) Sequential treatment with vindesine-ifosfamide-platinum (VIP) chemotherapy followed by platinum sensitized radiotherapy in stage IIIB non-small cell lung cancer: a phase II trial. Lung Cancer 22:45–53. doi:S0169-5002(98)00071-3 van Harskamp G, Boven E, Vermorken JB, van Deutekom H, Stam J, Njo KH, Karim AB, Tierie AH, Golding RP, Pinedo HM (1987) Phase II trial of combined radiotherapy and daily low-dose cisplatin for inoperable, locally advanced non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 13:1735–1738 Verweij J, Pinedo HM (1990) Mitomycin C: mechanism of action, usefulness and limitations. Anticancer Drugs 1:5–13 Ziegler W, Kopp JM (1987) The effect of combined treatment of HeLa cells with cisplatin and irradiation upon survival and recovery from radiation damage. Radiother Oncol 8:71–78

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

R. Bland P. Iyengar H. Choy (&) Department of Radiation Oncology, UT Southwestern Medical Center at Dallas, Dallas, USA e-mail: [email protected]

Abstract

Evidence shows that treating locally advanced non-small cell lung cancer (NSCLC) patients with concurrent radiation and second generation chemotherapy agents provides a survival benefit when compared to delivering the same therapy sequentially. However, survival results remain dismal and concurrent chemoradiation exhibits significant toxicity. As third generation chemotherapy agents have become available, their radiation-sensitizing properties 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 laboratory 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 chemotherapy, biologic agents, and external beam radiation. 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 well as topoisomerase targeted systemic agents have had a unique capacity to synergize with ionizing radiation in promoting lung tumor cell death. However, survival outcomes with these agents have not


291

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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 findings 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 synergy 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 chemotherapy 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 demonstrated 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

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 hamster 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 paclitaxelexposed 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 paclitaxel could provide radiation sensitization in the relatively radiation resistant human astrocytoma cell line and ovarian cell lines. In these studies, the concentration 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 advantage 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 preclinical 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 every3-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 conducted 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 carboplatin 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 irradiation, 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). Furthermore, 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 radiation 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 carboplatin and paclitaxel with concurrent radiation was effective and tolerable for locally advanced NSCLC, the benefit of either induction or consolidation fulldose chemotherapy in conjunction with concurrent chemoradiotherapy was uncertain. A phase II randomized 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 followed 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.

40

Phase II

Phase II

Phase II

Phase II

Phase I/II

Phase II

LAMP, Phase II

CALGB 9534, Phase II

Phase I/IIa

CTRT99/97 BROCAT, Phase III

S9712


Choy et al. (1998)


Ratanatharathorn et al. (2001)

Lau et al. (2001)

Solomon et al. (2003)

Kaplan et al. (2004)


Akerley et al. (2005)

Divers et al. (2005)

Huber et al. (2006)

Davies et al. (2006)

Vokes et al. (2007)

366

54

214

35

40

257

19

25

34

30

38

Number of patients

Study

Reference

Table 1 Summary of selected paclitaxel chemoradiation studies

Carbo/Pac/63 Gy

–

Carbo/Pac/66 Gy Carbo/Pac/66 Gy

– Carbo/Pac

Carbo/E/61 Gy

Pac/60 Gy

Carbo/Pac –

60 Gy

Gem/Pac q 3 weeks/60 Gy

Carbo/Pac

P/Gem

Carbo/Pac/66 Gy

Carbo/Pac/63 Gy

Carbo/Pac Carbo/Pac

63 Gy

Carbo/Pac/66 Gy

P/Pac(2/week)/60 Gy

Carbo/Pac(2/ week)/61 Gy

Carbo/Pac/60 Gy

Carbo/Pac/60-65 Gy

Carbo/Pac/66 Gy

Conc

Carbo/Pac

–

–

–

–

–

–

Ind

–

–

Pac

–

–

–

–

Carbo/Pac

–

–

Carbo/Pac

Carbo/Pac

Carbo/Pac

Carbo/Pac

–

Carbo/Pac

Cons

14

12

10.2

18.7

14.7

17

27% (3 years)

16.3

12.7

13

13.9

23.6

17

14.5

63% (1 year)

20.5

MST (months)

(continued)

Induction CT increased toxicity without survival benefit. Low MSTs possibly due to low dose 3rd generation CT.

Compared to S429, in poor risk patients, Pac consolidation does not increase survival.

Concurrent chemoradiation arm had improved survival.

Regimen is safe and effective in good performance status patients.

Included patients with [5% weight loss, but survival consistent with more selective studies.

Arm 3 was numerically most efficacious but most toxic.

Regimen is feasible and well tolerated.

Concurrent twice weekly Pac with weekly P is safe and active.

Concurrent twice weekly Pac with weekly Carbo is safe and active.

Effective and tolerable regimen.

Regimen appears safe and active.

Regimen appears safe and active.

Comments

294 R. Bland et al.

MST median survival time, LAMP locally advanced multi-modality protocol, CALGB Cancer and Leukemia Group B, WJTOG West Japan Thoracic Oncology Group, Carbo carboplatin, Pac paclitaxel, MVP mitomycin/vindesine/cisplatin, AM amofostine, CT chemotherapy, SS statistically significant

Carbo/Pac/60 Gy –

Carbo/Pac

22

Arm 3 was equally as efficacious but less toxic than other arms. 20.5

19.8 Carbo/ Irinotecan

MVP MVP/60 Gy (split)

Carbo/Irinotecan/60 Gy

–

–

WJTOG0105, Phase III Yamamoto et al. (2010)

456

Carbo/Pac/69.6 Gy, 1.2 Gy bid Carbo/Pac

–

17.9

With AM, no SS reduction in esophagitis but SS improvement in patient self-assessments. 17.3 – Carbo/Pac/69.6 Gy, 1.2 Gy/bid AM Carbo/Pac RTOG 9801, Phase III Movsas et al. (2003)

243

Study Reference

Table 1 (continued)

Number of patients

Ind

Conc

Cons

MST (months)

Comments


295

The first phase III trial to evaluate concurrent carboplatin and paclitaxel with radiation therapy for locally advanced NSCLC was conducted by the Cancer and Leukemia Group B (CALGB) (Vokes et al. 2007). CALGB 39801 was designed to test the value of induction chemotherapy in the context of concurrent chemoradiotherapy. Patients were randomized to carboplatin and paclitaxel with concurrent radiotherapy (concurrent arm), or to induction carboplatin and paclitaxel followed by carboplatin and paclitaxel based concurrent chemoradiotherapy (induction/concurrent arm). There was no statistically significant difference in survival. Median survival was 12 months on the concurrent arm versus 14 months on the induction/concurrent arm. Additionally, the induction/concurrent arm demonstrated increased neutropenia and overall maximal toxicity. This study failed to show a benefit for the role of induction chemotherapy in the context of concurrent chemoradiotherapy analogous to what was reported by Belani et al. (2005). One possible explanation for the poor performance of the concurrent arm, is that the patients on this arm never received systemic full dose chemotherapy. The radiation-sensitizing dose was given concurrently with radiation was not optimal for treating micrometastatic disease. Studies of concurrent chemoradiation demonstrated improved survival at the cost of increased toxicity, particularly esophagitis, when compared to sequential chemoradiation (Komaki et al. 2003). Movsas et al. performed a quality-adjusted survival (QAS) analysis of several RTOG lung cancer studies and found that the QAS of sequential chemoradiation was nearly equivalent to that of concurrent chemoradiation (Movsas et al. 1999). Reduction in esophageal, upper GI and lung toxicities was associated with the greatest improvement in QAS. In light of these findings, RTOG 98-01 was designed to test amofostine’s (AM) ability to reduce the severity of esophagitis in concurrent chemoradiation regimens (Movsas et al. 2003). AM is a cytoprotectant that is dephosphorylated in tissue and subsequently acts as a scavenger of radiation induced oxygen free radicals (Calabro-Jones et al. 1985; Wasserman and Chapman 2004). In RTOG 98-01, 243 patients with locally advanced NSCLC were administered induction carboplatin and paclitaxel followed by hyperfractionated radiotherapy (69.6 at 1.2 Gy bid) with concurrent carboplatin and paclitaxel. Patients were randomized


Czech Republic

Phase II

GFPC-GLOT-IFCT 02-01, Phase II

Phase III

Phase II

Phase II

Phase II

RTOG 0017, Phase I

ACROSS, Phase II

Phase II

Vokes et al. (2002)

Zatloukal et al. (2004)

Lee et al. (2005)

Fournel et al. (2006)

Kim et al. (2007)

Rusu et al. (2007)

Hirsh et al. (2007)

Krzakowski et al. (2008)

Choy et al. (2009)

Blanco et al. (2008)

Leong et al. (2010)

42

Gem/Vrb

P/Gem

–

8 44

–

PO Vrb/ P

Carbo/ Gem

Vrb/60-66 Gy

Gem/68.4 Gy

Gem/Pac/63 Gy

Carbo/Gem/63 Gy

PO Vrb/P/66 Gy

Gem/Pac/60 Gy

Platinum/Vrb/RT

P/Pac/66 Gy

– –

P/Pac/66 Gy

P/Vrb/66 Gy

– P/Gem

P/Vrb/66 Gy

P/E/63 Gy

P/Pac

Gem/Vrb

P/Vrb/60 Gy 60 Gy

P/Vrb/66 Gy

P/Vrb P/Vrb

P/Pac/66 Gy

P/Pac

P/Vrb

P/Gem/66 Gy

Concurrent

P/Gem

Induction

27

54

41

57

134

133

40

102

175

Patients

–

–

Carbo/Gem

Carbo/Gem

–

–

Platinum/Vrb

–

–

P/Pac

–

–

–

–

–

–

–

Consolidation

17

17.7

12.9

13.3

23.4

25

15

18.2

12.6

16.9

19.3

23.2

12.9

16.6

17.7

14.8

18.3

MST (months)

This non-platinum regimen is feasible, tolerable, and effective.

Regimen had substantial toxicity.

Lowest dose Gem/Pac too toxic with RT. Established MTD of Carbo/Gem with RT.

With oral Vrb, high rate of treatment completion. Phase III trial with oral Vrb underway.

Regimen is effective and well tolerated.

Regimen is active and well tolerated.

Induction arm had SS worse PFS.

Similar toxicities but numercially greater MST in arm 1.

Regimen had promising survival results.

SS survival benefit to concurrent CTRT.

Greater MSTs than in CALGB trials using squential CTRT.

Comments

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 chemoradiation, RT radiation therapy, CT chemotherapy, SS statistically significant, MTD maximum tolerated dose, PFS progression free survival

Study

Reference

Table 2 Summary of selected vinorelbine or gemcitabine chemoradiation studies

296 R. Bland et al.


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%). However, patient diaries reported significantly lower swallowing dysfunction with AM and the quality of life instrument (EORTC QLQ) demonstrated a significant 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 disconnect 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 subsequent trials (Radiation Therapy Oncology Group RTOG 0617). Phase III evidence demonstrating the benefit of concurrent chemoradiation over sequential chemoradiation for locally advanced NSCLC was initially provided by studies from the West Japan Lung Cancer Group (WJLCG) and the Radiation Therapy Oncology 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 administered 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 generation agents with more frequent radiosensitizing dose third generation agents for concurrent chemoradiotherapy, 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 mitomycin with concurrent radiation followed by cisplatin, 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 significant, 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 chemotherapy agents, such as vinorelbine and gemcitabine, 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 leucovorin in patients with advanced NSCLC (Crawford et al. 1996). Studies also demonstrated that vinorelbine 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 microtubules, 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

S9504, phase II

GFPC Phase II

Phase II

HOG, phase III

S0023, phase III

Phase II

Phase II

Phase III

Phase II

Gandara et al. (2003)

Vergnenègre et al. (2005)

Sakai et al. (2004)

Hanna et al. (2008)

Kelly et al. (2008)

Jain et al. (2009)

Movsas et al. (2010)

Segawa et al. (2010)

Senan et al. (2011)

70

200

83

61

243

203

32

40

83

Patients

P/Doce/66 Gy

–

P/Doce/60 Gy P/Doce/66 Gy

P/Doce

–

P/E/62 Gy M/V/P/60 Gy

– –

P/E/62 Gy

–

Carbo/Doce/63 Gy

P/E/61 Gy

–

P/E/61 Gy

–

P/E/59.4 Gy

–

P/E/59.4 Gy

–

Bi-weekly Carbo/Doce 60 Gy

Doce/66 Gy

P/E/61 Gy

Concurrent

–

–

P/Vrb

–

Induction

P/Doce

–

–

–

Gem/Doce

Gem

Carbo/Doce

Doce/ Gefinitib

Doce

Doce

–

Carbo/Doce

–

Doce

Consolidation

65.5% (1 year)

63.2% (1 year)

26.8

23.7

29.5

16.1

12

23

35

21.2

23.2

27

13

26

MST (months)

Both arms merit further testing in small volume (V20 \ 35%) disease.

Trend toward improved survival in the P/Doce arm.

Both arms were tolerable. In the Gem/Doce arm, survival rate is higher than previous trials.

Regimen has acceptable toxicity but disappointing survival data.

Gefinitib did not improve survival. Survival time compares favorably to other phase III studies.

Consolidation doce increased toxicity but not survival.

Concurrent bi-weekly CT regimen and RT was active with manageable toxicity.

Acceptable toxicity but modest survival rates.

Tolerable regimen with encouraging MST.

Comments

MST median survival time, P cisplatin, E etoposide, Carbo carboplatin, Doce docetaxel, SWOG Southwest Oncology Group, Hoosier Oncology Group

Study

Reference

Table 3 Summary of selected docetaxel chemoradiation studies

298 R. Bland et al.


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 arabinoside (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 paclitaxel and vinorelbine, gemcitabine was shown to be modestly superior to the second generation chemotherapy 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 sensitizer 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 compound 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 utilizing 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 chemoradiation (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 survival 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 generation 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 concurrent 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 previous phase III studies, the median survival was significantly 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 chemoradiotherapy 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 induction 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

Phase II

Phase II

Phase II


Phase II

Phase II

Phase II

PROCLAIM, Phase III

Gadgeel et al. (2008)

Gauden et al. (2009)

Germonpre et al. (2009)

Govindan et al. (2008)

Brade et al. (2010)

Choy et al. (2010)

Xu et al. (2010)

Vokes et al. (2009)

600, nonsquamous (planned)

21

76

39

99

30

25

21

Patients

P/Pem/66 Gy P/E/66 Gy

– –

Carbo/Pem/6066 Gy

P/Pem/64-68 Gy

– –

Carbo/Pem/6468 Gy

–

P/Pem/61-66 Gy

Carbo/Pem/Cetux/ 70 Gy

–

Carbo/Pem/70 Gy

–

Pem/60 Gy

–

Pem/60 Gy

–

Carbo/Doce/ 60 Gy

P/Pem/66 Gy

Concurrent

P/Pem

–

–

Induction

P/E or P/Vrb or Carbo/Pac

Pem

Carbo/Pem

Pem

Pem

P/Pem

Pem

Pem

P/Pem

–

Pem

Doce

Consolidation

NA

NA

NR

NR

NR

20

22

22

NR

NR

22

NR

MST (months)

Currently evaluating benefit of full dose pem in concurrent CTRT.

RR 86%

RR 38-41%

Full dose P/Pem/RT is active and tolerable.

Both regimens of full dose Carbo/Pem/RT are feasible and tolerable.

RR 69%

RR 76%

RR 53%

Comments

MST median survival time, P cisplatin, Pem pemetrexed, E etoposide, Carbo carboplatin, Vrb vinorelbine, CALGB Cancer and Leukemia Group B, CTRT chemoradiation

Study

Reference

Table 4 Summary of selected pemetrexed chemoradiation studies

300 R. Bland et al.


301

Table 5 Summary of selected studies with altered fractionation or escalated radiation doses Reference

Study

Patients

Induction

Concurrent

Consolidation

MST (months)

Comments

Choy et al. (2000)

Phase II

43

–

Carbo/Pac 1.2 Gy BID/ 69.6 Gy

Carbo/Pac

14.3

Regimen is well tolerated with encouraging response rate.

Reguart et al. (2004)

Phase II

37

Plat/Gem

Plat/Vrb/ 1.8 ? 0.88 Gy boost/61.64 Gy

Plat/Gem

15.4

Results are promising although toxicity is considerable.

Casas et al. (2011)

Phase II

32

Carbo/ Pac

Daily Pac/ 1.8 ? 0.88 Gy boost/61.64 Gy

Carbo/Pac

16.9

Acceptable efficacy and less toxicity than the trial in the row above.

Patel et al. (2007)

Phase II

35

Carbo/ Vrb

Topotecan/ 2 Gy bid, every other week, 60 Gy

–

17.9

Encouraging survival with no severe esophagitis.

Schild et al. (2006)

Phase I

15

–

Carbo/Pac/7078 Gy

–

37

MTD of RT was 74 Gy. Phase II portion is underway.

Stinchcombe et al. (2008)

Phase I/ II

62

Carbo/ Pac

Carbo/Pac/6074 Gy

–

25

Dose escalation compares favorably to previous trials.

Socinski et al. (2008)


69

Carbo/ Pac

Carbo/Pac/ 74 Gy

–

24.3

Carbo/ Gem

Gem/74 Gy

–

12.5 (closed early)

Encouraging MST and toxicity profile in arm 1. Arm 2 was too toxic.

RTOG 0117, Phase II

53

–

Carbo/Pac/ 74 Gy

Optional

25.9

Bradley et al. (2010)

Among the best MSTs in RTOG studies.

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 radiation. 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 chemoradiotherapy. 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 vinorelbine 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 survival 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 gemcitabine 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 concurrent 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 chemotherapy (Blackstock et al. 2001, 2006; Rosenman et al. 2002; Socinski et al. 2000), the CALGB conducted 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 radiotherapy (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 constraints. Gemcitabine is known to be an effective radiation sensitizer that may also excessively radiosensitize 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, concurrent chemoradiation has improved survival by reducing local recurrence with no effect on distant control (Schaake-Koning et al. 1992). Since concurrent phase chemotherapy is limited by toxicity, many trials have implemented induction or consolidation chemotherapy in hopes of reducing distant progression. Docetaxel, a taxane and third generation chemotherapy 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 phosphorylation, 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).


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 concurrent 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, documentation procedures for T4 or N, and concurrent chemoradiation regimen as was used in SWOG 9019. SWOG 9504 replaced the consolidation cisplatin and etoposide regimen used in SWOG 9019 with docetaxel with the idea that a comparison of the two trials could provide some relative information on the efficacy and safety of docetaxel as a consolidative regimen. 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) cisplatin and etoposide with concurrent radiation followed 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 carboplatin 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 radiotherapy 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 combination 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 dosedependent 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

R. Bland et al.

effects were seen when topotecan, another camptothecin derivative, was administered 2 and 4 h before radiation but not when administered 2 h after radiation. The consistent findings in these preclinical studies suggested irinotecan be administered before or during radiotherapy take full advantage of its radiosensitizing properties. After studies demonstrated concurrent chemoradiation 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 nausea, vomiting, and esophagitis as the dose limiting toxicities of weekly irinotecan and carboplatin with concurrent radiation. Additionally, these studies provided 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 chemotherapy 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 chemotherapy, 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

attenuated dose. Pemetrexed, unlike other third generation 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 premetrexed 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 fulldose concurrent phase pemetrexed with no trial requiring early termination due to toxicity. These phase I studies exhibited acceptable rates of hematologic toxicity, radiation pneumonitis, and esophagitis 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 treatment 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


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 chemoradiation for locally advanced NSCLC have explored novel chemotherapy agents and additional chemotherapy outside the concurrent phase. With 2D radiation 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 standard dose since it was established in RTOG 73-01 (Perez et al. 1982, 1987). However, with the development 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

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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 escalation 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 concurrent 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 escalating radiation dose with concurrent systemics in the setting of improved radiation delivery methods, limiting 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 therapy 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 Jeremic´, Sinisa Stanic, and Slobodan Milisavljevic

Contents

Abstract

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 .................................................... 9.1 Stereotactic Radiation Therapy ................................. 9.2 Accelerated Hypofractionated Radiation Therapy ...................................................................... 9.3 Accelerated Hyperfractionated Radiation Therapy and Concurrent Radiation Therapy with Chemotherapy ................................................... 10

332 332 333

334

Conclusions ............................................................... 334

References.......................................................................... 335

B. Jeremic´ (&) Institute of Lung Disease, Sremska Kamenica, Serbia e-mail: [email protected] S. Stanic, Department of Radiation Oncology, University of California Davis, Sacramento, USA S. Milisavljevic Department of Thoracic Surgery, University Hospital, Kragujevac, Serbia

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-smallcell 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 classification (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 outcome. There are, however, also data from surgical series


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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 frequently 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 surveillance 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 cardiopulmonary 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 radiation therapy alone, being frequently considered ‘‘standard’’ 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 concomitant 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, different 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 comparing 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-

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 practiced 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 supporting 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 precise immobilization, which cannot be tolerated by all patients. This chapter, therefore, summarizes achievements of conventional radiation therapy in early stage nonsmall-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 outcome 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 diagnostic 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 radiation 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 proportion 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 diagnostic 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 interpretation 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

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study of Fang et al. (2006) who evaluated the outcome of 200 patients with medically inoperable stage I nonsmall-cell lung cancer and compared three-dimensional with two-dimensional radiation therapy planning and execution. The overall survival, disease-specific survival, and locoregional control rates were significantly higher in patients treated with three-dimensional radiation 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 survival 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 onethird of patients having a history of a previous malignancy, 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 virtually 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. fractionation). Treatment machines used to deliver irradiation also ranged from orthovoltage X-rays through cobalt60 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

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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

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

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 available 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 pretreatment and treatment characteristics (available histology, staging, imaging, three-dimensional planning 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 substantially differing patient populations. An important underlying issue, namely, the reason for not undergoing 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 several 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%

(Jeremic et al. 2005). Interestingly, the highest median 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 correlates with the incidence of intercurrent deaths (6–16%) (Zhang et al. 1989; Sandler et al. 1990;


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 radiation therapy in recent years were occasionally compared 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 limited 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 biological premises in radiation oncology is that larger tumor sizes (presumably higher stage) require higher tumor doses.

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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

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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 therapeutic benefit when compared to two-dimensionally planned and executed radiation therapy used in the past. Indeed, the data on the use of high-dose radiation 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 nonsmall-cell lung cancer, In that study, multivariate analysis showed that there was a significant interaction 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 nonsmall-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).

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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 continuous 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 fractions over CHART. Bradley et al. (2005) performed a phase I–II doseescalation 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 radiation 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. Locoregional 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 stereotactic 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-dimensional conformal planning is considered, if possible to a total dose of 70 Gy with 2 Gy per fraction and the


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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.

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

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 hypofractionated radiation therapy, which typically employs

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 therapy for early stage non-small-cell lung cancer.

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4

Tumor Stage and Size

When influence of tumor stage and/or size on treatment 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 survival 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 significance. 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 survival 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 multivariate 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 outcomes 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 reasonable to expect that this would happen first at local/ regional level, and then on the overall survival,

providing causal relationship between local control and overall survival. Therefore, local/regional-recurrence free survival or disease-specific survival must be included in the analysis as important initial endpoints. The distant metastasis-free survival must be used, too, to provide better insight into the events other than those occurring locoregionally. The patterns 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 diseasefree 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 biological 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, computerenabled 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 intrathoracic nodal staging, PET has a definite role in communities in which mediastinoscopy is not available, 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


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 mediastinoscopy 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 medically inoperable patients with early stage non-smallcell lung cancer decline mediastinoscopy, as an invasive diagnostic procedure. In this situation, radiation 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 retrospective and literature apply here as well. Nevertheless, 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 mediastinum in cases of stage I or a part or whole of the mediastinum in stage II non-small-cell lung cancer.

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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 squamous-cell carcinoma of the head and neck, than one would need 50 Gy given with 2.0 Gy standard fractionation 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 otherwise 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 treatment 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 unintentional treatment contribution to the nodal areas at risk. This contribution for a particular radiation therapy 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

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institution (Hayman et al. 2001) showed no isolated elective nodal failures when three-dimensional conformal radiation therapy was used in patients with non-small-cell lung cancer, although there were 3(6%) failures in the lymph nodes outside the planning target volume. Rosenzweig et al. (2001) also used similar three-dimensional conformal radiation therapy (range, 50.4–81 Gy; median, 68.4 Gy) without 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 therapy (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-smallcell 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 Dosoretz 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 documented superior complete response rates and overall survival in patients undergoing elective nodal irradiation and lower distant metastasis rate in patients undergoing elective nodal irradiation.

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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 involvedfield 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) metastasis. If the initial clinical staging based on computerised 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 micrometastasis was an independent prognosticator of survival, 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


(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 predominant type of failure remains local, being reported as either isolated or initial in approximately 11–55% cases (ultimate up to 75%). An isolated/initial regional failure was reported to occur in only 0–7% cases (ultimate up to 15% cases), while the distant metastasis 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 microscopic 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 mediastinal lymph node enlargement on computed tomography. 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

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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 pathological analysis. Hence, the rates of false-negative staging by computerised tomography and false positive staging by positron emission tomography were due to differences in mediastinal lymph node assessment which is of particular importance when assessing 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 findings 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 computerised 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 advantages of PET is its ability to discriminate tumor tissue from atelectasis. Decreases in the target volumes in

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patients with atelectasis lead to decreases in normaltissue toxicity. Nevertheless, more information on various biological properties and actual differences between various subgroups of patients and tumors (e.g., histology, 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 combined to create risk groups for N1/N2/local/regional recurrence; they have found that the risk of subclinical 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 metastasis in 389 patients with clinical stage IA non-smallcell 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 metastases. 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) nonsmall-cell lung cancer by using the data such as age, gender, Brinkmann’s index, histology, grade of differentiation, tumor diameter and the level of carcinoembryonic antigen as factors involved in lymph node metastasis. They showed that this risk was low in those with well differentiated carcinoma and those

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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-smallcell lung cancer surgical resections specimens and found that the microscopic extension was different between adenocarcinoma and squamous-cell carcinoma. To cover 95% of microscopic extension, a margin of 8 and 6 mm must be added for adenocarcinoma 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 aspiration 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 nonsmall-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 planning 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) typically 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 microscopic tumor extension and create the CTV. Typically, 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


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 recommendations 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, identification of which must be one of the priorities of research in this field. Contrary to that, it is reasonable to assume that at least for small peripheral, lowgrade 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 information regarding biology of these tumors is needed because identification of potential factors contributing 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 tumorrelated, 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

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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 chemotherapy. However, Morita et al. (1997) found detrimental 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 causespecific survival or local and distant tumor control. Similar was observed by Firat et al. (2002) in a univariate analysis, though not confirmed by the multivariate 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

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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 survival/relapse-free survival as well. In the study of Lagerwaard et al. (2002) the World Health Organization 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 carcinoma) histology using both overall survival and relapse-free survival as endpoints. Lagerwaard et al. (2002) observed an independent and favorable influence of unknown histology (versus squamous-cell histology and non-squamous-cell histology) on overall 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.

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 systematically 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) esophagitis 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 insufficiency 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 treatment 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 toxicity. Jeremic et al. (1997) treated 49 patients with stage I non-small-cell lung cancer with hyperfractionated 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


the same fractionation. Jeremic et al. (1999) again used Radiation Therapy Oncology group (Cox et al. 1995) toxicity criteria to report on the same hyperfractionated radiation therapy regimen (69.6 Gy using 1.2 Gy b.i.d. fractionation) in 67 stage II non-smallcell lung cancer patients. Although elective mediastinal 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 bronchopulmonary and two esophageal late grade 3 toxicities (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 steroids after 64 Gy in 2 Gy fractions. Both patients had their mediastinum region encompassed. However, 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 Southwest 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 radiation therapy regimens, although Lagerwaard et al. (2002) used multivariate analysis to document detrimental 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 incidence 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.

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Major problem with the data from the literature is a great variety of both pre-treatment and radiation therapy-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 interruption 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 recurrencefree 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 independent influence as the reason for not undergoing surgery on overall survival (p = 0.035), but not on

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local recurrence-free survival (p = 0.084) or causespecific 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, causespecific 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 recurrence-free survival (p = 0.080). Late high-grade toxicity also becomes interesting from the standpoint of prolonged survival of these patients. Prolonged followup 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 diagnosed 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 threedimensional 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

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step in quantitative assessment of competitive treatment 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 probability (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). Nowadays, when intensity modulated radiation therapy is used; the question remains whether total lung V20 is enough to predict the incidence of radiation pneumonitis. Yom et al. (2007) was among the first to provide clinical data regarding the rate of high-grade radiation pneumonitis in patients treated with intensity 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


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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

receiving 20 Gy (V20) was 14.6%. (The clinical target volume was subtracted from the total lung volume for total lung V20 calculation.)

definitions, it can be sometimes difficult to compare data from two different institutions.

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

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 qualityadjusted survival time model which takes into account

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and concurrent radiochemotherapy and concurrent chemotherapy and hyperfractionated radiation therapy. 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 superior 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 pretreatment 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 analysis relating to early stage non-small-cell lung cancer.

9

Novel Approaches

9.1

Stereotactic Radiation Therapy

Stereotactic radiation therapy is an extremely hypofractionated form of radiation therapy for early stage non-small-cell lung cancer. Historically, high precision radiation therapy in a form of stereotactic radiosurgery was successfully introduced in cases of brain

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 fractionated radiation therapy is an effective treatment approach for both malignant and nonmalignant neoplasms because it combines the accurate focal dose delivery of stereotactic radiosurgery with the biological advantages of fractionated radiation therapy (Dunbar et al. 1994; Kooy et al. 1994; Varlotto et al. 1996). It was also indicated that stereotactic fractionated 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-smallcell 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, comparison of this data with modern data from the 3D era and stereotactic body radiation therapy is an unfair comparison.


9.2

Accelerated Hypofractionated Radiation Therapy

Accelerated hypofractionated radiation therapy is a moderately hypofractionated form of radiation therapy for early stage non-small-cell lung cancer. While stereotactic body radiation therapy typically employs C8 Gy, accelerated hypofractionated radiation therapy 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 feasible 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 requirements 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 cancer. 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 relapsefree survival was 76%, 2-year overall survival 56% and median overall survival 29 months Another Canadian study by Soliman et al. (2011) included 118

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patients, mostly medically inoperable with peripherally 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 inoperable 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 hypofractionated radiation therapy in 39 medically inoperable 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 fractions. 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 hypofractionated approach is not to develop a new type of stereotactic 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 necessary to deliver each fraction of radiation therapy. For patients who cannot tolerate stereotactic radiation therapy immobilization or treatment process, accelerated hypofractionated radiation therapy can be an alternative approach. This moderately hypofractionated regimen has a potential to become an alternative to stereotactic radiation therapy, particularly in small

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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 concurrent 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 hyperfractionated 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 prospective phase II trial, Jeremic et al. (2005) used concurrent hyperfractionated radiotherapy and lowdose 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

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 concurrent regimen. Also, the 2-year local progressionfree 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 conventional 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 examined 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 radiation therapy. Unfortunately, discrepancies between surgical and radiotherapeutic series regarding the staging procedures, treatment procedures in this disease as well as the documentation of the pattern of failure make any conclusion unreliable. They, however, call for more cooperation between technology and biology in order to more selectively apply one or another approach. Suggesting that limited field


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 characteristics occasionally examined gender and age probably do not influence survival. Performance status and weight loss may exert its influence on survival, 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 longterm 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 fractionated regimens, alone or with concurrent chemotherapy, mostly, however, without specifying its outcome. Pure hyperfractionated radiation therapy alone or with either induction or concurrent chemotherapy (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 hyperfractionated 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 randomized 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 randomized 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

Abstract

1

Introduction.............................................................. 343

2

Techniques and Technological Advances in SABR for Lung Tumors..................................... Patient Positioning and Immobilization.................... Daily Imaging for Patient Repositioning Prior to Treatment............................................................... Tumor Motion Assessment ....................................... Tumor Motion Control .............................................. Target Volume Delineation and Treatment Planning .....................................................................

2.1 2.2 2.3 2.4 2.5

Stereotactic ablative radiotherapy (SABR), also known as stereotactic body radiation therapy (SBRT) utilizes advanced techniques of immobilization, image guidance, and unique field arrangements to deliver precise, oligofractionated radiotherapy to a variety of tumor types. SABR has been established as a technologically innovative therapy for early stage non-small cell lung cancer (NSCLC) and has emerged as the standard treatment option for medically inoperable patients through utilization of prospective, multi-institutional 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 modalities 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.

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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

1 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: [email protected] J. H. Heinzerling Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Introduction

Stereotactic radiosurgery first emerged as a technique in the 1950s created by Lars Leskell to treat intracranial neoplasms using single large dose per fraction treatments (Leskell 1951). These treatments were a fundamental change from the perception of conventionally fractionated radiotherapy (CFRT) classically used to exploit the radiobiological differences between normal and neoplastic tissues. Leskell established the principles of immobilization and precise targeting


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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 technologies 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 respiration 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 convergence 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 Therapeutic 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 targeted tissues both disruption of cell division and function, leading to the associated term ‘‘ablative’’ radiotherapy. An order of magnitude of higher fractional 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 surrounding 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 typically 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 exploration 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 principles allow the reduction of normal tissue exposure to high and intermediate doses, minimizing the probability 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) published their best practice guidelines for SABR treatments including equipment and QA procedures (Benedict et al. 2010). Many of the technological advances within radiation therapy have been developed 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, consistent, reproducible, and comfortable patient immobilization 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

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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 implication 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

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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 cumbersome positions for the patient to support is of utmost importance when incorporating SABR into any radiation oncology program.

2.2

Daily Imaging for Patient Repositioning Prior to Treatment

Image guidance provides target localization and validation 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, pretreatment 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

prior to treatment (Wang et al. 2007), but improvements 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 monitoring 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 associated 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;


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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 correlated 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 techniques (Mageras and Yorke 2004), and respiratorycorrelated PET-CT or MRI (Kooch et al. 2004). If tumor motion exceeds 5–10 mm, tumor motion control as described below is recommended so as to avoid excess toxicity.

dampen tumor motion include abdominal compression, 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, reproducibility, as well as prudent implementation of motion data into treatment planning is essential for precise treatment delivery.

2.4

2.5

Tumor Motion Control

Several methods exist to control tumor motion and include techniques to reduce tumor motion (dampening), correlate treatment with tumor position (gating), or track the tumor position (chasing). Ways to

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

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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 breathing 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 structures, 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 delineating 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


b the poor correlation of tumor and diaphragm motion between inhalation and exhalation (i.e., the diaphragm moves considerably 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 multiple 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-coplanar beams are also preferred to provide more isotropic dose fall-off in all directions. Typical beam arrangements 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


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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

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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.

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 dimensions, allow evaluation of intermediate dose spillage that can cause more global organ damage. Conformality 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, fractionation, 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 evaluating 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

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, oligofractionated 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-quadratic (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 modifications 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-potentially lethal model, which accounts for ongoing radiation 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.


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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 during 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 treatment 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

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

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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 linearquadratic 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 parallel structures such as lung alveoli, kidney nephrons, 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


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 measurements 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; however, 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., functional 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 minimize exposing volumes of tissue at or above the threshold dose. As SABR is inherently a volumesparing 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 collections will reabsorb without any necessary intervention, but they are important to characterize because of their absence in CFRT. Other, more rare late effects with SABR that have been described in


serial tissues include aneurysms, fistulas, and neuropathies, 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 disease either adjuvantly or prophylactically because of its likelihood of causing collateral damage to normal tissues with high dose per fraction treatment. A disease 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-smallcell lung cancer (NSCLC) are conditions where SABR is unlikely to be used effectively except possibly as a boost to gross disease. Early stage NSCLC and limited lung metastases in patients with controlled systemic disease are diseases where the principles 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 approximately 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).

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Based on data suggesting a dose–response relationship 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 dosefractionation 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 toxicities seen with these treatments inadequate. Consequently, 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 doseescalation 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 escalation 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 continued 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

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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 (Timmerman 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 represent 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 control and survival of 88 and 42%, respectively

(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 medically 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 accreditation, conduct, and dosimetry constraints were developed prior to the opening of the trial by the RTOG Lung, Physics, and Image-Guided Therapy committees 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


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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)

Timmerman, 2003 (Timmerman et al. 2003a, b) McCarty et al. 2005)

8–16 Gy 9 3

60 (2 years)

20–44 Gy

18–24 Gy 9 3

90 (2 years)

50–68 Gy

Zimmerman, 2005 (Zimmermann et al. 2005)

12.5 Gy 9 3

87 (3 years)

43.5 Gy

Nyman, 2006 (Nyman et al. 2006)

15 Gy 9 3

80 (crude)

41 Gy

Timmerman, 2006 (Timmerman et al. 2006)

20–22 Gy 9 3

95 (2 ? years)

56–62 Gy

Europe/North America

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

20 Gy 9 1

84 (crude)

20 Gy

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

Pennathur, 2007 (Pennathur et al. 2007) Asia

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 7.5 Gy 9 6

T1 78, T2 40 (3-years)

41–46 Gy

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 mediastinal 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), exploration of utilizing SABR techniques within the medically 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 medically 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

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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

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 operable patients (JCOG 0403). All patients were treated


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. 3year overall survival was 76%, an encouraging result for the first prospective multicenter trial in this population. However, there were 25 patients with progressive 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 thoracic 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 salvage therapy with surgical resection could be performed. 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 Surgeons 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 sublobar 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 radiation 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 prospective 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-treatment 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. Cardiopulmonary 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 toxicity), 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 pulmonary toxicity in tumors adjacent to the central and perihilar structures within the lung. Low grade toxicities in this trial included fatigue, musculoskeletal pain, and radiation pneumonitis. Fourteen patients had more severe toxicity, including decline in pulmonary function tests, pleural effusions, and pneumonias, 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 stated above, investigation into different SABR regimens to treat tumors located within the zone of the proximal 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

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 creates paradigms to facilitate adaptive therapy (Song et al. 2005; Martinez et al. 2001; Bortfeld and Paganetti 2006). Within adaptive therapy, pretreatment 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 therapy, and utilizes a tailored approach to constantly reevaluate and respond to queues in order to redirect therapy toward better patient outcome. As we continue towards this goal of adapting therapy, it will continue to be crucial to utilize well designed prospective 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 1

Introduction.............................................................. 363

2

Patterns of Failure................................................... 364

3

Results of PORT in Stage I NSCLC ..................... 364

4

Results of PORT in Stage II and III (Node-Positive) NSCLC .......................................... 365

5

Indications for PORT.............................................. 366

6

Toxicity and Mortality Risks of PORT ................ 367

7

Techniques for PORT ............................................. 368

8

PORT and Adjuvant Chemotherapy .................... 368

9

Conclusions and Future Directions ....................... 369

Abstract

The role of post-operative radiotherapy (PORT) in treatment of non-small cell lung cancer (NSCLC) is unclear. Currently, the available evidence suggests that PORT is indicated for stage II and III (node-positive) NSCLC, but not for stage I NSCLC. However, it is still disputed in which cases patterns of failure necessitate further treatment following surgery, and if it is warranted, the question becomes whether to do radiotherapy instead of or with (before, during, or after) chemotherapy. Study of PORT is further complicated by the improvement of radiotherapy techniques in recent decades, and the shortage of 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.

References.......................................................................... 369

1 M. Machtay (&) Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH, USA e-mail: [email protected] E. Kim Case Western Reserve University School of Medicine, Cleveland, OH, USA

Introduction

Lung cancer treatment and prognosis depends on several factors, including tumor histology, patient performance status and extent of disease. The latter is usually indicated by TNM stage. Clinical staging is relatively unreliable, with disease often restaged to a more advanced stage according to results of pathologic staging following surgery.


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E. Kim and M. Machtay

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 staging 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’’ randomized 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 multiinstitutional 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 bronchial 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

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 survival 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 metaanalysis 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 retrospective 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 tomography (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 staging 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. reasonably 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 metaanalysis trialists Group 1998). Trodella et al’s controlled randomized study published 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 diseasefree 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 updated 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-analysis Trialists Group results, the situation for nodepositive (stage II/III) NSCLC is less clear than for

365

stage I NSCLC. Most randomized trials in node positive NSCLC suggest that PORT improves locoregional 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 statistically significantly different overall survival and disease-free survival. PORT was found to be a significant positive prognostic factor and an independent prognostic factor for overall survival in univariate and multivariate analyses. Furthermore, locoregional recurrence-free survival (LRFS) and distant metastasis-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 observation and 51% in adjuvant chemotherapy group).

366


Table 1 Results of selected randomized trials of postoperative radiotherapy (PORT) for NSCLC Study

# patients

Stage

XRT dose (Gy)

Survival with XRT (%)

Survival without XRT (%)

LRF with XRT (%)

LRF without 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

Stephens et al. (1996)

308

II, III

40

25

25

Mayer et al. (1997)

155

I–III

50–56

30

20 a

a

a

18

29a

6

24

Dautzenberg et al. (1999)

720

I–III

60

30

43

28

34

Debevec et al. (1996)

74

III

30

32

20

b

b

Trodella et al. (2002)

104

I

50

67a

58a

2a

22a

a b

Statistically significant difference (P \ 0.05) Data not available

However, quite different results were found when pathologic N1 and N2 stages were considered separately. 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 evaluators 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 identified; second, properly and appropriately used radiotherapy 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 disease 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 metastasis. 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


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 pulmonary 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 deterioration even in the absence of a recognized treatment-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 respiratory 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 chemoradiotherapy. 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 retrospective 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-dimensional (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 categorized 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 twentythree (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 reduces 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 limitations, 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 treated 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

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 radiationinduced 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 volume 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 following 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) concluded 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 concurrent paclitaxel/carboplatin and PORT found the combination to be safe and that it seemed to have an improved overall and progressionfree 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 substantially; 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, recognizing that adjuvant chemotherapy should be the higher priority for these patients because of the latter’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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369 lung cancer: promising long-term results of the Radiation Therapy Oncology Group–RTOG 9705. J Clin Oncol 23(15): 3480–3487. PMID: 15908657 Burdett S, Stewart L, PORT Meta-analysis Group (2005) Postoperative radiotherapy in non-small-cell lung cancer: update of an individual patient data meta-analysis. Lung Cancer 47(1):81–83. PMID: 15603857 Dai H, Hui Z, Ji W (2011) Postoperative radiotherapy for resected pathological stage IIIA-N2 non-small cell lung cancer: a retrospective study of 221 cases from a single institution. Oncologist 16(5):641–650. Epub 2011 Apr 11, PMID: 21482587 Dautzenberg B, Chastang C, Arriagada R et al (1995) Adjuvant radiotherapy versus combined sequential chemotherapy followed by radiotherapy in the treatment of resected nonsmall cell lung carcinoma. A randomized trial of 267 patients. GETCB (Groupe d’Etude et de Traitement des Cancers Bronchiques). Cancer 76(5):779–786. PMID: 8625180 Dautzenberg B, Arriagada R, Chammard AB et al (1999) A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma. Groupe d’Etude et de Traitement des Cancers Bronchiques. Cancer 86(2):265–273. PMID: 10421262 Debevec M, Bitenc M, Vidmar S et al (1996) Postoperative radiotherapy for radically resected N2 non-small-cell lung cancer: randomized clinical study 1988–1992. Lung Cancer 14(1):99–107. PMID: 8696724 Decker RH, Wilson LD (2008) Postoperative radiation therapy for non-small cell lung cancer. Semin Thorac Cardiovasc Surg 20(3):184–187. PMID: 19038726 Douillard JY, Rosell R, De Lena M et al (2008) Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys 72(3):695– 701. Epub 2008 Apr 24.18439766 Feng QF, Wang M, Wang LJ et al (2000) A study of postoperative radiotherapy in patients with non-small-cell lung cancer: a randomized trial. Int J Radiat Oncol Biol Phys. 47(4):925–929. PMID: 10863061 Keller SM, Adak S, Wagner H et al (2000) A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group. N Engl J Med 343(17): 1217–1222. PMID: 11071672 Kelsey CR, Light KL, Marks LB (2006) Patterns of failure after resection of non-small-cell lung cancer: implications for postoperative radiation therapy volumes. Int J Radiat Oncol Biol Phys 65(4):1097–1105. Epub 2006 May 6, PMID: 16682136 Kelsey CR, Marks LB, Wilson LD (2008) Postoperative radiation therapy for lung cancer: where do we stand? Oncology (Williston Park) 22(3):301–310; discussion 310, 314–315, 319. PMID: 18494356 Lafitte JJ, Ribet ME, Prevost BM et al (1996) Postresection irradiation for T2N0M0 non-small cell carcinoma: a prospective randomized trial. Ann Thorac Surg 62(3): 830–834. PMID: 8784014 Lally BE, Detterbeck FC, Geiger AM et al (2007) The risk of death from heart disease in patients with nonsmall cell lung

370 cancer who receive postoperative radiotherapy: analysis of the surveillance, epidemiology, and end results database. Cancer 110(4):911–917. PMID: 17620279 Le Pechoux C (2011) Role of postoperative radiotherapy in resected non-small cell lung cancer: a reassessment based on new data. Oncologist 16(5):672–681. Epub 2011 Mar 4, PMID: 21378080 Machtay M (2008) PORTable indications in non-small-cell lung carcinoma. Oncology 22:301–310 Machtay M, Lee JH, Shrager JB et al (2001) Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected non-smallcell lung carcinoma. J Clin Oncol 19(19):3912–3917. PMID: 11579111 Masson-Cote L, Couture C, Fortin A et al (2011) Postoperative radiotherapy for lung cancer: improvement in locoregional control using three-dimensional compared with twodimensional technique. Int J Radiat Oncol Biol Phys 80(3): 686–691 Matsugama H, Nakahara R, Ishikawa Y et al (2008) Postoperative radiotherapy for patients with completely resected pathological stage IIIA-N2 non-small cell lung cancer: focusing on an effect of the number of mediastinal lymph node stations involved. Interact Cardiovasc Thorac Surg 7(4):573–577. Epub 2008 Apr 15, PMID: 18413349 Mayer R, Smolle-Juettner FM, Szolar D et al (1997) Postoperative radiotherapy in radically resected non-small cell lung cancer. Chest 112(4):954–959. PMID: 9377958 Miles EF, Kelsey CR, Kirkpatrick JP et al (2007) Estimating the magnitude and field-size dependence of radiotherapyinduced mortality and tumor control after postoperative radiotherapy for non-small-cell lung cancer: calculations from clinical trials. Int J Radiat Oncol Biol Phys 68(4):1047–1052. Epub 2007 May 15, PMID: 7507176 Moretti L, Yu DS, Chen H et al (2009) Prognostic factors for resected non-small cell lung cancer with pN2 status: implications for use of postoperative radiotherapy. Oncologist 14(11):1106–1115. Epub 2009 Nov 6, PMID: 19897534 NSCLC Meta-analyses Collaborative Group, Arriagada R, Auperin A et al (2010) Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-smallcell lung cancer: two meta-analyses of individual patient data. Lancet 375(9722):1267–1277. Epub 2010 Mar 24, PMID: 20338627 Phlips P, Rocmans P, Vanderhoeft P et al (1993) Postoperative radiotherapy after pneumonectomy: impact of modern treatment facilities. Int J Radiat Oncol Biol Phys 27(3): 525–529. PMID: 8226144 PORT Meta-analysis Trialists Group (1998) Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet. 352(9124): 257–263. PMID: 9690404 Sawyer TE, Bonner JA, Gould PM et al (1997) The impact of surgical adjuvant thoracic radiation therapy for patients with nonsmall cell lung carcinoma with ipsilateral mediastinal lymph node involvement. Cancer 80(8):1399–1408. PMID: 9338463

E. Kim and M. Machtay Saynak M, Higginson DS, Morris DE et al (2010) Current status of postoperative radiation for non-small-cell lung cancer. Semin Radiat Oncol 20(3):192–200. PMID: 20685582 Scotti V, Meattini I, Saieva C et al (2010) Post-operative radiotherapy in N2 non-small cell lung cancer: a retrospective analysis of 175 patients. Radiother Oncol 96(1):84–88. Epub 2010 Jun 11, PMID: 20541823 Stephens RJ, Girling DJ, Bleehen NM (1996) The role of postoperativef radiotherapy in non-smalol cell lung cancer: a multicentre randomised trial in patients with pathologically staged T1-2N1-2M0 disease. Medical research council lung cancer working party. Br J Cancer 74(4):632–639. PMID: 8761382 Strauss GM, Herndon JE II, Maddaus MA et al (2008) Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 26(31):5043–5051. Epub 2008 Sept 22, PMID: 18809614 Taylor NA, Liao ZX, Stevens C et al (2003) Postoperative radiotherapy increases locoregional control of patients with stage IIIA non-small-cell lung cancer treated with induction chemotherapy followed by surgery. Int J Radiat Oncol Biol Phys 56(3):616–625. PMID: 12788166 Trodella L, Granone P, Valente S et al (2002) Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: definitive results of a phase III randomized trial. Radiother Oncol 62(1):11–19. PMID: 11830308 Van Houtte P, Rocmans P, Smets P et al (1980) Postoperative radiation therapy in lung caner: a controlled trial after resection of curative design. Int J Radiat Oncol Biol Phys 6(8):983–986. PMID: 6998936 Varlotto JM, Medford-Davis LN, Recht A (2010) Varying recurrence rates and risk factors associated with different definitions of local recurrence in patients with surgically resected, stage I nonsmall cell lung cancer. Cancer 116(10):2390–2400. PMID: 20225332 Wakelle HA, Stephenson P, Keller SM et al (2005) Postoperative radiotherapy (PORT) or chemoradiotherapy (CPORT) following resection of stages II and IIIA nonsmall cell lung cancer (NSCLC) does not increase the expected risk of death from intercurrent disease (DID) in Eastern Cooperative Oncology Group (ECOG) trial E3590. Lung Cancer 48(3):389–397. Epub 2005 Jan 5, PMID: 15893008 Weisenburger TH (1994) Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. LCSG 773. Chest 106(6 Suppl):297S–301S. PMID: 7988248 Winton T, Livingston R, Johnston D et al (2005) Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352(25):2589–2597. PMID: 15972865 Zou B, Xu Y, Li T et al (2010) A multicenter retrospective analysis of survival outcome following postoperative chemoradiotherapy in non-small-cell lung cancer patients with N2 nodal disease. Int J Radiat Oncol Biol Phys 77(2): 321–328. Epub 2009 Sept 21, PMID: 19775829

PDT-Lung Ron R. Allison

Contents 1

Introduction............................................................ 371

2

Historical Perspective............................................ 372

3 3.1

Fundamentals of PDT ........................................... 372 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: [email protected]

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 reaction, dosimetry and fluorescence. The actual treatment 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 pulmonary 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 multidisciplinary decision-making process and therapy of lung cancer.


371

372

2

R. R. Allison

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 cutaneous malignancy (Von Tappeiner and Jesionek 1907). Still, PDT did not firmly establish itself and was lost to medicine. The use of dyes and later porphyrins, for fluorescent detection, as potential radiation 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 commercially successful photosensitizing drug, light sources and clinical trials showing efficacy in a wide variety of malignancies particularly pulmonary lesions. During the early 1980s PDT achieved worldwide regulatory approval as an intervention for select thoracic tumors. Since those early approvals, the PDT treatment process has been refined and enhanced allowing for continued success today.

3

Fundamentals of PDT

Arbitrarily we will divide PDT into three components: 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

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 cosmetic 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 photosynthesis, 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 manufactured by numerous ‘‘unofficial’’ manufacturers whose drug appears similar to PhotofrinÒ in both name and content. This PS allows for treatment time of

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10–20 min per lesion which is satisfactory during bronchoscopy. Therapy is painless and with photofrinÒ highly reliable. It is usually dosed at 2 mg/kg and around 48 h post intravenous infusion a differential 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 potentially 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 photosensitivity. 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 twoday waiting period for photofrin. The drug is intravenously infused at 40 mg/m2.

4

Illumination

Each PS has both a specific activation wavelength and also intensity of light required for activation. As sunlight 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 wavelength 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 photosensitizer (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 illustrated 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.

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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.

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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 individualized 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 individuals 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 determined 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 (photobleached) 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

based on the patient’s metabolic and treatment characteristics. 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 fluorescence phenomena can be exploited to assist in determining the extent of disease which may be unclear to the naked eye in visible light. Under fluorescence lesions become very obvious compared to nearby non-fluorescing normal tissues. This fluorescence phenomenon is sometimes called photo diagnosis. 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 surveillance 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 pulmonary 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-disciplinary approach for pulmonary disease control either in a curative or palliative settings. Unlike other interventions PDT can be repeated to allow for

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Fig. 2 Obstructing lesion (left) of airway treated by photofrin PDT, 2 mg/kg, 200 J Red light. Two weeks post PDT (right) shows complete response. (Photo’s courtesy 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. Endobronchial tumors are generally approached endobronchially. 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. Fluorescent 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 outcome is shown in Figs. 2 and 3. The PDT procedure can be offered in stented regions as well. Selfexpanding 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

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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 additional 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 transbonchial application of the light source using endobronchial 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.

Current light sources produce intense illumination. During treatment both patients and practitioners need to wear eye protecting goggles. Eye injury or blindness can result from improper safety procedures.

11

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 electrocautery. 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 preservation of pulmonary function are routinely achieved (Weigel et al. 1999). Select publications from the PDT literature follow.

11.1

10

PDT-Morbidity

Morbidity can occur immediately following PS infusion as the individual becomes photosensitive within minutes of infusion. Individuals who will not follow sunlight precautions should not undergo PDT. Photosensitivity to sunlight exposed anatomy can occur even with only a few minutes of sunlight exposure. Clinically 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 routine 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).

Clinical Outcomes

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 endobronchial tumors. Response rates leading to pulmonary 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 palliative 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

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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 pulmonary 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 parenchyma, 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 sessions allowed a 100% pathologic complete response for lesions centrally located. No patient had pulmonary compromise and only one had sunlight sensitivity. 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

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 fluorescence 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 surgical 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 complete 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 preoperative PDT to no PDT for this cohort of patients.

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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 placement of illumination fibers and via bronchoscopy augmented with guidance. Using CT guidance, catheters 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 combination 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 pulmonary PDT explored the intentional combination of external beam therapy with PhotofrinÒ PDT (Lam et al. 1987). Patients with histologically proven, unresectable, 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 progressed by 12 week post therapy, compared to only 20% in the PDT + radiation group. Further only

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 nonsmall-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.

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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 established 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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380 Sibata CH, Colussi VC, Oleinick NL, Kinsella TJ (2000) Photodynamic therapy: a new concept in medical treatment. Braz J Med Biol Res 33:869–880 Sokolov VV, Telegina LV, Trakhtenberg AKH, Kolbanov KI, Pikin OV, Frank GA (2010) Enodobronchial surgery and photodynamic therapy for the treatment of multiple primary lung cancer. Khirurhiia 7:28–31 Usuda J, Tsutsui H, Honda H, Ichinose S, Ishizumi T, Hirata T, Inoue T, Ohtani K, Maehara S, Imai K, Tsunoda Y, Kubota M, Ikeda N, Furukawa K, Okunaka T, Kato H (2007) Photodynamic therapy for lung cancers based on novel photodynamic diagnosis using talaporfin sodium (NPe6) and autofluorescence bronchoscopy. Lung Cancer 58:317–323 Usuda J, Ichinose S, Ishizumi T, Hayashi H, Ohtani K, Maehara S, Ono S, Kajiwara N, Uchida O, Tsutsui H, Ohira T, Kato H, Ikeda N (2010) Management of multiple primary lung cancer

R. R. Allison in patients with centrally located early cancer lesions. J Thorac Oncol 5:62–68 Von Tappeiner H, Jesionek A (1907) The sensitizing action of fluorescent substances. An overall account of investigations on photodynamic phenomena. Leipzig, F.C.W. Vogel Von Tappeiner H, Jesionek A (1903) TherapeutischeVersuchemitfloreszierendenStofffen (Therapeutic experiments with fluorescent substances). Muench Med Wochenscr 47:2042–2044 Weigel TL, Kosco PJ, Dacic S, Yousem S, Luketich JD (1999) Fluorescence bronchoscopic surveillance in patients with a history of non-small cell lung cancer. Diagn Ther Endosc 6:1–7 Weinberg BD, Allison RR, Sibata C, Parent T, Downie G (2010) Results of combined photodynamic therapy (PDT) and high dose brachytherapy (HDR) in treatment of obstructive endobronchial non-small cell lung cancer (NSCLC). Photodiagnosis Photodyn Ther 7:50–58

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

J. M. Varlotto (&) J. A. Shelkey Radiation Oncology—CH63, Penn State Hershey Cancer Institute, 500 University Drive, PO Box 850, Hershey, PA 17033, USA e-mail: [email protected] R. P. Mahraj Department of Radiology, Penn State Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA

Abstract

Currently, the standard of care for stage I non-small cell lung cancer (NSCLC) is surgical resection. Although this treatment modality has been demonstrated to have 5 year survival rates approaching 80%, there need to be effective alternative treatments 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.

Abbreviations

AICD AZ C CA CN

Automatic implantable cardioverter defibrillator Ablation zone Centigrade Complete ablation Complete necrosis


381

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J. M. Varlotto et al.

CR CSS CTCAE DFS DR EBUS EP F/U GGA H&E H&M nodes IA IP LC LR MAM Mn NS NSCLC PFS PNB Pneumo R RECIST RF RFA RT RT-br RTOG S SBRT SVB

1

Complete response Cancer specific survival Common terminology criteria for adverse events Disease-free survival Distal recurrence Endobronchial ultrasound Extrapulmonary recurrence Follow-up Ground-glass attenuation Hematoxylin and eosin staining Hilar and mediastinal nodes Incomplete ablation Intrapulmonary recurrence Local control Local recurrence Monoclonal anti-mitochondrial antibodies Months Not stated Non-small cell lung cancer Progression-free survival Percutaneous biopsy Pneumothorax Recurrence Response evaluation criteria in solid tumors Radiofrequency Radiofrequency ablation External beam radiotherapy Brachytherapy Radiation therapy oncology group Survival Stereotactic body radiation therapy Supravital blue staining

Introduction

Interstitial hyperthermia via the radiofrequency ablation of a primary lung cancer was first described during an open thoracotomy in 1983 (Lilly et al. 1983). The first report of modern, percutaneous radiofrequency ablation in patients with lung malignancies was published in 2000 (Dupuy et al. 2000). Due to the technique’s minimal invasiveness, there has been considerable interest and multiple case series

concerning percutaneous RFA of lung neoplasms in the recent literature. This technique directly destroys tumor cells by delivering a high-frequency, alternating current with frictional heating and ionic agitation. Consequently, cell membrane alteration, protein denaturation, and necrosis around the electrode are directly produced. However, this process can indirectly stimulate the immune system because it releases large amounts of tumor antigen and tissue debris into the systemic circulation (Fietta et al. 2009; Widenmeyer et al. 2010). The treatment of lung neoplasms may be ideal for RFA because the surrounding pulmonary tissue may cause an insulating effect whereby the heat is concentrated within the tumor. The low thermal conductivity of the neighboring lung tissue has been demonstrated to greatly increase radiofrequency-induced temperatures within a defined ablation target (Liu et al. 2006). The purpose of this chapter is to describe the technique, results, complications, and follow-up evaluation of Stage I Non-small cell lung cancer (NSCLC) patients treated with RFA.

2

Patient Selection and Evaluation

The treatment approach for effective management of early stage NSCLC is evolving to mirror complex disease presentations and patient situations, as well as to accommodate the many different therapeutic options. For early stage lung cancer, surgery offers survival rates as high as 79.5% at 5 years (Koike et al. 1998). Many patients, however, are inoperable due to either co-morbidities or the development of new or recurrent lung cancer following past therapeutic intervention. Under these circumstances, radiofrequency ablation is a minimally-invasive technique that represents an additional tool to treat patients in these situations. The decision to offer this method of treatment is best considered in a multi-disciplinary group setting. Thoracic surgeons, radiation oncologists, thoracic interventional radiologists, and medical oncologists should be involved in determining the most appropriate treatment strategy. This plan should include evaluation of surgical technique (lobectomy versus limited resection), conventional radiotherapy versus SBRT, and RFA or combined modality treatment. RFA can be considered as a sole treatment option or with other 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 pneumonectomy, and uncorrectable coagulopathy. Furthermore, 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 represent a special risk and require expert electrophysiological management. Stereotactic body radiation therapy (SBRT), microwave, and cryoablation represent 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 guidelines, 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-fluoroscopic guidance into the lesion. The patient essentially 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 leading to frictional heat. The area of coagulation necrosis achieved is related to the strength of the radiofrequency energy, the current-carrying time, the diameter 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 system causes less collateral damage to normal tissues and prevents tissue charring (excessive tissue destructive near the electrode resulting in less effective treatment of distal tumor tissue) due to its use of a single small gauge needle and because of a continuous 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 ablation 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


in continuity with large blood vessels may be suboptimally treated with RFA. CT volumetric scanning with multi-planar reconstruction 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. Multiple 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 hemorrhage 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 enlargement of the solid portion of the tumor and the synchronous 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 repositioning 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 sedation or post-anesthesia recovery standards. The lung puncture site should be kept dependent for 2–3 h. Antitussive medications may be beneficial and adequate 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 discharged 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).


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

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, prospective study. A percutaneous, CT-guided RFA technique was used in most studies. Ambrogi et al. (2007), however, treated some tumors involving the chest wall with

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

9(11%) –RT-Br

Different Stages

Progression-focal enhancement [ 15 HU compared with unenhanced series

18% Nodal

18% IP

19(24%)-RT

(continued)

Median DFS 23 months*

NSCLC

LC-lack of contrast enhancement in AZ

NS

57%-no recurrence* 38% LR

79/2.5 (1.5-5.5 cm)

Beland* 2010

17

Prolonged air leak [ 5 days-5% Median time to local progression = 27 months

Modified RECIST-Based upon CT size and mass quality; higher SUV or larger area on PET Scan

Stage I NSCLC only

S-90, 84, 74 at 1, 2, and 3 years

S-95%-1 yr, 68%-2 yr

Pleural effusion-17%

Pneumothorax-57%

2 yr S-75% and CSS-92%

Survival

Pneumo-63%-pigtail catheter 29

Median time for local progression = 9 months

72, 63, & 63% at 1, 2, and 3 years

Minor complicationsself-limited 1. hemorrage-2.18% 2. pneumo-20.4% 3. effusion-8.02%

Major Complicationsdrainage needed* 1. Large or symptomatic pneumo-19.7%; 2. Pleural effusion2.9%

Complications

42% local progression

19/2.6 (1.6-3.8 cm)

Pennathur 2007

21.8

92% CSS

Local Control

CSS-100, 93, 83 at 1, 2, and 3 years

Progression-circumferential enlargement. Irregular, scattered, nodular, or eccentric foci in the AZ

CR-No contrast enhancement in entire ablation zone, or when the ablation zone exhibited a peripheral rim of contrast-enhancement that was concentric, symmetric and uniform with smooth margins.

15*

F/U (mn)

One chest tube placement-rest conservative treatment

IB-6

IA-14

20/ Mean tumor size = 2.4 (1.3-6 cm)

Stage I NSCLC only

Hiraki T 2007

CR = complete ablation of tumor lasting one year

Modified RECIST using CT Scan 1 month after treatment as reference

13/ all \ 3.5 cm, median 1.7*

Lencioni* 2008

NSCLC and Lung Metastases

LR Definition

#/size

Author Patient Pop.

Table 1 Summary of current clinical studies using RFA for treatment of Stage I lung cancer

386 J. M. Varlotto et al.


Rossi 2006

Stage I NSCLC only

Lanuti 2009

Author Patient Pop.

Growth on serial CT scans-used for patients intolerant of contrast

7% Stage IIIB

Progression of FDG H&M nodes after 3 mn-local failure

Increasing size or enhancement at tumor site-using 30 Day ct scan, repeat procedure-if 30 day positive, then mark as failure

3 with stable disease received RT

15 LUNG Ca/2.2 (1.0-3.5 cm)*

Lack of focal or diffuse enlargement of ablated lesion on CT and no evidence of eccentric enhancement on PET with minimum of 3 mn of FU;

Benign peritumoral enhancement-Symmetric rim of peripheral enhancement of \ 5 mm up to 6 mn after ablation

94% Stage I

31pts/2.0 (0.8-4.4 cm)

LR Definition

#/size

Table 1 (continued)

11.4 mn

17.3

F/U (mn)

No major complications* 5pneumo-no drainage* 4pneumonias*

13.3% IP progression 20% EP Progression

Transient recurrent nerve palsy-1%

Chest tube-8%

BP fistula-8%

Effusion-21%

Pneumonia-16%

Pneumo-13%

Complications

20% LR

50% LR with size [ 3 cm(3/6)

31.5% LR

R related to size and stage; RT and RT-br borderline significance for R

21% DR

6% Mixed

Local Control

(continued)

9/15 alive without disease progression

3 yr PFS and DFS-58%, 39%

S-2 & 4 yr-78%, 47%

Survival

The Role of Radiofrequency Ablation in the Treatment of Stage 1 Non-Small Cell Lung Cancer 387

50(36 StageI)/ NS, but all \ 5 cm

FU with contrast-enhanced ct scan, but no definition of LR given

31*

radiological CR-59%*

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

Different Stages

NSCLC

Ambrogi 2007

Complete necrosis in all 6 tumors \ 3 cm, and in 23%(6/26) tumors [ 3 cm

complete necrosis = nonenhancing area with a diameter [ initial viable tumor

60% CR

Local Control

40% PR

12.5 mn*

F/U (mn)

Previously enhancing, but currently unenhancing areas = necrosis;

Any residual portion of lesion with enhancement [ 10HU after contrast = viable tumor;

10/4.1 cm

Lee 2003


LR Definition

#/size

Author Patient Pop.

Table 1 (continued)

5/50-10% pneumothorax-2/ 5 required pleural drainage*

10% major compl including 2 pneumo-thoracostomy; 1ARDS*

Complications

Median S = 25 mn*

mean survival = 13.3 mn

Survival

388 J. M. Varlotto et al.


389

Table 2 Summary of ablate and resect studies using RFA for treatment of lung neoplasms Author Pt population

# with stage I NSCLC

Tumor size

Time interval

Method of assessment

Definition of response

Response

Conclusion

Schneider* Schneider et al. 2011

14

1.7–3.5

immediate

Histology-HE staining

CN

5 CN

CN in 35.7%

NADH (Supravital staining)performed in 22/32 procedures

Scattered vital tissue

7 Scattered vital tissue

High rate of tumor cells remaining after RFA casts doubt on RFA as curative concept


IA, [ 20% vital tissue 2 IA, [ 20% vital tissue

Monoclonal antimitochondrial Antibodiesperformed in 18/32 procedures

Ambrogi* Ambrogi et al. 2006

9

Max size of 3.5 cm

5/9 immediate resection;

NSCLCStage I and II

6-Stage I 3-StageII

Mean size 2.8 cm

4/9 resection after 15 days

HistologyH&E staining

IA did not depend whether primary or secondary, 2/ 10 primary lung and 2/7 mets with adenoca had IA Absence of tumor cells with H&E

CN in 6/9

Mean size 2.3 cm with CN

Mean size of lesion with IA = 3.1 cm

All 1 cm away from major blood vessels and airways

ALL IA-no more than 10% of treated area with viable tumor Margin \5 mm in all three cases of IA, average margin 8 mm in CA

Nguyen* Nguyen et al. 2005

8

NSCLCStage I and II

7-StageI 1-Stage II

Mean tumor size = 2.2 cm

Immediate resection

HistologyH&E

NADH

CN Complete necrosis, IA Incomplete ablation, CA Complete ablation

Absence of cells by NADH staining

CA in 3-all \2 cm; IA noted in 5 tumors, 3 of which were \2 cm

Routine H&E staining could not differentiate viable from nonviable cells

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 sporadically 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-significant trend in favor of reduced recurrences in patients receiving external beam radiotherapy (RT) or brachytherapy (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

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 primary 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 immediate 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 reduction 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,


391

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 sometimes be appreciated (Sharma et al. 2010). After 3 months, continued increase in growth of the ablation zone should be viewed as suspicious for incomplete tumor destruction and recurrent tumor (Bojarski et al. 2005). Successful treatment is associated with

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 residual activity before inflammation develops is likely to predict residual disease. Later assessment can demonstrate 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


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


393

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

6

Summary

Since the first published report of modern percutaneous 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

effusion, occurring in 13–63% and 10–21%, respectively. 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 different 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 considered 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 apertures) 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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J. M. Varlotto et al. for three-dimensional conformal radiotherapy planning. Int J Radiat Oncol Biol Phys 48:1015–1024 Higaki T, Okumura Y, Sato S et al (2008) Preliminary retrospective investigation of FDG-PET/CT timing in followup of ablated lung tumor. Ann of Nucl Med 22:125–163 Hiraki T, Gobara H, Iishi T et al (2007) Percutaneous radiofrequency ablation for clinical stage I non-small cell lung cancer: results in 20 nonsurgical candidates. J Thorac Cardiovasc Surg 134:1306–1312 Jin GY, Lee JM, Lee YC, Han YM, Lim YS (2004) Primary and secondary lung malignancies treated with percutaneous radiofrequency ablation: evaluation with follow-up helical CT. Am J Roentgenol 183:1013–1020 Koike T, Terashima M, Takizawa T, Watanabe T, Kurita Y, Yokoyama A (1998) Clinical analysis of small-sized peripheral lung cancer. J Thorac Cardiovasc Surg 115:1015–1019 Lanuti M, Sharma A, Digumarthy SR et al (2009) Radiofrequency ablation for treatment of medically inoperable stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 137:160–166 Lee JM, Jin GY, Goldberg SN et al (2003) Percutaneous radiofrequency ablation for inoperable non-small cell lung cancer and metastases: preliminary report. Radiology 230:125–134 Lencioni R, Crocetti L, Cioni R et al (2008) Response to radiofrequency ablation of pulmonary tumors: a prospective, intention-to-treat, multicentre clinical trial (the rapture study). Lancet Oncol 9:621–628 Lilly MB, Brezovich IA, Atkinson W et al (1983) Hyperthermia with implanted electrodes: in vitro and in vivo correlations. Int J Radiat Oncol Biol Phys 9:373–382 Liu Z, Ahmed H, Iishi T et al (2006) Characterization of the RF ablation-induced ‘‘oven effect’’: the importance of background tissue thermal conductivity on tissue heating. Int J Hyperthermia 22:32–42 Matsuoka T, Okuma T (2007) CT-guided radiofrequency ablation for lung cancer. Int J Clin Oncol 12(2):71–78 McTaggart RA, Dupuy DE (2007) Thermal ablation of lung tumors. Tech Vasc Interv Radiol 10(2):102–113 Nguyen CL, Scott WJ, Young NA et al (2005) Radiofrequency ablation of primary lung cancer. Chest 128:3507–3511 Okuma T, Matsuoka T, Yamamoto A et al (2007) Factors contributing to cavitation after CT guided percutaneous radiofrequency ablation of lung tumors. J Vasc Interv Radiol 18(3):399–404 Pennathur A, Luketich JD, Abbas G et al (2007) Radiofrequency ablation for the treatment of stage I non-small cell lung cancer in high-risk patients. J Thorac Cardiovasc Surg 134(4):857–864 Pennathur A, Abbas G, Schuchert MJ et al (2010) Imageguided radiofrequency ablation for the treatment of early stage non-small cell lung neoplasms in high-risk patients. Semin Thorac Cardiovasc Surg 22:53–58 Rose SC (2008) Radiofrequency ablation of pulmonary malignancies. Semin Respir Crit Care Med 29:361–383 Rose SC, Thistlethwaite PA, Sewell PE, Vance RB (2006) Lung cancer and radiofrequency ablation. J Vasc Interv Radiol 17:927–951

The Role of Radiofrequency Ablation in the Treatment of Stage 1 Non-Small Cell Lung Cancer Rossi S, Dore R, Cascina A et al (2006) Percutaneous computed tomography-guided radiofrequency thermal ablation of small unresectable lung tumors. Eur Respir J 27:556–563 Schneider T, Reuss D, Warth A et al (2011) The efficacy of bipolar and multipolar radiofrequency ablation of lung neoplasms-results of an ablate and resect study. Eur J Cardiothorac Surg in print Sharma A, Digumarthy SR, Kalra MK et al (2010) Reversible locoregional lymph node enlargement after radiofrequency ablation of lung tumors. Am J Roentgenol 194:1250–1256 Steinke K, King J, Glenn D, Morris DL (2003) Radiologic appearance and complications of percutaneous computed tomography-guided radiofrequency-ablated pulmonary metastases from colorectal carcinoma. J Comput Assist Tomogr 27:750–757 Steinke K, Haghighi KS, Wulf S et al (2005) Effect of vessel diameter on the creation of ovine lung radiofrequency lesions in vivo: preliminary results. J Surg Res 124:85–91 Timmerman R, McGarry R, Yiannoutsos C et al (2006) Excessive toxicity when treating central tumors in a phase

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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 radiation 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 technology 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 escalation. The present chapter reviews these studies and discusses the current status of radiation dose escalation for patients with stage III NSCLC.

Abbreviations

B. S. Hoppe (&) University of Florida Proton Therapy Institute, 2015 North Jefferson St, Jacksonville, FL 32206, USA e-mail: [email protected] K. E. Rosenzweig Mount Sinai School of Medicine, One Gustav L. Levy Place, Box 1236, New York, NY 10029, USA

RTOG NSCLC RT Gy SEER CT FDG-PET GTV

Radiation Therapy Oncology Group Non-small-cell lung cancer Radiation therapy Gray Surveillance, epidemiology and end result Computed tomography Fluorodeoxyglucose positron emission tomography Gross tumor volume


399

400

ENI CTV PTV kV 3D 4D PT IMRT BID MTD MSKCC UM NKI UNC 3D-CRT NTCP DVH Veff rMLD CALGB NCCTG

1

B. S. Hoppe and K. E. Rosenzweig

Elective nodal irradiation Clinical tumor volume Planning target volume Kilovoltage Three-dimensional Four-dimensional Proton therapy Intensity-modulated radiation therapy Twice daily Maximum tolerated dose Memorial Sloan–Kettering Cancer Center University of Michigan Netherlands Cancer Institute University of North Carolina Three-dimensional conformal radiotherapy Normal-tissue complication probability Dose-volume histogram V effective Relative mean lung dose Cancer and Leukemia Group B North Central Cancer Treatment Group

Introduction

Poor outcomes in patients with unresectable nonsmall-cell lung cancer (NSCLC) have been attributed, in part, to low rates of local control with traditional doses of definitive radiotherapy (RT). Overall survival rates in NSCLC are expected to improve with better local control rates, which is possible with higher radiation-dose levels. Unfortunately, the therapeutic ratio for treating lung cancer with radiation has traditionally been small, due to the sensitivity of the lung and resulting pneumonitis and esophagitis with higher radiation doses. Thus, dose escalation in patients with NSCLC has historically been a double-edged sword with improved local control rates with higher doses, but correspondingly higher treatment-related morbidity and mortality. Over the last 20 years the therapeutic ratio of RT for NSCLC has widened due to reduced normal lung tissue treated with high doses of radiation through a reduction in the target volume, more sophisticated

radiation delivery systems, and a better understanding of the relationship between radiation dose-volume histograms of critical organs and treatment-related morbidity. As a result, safe dose escalation over 60 Gy is now more feasible (even with larger tumors) and a major focus of current clinical research studies.

2

Reducing Target Volumes

Target volumes have reduced over the last 20 years due to reductions in: (1) gross tumor volume (GTV), because of improved imaging, (2) clinical target volume (CTV), because of the elimination of elective nodal irradiation, and (3) planning target volume (PTV), because of reduced set-up uncertainty from new imaging and immobilization techniques. Although computed tomography (CT) scanners have been in use since 1973, it took close to 20 years for them to become integrated into RT treatment planning. CT scans provide three-dimensional (3D) information regarding tumor volume as well as 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 treatment of thoracic malignancies increased from 2.4 to 77.6%. Patients who had CT-based simulation also had an improved survival as compared to patients who received conventional simulation (Chen et al. 2011). Over the last decade, fluorodeoxyglucose positron emission tomography (FDG-PET) imaging has also been used in conjunction with CT to aid in identifying malignant lymph nodes that were not enlarged (negative on CT scan) and aid in separating the actual tumor from atelectasis due to obstruction from the tumor. Thus, GTVs have become easier to identify and areas of uncertainties that were previously included in the GTV can now be more safely eliminated. Historically, elective nodal regions have been irradiated to doses of 45–50 Gy as part of the target volume in patients with NSCLC. However, following various series identifying distant and local relapses as the primary sites of relapse, researchers began to selectively eliminate the traditional elective nodal sites (Bradley et al. 2005; Rosenzweig et al. 2007; 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 pneumonitis (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. Margins 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 repositioning 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 possible 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 intensitymodulated 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 discussed 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 setup 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 fraction), 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 twodimensional (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 intensification 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 randomized 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 radiation to improve the therapeutic ratio, allowing for safer dose escalation. Radiation was delivered to the entire mediastinum, ipsilateral hilum, and contralateral 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 randomized 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 performance patients with stage III NSCLC. Interestingly, when the pattern of relapses in this study was evaluated, 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


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 significant 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 disease 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).


403

Table 1 Phase I dose escalation studies Study/ Author

RT technique

ENI

Chemotherapy

Lung constraint

# Of patients

Lowest dose (Gy)

Highest dose (Gy)

MTD (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 9311

3D-CRT

No

Induction (*15%)

V20 \ 25%

127

70.9

90.3

83.8

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

V20 \ 25%

15

72

78

78

V20 (25–37%)

20

72

78

78

China

3D-CRT

Yes

Induction and Adjuvant

V20 [ 37%

15

69

75

75

Carolinas

3D-CRT

Yes

Induction

V35 \ FEV1*35

44

73.6

86.4

80

RTOG 0117

3D-CRT

No

Concurrent

V20 \ 30%

17

74

75.25

74

UNC1

3D-CRT

Yes

Induction and Concurrent

V20 \ 35%

29

60

74

74

UNC2

3D-CRT

Yes

Induction and Concurrent

V20 \ 35%

29

78

90

90

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 eliminated ENI and included the GTV to PTV margin

between 10 and 15 mm. Furthermore, the protocol incorporated lung DVH data to ensure that the normal-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). Furthermore, 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 chemotherapy (allowed after 1997). The study results determined 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 survival 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 3DCRT 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 chemotherapy 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 fraction 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 escalated 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%.


CALGB 39904 was a prospective trial that assessed 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 performed a phase I study from 1997 to 2002 of 44 patients with stage III NSCLC who were given induction chemotherapy 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 demonstrated an MTD of 80 Gy, regardless of the chemotherapy 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 radiation 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 chemoradiation for locally advanced NSCLC. The RTOG began its chemoradiation studies with RTOG 88-04,


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 hyperfractionated RT to 69.6 Gy. Due to the excessive rate of hematologic toxicity in that study, it was subsequently followed up by RTOG 91-06, a study evaluating 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 treatment 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 chemoradiation 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.

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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 compared with 48% in arm 2. The investigators thus concluded 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 demonstrated with concurrent chemoradiation. Although RTOG 94-13 failed to demonstrate an improvement in survival with concurrent chemotherapy 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


Table 2 RTOG non-small cell lung cancer studies Study/ Author

Patients

RTOG 7301

97

40 Gy split

103 91 85

60 Gy

83

60 Gy BID

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 83-11

RTOG 88-08

RT dose

RT technique

ENI

2D

Yes

RTOG 0117

Late (%)

Grade 3/4/5 toxicity non-hematologic

40 Gy

10

7

50 Gy

11

6

12 2D

2D

69.6 Gy BID

RTOG 9410

Acute (%)

13

60 Gy

None

Median OS 9.3

60 Gy RTOG 9204

Chemotherapy

Yes

None

9.2

14 7.0

8.6

Yes

None

11.4

NA

NA

Yes

Induction

13.8

NA

NA

Yes

None

12.3

NA

NA

81

63 Gy

2D

Yes

Induction and concurrent

16.4

35.0

25.0

81

69.6 Gy BID

2D

Yes

Concurrent

15.5

54.0

40.0

2D

Yes

201

60 Gy

201

60 Gy

193

69.6 Gy BID

55

74 Gy

3D

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 generated to create the PTV. The first 29 patients comprised

No

Induction

14.6

NA

NA

Concurrent

17

48.0

NA

Concurrent

15.2

68.0

NA

Concurrent

21.6

61.0

22.0

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 determined 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


(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 toxicities 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 currently 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 paclitaxel 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 upto-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; however, overall survival and distant metastases remain a huge problem. Although dose escalation with concurrent 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 controlled 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.

References Belderbos JS, Heemsbergen WD, de Jaeger K, Baas P, Lebesque JV (2006) Final results of a Phase I/II dose escalation trial in non-small-cell lung cancer using threedimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 66:126–134 Bogart JA et al (2010) Phase I study of accelerated conformal radiotherapy for stage I non-small-cell lung cancer in patients with pulmonary dysfunction: CALGB 39904. J Clin Oncol: Off J Am Soc Clin Oncol 28(2):202–206 Bradley J, Graham MV, Winter K, Purdy JA, Komaki R, Roa WH, Ryu JK, Bosch W, Emami B (2005) Toxicity and outcome results of RTOG 9311: a phase I–II dose escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys 61:318–328 Bradley JD, Moughan J, Graham MV, Byhardt R, Govindan R, Fowler J, Purdy JA, Michalski JM, Gore E, Choy H (2010) A phase I/II radiation dose escalation study with concurrent chemotherapy for patients with inoperable stages I to III non-small-cell lung cancer: phase I results of RTOG 0117. Int J Radiat Oncol Biol Phys 77:367–372 Bral S, Duchateau M, Versmessen H, Verdries D, Engels B, De Ridder M, Tournel K, Collen C, Everaert H, Schallier D, De Greve J, Storme G (2010) Toxicity report of a phase 1/2 dose escalation study in patients with inoperable, locally advanced nonsmall cell lung cancer with helical tomotherapy and concurrent chemotherapy. Cancer 116:241–250 Chen AB et al (2011) Survival outcomes after radiation therapy for stage iii non-small-cell lung cancer after adoption of computed tomography-based simulation. J Clin Oncol: Off j Am Soc Clin Oncol 40:464 Cox JD, Azarnia N, Byhardt RW, Shin KH, Emami B, Pajak TF (1990) A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0–79.2 Gy: possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with radiation therapy oncology group stage III non-small-cell lung carcinoma: report of Radiation Therapy Oncology Group 83-11. J Clin Oncol 8:1543–1555 Curran W (2000) Phase III comparison of sequential vs. concurrent chemoradiation for patients with unresected stage III non-small-cell lung cancer (NSCLC): initial report of radiation therapy oncology group (RTOG) 9410. Pro Am Soc Clin Oncol 19S:1891a Dillman RO, Herndon J, Seagren SL, Eaton WL Jr, Green MR (1996) Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 88:1210–1215 Fried DB, Morris DE, Poole C, Rosenman JG, Halle JS, Detterbeck FC, Hensing TA, Socinski MA (2004) Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 22:4837–4845

408 Graham MV, Purdy JA, Emami B, Harms W, Bosch W, Lockett MA, Perez CA (1999) Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 45:323–329 Hayman JA, Martel MK, Ten Haken RK, Normolle DP, Todd RF, Littles JF, Sullivan MA, Possert PW, Turrisi AT, Lichter AS (2001) Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial. J Clin Oncol 19:127–136 Komaki R, Scott CB, Sause WT, Johnson DH, Taylor SG, Lee JS, Emami B, Byhardt RW, Curran WJ Jr, Dar AR, Cox JD (1997) Induction cisplatin/vinblastine, irradiation vs. irradiation in unresectable squamous cell lung cancer: failure patterns by cell type in RTOG 88–08/ECOG 4588. Radiation Therapy Oncology Group: Eastern Cooperative Oncology Group. Int J Radiat Oncol Biol Phys 39:537–544 Komaki R, Seiferheld W, Ettinger D, Lee JS, Movsas B, Sause W (2002) Randomized phase II chemotherapy and radiotherapy trial for patients with locally advanced inoperable non-small-cell lung cancer: long-term follow-up of RTOG 92-04. Int J Radiat Oncol Biol Phys 53:548–557 Narayan S, Henning GT, Ten Haken RK, Sullivan MA, Martel MK, Hayman JA (2004) Results following treatment to doses of 92.4 or 102.9 Gy on a phase I dose escalation study for non-small cell lung cancer. Lung Cancer 44:79–88 Perez CA, Stanley K, Rubin P, Kramer S, Brady L, PerezTamayo R, Brown GS, Concannon J, Rotman M, Seydel HG (1980) A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung: preliminary report by the Radiation Therapy Oncology Group. Cancer 45:2744–2753 Rosenman JG, Halle JS, Socinski MA, Deschesne K, Moore DT, Johnson H, Fraser R, Morris DE (2002) High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and

B. S. Hoppe and K. E. Rosenzweig results of a phase I/II trial. Int J Radiat Oncol Biol Phys 54:348–356 Rosenzweig KE, Fox JL, Yorke E, Amols H, Jackson A, Rusch V, Kris MG, Ling CC, Leibel SA (2005) Results of a phase I dose escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable nonsmall cell lung carcinoma. Cancer 103:2118–2127 Rosenzweig KE, Sura S, Jackson A, Yorke E (2007) Involvedfield radiation therapy for inoperable non small-cell lung cancer. J Clin Oncol 25:5557–5561 Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R, Emami B, Curran WJ, Byhardt RW, Turrisi AT et al (1995) Radiation therapy oncology group (RTOG) 88–08 and eastern cooperative oncology group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 87:198–205 Sejpal S, Komaki R, Tsao A, Chang JY, Liao Z, Wei X, Allen PK, Lu C, Gillin M, Cox JD (2011) Early findings on toxicity of proton beam therapy with concurrent chemotherapy for nonsmall cell lung cancer. Cancer Sura S, Gupta V, Yorke E, Jackson A, Amols H, Rosenzweig KE (2008) Intensity-modulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: the Memorial SloanKettering Cancer Center (MSKCC) experience. Radiother Oncol 87:17–23 Yeung AR, Li JG, Shi W, Newlin HE, Chvetsov A, Liu C, Palta JR, Olivier K (2009) Tumor localization using conebeam CT reduces setup margins in conventionally fractionated radiotherapy for lung tumors. Int J Radiat Oncol Biol Phys 74:1100–1107 Yuan S, Sun X, Li M, Yu J, Ren R, Yu Y, Li J, Liu X, Wang R, Li B, Kong L, Yin Y (2007) A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III non-small-cell lung cancer. Am J Clin Oncol 30:239–244

Radiochemotherapy in Locally Advanced Non-small-Cell Lung Cancer Branislav Jeremic´, Francesc Casas, and Asuncion Hervas-Moron

Contents 1

Introduction.............................................................. 409

2

Radiation Therapy Alone ....................................... 410

3

Neoadjuvant (Induction) Chemotherapy Followed by Radiation Therapy ............................ 412

4

Concurrent Radiochemotherapy............................ 415

5

Neoadjuvant (Induction) Chemotherapy Followed by Radiation Therapy Versus Concurrent Radiochemotherapy............................ 417

6

Optimization of Concurrent Radiochemotherapy ................................................. 420

7

New Approaches in Radiation Therapy and Chemotherapy of Locally Advanced Nonsmall-Cell Lung Cancer................................... 423

8

Conclusions ............................................................... 425

References.......................................................................... 425

B. Jeremic´ (&) Institute of Lung Diseases, Sremska Kamenica, Serbia e-mail: [email protected] F. Casas University Clinic, Barcelona, Spain A. Hervas-Moron Hospital Ramon y Cajal, Madrid, Spain

Abstract

Locally advanced nonsmall cell lung cancer is one of the major battlegrounds in clinical research in lung cancer due to opportunities for all the treatment options to be employed either alone or in various combinations in both curative and palliative setting. In curative setting, though, recent evidence reconfirms advantage of concurrent radiochemotherapy over other existing treatment options. It is expected that with novel radiotherapy technologies and new generations of drugs overall results in this disease are further improved.

1

Introduction

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-surgical patients in order to increase the overall number of patients suitable to analysis, increase statistical power to detect small difference, improve sensitivity analysis and, hence, provide necessary evolution of the staging principles in lung cancer. The series of articles extensively documented various aspects of


409

B. Jeremic´ et al.

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 invasion 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 structures. 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 component, 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 powerful 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 regimens with curative intention in stage III or palliative hypofractionated regimens in mostly stage IIIB patients) and chemotherapy (in stage IIIB in numerous clinical studies investigating effect of various chemotherapeutic agents) can all be used alone in this

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 (radiochemotherapy) or a trimodality approach, the latter one being detailed in another chapter.

2

Radiation Therapy Alone

Locally advanced nonsmall cell lung cancer has frequently 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 cooperative group study from the US patients were randomized to radiation therapy versus single agent vindesine (Johnson et al. 1990), while the third arm contained both modalities. The study showed no survival advantage 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 suggested 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 splitcourse 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 unsatisfactory, since the median survival time was approximately 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 prospective 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 subgroup 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 fractionation radiation therapy in inoperable non-smallcell lung cancer and it was shown be beneficial (Saunders et al. 1999). This treatment design was, unfortunately, extremely complicated for daily clinical 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 neoadjuvant 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 surprising 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 chemotherapy into the overall treatment plan: to improve both local/regional control and combat possible distant (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-radiation 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 considered as first-generation chemotherapy drugs, originating 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 platinumbased 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 concurrent 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 chemotherapy 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 paralleled 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.

B. Jeremic´ 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 targeted 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 micrometastatic 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 possible advantages if compared to concurrent administration. 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 demonstrated 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 radiochemotherapy versus radiation therapy alone for the treatment 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 radiation therapy alone. All patients had a good performance status and minimal weight loss. Induction chemotherapy consisted of cisplatin (100 mg/m2,

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 treatment-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 cisplatin-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 superiority of combined-modality therapy. However, longterm 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 radiation 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


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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 (%)

1

1995

III

4 yr (%)

5 yr (%)

61

64.8

–

8

7

7

5

56

64.8

CE

13

16

16

16

18

23

21

21

4

11

9

52

64.8

CE

2

1996

III

66

69.6

–

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

64

67.6

CT/d

28

37

28

26

5

2005

II

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). Longterm 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 survival 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 metastasis control a consequence of starting the treatment with induction chemotherapy or it was a mere reflection 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 followed 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 difference 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 randomized 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 radiation 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 chemotherapy 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 chemotherapy 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 difference in overall survival (the median survival time: 13.4 vs. 13.5 months; 4-year survival: 13% vs. 10%;

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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 therapy and concurrent chemotherapy that does not necessarily 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 cisplatin/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 outcome when one considers other combined modality options such as concurrent radiation therapy and chemotherapy. 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. Jeremic´ 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 insufficient 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 ineffective. 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 preand 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


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 confirmation 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 neoadjuvant chemotherapy at 2 (p = 0.050) and 3 years (p = 0.093). This meta-analysis highlighted the importance of shorter time to radiotherapy to maximize nonsmall cell lung cancer patients’ survival.

4

Concurrent Radiochemotherapy

This combined modality approach denotes the administration 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 employing third generation drugs (e.g. paclitaxel) also witnessed administration of the drug twice or trice weekly. Whatever was the design of concurrent radiation therapy–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 possible. This, unfortunately, may lead to increased toxicity (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 synergistic 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 Organization 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/radiation therapy, Jeremic et al. first used biweekly and weekly (Jeremic et al. 1995) and then daily (Jeremic et al. 1996) carboplatin/etoposide with hyperfractionated 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 chemotherapy given during the hyperfractionated radiation 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 consequence 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 therapy–chemotherapy in locally advanced non-small cell lung cancer. Each treatment arm consisted of 15 patients with histologically confirmed stage III nonsmall 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-generation 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 thoracic radiation therapy 60 Gy, followed by two courses of irinotecan (50 mg/sqm on days 1, 8)/carboplatin (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 significant 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 radiation 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, vindesine, 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. Jeremic´ 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 concurrent 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 chemotherapy (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 advantage of low-dose concurrent chemotherapy over highdose chemotherapy and concurrent radiation therapy is that the former type of concurrent radiochemotherapy 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


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 chronologically 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 unequivocally showed improvement in survival owing to the improvement in locoregional tumour control. Considered from the standpoint of exploitable mechanisms of combined radiation therapy and chemotherapy (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 locoregional 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 followed 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 (cisplatin–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 chemotherapy 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–chemotherapy (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 followed 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 therapy–chemotherapy arm had better median survival time than the induction arm (17.0 vs. 16.0 vs. 14.6 months), although only standard radiation therapy–chemotherapy was statistically significantly better than induction chemotherapy (Curran et al. 2000). Pattern of failure analysis showed that the best local control was in the hyperfractionated radiation therapy–chemotherapy arm, confirming indirectly the observations of Jeremic et al. (1995, 1996) that highdose hyperfractionated radiation therapy–chemotherapy 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 highdose 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 nonsmall cell lung cancer. In group 2, 6 mg/sqm of cisplatin was applied daily and concurrently with splitcourse 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. Jeremic´ 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 cisplatin 20 mg/sqm/d and etoposide 50 mg/sqm/d (days 1–5 and days 29–33); patients then received consolidation 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 concurrent 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, differences 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–chemotherapy, 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), pneumonitis 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, respectively), 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 continuous discussions in this field. While proponents of


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 inefficiency 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 thenexisting uncertainties, three meta-analyses/systematic reviews were performed. O’Rourke et al. (2010) identified nineteen randomised studies (totaling 2728 participants) of radiation therapy and concurrent chemotherapy versus radiation therapy alone. Radiation therapy and concurrent chemotherapy significantly reduced overall risk of death (HR 0.71, 95% CI 0.64–0.80; I(2) 0%; 1607 participants) and overall progression-free survival at any site (HR 0.69, 95% CI 0.58–0.81; I(2) 45%; 1145 participants). Incidence of acute oesophagitis, neutropenia and anaemia were significantly increased with radiation 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 chemotherapy 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; concurrent—1,019, induction—1,024) that compared radiation therapy and concurrent chemotherapy with induction chemotherapy followed with radiation therapy 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 concurrent chemotherapy determined a statistically significant 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-hematological 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). However, no difference in progression-free survival is shown. While careful interpretation of their conclusions 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 individual 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 outcomes 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 randomly assigned patients). Median follow-up was 6 years. There was a significant benefit of radiation therapy and concurrent chemotherapy on overall survival (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 progression-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;

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p \ 0.001). There was no significant difference regarding acute pulmonary toxicity. Overall conclusion 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 particular issue could easily be solved. Radiation therapy and concurrent cemotherapy is still labelled as CHEMORADIATION. More appropriate, however, terminology for a combination of radiation therapy and concurrent chemotherapy is RADIOCHEMOTHERAPY. 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. Therefore, RADIOCHEMOTHERAPY should be preferentially 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.

While Jeremic et al. (1998) tested the addition of weekend carboplatin/etoposide to concurrent hyperfractionated 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 weekend 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 chemotherapy, 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 accelerated 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 highgrade 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 chemotherapy (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 disease 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 chemotherapy consisting of twice weekly paclitaxel for 6 weeks and once weekly carboplatin for 6 weeks. Two cycles of consolidation paclitaxel and carboplatin were offered to patients who achieved a


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Table 2 Locally advanced nonsmall cell lung cancer consolidation chemotherapy studies Study

Year

Concurrent RT-CHT

Consolidation CHT

MST (mo)

Survival

Lau et al.

2001

RT/TC

TC 9 2

17

40% (2 yr)

Albain et al.

2002

RT/PE

PE 9 2

15

17% (5 yr)

Gandara et al.

2003

RT/PE

DOC 9 3

26

29% (5 yr)

Sakai et al.

2004

RT/DC

DC 9 2

27

61% (2 yr)

Sekine et al.

2006

RT/PV

DOC 9 3

30

43% (3 yr)

Hanna et al.

2008

RT/PE

No

23.2

26% (3 yr)

RT/PE

DOC 9 3

21.2

27% (3 yr)

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 concurrent cisplatin/etoposide/radiation therapy was followed 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%. Highgrade 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

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 common reason for discontinuation was pneumonitis, which developed in 14 (24%) of the 59 patients. During consolidation therapy, grade 3 or 4 neutropenia, 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 discussed 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 hospitalized 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

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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 adequate 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 survival. 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 reconfirmed 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 consolidation one. In various studies, the same or different 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. Jeremic´ et al.

with the patterns of failure. While these studies presented 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 concurrent 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 initial (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 candidates (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. eligibility 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 chemotherapy would be expected. In the CR patients, consolidation 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 microscopic 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


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 radiochemotherapy 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 fractionation; conventional, once daily or altered fractionation, employing multiple fractions per day (hyperfractionation). The Radiation Therapy Oncology 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 hyperfractionated radiation therapy when both given with concurrent chemotherapy. Interestingly, when compared to conventionally fractionated radiation therapy, hyperfractionated 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) conventionally 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 difference in treatment outcome, although hyperfractionated 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/carboplatin combination has similar efficacy and likely less toxicity than either cisplatin- or other multiagentbased 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 radiation 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 radiation therapy (63 Gy) in three schedules, Choy et al. (2002) used either pre-radiation therapy chemotherapy followed by radiation therapy (arm 1), pre-radiation therapy and concurrent radiochemotherapy (arm 2), and concurrent radiochemotherapy and post-radiation therapy chemotherapy (arm 3). Although this phase II randomized study was not designed to statistically 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 chemotherapy 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 testing for their radioenhancing potentials which would

424

go in parallel to its testing for anticancer chemotherapy 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 frequently 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, however, 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 escalation, the use of three-dimensional conformal radiation therapy also allows more accurate prediction of toxicity 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 stereotactic radiosurgery and stereotactic fractionated radiation therapy were initially used only for small (early stage) (Uematsu et al. 1998; Hara et al. 2002;

B. Jeremic´ 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, particularly 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 technologies in locally advanced and/or metastatic nonsmall cell lung cancer. On the other side, proper selection of patients suitable for any form of combined radiation therapy and chemotherapy, may enable using the two modality approach in noncurative 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 chemotherapy (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 treatment 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.


Several studies reported on the use of amifostine during radiation therapy and chemotherapy in lung cancer. Antonodou et al. (2001) performed a randomized 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 incidence 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 radiochemotherapy. 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 Oncology Group has just reported preliminary results on study Radiation Therapy Oncology Group 98-01, which randomized patients to intensive chemoradiation (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 radiation therapy. Although there was no difference in the rate of Grade 3 esophagitis, patient-reported areaunder-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 cancer. 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 continued 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, Intergroup0139 (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 conclude that the sum of the evidence to date supports the proposition that a non-surgical approach constitutes the ‘‘standard’’ for stage III patients. Radiation therapy and chemotherapy will therefore, further evolve in the near future and will bring us to the exiting era of more successful clinical research, leading ultimately 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 multidisciplinary 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 Nonsmall cell lung cancer Stage III Surgery Abbreviations J. P. van Meerbeeck (&) Department of Respiratory Medicine, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium e-mail: [email protected] J. P. van Meerbeeck Department of Respiratory Medicine, Lung Oncological Network Ghent University Hospital, Ghent, Belgium

NSCLC OS PFS SST R0 pCR

Non-small cell lung cancer Overall survival Progression-free survival Superior sulcus tumor Complete resection Pathological complete response

E. Vandenbroucke Department of Respiratory Medicine, Monica Hospital, Antwerp, Belgium


433

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 (Goldstraw et al. 2007)

Stage

Chest wall invasion including SST or tumor \2 cm distal to main carina

T3N1

IIIA

T3N1

IIIA

Central tumor with local invasion

T4N0-1

IIIB

T4N0-1

IIIA

Same lobe nodules

T4N0-1

IIIB

Without mediastinal lymph node involvement

Malignant pleural effusion

T3N0

IIB

T3N1

IIIA

T4N0-1

IIIB

M1a

IV

T1-3N2

IIIA

T1-3N2

IIIA

T4N2

IIIB

T3N2

IIIA

T4N2

IIIB

T1-4N3

IIIB

T1-4N3

IIIB

With mediastinal lymph node involvement Ipsilateral mediastinal nodes Same lobe nodules Central tumor with local invasion Contralateral or supraclavicular nodes

TNM tumor-node-metastasis, SST superior sulcus tumor

1

Introduction

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 presentation, at least 40% of patients are diagnosed in an advanced stage and about one-third have locallyadvanced (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.

2

Stage III Without Mediastinal 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 commonest 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 platinum-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 underwent thoracotomy. All patients, whether or not resected, received two additional cycles of chemotherapy. Median

Setting

Phase 2 trial

Prospective serie

Prospective serie

Retrospective serie

Setting

Kunitoh et al. (2008) JCOG 9806

Marra et al. (2007)

Pourel et al. (2008)

Yildizeli et al. (2008)

Author

Retrospective serie

Prospective serie

Retrospective serie

Retrospective serie

Retrospective serie

Retrospective serie

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)

Central T4 tumors

Phase 2 trial

Rusch et al. (2007) SWOG 9416 Intergroup trial 0160

Superior sulcus tumors

Author

PP (n = 126)

ITT (n = 126)

PP (n = 72)

ITT (n = 107)

PP (n = 29)

ITT (n = 31)

PP (n = 57)

ITT (n = 75)

PP (n = 88)

ITT (n = 110)

Analyzed populations

Spine

PV or LA

Not specified

Aorta SVC

PA LA Aorta Mediastinum Subclavian artery SST

Carina SVC Mediastinum

Extension

cT4 N0-1

cT3-4 N0-2

cT3-4 N0-3

cT3-4 N0-1

cT3-4 N0-1

Stage

23

46

1177

13 9

5 5 3 3 1 15

92 39 14

No. patients

NR

93

68

100 100

100 ITT n = 32 PP n = 27

100

cN0-1 (%)

Neoadjuvant treatment ? surgery ± adjuvant treatment

2 cycles CE + 45 Gy ? surgery ± adjuvant treatment

3 cycles CE or CP ? 1 cycle CE ? 45 Gy ? surgery

2 cycles MVP ? RT (45 Gy) ? surgery ± boost RT (21.6 Gy) if unresectable disease

2 cycles CE ? RT (45 Gy) ? surgery ? 2 cycles CE

Regimen

NR

7

22

0 0

0

0

cN2-3 (%)

3

—

21

—

1

—

1

30

20

5 0

— 11

87 32 12

Pneumonectomy (n)

0

—

1

—

0

—

1

—

— 0

2

—

—

NR

—

NR

—

48

—

61

43

42

100

22

4–8

0 0

100 100

23 36 43

NR

100

40–55

10 100

100 100

29 59 64

Adjuvant treatment (%)

Clinical response (%)

Neoadjuvant treatment (%)

Exploratory thoracotomy (n)

3

—

Pneumonectomy (n)

Table 2 Recent evidence for surgery in superior sulcus, central T4 and multifocal T4 NSCLC

83

NR

NR

100 NR

78 93

98 85 86

R0 resection (%)

90

—

90

—

100

—

—

68

—

76

R0 resection (%)

43

NR

NR

— —

NR 7

— — —

pCR (%)

—

NR

60

—

38

—

40

—

33

—

9

0

10

0 0

— 0

6 8 7

30 day mortality (%)

Pathological downstaging (%)

—

1

6

—

—

6

—

4

—

4.5

47

NR

NR

38 31

NR NR

28 19 37

—

28

36.4

26.7

—

54

—

—

94 (R0)

33

Median survival (mo)

NR-NR- 39 (R0)

NR-NR- 37

62-NR-51

55-NR-40

—

74-NR- 46

NR-NR- 70 (R0)

NR-62-56

NR-NR- 55 (R0)

NR-NR- 44

58 (3-year) 72 (R0)

22

20

31 11

74 77 (R0)

42 29 61

pN0-3 (%)

NR

29

28

100 NR

— —

40

pN0 (%)

NR

28

NR

37 NR

— —

47

NR

18 (3-year)

8

0 NR

— —

18

(continued)

pN1 (%)

—

—

20.9

15.2

—

52 (5year)

—

28

—

—

PFS (mo)

pN2-3 (%)

2-3-5-year survival (%)

5-year survival according to nodal status

Treatment mortality (%)


NR

—

39

—

45

—

—

16

36

29

pCR (%)

Tri-Modality Therapy in Locally Advanced Non-Small-Cell Lung Cancer 435

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, 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

47 64 57 68 0 49 9 91 86 4 51 35 Retrospective serie Rao et al. (2007)

cT4/ pT4

— 30 48 — — — 45.4 22.8 4 NR 0 100 30 NR 32 NR 100 NR 12 NR 0 NR 56 67 pT4N0 pT4N+ Retrospective serie Trousse et al. (2008)

cT4/ pT4 Retrospective serie Port et al. (2007)

Multifocal T4 tumors

Setting Author

Table 2 (continued)

Stage

53

No. patients

15

cT4 (%)

0

Pneumonectomy (n)

100

R0 resection (%)

81

1 satellite lesion (%)

19

[1 satellite lesion (%)

7

pN2/3 (%)

0

30 day mortality (%)

44


48

5-year survival (%)

58

pN0 (%)

NR

pN+ (%)


5-year survival according to nodal status

436

survival for all eligible patients was 33 months versus 94 months for the patients who underwent complete resection (R0). Pathological complete response (pCR) was a significant prognostic factor for survival. Relapse was predominantly distant with the brain as the commonest site. The Japanese Clinical Oncology Group (JCOG) (Kunitoh et al. 2008) included 75 patients with T3-4 N0-1 tumors from 19 centers. Of the patients who started induction treatment, 57 (76%) underwent surgical resection. Fiftyone (68%) patients had a R0 resection with pCR in 16%. In un-resected or incompletely resected cases, boost radiotherapy was administered. The 3- and 5-year overall and progression-free survival rates were 61, 56, 49, and 45%, respectively. In contrast to the SWOG trial (Rusch et al. 2007), subset analysis revealed that patients with clinical T3-disease had a better outcome than those with clinical stage T4. The clinical N-stage and histologic type of the tumor did not significantly affect the overall survival (OS) or progression-free survival (PFS). As expected, the survival rate was good in patients in 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 resected cases, loco-regional relapse was predominant. For completely resected cases, relapse at distant sites was the most frequent pattern of recurrence with some patients only relapsing in the brain. The results of both trials have further been confirmed by other recent prospective and retrospective series (Table 2) (Marra et al. 2007; Pourel et al. 2008; Yildizeli et al. 2008; De Leyn et al. 2009). A tri-modality approach is feasible in most series with a reasonably low mortality and tolerable morbidity rate. The survival data, with a 5-year OS rate in the intention-to-treat population of 44% in the US trial and 56% in the Japanese trial, are clearly superior to the historical value of 30%. Most if not all series show the following factors to be predictive of success: R0 resection, lobectomy, pCR and absence of invasion in either the intervertebral foramina, subclavian artery or brachial plexus. Ipsilateral supraclavicular lymph node involvement, only specified in the JCOG, was not prognostic. Other variables such as age, gender, performance status or histological subtype had no influence on survival. Although there are no formal randomized trials, preoperative chemoradiotherapy followed by surgical 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 chemoradiation, 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 pneumonectomy. 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 chemoradiation 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 broncho-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, nodenegative 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 surgical 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 correlation 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 pathologic examination (IIIA-1) or recognized intra-operatively (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). Preoperatively proven stage IIIA-3 disease is variably considered ‘resectable’ with or without induction or adjuvant therapy, whereas patients with stage IIIA-4

IIB(T3N0)

IIIA-N2

IIIA/B

Phase 3

Phase 3

Retrospective serie

Retrospective serie

Retrospective serie

Retrospective serie

Thomas et al. (2008) GLCCG

Gottfried et al. (2008)1

Uy et al. (2007)

Mansour et al. (2008)

Carretta et al. (2008)

Yap et al. (2008)

IIIA/B

IIIA(N2)

IIIAB(T4N0)

III-N2

25/33

Three cycles PG ? RT (50 Gy) ? surgery

GC ? surgery ? ± chemotherapy 18

0

0

70

84

100

100

NR

NR

24

12

\1

2

27

NR

MVP ? surgery ? ± RT 50–56 Gy

110

NR

10

NR

7

III: surgery alone

NR

17

3

5

93

0

NR

5

20

12

100

92

29

29

9

\1

9

7

8

PP

Mortality rate (%)

II: induction CT ? pN0-1 ? surgery

NR

74

32

60

–

5

24(R0)

3(R0)

PP

pCR (%)

32

0

53

46

46

0

41

–

27(R0)

PP

Nodal downstaging (%)

11

27

8

–

612

37

50

612

50

66

72

PP

R0 resection (%)

56

56

ITT

Clinical response (%)

I: induction CT ? persistent N2 ? surgery

Two cycles CE ? RT (45 Gy) ? surgery ? 2 cycles CE

39

8

8

–

14

23

11

PP

Exploratory thoracotomy (%)

28

40

II: three cycles NIP ? surgery ? 2 cycles NIP (n = 37)

I: three cycles NIP ? surgery (n = 42)

II: three cycles CE ? surgery ? conventional RT (54 Gy)

154/260

107/155

35

I: three cycles CE ? bid RT (45 Gy) ? carbovindesine ? surgery

142/264

35

–

II: three cycles platinumbased combined CT ? RT (60 Gy)

154/165

47

I: three cycles platinumbased combined CT ? surgery

43

39

PP

Pneumonectomy (%)

154/167

Three cycles cisplatingemcitabinedocetaxel ? surgery

Regimen

29.9

NR

15

27

28

40

31.8

32.3

17.6

15.7

17.5

16.4

16.8– 60.6(R0)

15.6– 36.9 (R0)

ITT

Median OS (months)

NR–NR36

NR–NR46

NR–NR12

NR–NR35

NR–NR32

NR-52NR

62-49NR

59-47NR

NR-2618

NR-2821

41-NR14

35-NR16

NR-3721

ITT

2-3-5year survival (%)

18.3

NR

NS

NS

NS

37.1

16.8

16.8

10

9.5

11.3

9.0

9.9

ITT

Median PFS (months)

2

study was closed prematurely because of low inclusion rate; 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)

1

IIIA/B

Phase 3

44/67

IIIB (T4N0-1)

Van Meerbeeck et al. (2007) EORTC 08941

46/69

PP/ITT

Analyzed populations

IIIA(N2)

Phase 2

Garrido et al. 2007 (2007) SLCG 9901

Stage

Setting

Author

Table 3 Outcome of surgery as part of combined modality treatment in stage III-N2/3 NSCLC

438 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 mediastinal 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. pneumonectomy) 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 chemotherapy, 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 confirmed. 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 influenced 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 characteristics 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) compared the intensity of the induction regimen: neoadjuvant concurrent chemoradiation versus chemotherapy alone. In the latter surgery was followed by radiotherapy 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 regimens—chemotherapy versus chemoradiotherapy— may be blurred by several other differences between the two groups: standard fractionation versus hyper-fractionation and preoperative versus postoperative radiotherapy. 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 prematurely because of a low inclusion rate. Of 107 patients operated, 37 were randomized to the adjuvant treatment 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 chemotherapy 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 chemoradiation 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

metastasis, sometimes only the brain, is the commonest 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, postoperative 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 incompletely resected patients is uncertain as the major relapse is still locoregional. Prophylactic cranial irradiation 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 currently 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 postoperative 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-surgical 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.

Phase 3

Standard definitive boost radiotherapy versus surgery following induction chemotherapy and neoadjuvant radiochemotherapy based on hyper-fracionated accelerated radiotherapy in NSCLC IIIA-N2/ III-B ESPATÜ-trial-GCS 2.1

I: chemotherapy (paclitaxelcisplatin) ? radiochemotherapy (cisplatin-vinorelbine ? 45 Gy bid) ?boost radiotherapy ? chemotherapy II: chemotherapy (paclitaxelcisplatin) ? radiochemotherapy (cisplatin-vinorelbine ? 45 Gy bid) ? surgery

II: chemotherapy ? surgery ? radiotherapy

I: chemotherapy ? radiotherapy

Schedule

Chemotherapy ± radiation therapy before surgery in treating patients with NSCLC stage IIIAN2 (Preoperative Chemoradiotherapy versus Chemotherapy Alone 2009)

Phase 3

I: chemotherapy (cisplatindocetaxel) ? surgery II: chemotherapy (cisplatindocetaxel) ? radiation ? surgery

Sequential chemoradiotherapy versus chemotherapy as induction treatment

Phase 3

Design

Neoadjuvant chemotherapy ± surgery in NSCLC stage IIIA-N2 (Scandinavian Neoadjuvant Phase III Study of Induction 2009)

Surgery versus no surgery

Title of study

Table 4 Ongoing phase 3 clinical trials including surgery in stage III NSCLC

Event-free survival Operability after chemotherapy

Overall survival

Overall survival

Primary objective

120

500

406

Estimated No. Patients

April 2001

July 2003

January 1998

Start

Recruiting

Recruiting

Recruiting

Study status

SAKK NCI

Essen Paris Tübingen

Rigshospitalet Denmark

Collaborators

Switzerland

Germany

Denmark

Country

Tri-Modality Therapy in Locally Advanced Non-Small-Cell Lung Cancer 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 treatment 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 treatment followed by surgical resection for patients with stage III-N2/3 NSCLC. Two large randomized controlled 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 chemoradiation 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 determined on resection specimen, and they are not helpful to the clinician’s preoperative decision-making. Whether surgery should be reserved only for patients with mediastinal clearance after induction chemotherapy is unclear. FDG-PET/CT-scan is of great interest, however the sensitivity in the detection of residual mediastinal lymph node disease is low. Post-induction mediastinoscopy has been reported to have a disappointing low sensitivity (De Leyn et al. 2006).

5

Conclusion

The preferred standard of care for most locallyadvanced 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 recommended. Comorbidities of patients have considerable influence on the overall treatment plan in each individual patient. Resection has to be decided on by

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

Abstract

1

Introduction.............................................................. 445

2

Risk Factors for Brain Metastases Development ............................................................. Disease Stage............................................................. Histological Subtype ................................................. Age ............................................................................. Neoadjuvant Chemotherapy ......................................

446 446 446 446 447

3.1 3.2 3.3 3.4 3.5

Randomized Controlled Trials of PCI in NSCLC ................................................................. VALG Trial ............................................................... Umsawasdi Trial........................................................ RTOG 84-03 .............................................................. SWOG Trial............................................................... RTOG 0214 ...............................................................

447 447 447 448 448 448

4

Incidence of Brain Metastases ............................... 448

2.1 2.2 2.3 2.4 3

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: [email protected]

The incidence of brain metastases following locoregional treatment for locally advanced non-small cell lung cancer (LA-NSCLC) is high. Brain metastases impair quality of life and are associated with a poor prognosis. The rationale behind prophylactic cranial irradiation (PCI) is to control or eradicate undetectable micrometastases before they become clinically significant without inducing severe adverse effects. Given the profound detrimental effect on survival, treatment that reduces the incidence of brain metastases in patients with LA-NSCLC might reasonably be expected to 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 locoregional 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


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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 (Priestman 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 chemotherapy 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 significantly 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 controlled 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.

2.1

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

Risk Factors for Brain Metastases Development

The risk of developing brain metastases after locoregional treatment for LA-NSCLC depends on several factors. In order to minimize the number of patients treated unnecessarily, it would be beneficial to identify a high risk population which might derive more benefit from PCI.

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 metastases. It would be expected that any benefit from PCI would be more pronounced in patients with the latter two histological subtypes.

2.3

2

Disease Stage

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 treatment

PCI dose

Brain met incidence (PCI vs no)

Survival (PCI vs no)

VALG

410

RT: 50 Gy/25F/5 weeks or 42 Gy/15F/3 weeks

20 Gy/10F

6 vs 13% (S)

35.4 vs 41.4 weeks (NS)1

Umsawasdi

100

Chemo-RT (50 Gy/25F/5 weeks), or combinations of surgery, RT and chemo

30 Gy/10F

4 vs 27% (S)

22 vs 23.5% at 3 years

RTOG 84-03

187

RT: 55–60 Gy/30F/6 weeks Post op: 50 Gy/ 25F/5 weeks

30 Gy/10F

9 vs 19% (NS)

8.4 vs 8.1 months (NS)1

SWOG

254

Primary RT: 58 Gy/29F or Neoadjuvant chemo then RT and adjuvant chemo

37.5 Gy/15F Or 30 Gy/15F

1 vs 11% (S)

8 vs 11 months (S)1

RTOG 0214

356

RT alone ([30 Gy) or combinations of surgery, RT and chemo

30 Gy/15F

7.7 vs 18% (S)

75.6 vs 76.9% (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 patterns in 109 patients with N2 disease treated with neoadjuvant chemotherapy prior to surgery compared to 185 patients treated with primary surgical resection. 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 published RCTs of PCI in NSCLC mainly or exclusively included patients with locally advanced disease.

3

Randomized Controlled Trials of PCI in NSCLC

There have been five published RCTs of PCI versus no PCI in patients with LA-NSCLC following locoregional 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

widely in the local therapy used and PCI dosefractionation schedules. All five trials required histological confirmation of the diagnosis. In four trials, patients were randomized to PCI or observation irrespective 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.

3.2

Umsawasdi Trial

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. Sixtythree patients received radical chemo-RT (thoracic RT dose 50 Gy in 25 fractions over 5 weeks) and

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34 patients received differing combinations of surgery, 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 inoperable or unresectable adenocarcinoma or large cell carcinoma confined to the chest and resected carcinomas of the same cell types (Russell et al 1991). Patients received primary RT 55–60 Gy in 30 fractions 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 inoperable 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 fractions, 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

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 significantly lower in the PCI arm compared to the observation 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 adenocarcinoma, 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%, squamous histology and stage III disease. The benefit for squamous cancers only is counter-intuitive as brain metastases are more common in patients with adenocarcinoma (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 metastases 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 metastases 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 observation arm. Again, this result was not statistically significant but RTOG 84-03 results strongly suggest


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 proportionally 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 fractions 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 investigators 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 treatment 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 survival 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 surprising. 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 evaluable 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 standard of care in SCLC. A subsequent meta-analysis of seven RCTs including 987 patients did however, demonstrate a small but significant increase in threeyear 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

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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 observation 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 toxicities occurred in 4 and 1% of patients, respectively. The grade 3 toxicities reported were acute fatigue, dyspnoea, ataxia, and depression. One patient reported acute grade 4 mood alteration/depression. Four patients reported grade 3 late toxicity including dyspnoea, syncope, weakness, and fatigue.

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 questionnaires. In total, 340 patients were evaluable in RTOG 0214. At baseline, 95% of patients completed QOL assessments but compliance to testing declined rapidly during the study. At 3 months, only 43% of potentially evaluable patients completed the assessments 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


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. Intriguingly, 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 consequence 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 fractions over 12 days. There were no significant differences 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 planning 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 locoregional treatment make any comparison between the trials inappropriate. In addition, no randomized trial has compared these (or any other) PCI regimens headto-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 treatment. 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 advantage. 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.

References Andre F, Grunenwald D, Pujol JL et al (2001) Patterns of relapse of N2 non-small cell lung carcinoma patients treated with preoperative chemotherapy: should prophylactic cranial irradiation be reconsidered? Cancer 91:2394–2400 Arriagada R, Le Chevalier T, Borie F (1995) Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Nat Cancer Inst 87:183–190 Arriagada R, Auperin A et al (2010) Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable nonsmall-cell lung cancer: two meta analyses of individual patient data. Lancet 375:1267–1277 Carolan H, Sun AY, Bezjak A et al (2005) Does the incidence and outcome of brain metastases in locally advanced nonsmall cell lung cancer justify prophylactic cranial irradiation or early detection? Lung Cancer 49:109–115 Ceresoli GL, Reni M, Chiesa G et al (2002) Brain metastases in locally advanced non-small cell lung carcinoma after multimodality treatment: risk factors analysis. Cancer 95: 605–612 Cox JD, Stanley K, Petrovich Z et al (1981) Cranial Irradiation in Cancer of the Lung of All Cell Types. JAMA 245:469–472

452 Dunant A, Pignon J-P, Le Chevalier T (2005) Adjuvant Chemotherapy for Non–Small Cell Lung Cancer: Contribution of the International Adjuvant Lung Trial. Clin Cancer Res 11:5017s Figlin RA, Piantadosi S, Field R (1988) Intracranial recurrence of carcinoma after complete surgical resection of stage I, II and III non-small cell lung cancer. N Engl J Med 318:1300– 1305 Gaspar L, Scott C et al (1997) Recursive partitioning analysis (RPA) of prognostic factors in three radiation therapy oncology group (RTOG) brain metastases trials. Int J Rad Onc Biol Phys 37:745–751 Gore EM, Bae K, Wong SJ et al (2011) Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: primary analysis of radiotherapy oncology group study RTOG 0214. J Clin Oncol 29:272–278 Gregor A, Cull A, Stephens RJ et al (1997) Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicentre randomised trial. Eur J Cancer 33:1752–1758 Hsu F, Carolan H, Nichol A et al (2010) Whole brain radiotherapy with hippocampal avoidance and simultaneous integrated boost for 1–3 brain metastases: a feasibility study using volumetric modulated arc therapy. Int J Radiat Oncol Biol Phys 76:1480–1485 Law A, Daly B, Madsen M et al (1997) High incidence of isolated brain metastases following complete response in advanced non-small cell lung cancer: a new challenge. Lung Cancer 18:65s Lester JF, Macbeth FR, Coles B (2005) Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small cell lung cancer: a cochrane review. Int J Radiat Oncol Biol Phys 63:690–694 Marsh JC, Godbole RH, Herskovic AM et al (2010) Sparing of the neural stem cell compartment during whole brain radiation therapy: a dosimetric study using helical tomotherapy. Int J Radiat Oncol Biol Phys 78:946–954 Miller TP, Crowley JJ, Mira J et al (1998) A randomized trial of chemotherapy and radiotherapy for stage III non-small cell lung cancer. Canc Ther 4:229–236 Nussbaum ES, Djalilian HR, Cho KH et al (1996) Brain metastases: histology, multiplicity, surgery, and survival. Cancer 78:1781–1788

J. F. Lester PCIOCG (The Prophylactic Cranial Irradiation Overview Collaborative Group). Cranial irradiation for preventing brain metastases of small cell lung cancer in patients in complete remission. Cochrane database of systematic reviews (2002), Issue 4. doi:10.1002/14651858.CD002805 Perez CA, Pajak TF, Rubin P et al (1987) Long term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Cancer 59:1874–1881 Priestman TJ, Dunn J et al (1996) Final results of the RCR trial comparing two different radiotherapy schedules in the treatment of cerebral metastases. Clin Oncol 8:308– 315 Robnett TJ, Machtay M, Stevenson JP et al (2001) Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small cell lung carcinoma. J Clin Oncol 19:1344–1349 Russell AH, Pajak TE, Selim HM et al (1991) Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomised trial conduced by the radiation therapy oncology group (RTOG 84–03). Int J Radiat Oncol Biol Phys 21:637–643 Salbeck R, Grau HC, Artmann H (1990) Cerebral tumor staging in patients with bronchial carcinoma by computed tomography. Cancer 66:2007–2011 Strauss GM, Herndon JE, Sherman DD et al (2005) Neoadjuvant chemotherapy and radiotherapy followed by surgery in stage III non-small cell carcinoma of the lung: a report of a cancer and leukemia group B phase II study. J Clin Oncol 10:1237–1244 Stuschke W, Eberhardt W, Pottgen C et al (1999) Prophylactic cranial irradiation in locally advanced non-small-cell lung cancer after multimodality treatment: long term follow-up and investigations of late neuropsychologic effects. J Clin Oncol 17:2700–2709 Umsawasdi T, Valdivieso M, Chen TT et al (1984) Role of elective brain irradiation during combined chemoradiotherapy for limited disease non-small cell lung cancer. J NeuroOncol 2:253–259 Wade DT (1992) Measurement in neurological rehabilitation. Oxford University Press, NY Westeel V (2003) Risk of brain metastases in non-metastatic non-small cell lung cancer. Lung Cancer 41:21s

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

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 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. 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. 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.

S. Sundstrøm (&) St Olav University Hospital, Trondheim, Norway e-mail: [email protected]


453

454

1

S. Sundstrøm

Introduction

The majority of patients with non-small lung cancer are diagnosed with advanced disease, either localised stage III or metastatic stage IV disease. Approximately 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 disease 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.

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 cancer (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 survival 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 borderline group; they will achieve less effect of chemotherapy, often with intolerable toxicity. Patients with WHO PS status of 3–4 should routinely not be offered chemotherapy. If treatment is required, palliative 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 strategy. 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; DehingOberije 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 in stage III patients

Good prognostic factors

Poor prognostic factors

WHO PS status 0–1

WHO PS status C2

Tumour size \8 cm in largest diameter

Tumour size [8 cm in largest diameter

Weight loss \10% last 3 months

Weight loss C10% 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. Occurrence 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

455

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 critical 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 considered as the maximal spinal cord tolerance. Recent updates designate 50 Gy using conventional fractionation as safe to the thoracic spine (Kirkpatrick et al. 2010). If a more protracted schedule with higher palliative dose is planned, a three-dimensional conformal 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.

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 radiotherapy 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 PS

Palliation

Survival

MRC I (1991)

369

17 Gy/2 versus 30 Gy/10

68/32

0–2(3)

Equal

Equal

MRC II (1992)

235


71/29

2–4

Equal

Equal

MRC III (1996)

509


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


76/24

0–3

Equal

20 Gy better

Sundstrøm et al. (2004)

407

17 Gy/2 versus 42 Gy/15 versus 50 Gy/25

78/22

0–3

Equal

Equal

Erridge et al. (2005)

148


Not reported

0–3

30 Gy better

Equal

Kramer et al. (2005)

297


52/48

0–3(4)

30 Gy better

30 Gy better

Senkus-Konefka et al. (2005)

100


84/16

1–3(4)

Equal

16 Gy 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; SenkusKonefka et al. 2005) comparing a strict hypofractionated 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 fractions (17 or 16 Gy/2) as the short-course experimental arm. The comparative arms were fractionated schedules 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 selfreported 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 fractions, and 30 Gy/10 fractions, respectively. One trial (Senkus-Konefka et al. 2005) reports a survival benefit 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 fractions (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/ IV

WHO PS

Palliation

Survival

Simpson et al. (1985)

316

20 Gy/20 versus 30 Gy/10 vs 40 Gy/20 split

100/0

0–2

Equal

Equal

Teo et al. (1987)

291

31.2 Gy/4 versus 45 Gy/18

90/3

0–3

45 Gy better

Equal

Abratt et al. (1995)

84


100/0

0–2

Equal

Not reported

Reinfuss et al. (1999)

240

40 Gy/10 (split 4 week) versus 50 Gy/25 vs wait and see

100/0

0–2

Not reported

Better 40/ 50 Gy

Nestle et al. (2000)

152

32 Gy/16 (twice/day) versus 60 Gy/30

79/21

1–2

Equal

Equal

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 esophagitis and dysphagia was most frequent in the highdose arms, although dysphagia was also detectable in the hypofractionated low-dose arms. Onset and duration of dysphagia was earlier and shorter in the hypofractionated 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

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 disease may have better survival with a protracted high-

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 disease 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%, respectively. 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.

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

S. Sundstrøm

concerning dose and fractionation no formal metaanalysis 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 regimen 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. Selfreported 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 treatment 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 radiotherapy 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 radiotherapy. 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 performance 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 primary palliative thoracic radiotherapy is a good option. Palliative radiotherapy can also be offered to patients

progressing during or after chemotherapy with less toxicity. Palliative thoracic radiotherapy is administered with the intention of treating symptoms from intrathoracic 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 development of later symptoms. A wait and see procedure is therefore advocated until the patient develops disease-related symptoms.

12

Summary

• Hypofractionated and moderately high-dose palliative 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.

References Abratt RP, Shepherd LJ, Mameena Salton DG (1995) Palliative radiation for stage 3 non-small cell lung cancer. A prospective study of two moderately high dose regimens. Lung Cancer 13:137–143 Bezjak A, Dixon P, Brundage M et al (2002) Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 54:719–728 Bradley JF, Ieumwananonthachai N, Purdy JA et al (2002) Gross tumor volume, critical prognostic factor in patients treated with three-dimensional conformal radiation therapy for non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys 52:49–57 Brundage MD, Davies D, Mackillop WJ (2002) Prognostic factors in non-small cell lung cancer. Chest 122:1037–1057 Dehing-Oberije C, de Ruysscher D, van der Weide H et al (2008) Tumor volume combined with number of positive

Palliative External Beam Thoracic Radiation Therapy of Non-Small Cell Lung Cancer lymph node stations is a more important prognostic factor than TNM stage for survival of non-small-cell lung cancer patients treated with (chemo)radiotherapy. Int J Radiat Oncol Biol Phys 70:1039–1044 Erridge SC, Gaze MN, Price A et al (2005) Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules. Clin Oncol 17:61–67 Fairchild A, Harris K, Barnes E et al (2008) Palliative thoracic radiotherapy for lung cancer: a systematic review. J Clin Oncol 26:4001–4011 Falk S, Girling DJ, White RJ et al (2002) Immediate versus delayed palliative thoracic radiotherapy in patients with unresectable locally advanced non-small cell lung cancer and minimal thoracic symptoms: randomised controlled trial. BMJ 325:465–468 Hopwood P, Stephens RJ (1995) Symptoms at presentation for treatment in patients with lung cancer: implications for the evaluation of palliative treatment. Br J Cancer 71:663–666 Kirkpatrick JP, van der Kogel AJ, Schultheiss TE (2010) Radiation dose-volume effects in the spinal cord. Int J Rad Oncol Biol Phys 76:suppl S42–S49 Kramer G, Wanders SL, Noordijk EM et al (2005) Results of the Dutch National Study of the palliative effect of irradiation using two different treatment schemes for nonsmall-cell lung cancer. J Clin Oncol 13:2962–2970 Lester JF, Macbeth FR, Toy E, Coles B et al (2006) Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev 18(4):CD002143 Lutz S, Norrell R, Bertucio C et al (2001) Symptom frequency and severity in patients with metastatic or locally recurrent lung cancer: a prospective study using Lung Cancer Symptom Scale in a Community Hospital. J Palliat Med 4:157–165 Mac Manus MP, Matthews JP, Wada M et al (2005) Unexpected long-term survival after low-dose palliative radiotherapy for nonsmall cell lung cancer. Cancer 116:1110–1116 MacBeth F, Wheldon TE, Girling DJ et al (1996) Radiation myelopathy: estimates of risk in 1,040 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancer. The Medical Research Council Lung Cancer Working Party. Clin Oncol (R Coll Radiol) 8:176– 181 Maher EJ, Coia L, Duncan G et al (1992) Treatment strategies in advanced and metastatic lung cancer: differences in attitude between the USA, Canada and Europe. Int J Radiat Oncol Biol Phys 23:239–244 Medical Research Council Lung Cancer Working Party (1992) A Medical Research Council (MRC) randomised trial of palliative radiotherapy with two fractions or a single fraction in patients with inoperable non-small cell lung cancer (NSCLC) and poor performance status. Br J Cancer 65:931–941 Medical Research Council Lung Cancer Working Party (1996) Randomised trial of palliative 2-fraction versus more intensive 13-fraction radiotherapy for patients with inoperable non-small cell lung cancer and good performance status. Clin Oncol 8:167–175 MRC Lung Cancer Working Party (1991) Inoperable nonsmall-cell lung cancer (NSCLC): a Medical Research

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Council randomised trial of palliative radiotherapy with two fractions or ten fractions. Br J Cancer 63:265–270 Nestle U, Nieder C, Walter K et al (2000) A palliative accelerated irradiation regimen for advanced non-small-cell lung cancer vs conventionally fractionated 60 Gy: results of a randomized equivalence study 48:195–203 NSCLC Meta-analysis collaborative group (2008) Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: A systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol 26:4617–4625 Perez CA, Stanley K, Grundy G et al (1982) Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung. Cancer 50:1091–1099 Rees GJG, Devrell CE, Barley VL et al (1997) Palliative radiotherapy for lung cancer: two versus five fractions. Clin Oncol (R Coll Radiol) 9:90–95 Reinfuss M, Glinski B, Kowalska T et al (1999) Radiothérapie du cancer bronchique non á petites cellules de stade III inopérable asymptomatique. Résultats définitifs d’un essai prospectif randomisé (240 patients). Cancer Radiother 3:475–479 Reinfuss M, Mucha-Malecka A, Walasek T et al (2011) Palliative thoracic radiotherapy in non-small cell lung cancer. An analysis of 1,250 patients. Palliation of symptoms, tolerance and toxicity. Lung Cancer 71:344– 348 Senkus-Konefka E, Dziadziuszko R, Bednaruk-Mlynski E et al (2005) A prospective randomised study to compare two palliative radiotherapy schedules for non-small-cell cancer (NSCLC). Br J Cancer 92:1038–1045 Simpson JR, Francis ME, Perez-Tamayo R et al (1985) Palliative radiotherapy for inoperable carcinoma of the lung: final report of a RTOG multi-institutional trial. Int J Radiat Onc Biol Phys 11:751–758 Sundstrøm S, Bremnes R, Aasebø U et al (2004) Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22:801–810 Sundstrøm S, Bremnes R, Brunsvig P et al (2005) Immediate or delayed radiotherapy in advanced non-small cell lung cancer (NSCLC)? Data from a prospective randomised study. Radiother Oncol 75:141–148 Sundstrøm S, Bremnes R, Brunsvig P et al (2006) Palliative thoracic radiotherapy in locally advanced non-small cell lung cancer: can quality-of-life assessments help in selection of patients for short- or long-course radiotherapy? J Thorac Oncol 1:816–824 Teo P, Tai TH, Choy D et al (1987) A randomized study on palliative radiation therapy for inoperable non small cell carcinoma of the lung. Int J Radiat Onc Biol Phys 14:867– 871 Yan S, Sun X Li MH et al (2007) A randomized study of involved field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III non small cell lung cancer. Am J Clin Oncol 30:239–244

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 Canõń, Ignacio Azinovic, and Rafael Martinez-Monge

Contents

8

Montpellier Regional Cancer Centre Experience ................................................................ 466

9

The Allegheny University Hospital of Philadelphia Experience..................................... 467

10

Madrid Institute of Oncology (Grupo IMO) Experience ................................................................ 467

1

Introduction.............................................................. 462

2

Tissue Tolerance Studies of IORT ........................ 462

3

Technical Considerations: IOERT ........................ 463

4

Clinical Indications: IOERT .................................. 464

11

USP Hospital San Jaime Experience .................... 467

5

International Intraoperative Electron Radiotherapy (IOERT) Clinical Experiences and Results ............................................................... 464

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

6

National Cancer Institute Experience................... 464

7

University Medical School of Graz Experience... 465

References.......................................................................... 475 F. A. Calvo (&) Department of Oncology, University Hospital Gregorio Marañón, University Complutense, Madrid, Spain e-mail: [email protected] J. Aristu L. Arbea Department of Oncology, University Clinic, University of Navarre, Pamplona, Spain S. Usychkin Department of Radiotherapy, Instituto Madrileño de Oncología, Madrid, Spain R. Cañón I. Azinovic Department of Radiation Oncology, Hospital San Jaime, Torrevieja, Spain R. Martinez-Monge Department of Radiation Oncology, Clinica Universitaria de Navarra, Pamplona, Spain

Abstract

Intraoperative radiotherapy is a feasible technical modality to improve precision and dose-escalation in high-local risk lung cancer patients. Methodology is described regarding the use of high-energy electron beams or brachytherapy. Results of normal tissue tolerance in experimental animal models and in clinical experiences are analyzed in detail. Characteristics of clinical experiences using IORT electrons or brachytherapy are reported and clinical outcome results are discussed. Ten IORT brachytherapy and six electron-based publications are identified proving the adaptability of IORT to the clinical-therapeutic scenario of lung cancer, its feasibility and the promotion of high local control rates in the context of dose-escalation trials.


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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 diagnosed 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-escalation to 83.8 Gy with three-dimensional conformal techniques (Bradley et al. 2005). In a recently published study (Dong-Soo et al. 2011) showed that clinical tumor response after concurrent chemoradiation 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 procedures is obtained with the displacement of radiosensitive 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.

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 fractionation 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 survival 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 intrathoracic 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 coagulative 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 pneumonectomy 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

463

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

Lung damage

Pathologic changes in heart and vessels

20 Gy

Normal healing

Transient mild dysphagia

Mild

Moderate

30 Gy

Normal healing

Chronic ulcerative esophagitis

Moderate

Moderate-severe

40 Gy

Normal healing

Esophageal perforation

Severe

Severe

Esophageal stricture

esophageal ulceration at 6 months without late stricture. In dogs given 30 and 40 Gy, esophageal damage was severe (esophagoaortic fistula and stenosis) and one dog developed carinal necrosis. The same institution 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 esophagus 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 dysphagia 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

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-plasmocytic 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 singledose 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 (energies recommended from 6 to 20 MeV), through the development of specially designed applicators for

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4

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 program combines the efforts of surgeons, anesthesiologists, 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 radiotherapeutic 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 approximately 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).

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 vascularized 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 dissemination 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


465

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 pneumonectomy (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 overlapping 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

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 intrabronchial 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 (median FEV1: 1,3) were treated with surgery, IORT (median dose 20 Gy) and EBRT (median dose 46 Gy).

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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

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 intraoperative 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

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

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


467

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. Microscopic 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 recurrence 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 preliminarily 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 experience 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 preoperatively and 5 postoperatively). Chemotherapy was administered to all patients. The median survival time

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-disciplinary 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 esophageal 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

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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 radiochemotherapy: 50 Gy with conventional fractionation, except two patients: one patient with local relapse after radiochemotherapy and then treated with hypofractionation (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 radiotherapy 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 mediastinal relapse.

12

The University Clinic of Navarra Experience

During the period from November 1984 to November 1993 104 patients with histologically confirmed nonsmall-cell lung cancers stage III were treated with

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 depending on tumor response as follows: 46 responders with respectable tumor were managed with surgery, IOERT and postoperative EBRT, non-responders with unresectable disease (17 patients) or Pancoast’s tumor (19 patients) received preoperative chemoradiotherapy, surgery and IOERT boost. The neoadjuvant chemotherapy consisted of cisplatin 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 carboplatin 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 bronchial stump was protected with a pleural or pericardial flap in order to prevent anastomotic leak. After surgical 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 preoperative external beam radiation therapy using the same total dose and fractionation than with postoperative external beam radiation therapy described

Intraoperative Radiotherapy in Lung Cancer Table 2 Patterns of failure according to disease stage and surgical residue in the University Clinic of Navarra Experience

469 Local controla

Distant failureb

IIIA

18/24 (75%)

7/24 (29)

IIIB

4/14 (29%)

4/14 (29)

Pancoast’s tumors

11/12 (92%)

2/12 (17)

IIIA

3/7 (43%)

6/7 (86)

IIIB

7/30 (23%)

12/30 (40)

Surgical residue Micro/Absent

Macroscopic/Unresected

Pancoast’s tumors 5/5 (100%) No local or distant failure b Distant failure alone or distant and local failure

1/5 (20)

a

above. All patients received concurrent chemotherapy with preoperative radiation using the same chemotherapy combination used as neoadjuvant or with cisplatinum 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

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 communicating 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 resection plus chest wall resection), and 10 Gy IORT boost (12 MeV). No viable microscopic tumor was encountered in the resected specimen and the necropsy findings 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 diagnosed with severe long-term fibrosis and required

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Table 3 IOERT international clinical experiences in NSCLC Authors (reference)

Number of patients

Stage

Treatment protocol

Local control

5-year survival

University Medical School of Graza (Smolle Juettner et al. 1994)

24

12 I 1 II 10 IIIA

IORT 10–20 Gy + EBRT 46–56 Gy

19/23 (83%)

15%

Montpellier Regional Cancer Centre (Carter et al. 2003)

17

3I 7 II 7 IIIA

S ? IORT (10–20 Gy) + EBRT 45 Gy

13/17 (76%)

18%

University Clinic of Navarra in Pamplona (Calvo et al. 1990, 1991, 1992; Aristu et al. 1997, 1999; Martínez-Monge et al. 1994)

104

19 IIIA (N0) 29 IIIA (N2) 56 IIIB

Multidisciplinary treatment (see text) with IORT 10–20 Gy ? EBRT (46 Gy) + CT

48/92 (52%)

40% (IIIA) 18% (IIIB)

The Allegheny University Hospital of Philadelphia (Aristu JJ, Fisher S, Calvo FA et al. 1999)

21

1I 2 II 15 IIIA 3 IIIB

Neoadjuvant CT ± preop EBRT + S ? IORT ± postop EBRT

18/21 (86%)

33%

Madrid Institute of Oncology (Grupo IMO) (Calvo et al. 1999)

18

11 IIIA 6 IIIB 1IV

Neoadjuvant CT ± preop EBRT + S ? IORT ± postop EBRT

16/18 (90%)

22%

USP Hospital San Jaime in Torrevieja (Cañon R et al. 2008)

8

1 IIA 1 IIIA 4 IIIB 1 IV 1 local relapse

Preoperative EBRT 50 Gy + S ? IORT 6–10 Gy

6/8 (75%)

Median OS 22 m, DFS 12 m

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 experiences 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 radiation boost technique in patients with residual disease


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). Perioperative high-dose-rate brachytherapy (PHDRB) using Ir-192 administered over the immediate postoperative period has been mainly used in R0–R1 tumor resections. 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 scanbased treatment planning; (iii) risk-adapted brachytherapy 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 institutions. 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

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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 follow-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 ranging 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 feasibility and outcomes of 125-I Vicryl mesh brachytherapy after sub-lobar resection (open or videoassisted thoracoscopic procedure) in stage I nonsmall-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.

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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 locoregional 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 recurrent 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 brachytherapy (Hilaris and Nori 1987). Patients without mediastinal nodes metastases achieved 71% local control versus 63% in patients with affected mediastinal 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, brachytherapy (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 postoperative 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).

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 incomplete 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 histologically 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.


473

Table 4 LDR- HDR-IORT international clinical experiences in stage I–II NSCLC Authors (reference)

Number of patients

Stage

Treatment protocol

Local control

Time point

Hilaris and Mastoras (1998)

55

T1-2N01

S ? I-125 (160 Gy) ± EBRT

100% (T1N0) 70% (T2N0) 71% (T12N1)

32% 5 year OS

Fleischman et al. (1992)

14

T1N0

S ? I-125 (80–200 Gy)

10/14 (71%)

MS 15.1 m

Fernando et al. (2005)

291

T1N0

Lobar resection (LR) versus Sublobar resection (SR) ± I125 (100–120 Gy)

96.5% (LR)a 95.6% (SR)a

MS 68.7 m (LR)a 50.6 m (SR)a

Lee et al. (2003)

33

T1-2N0

Limited resection + I-125

31/33 (94%)

5 year OS 67% (T1N0) 39% (T2N0)

Voynov et al. (2005)

110

T1-2N0

Limited resection + I-125 (100–120 Gy)

106/110 (96%) 5-y LC 90%

5 year OS 22% (T1N0) 12% (T2N0)

S surgery, EBRT external beam radiation therapy, MS median survival, OS overall survival Local recurrence and survival rates for the 2–3 cm tumors

a

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 permanent 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 distribution requirements. The authors describe a 0.8% of postoperative deaths and 17 patients (13%) presented nonfatal complications including wound infection, empyema with or without broncho-pleural fistula, bleeding, atelectasia or pneumonia and phlebitis. 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 HDRIORT clinical experiences from different centers is presented in Tables 4 and 5.

17

Summary and Final Considerations

The modern developments in the treatment of localized 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

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Table 5 LDR- HDR-IORT international clinical experiences in stage III NSCLC Authors (reference)

Stage

Treatment protocol

Local control

Time point

20

III

S ? PHDRB (16–40 Gy) or IOBT (10.12.5 Gy) or I-125/Pd-103 seeds (90–110 Gy)

89%

36% 6 year OS

Burt et al. (1987)

225

III

S ± I-125a/Ir-192

10/14 (71%)

MS 12 mb 22% 5 year OSb

Hilaris and Nori (1987)

322

Unresectable

Thoracothomy ? I-125 (160 Gy)

71%(N0) 63% (N2)

15% 3 year OS (N0) 3% 3 year OS (N +)

Hilaris et al. (1985)

100

IIIN2

I-125 (160 Gy)/Ir-192 (30 Gy) ± S ? EBRT (30-40 Gy)

89% (R0) 53% (R1) 72% (R2)

22% 5 year OS 22% 5 year OS (R2)

12

III (PSM)

± EBRT (45–60 Gy) + S + I-125/Pd-103 Gelfoam implant ± EBRT (45–60 Gy)

82%

45% 2 year OS

Valero et al. (2007)

Nori et al. (1995a)

Number of patients

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 neoadjuvant 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 multidisciplinary management of NSCLC in several small prospective single-institution pilot trials as a sophisticated 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 radiotherapy (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 treatment in locally-advanced NSCLC. Remarkable local control rates in Pancoast’s and stage IIIA tumors with microscopic residual disease have been detected.


The effect of IORT on the group of patients presenting 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 international cooperation among expert IORT institutions.

References Abe M, Takahashi M (1981) Intraoperative radiotherapy: the Japanese experience. Int J Radiat Oncol Biol Phys 7(7): 863–868 Arian-Schad Juellner FM, Ratzenhofer B et al (1990) Intraoperative plus external beam irradiation in nonresectable lung cancer: assessment of local response and therapy-relate side effects. Radiother Oncol 119:137–144 Aristu J, Rebollo J, Martínez-Monge R, Aramendía JM et al (1997) Cisplatin, mitomycin, and vindesine followed by intraoperative and postoperative radiotherapy for stage III non-small-cell lung cancer: final results of a phase II study. Am J Clin Oncol 20:276–281 Aristu JJ, Calvo FA, Martínez R, Dubois JB, Santos M, Fisher S, Azinovic I (1999) Lung cancer: EBRT with or without IORT. In: Gunderson LL, Willet CG, Harrison LB, Calvo FA, directores. Intraoperative irradiation. Techniques and results. Totowa: Humana Press pp 437–453 Barnes M, Pass H, De Luca A et al (1987) Response of mediastinal and thoracic viscera of the dog to intraoperative radiation therapy (IOERT). Int J Radiat Oncol Biol Phys 13:371–378 Biggs P, Noyes D, Willett C (2003) Clinical physics, applicators choice, technique and equipment for electron intraoperative radiation therapy. Surg Oncol Clin N Am 12:899–924 Bradley J, Graham MV, Winter K, Purdy JA, Komaki R, Roa WH et al (2005) Toxicity and outcome results of ROG 9311: a phase I–II dose-escalation study using threedimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys 61:318–328 Burt ME, Pomerantz AH, Bains MS et al (1987) Results of surgical treatment of stage III lung cancer invading the mediastinum. Surg Clin North Am 67:987–1000

475 Calvo FA, Ortiz de Urbina D, Abuchaibe O et al (1990) Intraoperative radiotherapy during lung cancer surgery: technical description and early clinical results. Int J Radiat Oncol Biol Phys 19:103–109 Calvo FA, Santos M, Ortiz de Urbina D (1991) Intraoperative radiotherapy in thoracic tumors. Front Radiat Ther Oncol 25:307–316 Calvo FA, Ortiz de Urbina D, Herreros J, and Llorens R (1992) Lung cancer, In: Calvo FA, Santos M, Brady LW (eds) Intraoperative Radiotherapy. Clinical Experiences and results. Springer-Verlag Berlin Heidelberg pp 43–50 Calvo FA, Aristu JJ, Moreno M et al (1999) Intraoperative radiotherapy for lung cancer. In: Van Houte P (ed) Progress and perspectives in the treatment of lung cancer. Springer, Berlin 173–182 Cañon R, Azinovic I, Ramis B et al (2008) Intraoperative radiation therapy using mobile linear accelerator in the multimodality approach to lung cancer. Rev Cancer (Madrid) 22:27 Carter YM, Jablons DM, DuBois JB et al (2003) Intraoperative radiation therapy in the multimodality approach to upper aerodigestive tract cancer. Surg Oncol Clin N Am 12: 1043–1063 Chen A, Galloway M, Landreneau R et al (1999) Intraoperative 125I brachytherapy for high-risk stage I non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys 44:1057–1063 d’Amato TA, Galloway M, Szydlowski G et al (1998) Intraoperative brachytherapy following thoracoscopic wedge resection of stage I lung cancer. Chest 114: 1112–1115 De Boer WJ, Mehta DM, Oosterhius JW et al (1989) Tolerance of mediastinal structures to intraoperative radiotherapy after pneumonectomy in dogs. Strahlenther Oncol 165:768 Dong-Soo L, Yeon-Sil K, Jin-Hyoung K, Sang-Nam L, YoungKyoun K, Myung-Im A et al (2011) Clinical responses and prognostic indicators of concurrent chemoradiation for nonsmall-cell lung cancer. Cancer Res Treat 43(1):32–41 Fakiris AJ, McGarry RC, Yiannoutsos CT et al (2009) Stereotactic body radiation therapy for early-stage nonsmall-cell lung carcinoma: four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys 75(3):677–682 Fernando HC, Santos RS, Benfield JR et al (2005) Lobar and sublobar resection with and without brachytherapy for small stage IA non-small-cell lung cancer. J Thorac Cardiovasc Surg 129:261–267 Fisher S, Fallahnejad M, Lisker S et al (1994) Role of intraoperative radiation therapy (IORT) for stage III nonsmall-cell lung cancer. Hepato-gastroenterol 41:15 Fleischman EH, Kagan AR, Streeter OE et al (1992) Iodine125 interstitial brachytherapy in the treatment of carcinoma of the lung. J Surg Oncol 49:25–28 Hansen EK, Roach M III (2010) Handbook of evidence-based radiation oncology, 2nd edn. Springer, New York, Heidelberg Dordrecht, London Hilaris BS, Gomez J, Nori D et al (1985) Combined surgery, intraoperative brachytherapy, and postoperative external radiation in stage III non-small-cell lung cancer. Cancer 55:1226–1231 Hilaris BS, Mastoras DA (1998) Contemporary brachytherapy approaches in non-small-cell lung cancer. J Surg Oncol 69:258–264

476 Hilaris BS, Martini N, Luomanen RK et al (1974) The value of preoperative radiation therapy in apical cancer of the lung. Surg Clin North Am 54:831–840 Hilaris BS, Martini N, Wong GY et al (1987) Treatment of superior sulcus tumor (Pancoast tumor). Surg Clin North Am 67:965–977 Hilaris BS, Nori D, Beattie EJ Jr et al (1983) Value of perioperative brachytherapy in the management of non-oat cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 9:1161–1166 Hilaris BS, Nori D (1987) The role of external radiation and brachytherapy in unresectable non-small-cell lung cancer. Surg Clin North Am 67:1061–1071 ISIORT0 98 (1998) In: Proceedings of the 1st congress of the international society of intraoperative radiation therapy. 6–9 Sep, Pamplona, España, Rev Med Univ Navarra vol XLII: n extraordinario pp 13–68 Jakse G, Kapp KS, Geyer E et al (2007) IORT and external beam irradiation (EBI) in clinical stage I-II NSCLC patients with severely compromised pulmonary function: an 52-patient single-institutional experience. Strahlenther Onkol 183(2):24–25 Jemal A, Center MM, DeSantis C, Ward EM (2010) Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev 19:1893–1907 Jeuttner FM, Arian-Schad K, Porsch G et al (1990) Intraoperative radiation therapy combined with external irradiation in non resectable non-small-cell lung cancer: preliminary report. Int J Radiat Oncol Biol Phys 18:1143–1150 Juettner Smolle, Geyer E, Kapp KS et al (1994) Evaluating intraoperative radiation therapy (IORT) and external beam radiation therapy (EBRT) in non-small-cell lung cancer (NSCLC). Eur J Cardio-thorac Surg 8:511–516 Kritskaia NG, Dobrodeev AI, Zav’ialov AA et al (2006) Morphofunctional changes in the bronchial epithelium in combined therapy for lung cancer. Arkh Patol 68:10–14 Kumar P, Herndon J, Langer M, Kohman LJ, Elias AD, Kass FC et al (1996) Patterns of disease failure after trimodality therapy of non-small-cell lung carcinoma pathologic stage IIIA (N2). Analysis of cancer and leukemia group b protocol 8935. Cancer 77(11):2393–2399 Lee W, Daly BD, DiPetrillo TA et al (2003) Limited resection for non-small-cell lung cancer: observed local control with implantation of I-125 brachytherapy seeds. Ann Thorac Surg 75:237–242 Lo SS, Fakiris AJ, Papiez L et al (2008) Stereotactic body radiation therapy for early-stage non-small-cell lung cancer. Expert Rev Anticancer Ther 8:87–98 Martínez-Monge R, Herreros J, Aristu JJ, Aramendía JM, Azinovic I (1994) Combined treatment in superior sulcus tumor. Am J Clin Oncol 17:317–322

F. A. Calvo et al. Merrick HW, Dobelbower RR (2003) Intraoperative radiation therapy in surgical oncology. Surg Oncol Clin N Am 12: 883–897 Nori D, Li X, Pugkhem T (1995a) Intraoperative brachytherapy using Gelfoam radioactive plaque implants for resected stage III non-small-cell lung cancer with positive margin: a pilot study. J Surg Oncol 60:257–261 Nori D, Li X, Pugkhem T (1995b) Intraoperative brachytherapy using Gelfoam radioactive plaque implants for resected stage III non-small-cell lung cancer with positive margin: a pilot study. J Surg Oncol 60:257–261 Pass HI, sindelar WF, Kinsella TJ et al (1987) Delivery of intraoperative radiation therapy after pneumonectomy: experimental observations and early clinical results. Ann Thorac Surg 44:14–20 Ramalingam SS, Owonikoko TK, Khuri FR (2011) Lung cancer: new biological insights and recent therapeutic advances. CA Cancer J Clin 61:91–112 Rengan R, Rosenzweig KE, Venkatraman E, Koutcher LA, Fox JL, Nayak R et al (2004) Improved local control with higher doses of radiation in large-volume stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 60:741–747 Sindelar WF, Hoekstra HJ, Kinsella TJ et al (1992) Response of the canine esophagus to intraoperative electron beam radiotherapy. Int J Radiat Oncol Biol Phys 25:663–669 Sura S, Greco C, Gelblum D, Yorke ED, Jackson A, Rosenzweig KE (2008) 18F-fluorodeoxyglucose positron emission tomography-based Assessment of local failure patterns in non-small-cell lung Cancer treated with definitive radiotherapy. Int J Radiat Oncol Biol Phys 70:1397–1402 Tochner ZA, Pass HI, Sindelar WF et al (1992) Long term tolerance of thoracic organs to intraoperative radiotherapy. Int J Radiat Oncol Biol Phys 22(1):65–69 Valero J, Martinez-Monge R, Pagola M et al (2007) Rescate quirúrgico con técnicas de braquiterapia intraoperatoria en cáncer de pulmón con enfermedad residual tras tratamiento quimiorradioterápico o con enfermedad recurrente tras radioterapia previa. Clin Transl Oncol 9(Ext 3):5 (a618) van Geel AN, Jansen PP, van Klaveren RJ et al (2003) High relapse-free survival after preoperative and intraoperative radiotherapy and resection for sulcus superior tumors. Chest 124:1841–1846 Voynov G, Heron DE, Lin CJ et al (2005) Intraoperative (125)I Vicryl mesh brachytherapy after sublobar resection for high-risk stage I non-small-cell lung cancer. Brachytherapy 4:278–285 Zhou GX, Zeng DW, and Li WH (1992) Acute responses of the mediastinal and thoracic viscera of canine to intraoperative irradiation. In: Schildberg FW, Wilich N, and Krämling HJ (eds.), Intraoperative radiation therapy, proceedings 4th internetional symposium, Munich pp 50–52

Brachytherapy for Lung Cancer A. Polo, M. Castro, A. Montero, and P. Navıó

Contents 1

Abstract

Introduction.............................................................. 478

2 Procedure for Lung Brachytherapy...................... 478 2.1 Endobronchial High-dose Rate Brachytherapy ........ 478 2.2 Interstitial Brachytherapy .......................................... 479 3

Clinical Results: Tumor Control and Palliation ........................................................... 3.1 Endobronchial Brachytherapy (EBB) with Curative Intention ..................................................................... 3.2 EBB with Palliative Intention ................................... 3.3 Interstitial Brachytherapy ..........................................

480 480 482 484

4

Clinical Results: Toxicity........................................ 484

5

Conclusion ................................................................ 486

References.......................................................................... 486

A. Polo (&) A. Montero Department of Radiation Oncology, Ramon y Cajal University Hospital, Madrid, Spain e-mail: [email protected] M. Castro P. Navío Department of Pneumology, Ramon y Cajal University Hospital, Madrid, Spain

Brachytherapy is the direct placement of a radioactive source inside or close to a tumor mass. The use of endobronchial brachytherapy for bronchogenic carcinoma is not new, being the initial use reported back in the early 1920s. Brachytherapy for lung cancer 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 largely 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 combination with external beam radiotherapy 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 brachytherapy has been described for the treatment of malignant thoracic tumors. Intraoperative permanent radioactive 125-I seed implantation can be used in the treatment of lung cancer when resection margins are close or involved with tumor or for palliation of inoperable disease. Percutaneous implantation of radioactive seeds has also been reported for the management of stage T1N0M0


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A. Polo et al.

medically inoperable NSCLC with CT-guided brachytherapy. During the last two decades, technological 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 largely 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 combination with external beam radiotherapy 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 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 medically inoperable NSCLC with CT-guided brachytherapy. 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

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 afterloading techniques during the 1950–1960s was essential for the widespread application of brachytherapy (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 brachytherapy 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 treatment 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 procedure (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. Performed 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 intravenous conscious sedation typically used in standard bronchoscopic procedures. After topical anesthetic is carefully applied to the nasal cavity and the nasopharynx, 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 recanalization 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 pulmonologist 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 catheter’ 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 localizations (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 bronchoscope 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 radiotherapy) and the tradition of the team.

2.2

Interstitial Brachytherapy

The techniques of interstitial implantation vary depending on the type of implantation used. Permanent 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 postsurgical 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.

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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 coordinates 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 threaded 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

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 microscopically 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


481

Table 1 Definitive brachytherapy alone: clinical results Author

n

EBRT (Gy)

BT Technique

Hilaris et al. (1987)

55

44% EBRT mediastinum

LDR/HDR

Schraube et al. (1993)

13

–

HDR

Sutedja et al. (1994)

2

–

Tredaniel et al. (1994)

29

Perol et al. (1997)

19

Total dose (dose per fraction/ number of fractions)

MFU (months)

LC (%)

CSS (%)

OS (%)

MST

54

63

NA

32

NA

5–30 (3–5/1–6)

NA

NA

NA

NA

9 months

HDR

30 (10/3)

40

NA

100

NA

NA

–

HDR

42 (7/6)

23

NA

NR

NA

Not reached

–

HDR

35 (7/5)

28

75 (1 years)

78 (1 years)

NA

28 months

58 (2 years) Taulelle et al. (1998)

23

–

HDR

24–40 (8–10/3–4)

32

NA

46 (2 years)

NA

17 months

Stout et al. (2000)

49

–

HDR

15 (15/1)

NA

NA

NA

2

250 days

50

30

–

–

10 P = 0.04

287 days P = 0.04

Peiffert et al. (2000)

33

No EBRT (18p)

HDR

30 (5/6)

50–60 (15p)

HDR

10–20 (5/2–4)

Marsiglia et al. (2000)

34

–

HDR

Hennequin et al. (2007)

106

–

HDR

Aumont-le Guilcher et al. (2011)

226

–

HDR

14

NA

53 (2 years)

80 (2 years)

23 months

30 (5/6)

29

85 (2 years)

NA

78 (2 years)

NA

30–42 (5–7/6)

48

60.3 (2 years)

67.9 (2 years)

47.4 (2 years)

21.4 months

51.6 (5 years)

48.5 (5 years)

24 (5 years)

68 (2 years)

81 (2 years)

57 (2 years)

50 (5 years)

56 (5 years)

29 (5 years)

24–35 (5–7/4–6)

30.4

28.6 months

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 brachytherapy (4.8 Gy scheduled, at 10 mm from the source axis) before and after external irradiation. In patients with squamous cell carcinoma, the HDR brachytherapy 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 microscopic 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 (Gy)

BT Technique

Total dose (dose per fraction/ number of fractions)

MFU

LC (%)

CSS (%)

OS (%)

MST (months)

Aygun et al. (1992)

62

50–60

HDR

15–25 (5/3–5)

18 months

NA

NA

NA

13

Cotter et al. (1993)

65

55–66

LDR

6–35

NA

NA

23 (2 years)

8

Nori et al. (1993)

17

*50

HDR

15 (5/3)

14.5 months

88 (6 months)

NA

NA

17.5

Speiser and Spratling (1993a)

50

60

HDR

22.5–30 (7.5–10/3)

NA

NA

NA

NA

11

Kohek et al. (1994)

39

50–70

HDR

5–25 (5/1–5)

NA

NA

NA

NA

13

Fuwa et al. (2000)

41

50

LDR

22

0– 60 months

NA

NA

61 (CR)

NA

Nomoto et al. (1997)

9

40–60

HDR

18 (6/3)

NA

NA

NA

64 (3 years)

NA

Huber et al. (1997)

56

60

HDR

9.6 (4.8/2)

2.5 years

12 weeks

NA

25 (1 year)

10

42

60

–

–

19 (1 year)

8 (P = 0.09)

Furuta et al. (1999)

5

40

HDR

18 (6/3)

36 months

100 (CR)

80 (CR)

60 (CR)

NA

Muto et al. (2000)

320

60

HDR

10–15 (5–10/1–3)

5– 36 months

NA

NA

NA

11

Saito et al. (2000)

64

40

LDR

25

44 months

87 (5 years)

96 (5 years)

72 (5 years)

NA

Langendijk et al. (2001)

48

30–60

HDR

15 (7.5/2)

12 months

NA

NA

47

30–60

–

–

Ozkok et al. (2008)

43

60

HDR

15 (5/3)

NA

NA

Wedge resection

HDR

24.5 (3.5/7)

13.5

92 (CR)

21 weeks

9 (CR)

7

15 (CR)

8.5

NA

25.5 (2 years)

11

NA

83 (CR)

NA

BT and Surgery McKenna et al. (2008)

48

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 procedure, should not present a significant active bleeding,


483

Table 3 Palliative brachytherapy: clinical results Author

n

Prior treatments

BT technique

BT schedule

Symptomatic response

Lo et al. (1992)

77

laser

LDR

45–60 Gy

Overall: 54%

Gollins et al. (1996)

322

EBRT, laser

HDR

15 Gy 9 1

Stridor: 92%; hemoptysis 88%; cough: 62%; dyspnea: 60%; pain: 50%; pulmonary collapse: 46%

laser

HDR

Speiser and Spratling (1993a)

109

20 Gy 9 1

7.5 Gy 9 3 5 Gy 9 3

Delclos et al. (1996)

81

EBRT

HDR

Ornadel et al. (1997)

117

EBRT, laser

HDR

Stout et al. (2000)

50

None

EBRT HDR

15 Gy 9 1

Kelly et al. (2000)

175

EBRT, laser

HDR

15 Gy 9 1

Overall: 66%

Celebioglu et al. (2002)

95

EBRT

HDR

7.5 Gy 9 3

Overall: 100%

Mallick et al. (2007)

95

NA

HDR

10 Gy 9 1

49

15 Gy 9 2

Overall: 70%; hemoptysis: 99%; pneumonia: 99%; dyspnea: 86%; cough: 85% Overall: 84% Cough: 62–77%; dyspnea: 32–56%; hemoptysis: 78–97%

30 Gy (3.75 9 8)

Improved symptom palliation for EBRT (83%) versus HDR (59%), P = 0.03

10 Gy 9 2 8 Gy 9 2 15 Gy 9 1

Kubaszewska et al. (2008)

270

Skowronek et al. (2009)

648

EBRT, BT

HDR

8 Gy 9 1 10 Gy 9 1

EBRT

HDR

7.5 Gy 9 3 (303p) 10 Gy 9 1 (345p)

Dyspnea: 92.5%; cough: 81%; hemoptysis: 97%; pneumonia: 91% Overall: 80%; dyspnea: 76%; cough: 77%; hemoptysis: 92%; pneumonia: 82% Overall:88%; no differences between schedules

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 endobronchial 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 palliation 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 evidence-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 endobronchial 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 endobronchial 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 brachytherapy procedure are not more frequent than those occurring during routine diagnostic flexible bronchoscopy. 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 endoluminal 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 occurrence of massive hemoptysis and the type of


485

Table 4 Interstitial brachytherapy: clinical results Author

n

Disease stage (AJCC)

BT Technique

Total dose (Gy)

LC (%)

OS (%)

Hilaris and Martini (1979)

470

I–III

125

160

80 (5 years, stages I, II) 80 (5 years, stage III)

7 (5 years)

Hilaris and Martini (1988)

88

T1–3 N2

125

160; 30

76 (2 years)

51 (2 years)

225

T3N0

I

I; HDR

22 (2 years)

I–III, close/positive margins

125

160

HDR

10–20

Ginsberg et al. (1994)

102

Brach et al. (1994)

20

I, tumor \2 cm

HDR

Chen et al. (1999)

23

I

Santos et al. (2003)

203

IA–B

Lee et al. (2003)

33

I

I

NA

41 (5 years)

10–20

NA

75% (CR, 3–30 months)

125

100–120

100 (CR)

83 (CR)

125

100–120

98 (CR)

60 (4 years)

–(102p)

–

81 (CR)

67 (4 years)

125

125–140

94 (5 years)

47 (5 years)

85–129

87 (5 years)

18 (5 years)

I I (101p) I

Voynov et al. (2005)

118

IA–B

125

Birdas et al. (2006)

167

IB

Sublobar resection ? 125 I (41p) Lobectomy (126p)

100–120

95.2 (CR)

54 (4 years)

–

96.8 (CR)

52 (4 years)

125

120

NA

35 (5 years)

Colonias et al. (2011)

145

IA–B

I

I

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). Sometimes 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 brachytherapy 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, circumferential 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 administration of steroids, oxygen, balloon dilatation, laser resection, or endobronchial prosthesis placement in case of severe stenosis (Vergnon et al. 2006).

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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, photodynamic 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 multimodality treatment is employed. Endoluminal brachytherapy 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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487 brachytherapy of recurrent bronchogenic carcinoma: a new approach using the flexible fiberoptic bronchoscope. Radiology 147:253–254 Muto P, Ravo V, Panelli G, Liguori G, Fraioli G (2000) Highdose rate brachytherapy of bronchial cancer: treatment optimization using three schemes of therapy. Oncologist 5:209–214 Nag S, Kelly JF, Horton JL, Komaki R, Nori D (2001) Brachytherapy for carcinoma of the lung. Oncology (Williston Park) 15:371–381 Nomoto Y, Shouji K, Toyota S et al (1997) High dose rate endobronchial brachytherapy using a new applicator. Radiother Oncol 45:33–37 Nori D, Allison R, Kaplan B, Samala E, Osian A, Karbowitz S (1993) High dose-rate intraluminal irradiation in bronchogenic carcinoma. Technique and results. Chest 104:1006–1011 Ornadel D, Duchesne G, Wall P, Ng A, Hetzel M (1997) Defining the roles of high dose rate endobronchial brachytherapy and laser resection for recurrent bronchial malignancy. Lung Cancer 16:203–213 Ozkok S, Karakoyun-Celik O, Goksel T et al (2008) High dose rate endobronchial brachytherapy in the management of lung cancer: response and toxicity evaluation in 158 patients. Lung Cancer 62:326–333 Peiffert D, Spaeth D, Menard O, Winnefeld J (2000) High dose endobronchial brachytherapy: a curative treatment. Cancer Radiother 4:197–201 Perol M, Caliandro R, Pommier P et al (1997) Curative irradiation of limited endobronchial carcinomas with highdose rate brachytherapy. Results of a pilot study. Chest 111:1417–1423 Rodrigues G, Videtic GM, Sur R (2011) Palliative thoracic radiotherapy in lung cancer: an American Society for Radiation Oncology evidence-based clinical practice guideline. Pract Radiat Oncol :60–71 Saito M, Yokoyama A, Kurita Y, Uematsu T, Tsukada H, Yamanoi T (2000) Treatment of roentgenographically occult endobronchial carcinoma with external beam radiotherapy and intraluminal low-dose-rate brachytherapy: second report. Int J Radiat Oncol Biol Phys 47:673–680 Santos R, Colonias A, Parda D et al (2003) Comparison between sublobar resection and 125Iodine brachytherapy after sublobar resection in high-risk patients with Stage I non-small-cell lung cancer. Surgery 134:691–697 discussion 697 Schraube P, Fritz P, Becker HD, Wannenmacher M (1993) The results of the endoluminal high-dose-rate irradiation of central non-small cell bronchial carcinomas. Strahlenther Onkol 169:228–234 Schray MF, McDougall JC, Martinez A, Edmundson GK, Cortese DA (1985) Management of malignant airway obstruction: clinical and dosimetric considerations using an iridium-192 afterloading technique in conjunction with the neodymium-YAG laser. Int J Radiat Oncol Biol Phys 11:403–409 Schray MF, McDougall JC, Martinez A, Cortese DA, Brutinel WM (1988) Management of malignant airway compromise with laser and low dose rate brachytherapy. The Mayo Clinic experience. Chest 93:264–269 Seagren SL, Harrell JH, Horn RA (1985) High dose rate intraluminal irradiation in recurrent endobronchial carcinoma. Chest 88:810–814

488 Sider L, Mittal BB, Nemcek AAJ, Bobba VS (1988) CT-guided placement of iodine-125 seeds for unresectable carcinoma of the lung. J Comput Assist Tomogr 12:515–517 Skowronek J, Kubaszewska M, Kanikowski M, Chichel A, Mlynarczyk W (2009) HDR endobronchial brachytherapy (HDRBT) in the management of advanced lung cancer— Comparison of two different dose schedules. Radiother Oncol 93:436–440 Speiser BL, Spratling L (1993a) Remote afterloading brachytherapy for the local control of endobronchial carcinoma. Int J Radiat Oncol Biol Phys 25:579–587 Speiser BL, Spratling L (1993b) Radiation bronchitis and stenosis secondary to high dose rate endobronchial irradiation. Int J Radiat Oncol Biol Phys 25:589–597 Stewart AJ, Mutyala S, Holloway CL, Colson YL, Devlin PM (2009) Intraoperative seed placement for thoracic malignancy—a review of technique, indications, and published literature. Brachytherapy 8:63–69 Stout R, Barber P, Burt P et al (2000) Clinical and quality of life outcomes in the first United Kingdom randomized trial of endobronchial brachytherapy (intraluminal radiotherapy) vs. external beam radiotherapy in the palliative treatment of inoperable non-small cell lung cancer. Radiother Oncol 56:323–327

A. Polo et al. Sutedja G, Baris G, van Zandwijk N, Postmus PE (1994) Highdose rate brachytherapy has a curative potential in patients with intraluminal squamous cell lung cancer. Respiration 61:167–168 Taulelle M, Chauvet B, Vincent P et al (1998) High dose rate endobronchial brachytherapy: results and complications in 189 patients. Eur Respir J 11:162–168 Tredaniel J, Hennequin C, Zalcman G et al (1994) Prolonged survival after high-dose rate endobronchial radiation for malignant airway obstruction. Chest 105:767–772 Ung YC, Yu E, Falkson C et al (2006) The role of high-doserate brachytherapy in the palliation of symptoms in patients with non-small-cell lung cancer: a systematic review. Brachytherapy 5:189–202 Vergnon JM, Huber RM, Moghissi K (2006) Place of cryotherapy, brachytherapy and photodynamic therapy in therapeutic bronchoscopy of lung cancers. Eur Respir J 28:200–218 Voynov G, Heron DE, Lin CJ et al (2005) Intraoperative (125)I Vicryl mesh brachytherapy after sublobar resection for high-risk stage I non-small cell lung cancer. Brachytherapy 4:278–285 Yankauer S (1922) Two cases of lung tumor treated bronchoscopically. NY Med J 21:741

Limited-Disease Small-Cell Lung Cancer Branislav Jeremic´, Zˇeljko Dobric´, 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. Jeremic´ (&) Zˇ. Dobric´ Institute of Lung Diseases, Sremska Kamenica, Serbia e-mail: [email protected]

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 particular, 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 landmark 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 suboptimally investigated due to lack of clinical studies investigating it and, therefore, poor guidelines for daily clinical practice.

F. Casas University Clinic, Barcelona, Spain


491

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492

1

Introduction

Small-cell lung cancer is highly aggressive carcinoma representing approximately 15–20% of all lung cancer 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 cornerstone 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 neuropathy, cerebellar ataxia, limbic encephalopathia, and retinal degeneration (Curran 2001). More than 4 decades ago, the Veterans Administration Lung Group had proposed dividing all smallcell 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 considered 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 therapy treatment field’’. It was not always easy to denote and compare it between clinicians, especially radiation oncologists. This, however, may be more easily solved nowadays due to normal lung constraints and

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 recommended 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, cyclophosphamide, doxorubicin, methotrexate, and vincristine (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/etoposide, 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/doxorubicin/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 smallcell 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/etoposide/vincristin arms, respectively (p = 0.0004). In subgroup analysis done for 214 patients with limiteddisease, 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 survival 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 longknown facts about favorable toxicity profile of cisplatin/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/etopopside 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 combination 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 symptoms, 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 demonstrated a survival advantage for limited-disease smallcell 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 continuous chemotherapy (Byrne et al. 1989). The lack of survival improvement and increased toxicity of prolonged 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 chemotherapy courses. Here, no survival benefit was seen for 8 cycles of cyclophosphamide/etoposide/vincristine 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 preliminary 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 introduction 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-stimulating factor support (Ardizzoni et al. 2002). Improved survival was noted in the dose-intensive arm in 3 studies, with two trials showing significant improvement. 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, unfortunately, 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 highdose 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 standarddose chemotherapy arms, respectively. No differences were observed between the two arms in overall response and complete response, respectively. Highdose treatment was predictably associated with severe

B. Jeremic´ 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 hematological toxicity was seen more frequently in the cisplatin/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 extensive disease small-cell lung cancer patients and compared 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 taxanes, 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 vincristine 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


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 therapy part of the combined modality program was followed 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 Organization 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 limiteddisease 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 combination (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 concurrent 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 chemotherapy, and total dose and fractionation used, have attracted most of the attention of researchers. When timing of combined radiation therapy and chemotherapy 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 portion 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 regimens, 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 radiation therapy or suggested no difference when compared to early thoracic radiation therapy and chemotherapy (Work et al. 1997). Likely the explanation 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 chemotherapy. More recent studies using cisplatin/etoposide (Jeremic et al. 1997; Takada et al. 2002) or cisplatin/ etoposide alternating with cyclophosphamide/doxorubicin/vincristin (Murray et al. 1993) showed clear superiority for early administration of thoracic radiation 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 considerations 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 chemotherapy was capable of achieving 5-year survival of [20%, while late thoracic radiation therapy usually

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496

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 (weeks)

MST (months)

Survival (5 year) (%)

Perry et al.

1987

125

CEVA

50 Gy/24 fr/ QD

1

13.04

7

145

same

Same

9

14.54

13

155

CAV/PE

40 Gy/15 fr/ QD

3

21.2

20

Murray et al.

1993

Work et al.

1997

153

Jeremic et al.

1997

Takada et al.

2002

Spiro et al.

2006

same

15

16.0

11

99

PE ? CAV

40–45 Gy/22 fr/QD

1

10.7

11

100

same

same

18

12.9

12

52

PE (CpE with RT)

54 Gy/36 fr/ BID

1

34

30

51

same

same

6

26

15

114

PE

45 Gy/30 fr/ BID

1

27.2

24

114

same

same

15

19.7

18

159

CAV/PE

40 Gy/15fx/ QD

3

13.7

16*

166

same

same

15

15.1

22*

Outcome (p)

0.08

0.008

0.4

0.052

0.097

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

Fried et al.

2004

2

1.17

1.021.35

0.03

3

1.13

0.92–1.39

0.2

Huncharek/McGarry Pijls-Johannesma et al.

2004 2005

p

2

1.60

1.29–1.99

\0.01

3

1.49

1.15–1.93

\0.01

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 therapy 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/cisplatin/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-disease 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


advantage for early radiation therapy and chemotherapy. Finally, Spiro et al. (2006) found no difference 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 ambiguities, 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 percentage 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’’ administration, (c) inclusion of ‘‘grey literature’’, (d) different 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 hyperfractionation (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 systemic 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 relationship. 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. Subsequently, 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 topotecan, with the median overall survival of 19.8 months with a 1-year survival rate of 70% the median failurefree 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) chemotherapy. 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 survival 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 fractionation, hypofractionated radiation therapy regimens 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 fractionated 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 cisplatin/etoposide (Bonner et al. 1999). There was no difference in a 3-year overall and locoregional control. 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 hyperfractionation (To put it in other words, hyperfractionation given with a split equals conventional, once-daily

B. Jeremic´ 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 smallcell lung cancer using Quality Time Without Symptoms 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 evidence 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 fractionation 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 Intergroup 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 chemotherapy. 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 twicedaily groups, respectively. Isolated in-field failures


were similar between the two groups. While this analysis did not detect a statistically significant difference in acute toxicities, disease control, or survival 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 implemented in practice concurrently with low-dose chemotherapy 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 postchemotherapy disease volume and the second one is related to the elective nodal irradiation. When radiation 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 chemotherapy. 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 nonplatinum-based chemotherapy to radiation therapy fields based either on the pre- or on post-chemotherapy volume of disease. No statistical differences in survival or recurrence patterns were noted as a function of volume treated. Postchemotherapy volumes were, therefore, judged appropriate for target delineation, not risking higher incidence of marginal failures. Several retrospective analyses have assessed preversus 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 provide improved local control and, therefore, be preferentially 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 postchemotherapy tumor volumes and 31 with prechemotherapy tumor volumes. Of a total group, 10 of 31 patients treated with radiation therapy fields that encompassed prechemotherapy 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 postchemotherapy 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 Intergroup 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 prospectively 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 recurrence. 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

B. Jeremic´ et al.

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 involvedfield 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 limiteddisease small-cell lung cancer. In the most comprehensive review of the use of elective nodal irradiation in limited-disease small-cell lung cancer, authors recently noted the absence of strong evidence supporting 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 reduction of treatment-related toxicities with involved fields in the decision-making process (Videtic et al. 2008).

5

because they resembled limited-disease small-cell lung cancer patients at most. In them, after 3 initial cycles of cisplatin/etoposide, accelerated hyperfractionated 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/etoposide. 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.

Conclusions

The standard treatment for the majority of patients with limited-disease small-cell lung cancer is combination of thoracic radiation therapy and cisplatin/ etoposide, given concurrently, with thoracic radiation therapy being started early. While majority of institutions worldwide use 4 cycles of cisplatin/etoposide, numerous thoracic radiation therapy and chemotherapy issues remain unsolved. Ongoing studies will help clear these important issues in optimizing the treatment approach and outcome in this disease. The lessons 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 randomized 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 complete response at distant sites accompanied with either complete response or partial response intrathoracically. They were chosen as a subject of our study

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504 Fukuda H, Saijo N (2002) Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan clinical oncology group study 9104. J Clin Oncol 20:3054–3060 Thatcher N, Girling DJ, Howood P, Sambrook RJ, Qian W, Stephens RJ (2000) Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with granulocyte colony-stimulating factor support: results of a British medical research council multicenter randomised trial. J Clin Oncol 18:395–404 Travis WD, Brambilla E, Muller-Hermlink HK, Harris CC (2004) World health organziation classification of tumours. Pathology and genetics of tumours of the lung, pleura, thymus and heart. IARC Press, Lyon Turrisi AT, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, Wagner H, Aisner S, Johnson DH (1999) Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:264–271 Videtic GMM, Truong PT, Dar AR, Yu EW, Stitt LW (2003) Shifting from hypofractionated to ‘‘conventionally’’ fractionated thoracic radiotherapy: a single institutions’s 10year experience in the management of limited-stage smallcell lung cancer using concurrent chemoradiation. Int J Radiat Oncol Biol Phys 57:709–716 Videtic GM, Belderbos JS, Spring Kong FM, Kepka L, Martel MK, Jeremic B (2008) Report from the international atomic energy agency (IAEA) consultants’ meeting on elective nodal irradiation in lung cancer: small-cell lung cancer (SCLC). Int J Radiat Oncol Biol Phys 72:327–334 Warde P, Payne D (1992) Does thoracic radiation improve survival and local control in limited-stage small cell carcinoma of the lung? J Clin Oncol 10:890–895 Watkins JM, Fortney JA, Wahlquist AE, Shirai K, GarrettMayer E, Aguero EG, Sherman CA, Turrisi AT 3rd, Sharma AK

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Radiation Therapy in Extensive Disease Small Cell Lung Cancer Branislav Jeremic´ 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

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, chemotherapy 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-institutional studies from Canada and China seem to confirm this, while two ongoing prospective studies should help further refine radiation therapy approach in this disease.

References.......................................................................... 510

B. Jeremic´ (&) Institute of Lung Diseases, Sremska Kamenica, Serbia e-mail: [email protected]

1

L. Wang Department of Radiation Oncology, Chinese Academy of Medical Sciences, Beijing, China

For decades, clinicians and investigators considered chemotherapy as the standard treatment option for patients with extensive disease small cell lung cancer.

Introduction


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B. Jeremic´ and L. Wang

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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 chemotherapy, 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 chemotherapy 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 combat poor prognosis in patients with this disease when treated with chemotherapy alone, various approaches aiming intensification of the treatment were attempted. 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. Accumulated 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 radiation therapy and/or prophylactic cranial irradiation could be of a benefit in suitable patients with extensive 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 radiation 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, complete response rates, overall response rates, the median survival time, and 2-year disease-free survival were identical for patients treated with chemotherapy alone and those treated with chemotherapy and

thoracic radiation therapy (Bunn and Ihde 1981). It should be clearly noted, however, that the majority of studies from that report were performed and published in 1960s and 1970s. Therefore, major characteristics of radiation therapy course such as total tumor dose, dose per fraction, and timing as well as rather primitive treatment planning cannot be considered 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 possible effect on local control and, subsequently, survival 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 irradiation, 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 continued 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 cancer defined as the tumor beyond the confines of the hemithorax, mediastinum, and ipsilateral or contralateral 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 cytology 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 nervous system metastases or other abnormality when substantially impairing mental status. For staging purposes chest X-rays and tomography, bronchoscopy, 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 recommended 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 treatment day, followed by prophylactic cranial irradiation and then by additional two cycles of cisplatin-etoposide (group I) or (b) four additional cycles of cisplatin-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 achieving complete response or partial response within thorax, but only a partial response elsewhere (group III and group IV), were offered two additional cisplatin-etoposide cycles followed by the same accelerated 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

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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 mediastinum with a 1 cm margin and both supraclavicular fosse were routinely irradiated. Anteroposterior-posteroanterior 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 parallel—opposed lateral fields in groups I and II. Patients in groups III and IV also received prophylactic 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 following: 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 progression. 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 metastasisfree survival was similar between the two groups. Although group II patients treated with chemotherapy only achieved longer median time to distant metastasis 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 recurrencefree survival rate was only marginally insignificant and distant metastasis-free survival rate was not significantly 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


radiation therapy/carboplatin-etoposide (group I) or two additional cycles of PE (group II) were administered), 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 hyperfractionated radiation therapy had been added to three cycles of cisplatin-etoposide. Furthermore, the 6th and 7th cycles of cisplatin-etoposide in the chemotherapy 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 chemotherapy in chemotherapy alone group (II) added no visible gain in response rates. These data altogether question the duration (number of cycles) of chemotherapy 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., cisplatin-etoposide) with or without thoracic radiation therapy. Haematological high-grade ([3) toxicity (leucopoenia, 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). Highgrade 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 bronchopulmonary 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 multivariate 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 survival, disease-free survival, local control, and toxicity. Thirty-two of 33 accrued patients were evaluable. Seventeen patients had \3 metastases, while 2 patients had at least three metastases. Bulky intrathoracic 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 complete and 28 partial responses to chemotherapy. All study patients received prophylactic cranial irradiation. 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 recurrences 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 carboplatin-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 treatment 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 radiochemotherapy 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 confirmatory 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

programs of Orange, San Diego, and Imperial countries in southern California covering an area with estimated population of 6.2 million. Small cell lung cancer patients diagnosed between 1991 and 2005 who had complete follow-up data were included in the study. Extensive disease was defined as distant disease stage according to Surveillance, Epidemiology, and end results summary staging. There were 3,428 such patients. Of them, radiation therapy was given in 1,204 (35.1%) patients. A number of clinicopathologic characteristics were analyzed upon their influence on the outcome. The 1-year, 2-year, and median overall survival of extensive disease small cell lung cancer patients who received radiation therapy were 27.8, 9.3%, and 8 months and were significantly better than extensive disease small cell lung cancer patients who did not receive radiation therapy (16.2, 3.8%, and 4 months, respectively; p \ 0.0001). Cox multivariate analysis of potential prognostic factors confirmed independent positive influence of delivered radiation therapy on treatment outcome (HR, 0721; 95% CI, 0-670-0.776; p \ 0.001). Unfortunately, other important characteristics of radiation therapy (e.g., curative vs. palliative, time-dose-fractionation patterns, sequencing of chemotherapy and radiation therapy) were not provided as to enable better insight into patterns of practice of radiation therapy in this disease. Nevertheless, these data suggest that radiation therapy is practiced in about 1/3 of these patients improving survival. These may be a good starting point for more practicing in the near future, especially once we have more solid data from ongoing trials.

4

Ongoing Studies

After a gap of almost 10 years following the publication of this landmark study (i.e., 20 years since its start!), investigators over the world finally started with preparations for additional prospective randomized trials of thoracic radiation therapy in extensive disease small cell lung cancer. The Radiation Therapy Oncology Group in the US planned and opened up a study (RTOG 0835) in which patients with extensive disease small cell lung cancer and no brain metastasis, having Eastern Cooperative Oncology Group performance status 0–2 are enrolled. Patients would have to achieve either complete response or partial response,

Table 1 Basic comparison RTOG 0835 vs. CREST Trial

Nature

Diagnosis (classic/ pet)

Patients (n mets)

Sequencing Rt-chemo

RTOG

Curative

More precise

More favorable

Sequential

CREST

Palliative

Less precise

Less favorable

Sequential

with brain restaging done and with 0–1 residual sites of extrathoracic disease present at the time of restaging. Radiotherapy part of the study includes thoracic radiation therapy dose of 45 Gy in 15 fractions, prophylactic cranial irradiation of 25 Gy in 10 fractions, while 45 Gy in 15 fractions will be given to metastatic lesions. Major objectives of the trial included (1) overall median and 1-year survival (2) recurrence patterns and time to failure, as well as (3) acute and late toxicity. Similarly, the Dutch Lung Cancer Study Group is executing a chest radiotherapy in extensive disease small cell lung cancer trial (CREST) with the primary endpoint being overall survival. Secondary endpoints include pattern of relapse and toxicity. In CREST trial, patients with extensive disease small cell lung cancer without brain metastasis or pleural metastasis undergo chemotherapy. Those achieving any response to 4–6 cycles of chemotherapy are randomized to prophylactic cranial irradiation and no thoracic radiation therapy versus those treated with prophylactic cranial irradiation and thoracic radiation therapy (30 Gy in 10 fractions) given only if the toxicity of the required fields will not be prohibitive. These two trials are different in many characteristics, and some of major strategic characteristics are briefly outlined in a Table 1. It is expected that these two studies will bring additional substance to the data of Jeremic et al. (1999) and help optimize both treatment approach with thoracic radiation therapy and identification of suitable patients for thoracic radiation therapy.

References Beck LK, Kane MA, Bunn PA Jr (1988) Innovative and future approaches to small cell lung cancer treatment. Semin Oncol 15:300–314 Bunn PA Jr (1992) Clinical experience with carbolatin (paraplatin) in lung cancer. Semin Oncol 19(suppl 2):1–11

Radiation Therapy in Extensive Disease Small Cell Lung Cancer Bunn PA, Ihde DC (1981) Small cell bronchogenic carcinoma: a review of therapeutic results. In: Liv-ingston RB (ed) Lung Cancer. Boston, Martin Nijhoff, pp 169–208 Bunn PA Jr, Cohen MH, Ihde DC, Fossieck BE Jr, Matthews MJ, Minna JD (1977) Advances in small cell bronchogenic carcinoma: a commentary. Cancer Treat Rep 61: 333–342 Ihde DC, Mulshine JL, Kramer BS, Steinberg SM, Linnoila RI, Gazdar AF, Edison M, Phelps RM, Lesar M, Phares JC (1994) Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small cell lung cancer. J Clin Oncol 12:2022–2034 Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S (1997) Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small cell lung cancer. J Clin Oncol 15:893–900 Jeremic B, Shibamoto Y, Nikolic N, Milicic B, Milisavljevic S, Dagovic A, Aleksandrovic J, Radosavljevic-Asic G (1999) The role of radiation therapy in the combined modality treatment of patients with extensive disease small-cell lung cancer (ED SCLC): a randomized study. J Clin Oncol 17:2092–2099 Leyvraz S, Pampallona S, Martinelli G, Ploner F, Perey L, Aversa S, Peters S, Brunsvig P, Montes A, Lange A, Yilmaz U, Rosti G (2008) Solid tumors working party of the European group for blood and marrow transplantation. A threefold dose intensity treatment with ifosfamide, carboplatin, and etoposide for patients with small cell lung cancer: a randomized trial. J Natl Cancer Inst 100:533–541 Murray N, Coy Pater J, Hodson I, Arnold A, Zee BC, Payne D, Kostashuk EC, Evans WK, Dixon P (1993) Importance of timing for thoracic irradiation in the combined modality

511 treatment of limited stage small cell lung cancer. J Clin Oncol 11:336–344 Ou S-H, Ziogas A, Zell JA (2009) Prognostic factors for survival in extensive stage small-cell lung cancer (EDSCLC). The importance of smoking history, socioeconomic and marital statuses, and ethnicity. J Thorac Oncol 4:37–43 Schiller JH, Adak S, Cella D, DeVore RF 3rd, Johnson DH (2001) Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593– a phase III trial of the Eastern cooperative oncology group. J Clin Oncol 19:2114–2122 Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, Postmus P, Collette L, Musat E, Senan S (2007) EORTC Radiation oncology group lung cancer group prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357:664–672 Splinter TAW (1989) Chemotherapy of small cell lung cancer (SCLC): duration of treatment. Lung Cancer 5:186–196 Takada M, Fukuoka M, Kawahara M, Sugiura T, Yokoyama A, Yokota S, Nishiwaki Y, Watanabe K, Noda K, Tamura T, Fukuda H, Saijo N (2002) Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan clinical oncology group study 9104. J Clin Oncol 20:3054–3060 Yee D, Butts C, Chu Q (2010) Phase II trial of consolidation chest radiotherapy for extensive stage small cell lung cancer [Abstract]. Radiother Oncol 96(1):102 Zhu H, Zhou Z, Wang Y, Bi N, Feng Q, Li J, Jima LV, Chen D, Shi Y, Wang L (2010) Thoracic radiation therapy improves the overall survival of patients with extensive disease small cell lung cancer with distant metastasis. proc. Am Soc Ther Oncol Radiol 72, Abstract 2211

Prophylactic Cranial Irradiation in Small-Cell Lung Cancer Michael C. Stauder and Yolanda I. Garces

Contents

Abstract

1

Introduction.............................................................. 514

2

Studies Evaluating Prophylactic Cranial Irradiation ................................................................ Retrospective Studies ................................................ Randomized Trials..................................................... Meta-Analyses ........................................................... Extensive Stage Small-Cell Lung Cancer ................

2.1 2.2 2.3 2.4

514 514 514 515 516

3 Treatment Schedule................................................. 516 3.1 Dose and Fractionation ............................................. 516 3.2 Timing of PCI............................................................ 516 517 517 517 518

4 4.1 4.2 4.3

Neurotoxicity and Quality of Life ......................... Retrospective Studies ................................................ Prospective Trials ...................................................... Extensive Stage Small-Cell Lung Cancer ................

5

Patterns of Care....................................................... 518

6

Future Directions..................................................... 519

7

Conclusions ............................................................... 519

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 studies have shown that PCI reduces the rate of brain metastases and improves survival. However, the use of PCI in the management of small-cell lung cancer 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 definitive conclusions regarding the side-effects of treatment. As the survival of patients with SCLC improves, the controversies regarding the neurotoxic effect of PCI may become more defined. Certainly, well-designed prospective clinical trials addressing these issues are needed and are ongoing.

References.......................................................................... 519

Abbreviations

Gy Fx BID LS ES SCLC NSCLC

Gray Fractions Twice-daily Limited stage Extensive stage Small-cell lung cancer 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: [email protected]


513

514

1

M. C. Stauder and Y. I. Garces

Introduction

Small-cell lung cancer (SCLC) comprises 15–25% of all lung cancer cases. A complete response to treatment 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 controversial 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 prolonged survival after the use of novel chemotherapeutic 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 performed in the mid 1970s by Komaki and colleagues. A total of 131 patients were analyzed for the incidence of brain metastasis of patients when PCI was included as part of their small-cell lung cancer therapy. 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).

Similarly, other trials from the 1970s also concluded 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 incidence 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 complete 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 nonstatistically 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

Study

N

PCI dose*

Arriagada et al. (1995)

300

24 Gy/8 Fx

Laplanche et al. (1998) Ohonoshi et al. (1993) Gregor et al. (1997) Aupérin et al. (1999) Slotman et al. (2007)

211 46 314 987 286

24 Gy/8 Fx 40 Gy/20 Fx 30 Gy/10 Fx 24–25 Gy/8–12 Fx 20 Gy/5 Fx

Brain metastasis

Overall survival

PCI

PCI

No-PCI

No-PCI

40%

67%

29%

21.5%

2 years

2 years

2 years

2 years

44%

51%

22%

16%

4 years

4 years

4 years

4 years

22%

52%

22%

13%

5 years

5 years

30%

38%

25%

19%

2 years

2 years

2 years

2 years

33.3%

58.6%

20.7%

15.3%

3 years

3 years

3 years

3 years

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 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 metastases. 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.

2.3

Meta-Analyses

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 chemoradiotherapy (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 randomized trials and 1547 patients had a similar conclusion (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 metastatic 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 performed 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 chemotherapy (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 Prophylactic Cranial Irradiation Overview Collaborative Group (Aupérin et al. 1999). Conflicting data comes from Canadian investigators 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

was seen among the patients in this study. Additionally, 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 number 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 metastasis and promote improved survival. A single institution 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 effectiveness of a higher PCI dose or altered fractionation, a 25 Gy/10 fraction regimen, corresponding to the standard-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.


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 metastases before PCI started (Lee et al. 1987). A radiobiologic analysis was performed to evaluate 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 relationship was not seen, however, if PCI was delayed and delivered after 60 days. Also, in patients receiving early PCI (\60 days), the dose of radiation needed 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

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(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 testing. 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 coordination. 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 deterioration (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 neuropsychological 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 participated in extensive psychometric testing that was performed at randomization and every six months (Gregor et al. 1997). Up to 41% of patients analyzed

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had significant abnormalities on individual tests before PCI and additional impairment was seen at 6 months and 1 year. There were no notable differences, 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 receiving 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 predefined in the protocol design (Slotman et al. 2009). Patients receiving PCI had an increased rate of severe

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 differences, 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 Intergroup 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 regimen (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.


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 proliferation in vitro (Monje et al. 2002). Abnormal hippocampal 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 hippocampal 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, 5dimethyladamantan-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 recommended for all limited stage SCLC patients in complete 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

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part of comprehensive treatment for SCLC. Certainly, well-designed prospective clinical trials addressing these issues are needed and are ongoing.

References Abayomi OK (1996) Pathogenesis of irradiation-induced cognitive dysfunction. Acta Oncol 35(6):659–663 Arriagada R, Le Chevalier T et al (1995) Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 87(3):183–190 Aupérin A, Arriagada R et al (1999) Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med 341(7):476–484 Bremnes RM, Sundstrom S et al (2001) Multicenter phase II trial of paclitaxel, cisplatin, and etoposide with concurrent radiation for limited-stage small-cell lung cancer. J Clin Oncol 19(15):3532–3538 Broadbent NJ, Squire LR et al (2004) Spatial memory, recognition memory, and the hippocampus. Proc Natl Acad Sci USA 101(40):14515–14520 Cox JD, Petrovich Z et al (1978) Prophylactic cranial irradiation in patients with inoperable carcinoma of the lung: preliminary report of a cooperative trial. Cancer 42(3):1135–1140 Giuliani M, Sun A et al (2010) Utilization of prophylactic cranial irradiation in patients with limited stage small cell lung carcinoma. Cancer 116(24):5694–5699 Gondi V, Tolakanahalli R et al (2010) Hippocampal-sparing whole-brain radiotherapy: a ‘‘how-to’’ technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 78(4): 1244–1252 Gore EM, Bae K et al (2011) Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non–small-cell lung cancer: primary analysis of radiation therapy oncology group study rtog 0214. J Clin Oncol 29(3):272–278 Gregor A, Cull A et al (1997) Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicentre randomised trial. Eur J Cancer 33(11):1752–1758 Grosshans DR, Meyers CA et al (2008) Neurocognitive function in patients with small cell lung cancer. Cancer 112(3):589–595 Gutierrez AN, Westerly DC et al (2007) Whole brain radiotherapy with hippocampal avoidance and simultaneously integrated brain metastases boost: a planning study. Int J Radiat Oncol Biol Phys 69(2):589–597 Hansen HH (1973) Should initial treatment of small cell carcinoma include systemic chemotherapy and brain irradiation? Cancer Chemother Rep 3, 4(2):239–241 Hsu F, Carolan H et al (2010) Whole brain radiotherapy with hippocampal avoidance and simultaneous integrated boost for 1–3 brain metastases: a feasibility study using volumetric modulated arc therapy. Int J Radiat Oncol Biol Phys 76(5):1480–1485

520 Jackson DV Jr, Richards F 2nd et al (1977) Prophylactic cranial irradiation in small cell carcinoma of the lung. a randomized study. JAMA 237(25):2730–2733 Jeremic B, Shibamoto Y et al (1999) Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study. J Clin Oncol 17(7):2092 Komaki R, Cox JD et al (1981) Risk of brain metastasis from small cell carcinoma of the lung related to length of survival and prophylactic irradiation. Cancer Treat Rep 65(9–10): 811–814 Komaki R, Meyers CA et al (1995) Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation. Int J Radiat Oncol Biol Phys 33(1):179–182 Laplanche A, Monnet I et al (1998) Controlled clinical trial of prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Lung Cancer 21(3):193–201 Le Pechoux C, Dunant A et al (2009) Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99– 01, EORTC 22003–08004, RTOG 0212, and IFCT 99–01): a randomised clinical trial. Lancet Oncol 10(5):467–474 Lee JS, Umsawasdi T et al (1987) Timing of elective brain irradiation: a critical factor for brain metastasis-free survival in small cell lung cancer. Int J Radiat Oncol Biol Phys 13(5):697–704 Lee JJ, Bekele BN et al (2006) Decision analysis for prophylactic cranial irradiation for patients with small-cell lung cancer. J Clin Oncol 24(22):3597–3603 Levitan N, Dowlati A et al (2000) Multi-institutional phase I/II trial of paclitaxel, cisplatin, and etoposide with concurrent radiation for limited-stage small-cell lung carcinoma. J Clin Oncol 18(5):1102–1109 Meert AP, Paesmans M et al (2001) Prophylactic cranial irradiation in small cell lung cancer: a systematic review of the literature with meta-analysis. BMC Cancer 1:5 Monje ML, Mizumatsu S et al (2002) Irradiation induces neural precursor-cell dysfunction. Nat Med 8(9):955–962 Nugent JL, Bunn PA Jr et al (1979) CNS metastases in small cell bronchogenic carcinoma: increasing frequency and

M. C. Stauder and Y. I. Garces changing pattern with lengthening survival. Cancer 44(5): 1885–1893 Ohonoshi T, Ueoka H et al (1993) Comparative study of prophylactic cranial irradiation in patients with small cell lung cancer achieving a complete response: a long-term follow-up result. Lung Cancer 10(1–2):47–54 Shaw E, Su J et al (1994) Prophylactic cranial irradiation in complete responders with small-cell lung cancer: analysis of the mayo clinic and north central cancer treatment group data bases. J Clin Oncol 12(11):2327–2332 Slotman B, Faivre-Finn C et al (2007) Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357(7):664–672 Slotman BJ, Mauer ME et al (2009) Prophylactic cranial irradiation in extensive disease small-cell lung cancer: short-term health-related quality of life and patient reported symptoms—results of an international phase III randomized controlled trial by the eortc radiation oncology and lung cancer groups. J Clin Oncol 27(1):78–84 Sun A, Bae K et al (2011) Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non–small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol 29(3):279– 286 Suwinski MD, PDR, MSSP, Lee MD et al (1998) Dose– response relationship for prophylactic cranial irradiation in small cell lung cancer. Int J Radiat Oncol. Biol Phys 40(4):797–806 Tai P, Tonita J et al (2003) Twenty-year follow-up study of long-term survival of limited-stage small-cell lung cancer and overview of prognostic and treatment factors. Int J Radiat Oncol Biol Phys 56(3):626–633 Turrisi AT, Kim K et al (1999) Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340(4):265–271 Wolfson AH, Bains Y et al (2001) Twice-daily prophylactic cranial irradiation for patients with limited disease small-cell lung cancer with complete response to chemotherapy and consolidative radiotherapy: report of a single institutional phase II trial. Am J Clin Oncol 24(3):290–295

Radiation Therapy for Lung Cancer in Elderly Branislav Jeremic´ and Zˇeljko Dobric´

Contents

Abstract

1

Introduction.............................................................. 523

2 2.1 2.2 2.3

Non-Small-Cell Lung Cancer................................. Early Stage Non-Small-Cell Lung Cancer ............... Locally Advanced Non-Small-Cell Lung Cancer .... Metastatic Non-Small-Cell Lung Cancer .................

3

Small-Cell Lung Cancer ......................................... 533

4

Conclusions ............................................................... 538

Western world is rapidly aging, yet the exact threshold age for differentiating elderly versus non-elderly is not widely adopted. Elderly are also underrepresented in clinical trials and level of evidence of preferred treatment in both non-small-cell and small-cell lung cancer is basically lacking. From the existing evidence, however, it seems that radiation therapy is safe and effective treatment modality in patients with early stage non-small-cell lung cancer. It is so also in locally 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. Similarly, 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 smallcell 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.

525 525 529 532

References.......................................................................... 538

1 B. Jeremic´ (&) Zˇ. Dobric´ Institute of Lung Diseases, Sremska Kamenica, Serbia e-mail: [email protected]

Introduction

Epidemiologic data are clearly showing that the Western world is rapidly ageing. Individuals over the age of 65 years compose the fastest-growing segment


523

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of the population. In the year 1930, 1 out of 15 persons 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 population in the United States, and by the year 2030 they will constitute approximately 25% of all population 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 definition of an elderly person exists. Cut-off age thresholds 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. Jeremic´ and Zˇ. Dobric´

incidence is 69 years in males and 67 years in females. In patients with early/localized disease treatment approaches with curative intention are feasible. However, the widely accepted ‘‘evidence’’ is usually based on studies which are performed with selected patients, the elderly patients being underrepresented in clinical trials. Disturbing observation from daily practice worldwide is that elderly are less likely to be vigorously screened and staged, and frequently less aggressively treated (Nugent et al. 1997; Higton et al. 2010). Importantly, though, when evaluated for the specific 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 comprehensive 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 followup (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 database. 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 comparable 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 approximately 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 chemotherapy. 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 significant 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, Epidemiology, 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 compared 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 radiation 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 observations 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 treatment 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


survival, disease-specific survival or local progression-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, treated 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 survival 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 nonsmall-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 nonelderly, 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 multivariate analysis was done using disease-specific survival 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 similar 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


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 progression 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 incidence 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. Radiographic 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 survival 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

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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-smallcell 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. Analysis 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% Radiation-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 histologically confirmed, unresected Stage I–II non-smallcell 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 intermediate 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 radiation 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

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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-smallcell lung cancer. In a study from The Netherlands (Palma et al. 2010b), the impact of introducing stereotactic 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


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 improvements 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 stereotactic 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 comorbidities 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 compared surgery with continuous hyperfractionated accelerated radiation therapy in elderly with Stage I non-small-cell lung cancer (Ghosh et al.2003). Onehundred 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


recurrence was similar between the groups, while no other endpoints were used in that study (e.g. causespecific 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 survival 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 prognostic nutritional indexes before and after radiation therapy in elderly group patients. Hayakawa et al. (2001) also reported on an inferior survival in subgroup 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) investigated 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

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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 experiencing no complications at 4 years post-treatment. Only grade 2 late esophagitis demonstrated a significant trend to be more frequent in older patients (P = 0.01), but this difference disappeared after adjustment on study (P = 0.32). Gava (1999) reported 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 fractions. 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 treatmentrelated mortality was observed and no clinically significant 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

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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 reconfirmed 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 prospective trials. Elderly patients had the best qualityadjusted survival with radiation therapy alone, which was in sharp contrast to their younger counterparts who benefited mostly from more aggressive, combined radiochemotherapy approaches. The third retrospective 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 unequivocally stand unified against the more intensive treatment 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 chemotherapy followed by either radiation therapy alone or concurrent radiochemotherapy for locally advanced non-small-cell lung cancer. Patients [70 years completed 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 Radiation Therapy Oncology Group 94–10 study by Langer et al. (2001) investigated the influence of age on


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 radiochemotherapy 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 combined radiochemotherapy. In patients [65 years of age, combined radiochemotherapy was found to be superior to radiation therapy alone. This was, however, achieved at the expense of higher incidence of toxicity in the combined-modality group. In a subgroup (age) analysis of the original Hoosier Oncology Group study which showed the failure of use of consolidation chemotherapy in locally advanced nonsmall-cell lung cancer (Hanna et al. 2008, Sgroi et al. 2007) preliminarily reported that elderly had similar median survival time when compared to their nonelderly 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,


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 distant 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 nonelderly 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 lowdose 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 analysis, 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 highgrade toxicity was observed during this study. In an attempt to selectively target tumor cells with cisplatin while decreasing the toxicity concurrent radiochemotherapy 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

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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 survival achieved at no increase in life-threatening toxicity. Most recently, a phase II study (Giorgo et al. 2007) evaluated safety and efficacy of sequential platinumbased chemotherapy followed by concurrent radiochemotherapy 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 statistical significance. Four patients died of treatmentrelated toxicity (three in radiochemotherapy arm), 60% patients had protocol violations, 7% patients had violation 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


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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 identified 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 survival. 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 multimodality ([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

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). Survival 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 associated 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 populationbased cohort study was performed using linked Surveillance, Epidemiology, and End Results-Medicare data to identify 11,084 Medicare beneficiaries aged C65 years who presented with Stage IV non-smallcell 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-morbidities (p \ 0.001). Factors positively associated with the receipt of radiation therapy included income (P = 0.001), hospitalization (P \ 0.001), and treatment 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


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 administered 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 Oncology Group), grade 3 esophageal was observed in nine (19%) patients while only four (9%) patients experienced 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 evaluating the effectiveness of this approach and possible chemotherapy- and/or radiation therapy dose escalation in elderly patients with Stage IV (metastatic) non-small-cell lung cancer.

3


Small-cell lung cancer represents 15–20% all lung cancers cases. Its chemosensitivity and great metastatic potential makes it a good candidate for chemotherapy. However, with chemotherapy alone the outcome of small-cell lung cancer is poor. Although

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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 present with a tumor confined to the hemithorax of origin, the mediastinum or the supraclavicular lymph nodes, designated as having ‘limited disease’ smallcell lung cancer. All other patients present with disseminated, 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 reductions for toxicity may be required. The survival benefit 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) retrospectively 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. Twentyfour (53%) of the 45 patients were treated with combination chemotherapy and/or thoracic radiation

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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. Median survival time and 1-year survival of the treated patients were 13.0 months and 57% for limited disease 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 performance status 2–3 or a moderate degree of comorbidity 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 smallcell 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 radiation 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 demonstrating that prophylactic cranial irradiation improves survival for limited disease small-cell lung cancer patients in complete remission after radiochemotherapy (Auperin et al. 1999), prophylactic cranial irradiation 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


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 chemotherapy in small-cell lung cancer. Findlay et al. (1991) observed significantly more toxicity in the intensively treated group (cyclophosphamide, doxorubicin, vincristin) 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. However, 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 frequent dose emissions/reduced number of chemotherapy 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


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 70: 88

78%; n.s. 82%; n.s.

5 yr.OS: 8%; n.s. 5 yr.OS: 11%; n.s.

Only cardiac grade 3/ 4 toxicity More frequent in patients 70

All LD; CAV/ PE ? TI ? PCI (if CR) age not a prognostic factor in multivariate

Dajczman et al.

1996

\60: LD 45, ED 55 60–60: LD 48, ED 73 70: LD 43, ED 57

49%; n.s. 52%; n.s. 51%; n.s.

2 yr. OS: 45 2 yr. OS: 48 2 yr. OS: 43

Fewer high-grade toxicity and the mean number of toxicities in elderly

N = 123 LD, N = 89 ED; CAV or PE ? TI; No separate analysis for LD ? ED [70: only 23% received optimal treatment (compared to 43%/50% in the younger groups)

Nou

1996

70: 243 [70: 110

All: 72% (n.s.)

5 yr.OS: 5%; n.s. 5 yr.OS: 1,3%; n.s.

No difference between 70 and [70

50% LD 50% ED; (85% of LD and 15% of ED treated with CHT (various) ? TI

Jara et al.

1999

\70: 25 70: 12

46%; n.s. 50%; n.s.

MST: 12.3 mo. MST: 14.9 mo.

No difference between 70 and [70

Only LD evaluated; PE or cPE ? TI

Yuen et al.

2000

\70: 271 70: 50

80%; n.s. 88%; n.s.

5 yr.EFS: 19%; n.s. 5 yr.EFS: 16%; n.s.

Grade 3/4 hematological toxicity higher in the elderly group, all other adverse effects: no difference

All LD, except data for LD (N = 37) ? ED (N = 57)

Ludbrok et al.

2003

\65: 55 65–74: 76 [75: 43

91% 79% 74%

MST: 17 mo. 2 yr OS: 37% MST: 12 mo. 2 yr OS: 22% MST: 7 mo. 2 yr OS: 19% p = 0.003

No difference in the incidence of acute or late grade 3/4 toxicity

Age not significant prognosticator in multivariate analysis since elderly were less frequently treated with RT/CHT, intensive CHT, and PCI

Schild et al.

2005

\70: 209 [70: 54

n.a n.a

2 yr: 48%;5 yr : 22% 2 yr: 33%;5 yr : 17%

Of all non-grade 5 toxicity, only grade 4 pneumonitis more frequent in group [70

Grade 5 toxicity occurred in 6% of those [70 yrs, and in 0.5% of those \ 70 yrs (p = 0.03)

RR response rates; n.s. not significant; LD limited disease; CAV cyclophosphamide, doxorubicine, vincristin; PE cisplatin, etoposide; 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 multivariate 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 performance status of B2 who were randomized to receive once-daily radiation therapy or split-course hyperfractionated 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 performance 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 investigators 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 survivals 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


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 compliance, 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/etoposide 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 (cyclophosphamide/doxorubicin/vincristin and cisplatin/etoposide) 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 survival 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 chemotherapy (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 treatment days using 1.5 Gy b.i.d. fractionation) in 75 patients C70 years with a Karnofsky performance


537

Table 2 Phase II studies of radiation therapy and chemotherapy in elderly and/or frail patients with LD-SCLC AUTHOR (yr)

N

CHT

RT (Gy/fx)

N

Age [ 70 (yrs) (%)

PS [ 2 (%)

Westeel et al. (1998)

25

PAVEx3, PEx1

20/5 30/10 40/5

25

med. 72

28

Murray et al. (1998)

55

CAVx1, PEx1

20/5

55

67

45

72

100

17

16

100

n.a.

30/10 Jeremic et al. (1998a)

72

CBDCA/oral Ex2

45/30 (BID)

Matsui et al. (1998)

16

CBDCA/oral Ex4

45/24

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 smallcell 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 thrombocytopenia 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 chemotherapy 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.

What summary of retrospective and prospective studies also showed is a similar outcome of elderly and non-elderly patients with limited disease smallcell 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 survival was detected between them and their nonelderly 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, standard 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 chemotherapy 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 consideration of cut-off age, histology or stage or whether radiation therapy had been used alone or in combination 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. Biological 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 comprehensive geriatric assessment. Major issue in this field remains the lack of prospective clinical studies investigating ‘‘optimal’’ treatments in this setting. This is especially so, since

accumulated evidence clearly show that ‘‘fit’’ elderly may tolerate the treatments considerably well, regardless 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 dedicated to elderly. In addition, every caution should be undertaken in order not to over emphasize the results of recent studies which are, unfortunately, mostly retrospective. 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 protocol. 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 Jeremic´, Jai Prakash Agarwal, and Sherif Abdel-Wahab

Contents 1

Introduction.............................................................. 543

2

Surgery...................................................................... 545

3

External Beam Radiation Therapy in Locoregional Post-Surgical Recurrences of Non-Small-Cell Lung Cancer ............................ 545

4

External Beam Radiation Therapy in Reirradiation of Locally Recurrent Lung Cancer ....................................................................... 546

5

Radiation Therapy in Reirradiation of Small-Cell Lung Cancer............................................................. 556

6

Endobronchial Brachytherapy in Reirradiation of Locally Recurrent Lung Cancer ....................... 556

Abstract

Recurrence is still a dominating and bitter event after the treatment of lung cancer regardless of histology, stage, or initial treatment. All recurrences can be broadly divided into the local (e.g., lung parenchyma, bronchial stump, or chest wall), regional (e.g., mediastinal lymph nodes), and distant (e.g., brain, liver, or bones). Recurrent disease almost always present as fatal event and only anecdotal reports indicated potential for a treatment to lead to cure. Beside surgery and chemotherapy, radiation therapy has been used in this setting and was shown that it was 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, especially 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 nonsmall-cell lung cancer. These results were obtained at the expense of low toxicity.

References.......................................................................... 557

B. Jeremic´ (&) Institute of Lung Diseases, Institutski Put 4, 21204 Sremska Kamenica, Serbia e-mail: [email protected] B. Jeremic´ Institute of Pulmonary Diseases, Sremska Kamenica, Serbia J. P. Agarwal Department of Radiation Oncolgoy, Tata Memorial Center, Mumbai, India S. Abdel-Wahab Department of Oncology, Ain Shams University, Cairo, Egypt

1

Introduction

Lung cancer remains one of the most prevalent and deadliest malignancies worldwide. It was estimated that in the US in 2009 there were 219.440 new cases


543

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 International Agency for the Research of Cancer (IARC) showed that in 2008 worldwide there was an estimated 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 orchestrated 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 surgery, 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, importantly, 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-smallcell lung cancer patients and almost all with smallcell 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 technological 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. Jeremic´ 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 diagnosis 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 subjects, frequently without investigation of prognostic factors which may have contributed to better understanding 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 curative 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 recurrence, 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 recurrence, 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 survival 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 significantly 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 qualitatively 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 undergoing 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 nonsmall-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 intrathoracically. 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. Radiation 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 observation was that location of recurrence may influence treatment outcome, bronchial stump recurrences faring 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

B. Jeremic´ et al.

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 survival 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 nonsmall-cell lung cancer patients treated with radiation therapy or radiochemotherapy. The study population consisted of 661 consecutive patients with non-smallcell 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 survival (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

for 5-year progression-free survival (p = 0.027). This study have shown that patients with postresection recurrent non-small-cell lung cancer achieved survival comparable to that of newly diagnosed nonsmall-cell lung cancer patients when they were both treated with radiation therapy or radiochemotherapy. These findings also suggested that patients with postresection 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 therapy 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 outcome 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 therapy underwent reirradiation during the natural course


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 utilization rate as well as reirradiation rate in lung cancer. In general, there is both limited data in the available literature, vast majority of it being of retrospective 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) provided 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 thoroughly discussed, but only in two most recent studies (Coon et al. 2008; Chang et al. 2008). Similarly, positron emission tomography-computerized scanning was specified as done for the purpose of staging and evaluation of response (not for treatment planning) 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 reirradiation (as salvage radiation therapy) per se, but combined initial radiation therapy and reirradiation and perhaps compare it with the data obtained in patients

B. Jeremic´ et al.

548 Table 1 Patient and tumor characteristics Author (year)

N

Sex (M/F)

Age range (median)

Initial tumor staging (%)

Green and Melbye (1982)

29

23/6

35–85 (57)

n.s.

Histology (%)

PS at re-RT range (median)

Time interval from 1st to 2nd RT (median)

SCC-66

n.s.

3–40 months (10)

n.s.

5.7–48.5 months (15)

KPS 40–100 (60)

n.s. (12)

n.s.

3–156 months (15)

PS0-1 = 41% PS C 2 = 59% (PS2)

5–87 months (23)

KPS 70–100

6–42 months (13)

ADC-14 LC-14 SCLC-6

Jackson and Ball (1987)

22

Montebello et al. (1993)

30

21/1

45–76 (62)

n.s.

SCC-50 ADC-36 Other-14

18/12

45–83 (62)

I-II-23;

SCC-53;

IIIA-47

ADC-27

IIIB-30

LC-10 Other-10

Gressen et al. (2000)

23

13/10

47–87 (66)

n.s.

SCC-35 ADC-30 LC-9 Other-27

Okamoto et al. (2002)

Wu et al. (2003)

34

23

29/5

21/2

38–85 (69)

43–79 (68)

I-II-9

SCC-50

IIIA-29

ADC-18

IIIB-53

LC-6

IV-9

Other-24

II-30

SCC-40

III-70

ADC-30 SCLC-30


28

27/1

52–83 (68)

n.s.

All NSCLC

6–72 months (17)

Tada et al. (2005)

19

17/2

49–84 (64)

IIIA = 21

SCC-74

PS0-1 = 42%

IIIB = 79

ADC-21

PS2-3 = 58%

5–60 months (16)

LC-5 Poltinnikov et al. (2005)

17

Ebara et al. (2007)

44

10/7

45–79 (66)

n.s.

SCC-35

KPS 60–90 (80)

2–39 months (13)

SCC-43

PS0-1 = 86%

5.8–47.2 months (12.6)

ADC-27

Other = 14%

ADC-59 Other-6 n.s.

49–86 (71)

n.s.

SCLC-20 Other-10 Cetingoz et al. (2009)

38

35/3

33–80 (58)

IIB = 5

SCC-61

IIIA = 10

ADC-13

IIIB = 84

Other-26

n.s.

1–47 months (9)

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


549

Table 2 Treatment characteristics Author

Initial RT dose Gy (median)

Re-RT dose Gy (median)

Cumulative RT dose Gy (median)

RT fields/volume

RT field size cm2 (median)

CHT (%)


40–65 (53)

6–54 (35)

60–166* (82)

Tumor only = 76% Uninvolved mdstnm = 24%

Average, 80

24


50–61 (55)

20–30 (30)

70–90 (85)

Volume encompassing the disease causing symptoms

n.s.

n.s.


28–66 (60)

15–57 (30)

43–122* (88)

Large fields** = 4–25 pts Tumor = 30 pts (85)

(96)

23


25–66 (59)

6–40 (30)

60–101 (86)

Tumor ? 1–2 cm

30–315 (81)

61


30–80 (66)

10–70 (50)

56.5–150 (110)

Radical = tumor only Palliative = affected region

20–238 (65)

47

Wu et al. (2003)

30–78 (66)

46–60 (51)

n.s.

Tumor ? 1.5–2.0 cm

42–210 (104)

100


40–60 (n.s.)

16 (16)

56–76 (n.s.)

‘‘Limited RT’’

n.s.

n.s.

Tada et al. (2005)

50–70 (n.s.)

50–60 (50)

n.s.

‘‘Limited RT’’

30–204 (64)

6

Poltinnikov et al. (2005)

50–66 (52)

4–42 (32)

n.s.

GTV ? 5 mm

95 (30–189)

29

Ebara et al. (2007)

50–70-(60)

30–60 (40)

80–130 (102)

Tumor ? 5–10 mm

n.s.

57

Cetingoz et al. (2009)

29–67 (30)

5–30 (25)

n.s.

Tumor ? 1–2 cm

25–245 (89)

24

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 progressionfree survival after reirradiation, while two studies provided data as median distant metastasis-free survival (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, available 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 toxicity, 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

1 yr = 14% 5 yr = 3%

5 (1–54)

5.4 (n.s)

5 (n.s.)

4.9 (n.s.)

8 (n.s.)

14 (2–37)

5.6 (n.s.)

7.1 (n.s.)

5.5 (2.5–30)

6.5

3 (n.s.)






Wu et al. (2003)


Tada et al. (2005)

Poltinnikov et al. (2005)

Ebara et al. (2007)

Cetingoz et al. (2009)

MST median survival time; OS overall survival; n.s. not stated; G grade

1 yr = 8.7% 2 yr = 5.8%

1 yr = 27.7%

n.s.

1 yr = 26% 2 yr = 11%

1 yr = 18%

1 yr = 59% 2 yr = 21%

1 yr = 43% 2 yr = 27%

1 yr = 13%

n.s.

1 yr = 38% 2 yr = 15%

OS

MST (range) months

Author

Table 3 Treatment outcomes (from reirradiation)

n.s. 77

86

n.s.

n.s.

67

n.s.

n.s.

60

64

50

55

n.s.

n.s.

n.s.

100

n.s.

n.s.

100

89

83

33

Cough (%)

Symptom improvement Hemoptysis (%)

60

n.s.

n.s.

80

n.s.

n.s.

n.s.

80

77

40

n.s.

Chest pain (%)

69

81

65

100

35

n.s.

n.s.

73

53

67

44

Dyspnea (%)

78

n.s.

71

n.s.

75

72

70

50

48

Overall (%)

G3 esophagitis-4

G1-2 esophagitis-77

G3 pneumonitis-7

G2 pneumonitis-7

G1 pneumonitis-6

G2 esophagitis-24

G1 esophagitis-18

G2 esophagitis-16

G3 pneumonitis-5

G2 esophagitis-4

G3 late fibrosis-9

G1-2 pneumonitis-22

G1-2 esophagitis-9

G3 esophagitis-6

G2 esophagitis-12

G3 pneumonitis-21

G2 pneumonitis-35

Grade 5 (fatal)—4

pneumonitis-3

skin-13

Esophagitis-20

Myelopathy-5

Rib fracture-3 pneumonitis-3

Toxicity (%)

550 B. Jeremic´ et al.


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 occurred 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 summarized 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 nonsmall-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), leading 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 survival 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 computerized 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 toxicity. This may be especially important with expected better results, including longer survivals newer technological tools may bring with successful dose escalation 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 duration 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 prescribed reirradiation dose. Overall response rate was 43%. The overall 1-year and 2-year survival rates were 26 and 11%, respectively, and the median survival 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 experiencing 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 palliative intent due to poor prognostic factors such as advanced disease, poor performance status and pronounced 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 nonsmall-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 conventional 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

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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) delivered with concurrent chemotherapy in all cases. The median time interval between completion of the first course of radiation therapy and the start of reirradiation 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 tomographybased 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 radiation 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 tomography scans were performed to aid in delineation of tumor volume. Also, all patients received regularly scheduled follow-up planned computerized tomography or positron emission tomography-computerized tomography imaging. Overall response rate was 75%,


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) retrospectively 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 radiation 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 experienced worsening of dyspnea after stereotactic radiation therapy, with 19% requiring oxygen supplementation; 30% of patients experienced chest wall pain and 8% grade 3 esophagitis. No grade 4 or 5 toxic effects were noted. This study confirmed previous, 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 indicated 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 summarized, 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 reirradiation doses which achieved the median survival time of 4.9–5.6 months, indicating possible doseeffect. 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

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8 months and a 2-year survival was 27%, for the patients treated with curative intent and higher radiation 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 anecdotal event. These data may have suffered from both underreporting and the lack of detailed scoring systems 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 reirradiation 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

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was the only prospective study which have enabled prospective data collection and therefore, better documentation of the events, especially important for late toxicity. Toxicity data also reconfirmed that occasional 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 progression 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 particular, 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 advantageous 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 versus \10 months), did not influence outcome, similarly to the study of Ebara et al. (2007) who could not document it when cut-off value was 13 months. Doseresponse 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

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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, especially 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 nonsmall-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 radiation 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 radiobiological modeling was ever attempted to bring more insight into ‘‘recommended’’ dose(s), these ‘‘observations’’ 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 margins during treatment planning, especially in more recent studies, using sophisticated techniques of treatment planning; they allow highprecision of dose delivery to as conformal volumes as possible as necessary mode of achieving total cumulative doses that surpass known total tolerance doses in cases of primary, treatmentnaive non-small-cell lung cancer (Emami et al. 1991),


(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 sometimes 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 therapy and reirradiation were specified more frequently 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 therapy may be an important issue for better understanding 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. Reirradiation 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 radiation 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 radiation therapy also influenced treatment outcome:

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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 independent 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 oncologists to use higher doses with prolonged time intervals between first radiation therapy and reirradiation. 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. Interestingly, in a large systematic review of palliative thoracic radiation therapy there was more reirradiation 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 therapeutic, 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 necessary tool for reirradiating local recurrence which need radiation therapy with or without concurrent chemotherapy. Taking into account previous radiation therapy characteristics, performance status and time interval between initial radiation therapy and irradiation could be seen as a starting point for discriminating 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 accumulated data from the literature, current wisdom calls for

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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 symptomatic 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 harboring 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

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 satisfactory palliative results. Subsequent studies provided 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 pretreatment 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 clinically, while hemoptysis in 5 (36%) patients recovered. However, the mean period of palliation was disappointingly low, being only 45 days (range, 0–9 months). The period of palliation was significantly longer in patients with high Karnofsky Performance 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,


while 10% of patients showed no response to treatment and 15% had progressive disease. In other studies, objective response measured during bronchoscopy 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 complications have been observed; the most feared being fatal bleeding. Incidence of severe pulmonary bleeding 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 incidence of fatal bleeding, no firm conclusion could be drawn due to different nature of reporting (crude versus actuarial), and due to frequently lacking pretreatment 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 hemoptysis. 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, penumothoraces 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

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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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B. Jeremic´ et al. Jackson MA, Ball DL (1987) Palliative retreatment of locally recurrent lung cancer after radical radiotherapy. Med J Aust 147:391–394 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer Statistics. CA Cancer J Clin 59:225–249 Jereczek-Fossa BA, Kowalczyk A, D’Onofrio A (2008) Threedimensional conformal or stereotactic reirradiation of recurrent, metastatic or new primary tumors. Analysis of 108 patients. Strahlenther Onkol 184:36–40 Jeremic B, Bamberg M (2002) External beam radiation therapy for bronchial stump recurrence of non-small-cell lung cancer after complete resection. Radiother Oncol 64:251–257 Jeremic B, Shibamoto Y, Acimovic LJ, Milisavljevic S (1997) Hyperfractionated radiotherapy alone for clinical stage I nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 38:521–525 Jeremic B, Shibamoto Y, Milicic B, Milisavljevic S, Nikolic N, Dagovic A, Aleksandrovic J, Radosavljevic-Asic G (1999) External beam radiation therapy alone for loco-regional recurrence of non-small-cell lung cancer after complete resection. Lung Cancer 23:135–142 Kagami Y, Nishio M, Narimatsu N, Mjoujin M, Sakurai T, Hareyama M, Saito A (1998) Radiotherapy for locoregional recurrent tumours after resection of non-small cell lung cancer. Lung Cancer 20:31–35 Kelly JF, Delclos ME, Morice RC, Huaringa A, Allen PK, Komaki R (2000) High-dose-rate endobronchial brachytherapy effectively palliates symptoms due to airway tumours: the 10-year M. D. Anderson cancer center experience. Int J Radiat Oncol Biol Phys 48:697–702 Kelly P, Balter PA, Rebueno N, Sharp HJ, Liao Z, Komaki R, Chang JY (2010) Stereotactic body radiation therapy for patients with lung cancer previously treated with thoracic radiation. Int J Radiat Oncol Biol Phys 78:1387–1393 Kelsey CR, Clough RW, Marks LB (2006) Local recurrence following initial resection of NSCLC: salvage is possible with radiation therapy. Cancer J 12:283–288 Kono K, Murakami M, Sasaki R (1998) Radiation therapy for non-small cell lung cancer with postoperative intrathoracic recurrence. Nippon Igaku Hoshasen Gakkai Zasshi 58: 18–24 Kopelson G, Choi NCH (1980) Radiation therapy for postoperative local-regionally recurrent lung cancer. Int J Radiat Oncol Biol Phys 6:1503–1506 Kramer GWPM, Gans S, Ullmann E, van Meerbeck JP, Legrand C, Leer JWH (2004) Hypofractionated external beam radiotherapy as retreatment for symptomatic nonsmall-cell lung carcinoma: an effective treatment? Int J Radiat Oncol Biol Phys 58:1388–1393 Law MR, Henk JM, Lennox SC, Hodson ME (1982) Value of radiotherapy for tumour on the bronchial stump after resection of bronchial carcinoma. Thorax 37:496–499 Lesser T, Brenner A, Bartel M (1997) Das rezidiv beim kurativ operierten nicht-kleinzelligen bronchialkarzinom. Zentralbl Chir 122:642–648 Leung J, Ball D, Worotniuk T, Laidlaw C (1995) Survival following radiotherapy for post-surgical locoregional recurrence of non-small cell lung cancer. Lung Cancer 13: 121–127 Martini N, Melamed MR (1975) Multiple primary lung cancers. J Thorac Cardiovasc Surg 70:606–612

Radiation Therapy for Recurrent Disease Mehta MP, Shahabi S, Jarjour NN, Kinsella TJ (1989) Endobronchial irradiation for malignant airway obstruction. Int J Radiat Oncol Biol Phys 17:847–851 Mendiondo OA, Dillon M, Beach LJ (1983) Endobronchial brachytherapy in the treatment of recurrent bronchogenic carcinoma. Int J Radiat Oncol Biol Phys 9:579–582 Micke O, Prott FJ, Scaaher U (1995) Endoluminal HDR brachytherapy in the palliative treatment of patients with the recurrence of a non-small-cell bronchial carcinoma after prior radiotherapy. Strahlenther Onkol 171:554–559 Montebello JF, Aron BS, Manatunga AK, Horvath JL, Peyton FW (1993) The reirradiation of recurrent bronchogenic carcinoma with external beam irradiation. Am J Clin Oncol 16:482–488 Morita K, Fuwa N, Suzuki Y, Nishio M, Sakai K, Tamaki Y, Niibe H, Chujo M, Wada S, Sugawara T, Kita M (1997) Radical radiotherapy for medically inoperable non-small cell lung cancer in clinical stage I: retrospective analysis of 149 patients. Radiother Oncol 42:31–36 Mountain CF (1986) A new international staging system for lung cancer. Chest 89:225S–233S Naruke T, Goya T, Tsuchiya R, Suemasu K (1988) Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 96:440–447 Neri S, Kitamura J, Komatsu T, Takahashi Y, Tajeshima Y, Kaji R, Hayashi M, Nishimura T, Tomii K, Katakami N, Ishihara K, Kokubo M (2009) Lobectomy for local recurrence following stereotactic radiotherapy to non-small cell lung cancer. Kyobu Geka 62:812–815 Ochs JJ, Tester WJ, Cohen MH, Lichter AS, Ihde DC (1983) Salvage radiation therapy for intrathoracic small cell carcinoma of the lung progressing on combination chemotherapy. Cancer Treat Rep 67:1123–1126 Okamoto Y, Murakami M, Yoden E, Sasaki R, Okuno Y, Nakajima T, Kuroda Y (2002) Reirradiation for locally recurrent lung cancer previously treated with radiation therapy. Int J Radiat Oncol Biol Phys 52:390–396 Ono R, Egawa S, Suemasu K, Sakura M, Kitagawa T (1991) Radiotherapy in inoperable stage I lung cancer. Jpn J Clin Oncol 21:125–128 Ornadel D, Duchesne G, Wall P, NgA HetzelM (1997) Defining the roles of high dose rate endobronchial brachytherapy and laser resection for recurrent bronchial malignancy. Lung Cancer 16:203–213 Pairolero PC, Williams DE, Bergstralh EJ, Piehler JM, Bernatz PE, Payne WS (1984) Postsurgical stage I bronchogenic carcinoma: morbid implications of recurrent disease. Ann Thorac Surg 38:331–336 Poltinnikov IM, Fallon K, Xiao Y, Reiff JE, Curran WJ Jr, WernerWasik M (2005) Combination of longitudinal and circimferential three-dimensional esophageal dose distribution predicts acute esophagitis in hypofractionated reirradiation of patients with non-small-cell lung cancer treated in stereotactic body frame. Int J Radiat Oncol Biol Phys 62:652–658 Regnard JF, Icard P, Magdeleinat P, Jauffret B, Farés E, Levasseur P (1999) Completion pneumonectomy:

559 experience in eighty patients. J Thorac Cardiovasc Surg 117:1095–1101 Salazar OM, Yee GJ, Slawson RG (1991) Radiation therapy for chest recurrence following induction chemotherapy inj small cell lung cancer. Int J Radiat Oncol Biol Phys 21:645–650 Seagren SL, Harrell JH, Horn RA (1985) High dose rate intraluminal irradiation in recurrent endobronchial carcinoma. Chest 88:810–814 Shaw EG, Brindle JS, Creagan ET, Foote RL, Trastek VF, Buskirk SJ (1992) Locally recurrentnon-small-cell lung cancer after complete surgical resection. Mayo Clin Proc 67:1129–1133 Sibley GS, Jamieson TA, Marks LB, Anscher MS, Prosnitz LR (1998) Radiotherapy alone for medically inoperable stage I non-small-cell lung cancer: The Duke experience. Int J Radiat Oncol Biol Phys 40:149–154 Sutedja G, Baris G, Schaake-Koning C, van Zandwijk N (1992) High dose rate brachytherapy in patients with local recurrences after radiotherapy of non-small cell lung cancer. Int J Radiat Oncol Biol Phys 24:551–553 Suzuki T, Horio H, Sakaguchi K, Yamamoto M (2007) Lobectomy for local recurrence of lung cancer after 3-dimensional-conformal radiotherapy. Kyobu Geka 60: 830–833 Tada T, Fukuda H, Matsui K, Hirashima T, Hosono M, Takada Y, Inoue Y (2005) Non-small-cell lung cancer: reirradiation for loco-regional relapse previously treated with radiation therapy. Int J Clin Oncol 10:247–250 Voltolini L, Paladini P, Luzzi L, Ghiribelli C, Di Bisceglie M, Gotti G (2000) Iterative surgical resections for local recurrent and second primary bronchogenic carcinoma. Eur J Cardiothorac Surg 18:529–534 Watanabe Y, Shimizu J, Oda M, Tatsuzawa Y, Hayashi Y, Iwa T (1992) Second surgical intervention for recurrent and second primary bronchogenic cracinoma. Scand J Thorac Cardiovasc Surg 26:73–78 Westeel V, Choma D, Clement F, Woronoff-Lemsi M-C, Pugin J-F, Dubiez A, Depierre A (2000) Relevance of an intensive postoperative follow-up after surgery for non-small cell lung cancer. Ann Thorac Surg 70:1185–1190 Wu K-L, Jiang G-L, Qian H, Wang L-J, Yang H-J, Fu X-L, Zhao S (2003) Three-dimensional conformal radiotherapy for locoregionally recurrent lung carcinoma after external beam irradiation: a prospective phase I-II clinical trial. Int J Radiat Oncol Biol Phys 57:1345–1350 International Agency for Research on Cancer (IARC) (2010). http://globocan.iarc.fr Yano T, Hara N, Ichinose Y, Asoh H, Yokoyama H, Ohta M, Hata K (1994) Local recurrence after complete resection for nonsmall-cell carcinoma of the lung. Significance of local control by radiation treatment. J Thorac Cardiovasc Surg 10:8–12 Zorlu AF, Selek U, Emri S, Gurkayanak M, Akyol FH (2008) Second line palliative endobronchail radiotherapy with HDR Ir 192 in recurrent lung carcinoma. Yonsei Med J 49:620–624

Radiation Therapy for Metastatic Disease Dirk Rades

Contents Bone Metastases ....................................................... Background ................................................................ Radiation Therapy of Bone Metastases.................... Radiation Therapy of Bone Metastases: MetaAnalyses..................................................................... 1.4 Re-irradiation (Re-RT) for Recurrent Bone Pain..... 1.5 Complicated Bone Metastases .................................. 1 1.1 1.2 1.3

Abstract 562 562 562 563 564 564 564 564

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..........................................

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3 3.1 3.2 3.3

Brain Metastases...................................................... Background ................................................................ Radiation Therapy of Multiple Brain Metastases .... Radiation Therapy of 1–3 Brain Metastases ............

566 566 566 568

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 ..................................................................

568 568

565 565

569 570

References.......................................................................... 570

D. Rades (&) Department of Radiation Oncology, University of Lübeck, Lübeck, Germany e-mail: [email protected]

Bone metastases occur in up to 40% of NSCLC patients. If associated with pathological fractures or metastatic spinal cord compression (MSCC), they are considered ‘‘complicated’’ lesions. Otherwise, they are considered ‘‘uncomplicated’’. 1x8 Gy of radiation therapy (RT) can be considered the standard treatment of most uncomplicated painful bone metastases. Single-fraction RT requires re-RT more often than multi-fraction RT regimens. However, re-RT after 1x8 Gy is safe and effective. If re-RT is required after longer-course RT with 10x3 Gy or 20x2 Gy, the second RT course should be delivered using highprecision techniques. For a pathological fracture, surgical stabilisation followed by RT should be performed. Remineralization of the osteolytic bone is better after multi-fraction RT. For MSCC, shortcourse RT is as effective as longer RT programs regarding motor function. Local control of MSCC is better after longer-course RT. Patients with MSCC from NSCLC and a favorable survival prognosis may be considered candidates for decompressive surgery followed by longer-course RT. Decompressive 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


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more favourable prognosis are candidates for longercourse 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 symptoms 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 fractures or metastatic spinal cord compression, they are considered ‘‘complicated’’ lesions. Otherwise, they are considered ‘‘uncomplicated’’. The survival prognosis 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 treatment for uncomplicated painful bone metastases. The treatment volume generally encompasses the

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% (AmouzegarHashemi 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 randomized 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 different. 8 Gy may be considered as probably ‘‘lowest’’ optimal single-fraction RT. Also, several randomized trials compared singlefraction RT of 1 9 8 Gy to a multi-fraction shortcourse regimen such as 5 9 4 or 6 9 4 Gy given in five or six working days. Two large trials are mentioned 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

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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 considerably 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), complete 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).

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

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pathological fracture rates were 3.0 and 1.6%, respectively (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 significantly 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 stabilisation should be performed whenever possible. Because surgery usually does not result in complete removal of

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 osteolytic bone, which appears better after multi-fraction than after single-fraction radiation therapy (Koswig and Budach 1999). Because significant remineralization 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 challenge, in particular when one intends to tailor the treatment to each patient. The most common symptom 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 deficits, the situation can be described as impending MSCC. Dysfunction of bladder or bowel control occurs late and requires surgical intervention whenever 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 intermediate dose of 12–40 mg/day with a taper during or immediately after RT is recommended.


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 considered the most relevant endpoint. Four published prospective studies compared different RT regimens with respect to functional outcome (Rades et al. 2004, 2011; Maranzano et al. 2005, 2009). In 2004, a nonrandomized 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 shortcourse (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 outcome after RT than patients with other primary

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tumors. Besides functional outcome, local control of MSCC is another important endpoint, in particular 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 shortcourse 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 osteolytic bone and better local control of MSCC. The survival prognosis of MSCC patients can be estimated 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 compared with RT are immediate decompression of the spinal cord and direct mechanical stabilization of the spine. Indications for spinal surgery include intraspinal 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). Significantly 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 statistically 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

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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 decompressive 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 irradiated 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 recurrence 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 biologically 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 effective (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 cumulative 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-

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, nausea, motor deficits, and others.

3.2

Radiation Therapy of Multiple Brain Metastases

Patients with multiple brain metastases usually receive whole-brain radiotherapy (WBRT) plus dexamethasone (12–40 mg/day with a taper during or immediately 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 preferable, 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 shortcourse 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


567

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 survival prognosis may be candidates for longer-course

WBRT with lower doses per fraction, as it has been suggested that the risk of radiation induced neurocognitive deficits is lower with doses per fraction of \3Gy (De Angelis et al. 1989). The survival prognosis 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

D. Rades

Radiation Therapy of 1–3 Brain Metastases

Patients with 1–3 brain metastases have a considerably better survival prognosis than patients with C4 lesions and may benefit from a more intensive treatment 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 retrospective 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), respectively. 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)

(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 radiosurgery 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 important 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 subgroup 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 radiosurgery ? 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 significantly (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 radiosurgery ? 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 preferable to surgery ? WBRT for both patients with a single lesion and patients with 1–3 lesions. WBRT should be performed as longer-course WBRT, preferably with doses per fraction of \3 Gy, in order to further reduce the risk of post-treatment neurocognitive 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


569

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. Generally, 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

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%, respectively. 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 different 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 (Kavanagh 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

D. Rades

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 planning 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 peripherally, 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

Abstract

1

Introduction.............................................................. 575

2 2.1 2.2 2.3

Dyspnea ..................................................................... Hypoxia...................................................................... Chronic Obstructive Pulmonary Disease .................. Endobronchial Disease ..............................................

3

Pleural Disease ......................................................... 584

4

Tracheoesophageal Fistula...................................... 587

5

Cough ........................................................................ 587

6

Hemoptysis................................................................ 588

7

Conclusion ................................................................ 589

576 576 576 577

References.......................................................................... 589

M. J. Simoff (&) Bronchoscopy and Interventional Pulmonology, Pulmonary and Critical Care Medicine, Henry Ford Medical Center, Wayne State University School of Medicine, Detroit, MI 48202, USA e-mail: [email protected]

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

1

Introduction

The majority of patients with lung cancer will experience 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 cancer. In this chapter a broader view of palliation will be used. As an example of this, relief of an airway obstruction in a patient with end-stage lung cancer may allow them not to suffocate as their cause of death, versus a patient diagnosed with an airway obstruction, subsequently proven to be cancer. This patient’s airway obstruction is relieved and the patient can breathe better and thereby undergo more


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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 bronchoscopy 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.

2.1

Hypoxia

When a patient is short of breath, it is often an automatic response by patients, nurses and physicians 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 developing 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 breathlessness. It must be remembered by practitioners that oxygen should be prescribed for patients with hypoxia, but if a patient is not hypoxic other etiologies 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, particularly chronic obstructive pulmonary disease (COPD). During therapy for lung cancer, the treatments themselves and/or infections brought on by immunosuppression of the treatments can lead to exacerbations of a patient’s chronic underlying disorder. 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

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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 management 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 benefit 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 endof-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 armamentarium 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

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Fig. 3 Rigid bronchoscope

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 highoxygen 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 techniques 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 bronchoscopy in the late 1960s in Japan and in 1970 in the United States, the flexible bronchoscope has

become the most wide-spread tool for evaluating and diagnosing diseases of the airways and lungs (Fig. 2) (Ikeda 1970, 1995). The rigid bronchoscope, the flexible bronchoscope’s predecessor, was in many regards forgotten as a tool until interventional pulmonology evolved in the 1980s. Interventional 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 pulmonology, 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 pulmonologist, one of which is superior control of the airway. 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


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) described 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 larger 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 bronchoscope is a more difficult instrument to use than a flexible bronchoscope, and the rigid bronchoscope requires additional training beyond the typical fellowship. Rigid bronchoscopy is also most commonly performed in the operating room with general anesthesia, limiting its availability to some pulmonary 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), potassiumtitanyl-phosphate (KTP), and carbon dioxide (CO2). Newer diode as well as the yttrium–aluminum– perovskite (YAP) lasers have also entered the marketplace. 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 bronchoscopes. 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.

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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 endobronchial 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., Cambridge, 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 thermal 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 significant 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.

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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

Fig. 5 Montgomery T-tube

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 possible. 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

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 improvement 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 obstruction. 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 tracheotomy. 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).


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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 placed prior to the initiation of radiotherapy, chemotherapy, or both. Both external beam radiotherapy and brachytherapy can be used with a Dumon stent in place. Another advantage of the Dumon stent is the ease of its removal. This can be important when endobronchial procedures are used early in the management of cancer patients. After definitive therapies have been used (radiation, chemotherapy), re-evaluation of the airway can be performed, at which time the stent can be left in place, removed (if deemed of no further clinical advantage), or replaced with a larger stent that would further improve the caliber and stability of the airway. The disadvantages of the Dumon stent are the potential for migration and the need for a rigid bronchoscope for placement. Migration occurs less often when an experienced interventional endoscopist places the stent (Petrovich et al. 1981; Dumon 1990; Mehta 2008; Diaz-Jimenez et al. 1994; Freitag et al. 1995; Clarke et al. 1994).

Fig. 7 The Hood bronchial stent

Another silastic stent is the hood stent (Hood Laboratories, Decatur, Georgia). The Hood stent is similar to the Dumon stent in design and use. The Hood stent is placed in the same manner as the Dumon stent, using a rigid bronchoscope (Fig. 7) (Gaer et al. 1992). 2.3.3.2 Metallic Stents Metallic stents, such as the ultraflex (Boston Scientific, Boston, MA) and AERO stent (Merit Medical Systems, Inc., South Jordan, Utah) have been used in the endobronchial management of lung cancer. The advantage of metal stents is the relative ease for placement via a flexible bronchoscope with fluoroscopic assistance. This ease of placement has led some bronchoscopists to use these stents as their only method to manage endobronchial disease. Such a

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Fig. 9 The AERO stent

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 conforms 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 endto-end. This added covering can assist interventionalists in limiting tumor from reinvading airways after resection. It has also been demonstrated that the AERO stents complete coverage allows less complicated removal, much like the Dumon stent (Dumon 1990). The uncovered portions of metal stents epithelialize as they remain in the airways, thereby becoming incorporated into the wall of the bronchus. This

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 situations 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 available 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,


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 prevents 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 disease. 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 administered 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

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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 intracellular 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 intubated 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 neoplastic tissue effectively and is an outstanding therapeutic 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 endobronchial treatments, but the time delays and multiple steps of management make it a more cumbersome therapy for the management of late-stage endobronchial 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

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approximately 1 cm in diameter of the probe tip. The vascular thrombosis that occurs with the supercooling 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 coagulation (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 unipolar contact delivery mechanism for electrical energy, uses ionized argon gas as the conductance medium between the electrode and tissue. This noncontact 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 electrocautery 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 distribution 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


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: thoracentesis, closed needle pleural biopsy, and pleuroscopy or medical thoracoscopy. Thoracentesis is the most common technique used in the initial evaluation of pleural effusion. Pleural fluid obtained by thoracentesis yields cytology positive 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 cytology 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 commonly 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 populations. 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 representative 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 performed less than 10% of effusions remain undiagnosed (Boutin et al. 1981; Canto et al. 1977; Loddenkemper 1981; Martensson et al. 1985), while after thoracentesis for cytology and closed-needle

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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 spontaneously breathing, and three incisions will be made rather than the typical one (two for certain procedures). 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 loculated, 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 experienced by a patient is considered to be due to the

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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 subpopulation to minimize reducing the pleural pressure rapidly and increasing the risk of re-expansion pulmonary 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 physiologic manner. The use of this technique may minimize 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 monitoring may be a more objective assessment for trapped lung than chest radiograph assessment but is complex and not regularly practiced. Therapeutic modalities for managing malignant pleural effusions include repeated therapeutic thoracentesis, 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 videoassisted thoracic surgery, with talc poudrage. Poudrage and slurry pleurodesis methods demonstrated clinical success rates of 91% with no significant 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 developing 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 commonly 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 tetracycline, 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 evaluated 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


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 experience due to this complication. When used daily, one study (Putnam et al. 1999) suggests that approximately 50% of these patients will experience pleurodesis 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 persistent 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 management 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

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of the lung, and ensure the patient receives nutrition and fluid. By addressing all of these issues, the most debilitating 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 technique. With limited published information, our clinical 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 etiology of the cough should be identified to best treat a patient. Cough can be a manifestation of endobronchial disease, pleural disease, or tracheoesophageal fistula as discussed above. Cough can also originate from something as uncommon as endobronchial irritation status-post resection, when the staples migrate endobronchially and become foreign bodies in the airways. Or cough may be a manifestation of something 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).

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M. J. Simoff

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 commonly 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 bronchogenic 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 management of cardiovascular/hemodynamic status has to take place for proper management of the patient with

hemoptysis (Cahill and Ingbar 1994; Jean-Baptiste 2000). Reversal of any coagulation disorders should to be considered at the time of hemodynamic management. If the bleeding site is known, the bleeding lung should be placed in the dependent position to help protect the non-bleeding lung. Cough suppression 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 undiagnosed 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 management 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


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 visualized 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 identified, attempts with vasoactive drugs can be used, but often this type of bleeding requires a more aggressive mode of management. Use of Nd:YAG photocoagulation 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 followup 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 surgical 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

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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 lifethreatening 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 mainstem bronchus with massive persistent bleeding. After stabilizing the patient, we had the entire right pulmonary artery embolized, through a complex procedure. 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 cancer that can be palliated to allow patients the opportunity 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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592 Loddenkemper R, Grosser H, Gabler A (1983) Prospective evaluation of biopsy methods in the diagnosis of malignant pleural effusions: intrapatient comparison between pleural fluid cytology, blind needle biopsy and thoracoscopy. Am Rev Respir Dis 127(suppl 4):114 Luomanen RKJ, Watson WL (1968) Autopsy findings. In: Watson WL (ed) Lung cancer: a study of five thousand memorial hospital cases. St Louis, MO: CV Mosby Co, pp 504–510 Macha HN, Becker KO, Kemmer HP (1994) Pattern of failure and survival in endobronchial laser resection: a matched pair study. Chest 105:1668–1672 Magee G, Williams MH Jr (1982) Treatment of massive hemoptysis with intravenous Pitressin. Lung 160:165–169 Maiwand MO, Homasson JP (1995) Cryotherapy for tracheobronchial disorders. Clin Chest Med 16:427–443 Mal H, Rullon I, Mellot F (1999) Immediate, long-term results of bronchial artery embolization for life-threatening hemoptysis. Chest 115:996 Martensson G, Pettersson K, Thiringer G (1985) Differentiation between malignant, non-malignant pleural effusion. Eur J Respir Dis 67:326 Martinez-Moragon E, Aparicio J, Rogado MC (1997) Pleurodesis in malignant pleural effusions: a randomized study of tetracycline versus bleomycin. Eur Respir J 10:2380 Mathisen DJ, Grillo HC (1989) Endoscopic relief of malignant airway obstruction. Ann Thorac Surg 48:469–475. A fiveyear experience with 1,396 applications in 1,000 patients McDougall JC, Corese DA (1983) Neodymium-YAG laser therapy of malignant airway obstruction: a preliminary report. Mayo Clin Proc 58:35–39 McGuiness G, Beacher JR, Harkin TJ (1994) Hemoptysis: prospective high-resolution CT/bronchoscopic correlation. Chest 105:1155 Mehta AC (2008) AERO self expanding hybrid stent for airway stenosis. Expert Rev Med Devices 5:553–557 Mehta AC, Golish JA, Ahmad M (1985) Palliative treatment of malignant airway obstruction by Nd-YAG laser. Cleve Clin Q 52:513–524 Menzies R, Charbonneau M (1991) Thoacoscopy for the diagnosis of pleural disease. Ann Intern Med 114:271 Milanez Campos JR, Werebe EC, Vargas FS (1997) Respiratory failure due to talc. Lancet 349:251–252 Miller RR, McGregor DH (1980) Hemorrhage from carcinoma of the lung. Cancer 46:200 Moffett MJ, Ruckdeschel JC (1992) Bleomycin, tetracycline in malignant pleural effusions: a review. Semin Oncol 19:59 Moghissi K, Dixon K, Stringer M (1999) The place of bronchoscopic photodynamic therapy in advanced unresectable lung cancer: experience of 100 cases. Eur J Cardiothroac Surg 15:1–6 Montgomery WW (1965) T-tube tracheal stent. Arch Otolaryngol 82:320–321 Morice RC, Ece T, Ece F, Keus L (2001) Endobronchial argon plasma coagulation for treatment of hemoptysis and neoplastic airway obstruction. Chest 119:781–787 Muller NL (1994) Hemoptysis: High-resolution CT vs bronchoscopy. Chest 105:982 Oldenburg FA Jr, Newhouse MT (1979) Thoracoscopy: a safe accurate diagnostic procedure using the rigid thoracoscope, local anesthesia. Chest 75:45

M. J. Simoff Osaki S, Nakanishi Y, Wataya H (2000) Prognosis of bronchial artery embolization in the management of hemoptysis. Respiration 67:412 Patz EF, McAdams HP, Erasmus JJ (1998) Sclerotherapy for malignant pleural effusions: a prospective randomized trial of bleomycin vs doxycycline with small-bore catheter drainage. Chest 113:1305 Petrou M, Kaplan D, Goldstraw P (1995) The management of recurrent malignant pleural effusions: the complementary role of talc pleurodesis, pleuro-peritoneal shunting. Cancer 75:801 Petrovich Z, Stanley K, Cox JD (1981) Radiotherapy in the management of locally advanced lung cancer of all cell types: final report of randomized trial. Cancer 48: 1335–1340 Pien GW, Gant MJ, Washam CL, Sterman DH (2001) Use of an implantable pleural catheter for trapped lung syndrome in patients with malignant pleural effusion. Chest 119:1641–1646 Poe RH, Israel RH, Utell MJ (1984) Sensitivity, specificity, predictive values of closed pleural biopsy. Arch Intern Med 144:325 Pollak JS, Burdge CM, Rosenblatt M, Houston JP, Hwu WJ, Murren J (2001) Treatmet of malignant pleural effusion with tunneled long-term drainage catheters. J Vasc Interv Radiol 12:201–208 Ponn RB, Blancaflor J, D’Agostino RS, Kiernan ME, Toole AL, Stern H (1991) Pleuroperitoneal shunting for intractable pleural effusions. Ann Thor Surg 51:605–609 Pope AR, Joseph JH (1989) Pleuroperitoneal shunt for pneumonectomy cavity malignant effusion. Chest 96:686–688 Prakash UBS, Reiman HM (1985) Comparison of needle biopsy with cytologic analysis for the evaluation of pleural effusions: analysis of 414 cases. Mayo Clin Proc 60:158 Prakash UB, Stubbs SE (1991) The bronchoscopy survey: some reflections. Chest 100:1660–1667 Pulsiripunya C, Youngchaiyud P, Pushpakom R (1996) The efficacy of doxycycline as a pleural sclerosing agent in malignant pleural effusion: a prospective study. Respirology 1:69 Putnam JB, Light RW, Rodriquez RM (1999) Randomized comparison of indwelling pleural catheter with doxycycline pleurodesis in the management of malignant pleural effusion. Cancer 86:1992–1999 Rehse DH, Aye RW, Florence MG (1996) Respiratory failure following talc pleurodesis. Am J Surg 162:2023–2026 Reich H, Beattie EJ, Harvey JC (1993) Pleuroperitoneal shunt for malignant pleural effusions: a one-year experience. Semin Surg Onc 9:160–162 Rodriguez-Panadero F, Lopez-Mejias L (1989) Low glucose, pH levels in malignant effusions; diagnostic significance, prognostic value in respect to pleurodesis. Am Rev Respir Dis 139:663 Ross DJ, Mohsenifar Z, Koerner SK (1990) Survival characteristics after Neodymium:YAG laser photoresection in advanced stage lung cancer. Chest 98:581–585 Sahebjami H (1976) Iced saline lavage during bronchoscopy. Chest 69:131 Schlehe H, Fritsche HM, Daum S (1984) A new method for treatment of bronchial and lung bleeding. In: Nakhosteen JA, Maassen W (eds) Bronchology: Research, Diagnostic, and Therapeutic Aspects. Springer 1981, Nijhoff, Haag, p 111

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Hematological Toxicity in Lung Cancer Francesc Casas, Ferran Ferrer, and Nu´ria Vinõlas

Contents 1

Introduction.............................................................. 598

2

Toxicity in Chemotherapy ...................................... 598

3

Toxicity in Radiotherapy ........................................ 600

4

Hematologic Toxicity After Combined Chemo and Radiotherapy .................................................... 600

5

Preventive or Support Treatment of Hematologic Toxicity in Lung Cancer......................................... 603

References.......................................................................... 606

F. Casas (&) Radiation Oncology Department, Hospital Clínic i Universitari, Villarroel 170, 08036 Barcelona, Spain e-mail: [email protected] F. Ferrer Radiation Oncology Department, Institut Català d’Oncologia, Gran Via de les Corts Catalanes, Bellvitge, Spain N. Viñolas Medical Oncology Department, Hospital Clínic i Universitari, Villarroel 170, 08036 Barcelona, Spain

Abstract

The toxicity of tumor cells after chemo and radiotherapy, administered either alone or in combination is dose-dependent. Aggression to the bone marrow, which is expressed by a reduction in circulating blood cells, is often the main doselimiting toxicity because of the risks of anemia, bleeding, and infection. Prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs) is available to reduce the risk of 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 recommendations concerning the treatment of anemia with r-Hu-EPO. For patients with chemotherapyassociated anemia the Committee continues to recommend the implementation of an erythropoiesis-stimulating agent (ESA) when hemoglobin (Hb) values approach or fall below 10 g/dL, to increase Hb values and decrease transfusions. An individual patient data-analysis has shown that ESA increase the mortality in all patients with cancer, and a similar increase might exist in patients on chemotherapy. Finally, only a few trials have examined indications for ESA similar to the indications approved by the Food and Drug Administration.


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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 treatments and the management of these secondary effects are proposed. The toxicity of tumor cells after chemo and radiotherapy, administered either alone or in combination is dose-dependent. Aggression to the bone marrow, which is expressed by a reduction in circulating blood cells, is often the main dose-limiting toxicity because of the risks of anemia, bleeding, and infection. Strategies aimed at protecting the hematopoietic 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 erythrocytes, 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 differentiation have been identified. The hematopoietic progenitor cells and their daughter cells are enveloped in a stroma of endothelial cells, adventitial cells, fibroblasts, macrophages, and fat cells in the sinus of the bone marrow. This microscopic medium physically supports and directs the development of the replication 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

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. Peripheral determination of the blood cells fails to demonstrate 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 chemotherapy (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 produces 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 administration. For most of the compounds, neutropenia and thrombocytopenia are reversible and not accumulative. 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 erythropoietin 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 potentially 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 setting 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 Supportive 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 administering 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). Consideration 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 anticancerous drugs. Thus, one of the general principles 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 paclitaxel–carboplatin: paclitaxel decreases the platelet toxicity of carboplatin in relation to a non pharmacokinetic mechanism (Calvert et al. 1999). The most frequent schedules of CH currently used in NSCLC include combinations of cisplatin or carboplatin 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 toxicity, 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 percentage of thrombocytopenia (Cardenal et al. 1999). Patients with carboplatin-based chemotherapy are more likely to experience thrombocytopenia (Luo et al. 2010).

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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 paclitaxel. Platelet toxicity is not of note in schemes including paclitaxel combined with carboplatin suggesting 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 hematologic 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 compensatory mechanisms are mainly relevant for the knowledge of long-term effects, some effects are acute. Thus, when volumes limited to the bone marrow 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 compensatory 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 communication 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 production 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 radiotherapy treatment in lung cancer. Nonetheless, this

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 myelotoxicity 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 populations of hematopoietic cells determines the temporary 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 sensitivity 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 treatment an increase was observed in both hematopoietic toxicity and in the circulating number of progenitor cells suggesting that the toxicity of concurrent treatment 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 irradiation 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.


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Table 1 Hematologic toxicity in randomised concurrent hyperfractionated arms on SCLC Leukopenia Grade Jeremic et al. (1995, 1997) Turrisi et al. (1999) Takada et al. (2002)

Trombocytopenia %

Grade

Anemia %

Grade

%

3

21

3

25

3

11

4

11

4

13

4

2

3

38

3

13

3

23

4

44

4

8

4

5

3

51

3

23

3

54

4

38

4

5

4

–

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 hyperfractionation vs. standard fractionation) in patients with SCLC condition changes in hematological toxicity. 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 hyperfractionated 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 fractionated 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

Concurrent ONce daily vErsus twice daily RadioTherapy (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 randomized studies in NSCLC were performed evaluating 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 cyclophosphamide. 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 neutropenic infection was more prevalent in the patients receiving CH with double the number of admissions due to severe infections versus the patients administered 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

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F. Casas et al.

Table 2 Hematologic toxicity in randomised trials on NSCLC Hematologic toxic effect

RT group (%)

CH ? RT group (monthly CH) (%)

CH ? RT group (daily CH) (%)

Le Chevalier et al. (1991) (sequential)

Grade 2–5

1.4

4.2

–

Trovo et al. (1992) (concurrent)

Hemoglobin (grade 1–2)

1.7

–

2.3

Leukopenia

1.1

–

1.7

Leukopenia (grade 3–4)

3.3

6.6 (weekly CH)

14.5

Trombopenia (grade 3–4)

0.6

0.9 (weekly CH)

1.8

Neutropenia

3

7

–

Schaake-Konig et al. (1992) (concurrent)

Dillman et al. (1990) (sequential)

to receive 56 Gy administered by split-course or the same radiotherapy plus 30 mg/m2 of cisplatin administered 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 administration with weekly cisplatin compared to radiotherapy 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 irradiation 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 administered 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

greater than sequential. This was corroborated by Furuse 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 concurrent treatment arm. A second similar trial published involved concurrent 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 Leukemia 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


603

Table 3 Hematologic toxicity in randomised trials studying the role of induction CH in concurrent CH-RT on NSCLC

Huber et al. (2006) (weekly CH-RT vs. RT alone after induction CH)

Vokes et al. (2007) (inmediate CH-RT vs. induction CH-RT)

Hematologic toxic effect

Induction group (%)

RT group (%)

CH ? RT group (%)

Leukopenia (grade 3–4)

3.8

0

0

Anemia (grade 3–4)

–

0

0

Inmediate CH-RT

After induction

Granulocytopenia Grade 3

18

11

24

Grade 4

20

4

7

Grade 3

1

5

12

Grade 4

0

0

0

Anemia

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 gemcitabine. With this background the CALGB made a phase III trial on immediate concurrent radioCH with carboplatin 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 placlitaxel 200 mg/m2 administered every 21 days followed 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 febrile 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 evidence 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 radiotherapy dose and fractionation, specifically after survival improving metaanalysis with accelerated radiotherapy (Saunders et al. 2010) based on pulmonary function, tumor volumes, and newer radiotherapy 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 published 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 longterm 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 intrathoracic 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 cancer 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 versus 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 doseintensity 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 surgery 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 hematological 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 inappropriate 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


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 epoeitinalfa (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 Karnofsky 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 concurrent 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 hematologic 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 glutation 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 randomized 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 radiotherapy 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 radiotherapy 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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608 Oncology/American Society of Hematology Clinical Practice Guideline Update. J Clin Oncol 26:132–149 Sandler A, Gray R, Perry MC et al (2006) Placlitaxel– carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550 Saunders MI, Mauguen A, Le Pechoux C, Schild S, Turrisi et al (2010) Meta-analysis of modified fractionation radiotherapy in lung cancer on 9 randomized trials. In: Proceedings ESTRO 29 Barcelona, p 29 Sause WT, Scott C, Taylor S et al (1995) Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresected non-small cell lung cancer. J Natl Cancer Inst 87:198–205 Schaake-Koning C, van der Bogaert W, Dalesio O et al (1992) Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 326:524–530 Schiller JH, Harrington D, Belani CP et al (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Eng J Med 346:92–98 Schmidinger M, Budinsky AC, Wenzel C, Piribauer M et al (2000) Glutathione in the prevention of cisplatin induced toxicities. A prospectively randomized pilot trial in patients with head and neck cancers and non small cell lung cancer. Wien Klin Wochenschr 28:617–623 Takada M, Fukuoka M, Kawahara M et al (2002) S. Phase III Study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limitedstage small-cell lung cancer: results of the Japan Clinical Oncology Group study 9104. J Clin Oncol 20:3054–3060 Timmer-Bonte JN, de Boo TM, Smith HJ et al (2005) Prevention of chemotherapy-induced febrile neutropenia by prophylactic antibiotics plus or minus granulocyte colony-stimulating factor in small-cell lung cancer: a Dutch randomized phase III study. J Clin Oncol 23:7994–84 Trovo MG, Minatel E, Franchin G, Boccieri MG et al (1992) Radiotherapy versus radiotherapy enhanced by cisplatin in stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys 254:11–15

F. Casas et al. Tubiana M, Frindel E, Croizat H (1979) Effects of radiation on bone marrow. Pathol Biol 27:326–334 Turrisi AT, Kim K, Blum R et al (1999) Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:265–271 Vadhan-Raj S (2005) Thrombopoietic growth factors and cytokines. Curr Hematol Rep 4:137–144 Van de Wetering MD, de Witte MA, Kremer LC et al (2005) Efficacy of oral prophylactic antibiotics in neutropenic afebrile oncology patients: a systematic review of randomised controlled trials. Eur J Cancer 41:1372–1382 Vokes EE, Herdon JE, Kelley MJ, Cichetti MG et al (2007) Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III NSCLC: Cancer and leucemia Group B. J Clin Oncol 13:1698–1704 Vokes EE, Rendón JE, Crawford J, Leopold KA, Perry MC et al (2002) Randomized phase II study of cisplatin with gemcitabine or placlitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: cancer and leukemia group B study 9431. J Clin Oncol 20: 4191–4198 Winton T, Livingston R, Johnson D, Rigas J et al (2005) Vinorelbine plus cisplatin vs. observation in resected nonsmall-cell lung cancer. N Eng J Med 352:2589–2597 Woll PJ, Hodgetts J, Lomax L et al (1995) Can cytotoxic doseintensity be increased by using granulocyte colony-stimulating factor? A randomized controlled trial of lenograstrim in small-cell lung cancer. J Clin Oncol 13:652–659 Wright JR, Ung YC, Julian JA et al (2007) Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 25:1027–1032 Zatloukal P, Petruzelka L, Zemanova M, Havel L, Janku F, Judas L et al (2004) Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 46:87–98

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 Pulmonary Effects of Thoracic Radiation Therapy..................................................................... 609 1.1 Clinical RT-Induced Lung Toxicity ......................... 609

4

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

5

Cardiotoxic Effects of Thoracic Radiation Therapy..................................................................... 617

1

2

Biology of Radiation-Induced Lung Injury.......... 612

3

Predictors of RT-Induced Lung Injury ................ 614

References.......................................................................... 620

Abstract

For many patients with lung cancer, thoracic radiation therapy (TRT) is an integral part of their treatment. The effect of TRT on normal structures is an important consideration when optimizing treatment plans for patients. This chapter will review radiation therapy (RT)-induced lung and heart injury including both the clinical and biological mechanisms for these toxicities. It will also analyze the variety of predictors of RT-induced lung and heart damage as well as methods to prevent and treat these toxicities.

L. Xie L. Marks (&) Department of Radiation Oncology, University of North Carolina, Campus Box 7512, 101 Manning Drive, Chapel Hill, NC 27514, USA e-mail: [email protected] L. Xie X. Yu Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 200032 Shanghai, China Z. Vujaskovic Radiation Oncology and Pathology, Department of Radiation Oncology, Duke University Medical Center, Box 3455, Durham, NC 27710, USA M. S. Anscher Department of Radiation Oncology, Virginia Commonwealth University School of Medicine, 401 College Street, PO Box 980058, Richmond, VA 23298-0058, USA T. D. Shafman Landmark Medical Centre, 115 Cass Ave, Woonsocket, RI 02895, USA K. Miller 21st Century Oncology, Fort Myers, FL, USA R. Prosnitz Department of Radiation Oncology, University of Pennsylvania School of Medicine, 2 Donner Building, 3400 Spruce Street, Philadelphia, PA 19104, USA

1

Pulmonary Effects of Thoracic Radiation Therapy

1.1

Clinical RT-Induced Lung Toxicity

1.1.1 Introduction Radiation-induced lung toxicity is a common occurrence in patients treated with curative intent for lung cancer. Approximately 5–20% of patients treated with RT for lung cancer have been reported to develop RT-induced lung injury (Favaretto et al. 1996; Segawa et al. 1997; Fu et al. 1997; Monson et al. 1998; Yamada et al. 1998; Nyman et al. 1998;


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Table 1 Incidence of RT-induced clinical and radiologic lung injury Reference (No)

Number of patients

Symptom rate (%) Grade 1

Grade 2

Grade 3

Grade 4

Favaretto et al. (1996)

39

Segawa et al. (1997)

89

38a

5.6

8.9

5.6

Fu et al. (1997)

60

–

17a

8

–

Monson et al. (1998)

83

8

Yamada et al. (1998)

60

–

13.3a

Nyman et al. (1998)

90

–


23

–

Makimoto et al. (1999)

111

Graham et al. (1999)

99

–

Robnett et al. (2000)

144

–

–

Sunyach et al. (2000)

54

–

29 (Lent-Soma scale)

Inoue et al. (2001)

191

36a

Hernando et al. (2001)

201

–

Oetzel et al. (1995)

46

Perry et al. (1987)

391

Gross (1977)

_

Simpson et al. (1985)

316

Kwon et al. (2000)

47

Incidence of radiologic changes (%)

13

64–90

2

58

– 23

7

34

C4

11.6

3.4

85

C6

–

8a

–

22 (minimum)

–

11a

–

[24 \6

15 14–20a

24 (median)

8.3a

11.5 (median) 37

13 13

4

C6 [3

7

17.3 (median)

5–15

65

3 8.5a

C6 C12

–

20

–

Follow-up duration (months)

_ 36

–

–

2–33

Perez et al. (1980)

365

4

60

Martel et al. (1994)

42

21.4

[7

Tucker et al. (2010)

442

a b

14.9a

4.5

22.2

2.5

–

22.6b

21

0.5

C6

RTOG criteria 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 hospitalization, 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 pulmonary 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. Treatment 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 following TRT, and also among patients who do not have symptoms of RT-induced lung injury. The frequency 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 sensitive 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 structures 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 RTinduced 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 conducting airways, and transfer of gases through the alveolar surfaces. Spirometry assesses the rate of gas movement 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 (fibrosis) 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 measurements 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 RTinduced 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.


613

Table 2 Percent reduction in pulmonary function parameters after thoracic radiation therapy Reference (No)

FEV1

DLCO

Sunyach et al. (2000)

+0.1

4.3

Marks et al. (1993)

FVC

TLC

VC

6.5

27

16


10

25

15

Mattson et al. (1987)

18

28

Choi and Kanarek (1994)

11

Rubenstein et al. (1988) Brady et al. (1965)

22

10

5.5

+6

20

14 8

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 degradation 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 eventually impairment of gas exchange. Radiation causes the early release of surfactant by type II pneumocytes and this results in alterations in alveolar surface tension 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 pleomorphic, 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 macrophage 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

11.5

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 activation 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 fibrosis. 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 anhydrase9. 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)].

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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 distribution. 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 symptomatic 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

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 healthy 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 utilized 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


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 incidence 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 associated 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, cyclophosphamide, 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

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with more modern agents (e.g. docetaxel and gemcitabine) 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 hypoperfusion had improvements in DLCO following radiation, 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 smoking 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 ventilation or perfusion differences (Theuws et al. 1998). A multivariate analysis evaluated SPECT-generated

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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 pharmacological 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 different 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 dosimetric variations, pharmacologic agents, and altering dose using patient-specific biological information. There have been several randomized trials of the cytoprotector amifostine (WR-2721) in patients receiving 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 pneumoprotective 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

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 chemotherapy 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 concurrent 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 amifostine. 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


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 functional 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. Perfusion-weighted optimization using perfusion dosefunctional 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 incidental 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 timing 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 treatment 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 longstanding 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

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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-tissue 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 targeted. 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

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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 concurrent 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 radiationinduced 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 associations also exist for a wide range of clinical syndromes 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 syndromes 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 radiotherapy 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; Pohjola-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-mastectomy 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 techniques 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 cardiac 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 toxicity may result. Modern techniques typically incorporate 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 following radiation for breast cancer is related to the


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. Nonlethal 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 medulloblastoma (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), echocardiogram (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. Conversely, 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

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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 metaanalysis, 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 controls. Five percent of the irradiated patients died of cardiac disease; non-lethal morbidity was not addressed (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 longterm survivors of lung cancer. The concern for RT-induced cardiotoxicity is heightened by the widespread use of potentially cardiotoxic systemic therapy and the high prevalence of cardiac risk factors in the lung cancer patient population. 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 cholesterol/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 inferiorlung may be a barometer for incidental cardiac irradiation, 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

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competing morbidity/mortality. The possibility of RT-associated cardiac dysfunction should be considered 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.

References

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 during 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 setting, one is often able to shadow the primary tumor with the nodal disease and therefore the beam aperture 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

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Spinal Cord Toxicity Timothy E. Schultheiss

Contents

Abstract

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 ............................................................... 6.1 Differential Sensitivity—Cervical Versus Thoracic......................................................... 6.2 Fractionation .............................................................. 6.3 Experimental Studies................................................. 6.4 Dose Gradients ..........................................................

630 630 631 631 632

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: [email protected]

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 complication 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 myelopathy. Fortunately, the morbidity of thoracic radiation 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 complication 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


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fractions per day) sometimes resulted in an unexpectedly high incidence of radiation myelopathy because of unexpected changes in the dose distribution 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 idiosyncratic 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 radiation 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, hyperreflexia. 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 diseases 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.

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 myelopathy 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 condition 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 conditions 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 conduction 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 pathognomonic 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

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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, thrombosis, 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 macrophages 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 identification 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 irradiated 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 astrocytes. Up-regulation of VEGF is associated with increased vascular permeability, edema, and hypoxia in the CNS.

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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 progenitor 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 different 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 (Blakemore 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.

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 endothelium 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

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 accepted 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 therapeutic 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

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 administration 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 undergoing brain irradiation. These were compared to rats

Dose Limits

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


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 thoracic 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 circumstances 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 myelopathy have been collected and published elsewhere (Schultheiss et al. 1995). Generally, the dose schedules in which more than one occurrence of radiation myelopathy has been seen have employed doses per fraction larger than 2 Gy. This is especially 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 nonhuman 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

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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 incidence is so low that the responses are statistically indistinguishable at this time. Generally a lower tolerance 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 dependence 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 calculated 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

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used in hyperbaric oxygen treatments, and hypofractionation with insufficient spinal cord shielding. The initial experimental work on radiation myelopathy 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 chondrosarcomas 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 myelopathy 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

volumes of spinal cord, inhomogeneously irradiated. The latency for these cases is consistent with conventional 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 following 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 treatments. 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 treatments are nearly concurrent or the chemotherapy neurotoxic on its own. Although recommended dose limits apply in the absence of chemotherapy treatments and chemotherapy may reduce the radiation tolerance, 45 Gy in conventional fraction sizes should still be well tolerated.


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 therapy. Reasoning that upregulation of VEGF may contribute 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 bevacizumab 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.

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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 symptoms and two showed only MRI progression. Five of the placebo patients crossed over to receive bevacizumab 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 consistently 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 elucidated, we may reasonably expect progress in the treatment and prevention of radiation myelopathy.

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Spinal Cord Toxicity Morris GM, Coderre JA, Hopewell JW, Micca PL, Nawrocky MM, Liu HB, Bywaters A (1994a) Response of the central nervous system to boron neutron capture irradiation: evaluation using rat spinal cord model. Radiother Oncol 32:249–255 Morris GM, Coderre JA, Whitehouse EM, Micca P, Hopewell JW (1994b) Boron neutron capture therapy: a guide to the understanding of the pathogenesis of late radiation damage to the rat spinal cord. Int J Radiat Oncol Biol Phys 28: 1107–1112 Morris GM, Coderre JA, Bywaters A, Whitehouse E, Hopewell JW (1996) Boron neutron capture irradiation of the rat spinal cord: histopathological evidence of a vascularmediated pathogenesis. Radiat Res 146:313–320 Morris GM, Coderre JA, Hopewell JW, Rezvani M, Micca PL, Fisher CD (1997a) Response of the central nervous system to fractionated boron neutron capture irradiation: studies with borocaptate sodium. Int J Radiat Biol 71:185–192 Morris GM, Coderre JA, Micca PL, Fisher CD, Capala J, Hopewell JW (1997b) Central nervous system tolerance to boron neutron capture therapy with p-boronophenylalanine. Br J Cancer 76:1623–1629 Morris GM, Coderre JA, Hopewell JW, Micca PL, Wielopolski L (1998) Boron neutron capture therapy: re-irradiation response of the rat spinal cord. Radiother Oncol 48:313–317 Myers R, Rogers MA, Hornsey S (1986) A reappraisal of the roles of glial and vascular elements in the development of white matter necrosis in irradiated rat spinal cord. Br J Cancer-Supple 7:221–223 Nieder C, Price RE, Rivera B, Andratschke N, Ang KK (2005) Effects of insulin-like growth factor-1 (IGF-1) and amifostine in spinal cord reirradiation. Strahlenther Oncol 181:691–695 Nordal RA, Wong CS (2005) Molecular targets in radiationinduced blood-brain barrier disruption. Int J Radiat Oncol Biol Phys 62:279–287 Nordal RA, Nagy A, Pintilie M, Wong CS (2004) Hypoxia and hypoxia-inducible factor-1 target genes in central nervous system radiation injury: a role for vascular endothelial growth factor. Clin Cancer Res 10:3342–3353 Otsuka S, Coderre JA, Micca PL, Morris GM, Hopewell JW, Rola R, Fike JR (2006) Depletion of neural precursor cells after local brain irradiation is due to radiation dose to the parenchyma, not the vasculature. Radiat Res 165:582–591 Philippo H, Huiskamp R, Winter AM, Gharbaran B, van der Kogel AJ (2000) Age dependence of the radiosensitivity of glial progenitors for In vivo fission-neutron and X irradiation. Radiat Res 154:44–53 Philippo H, Winter EA, van der Kogel AJ, Huiskamp R (2005) Recovery capacity of glial progenitors after in vivo fissionneutron or X irradiation: age dependence, fractionation and low-dose-rate irradiations. Radiat Res 163:636–643 Ruifrok AC, Stephens LC, van der Kogel AJ (1994) Radiation response of the rat cervical spinal cord after irradiation at different ages: tolerance, latency and pathology. Int J Radiat Oncol Biol Phys 29:73–79 Ryu S, Jin JY, Jin R, Rock J, Ajlouni M, Movsas B, Rosenblum M, Kim JH (2007) Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery. Cancer 109:628–636

635 Sahgal A, Ma L, Gibbs I, Gerszten PC, Ryu S, Soltys S, Weinberg V, Wong S, Chang E, Fowler J, Larson DA (2010) Spinal cord tolerance for stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 77:548–553 Schultheiss TE (2008) The radiation dose-response of the human spinal cord. Int J Radiat Oncol Biol Phys 71:1455–1459 Schultheiss TE, Stephens LC (1992) Permanent Radiation Myelopathy. Br J Radiol 65:737–753 Schultheiss TE, Orton CG, Peck RA (1983) Models in radiotherapy: volume effects. Med Phys 10:410–415 Schultheiss TE, Higgins EH, El-Mahdi AM (1984a) The latent period in clinical radiation myelopathy. Int J Radiat Oncol Biol Phys 10:1109–1115 Schultheiss TE, Higgins EM, El-Mahdi AM (1984b) Extrinsic versus intrinsic dose dependence of latency in radiation myelopathy. Int J Radiat Oncol Biol Phys 10:2389 Schultheiss TE, Stephens LC, Peters LJ (1986) Survival in radiation myelopathy. Int J Radiat Oncol Biol Phys 12:1765–1769 Schultheiss TE, Stephens LC, Maor MH (1988) Analysis of the histopathology of radiation myelopathy. Int J Radiat Oncol Biol Phys 14:27–32 Schultheiss TE, Stephens LC, Jiang GL, Ang KK, Peters LJ (1990) Radiation myelopathy in primates treated with conventional fractionation. Int J Radiat Oncol Biol Phys 19:935–940 Schultheiss TE, Stephens LC, Ang KK, Jardine JH, Peters LJ (1992) Neutron RBE for primate spinal cord treated with clinical regimens. Radiat Res 129:212–217 Schultheiss TE, Stephens LC, Ang KK, Price RE, Peters LJ (1994) Volume effects in rhesus monkey spinal cord. Int J Radiat Oncol Biol Phys 29:67–72 Schultheiss TE, Kun LE, Ang KK, Stephens LC (1995) Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys 31:1093–1112 Snooks SJ, Swash M (1985) Motor conduction velocity in the human spinal cord: slowed conduction in multiple sclerosis and radiation myelopathy. J Neurol Neurosurg Psychiatry 48:1135–1139 Stephens LC, Hussey DH, Raulston GL, Jardine JH, Gray KN, Almond PR (1983) Late effects of 50 MeV neutron and cobalt-60 irradiation of rhesus monkey cervical spinal cord. Int J Radiat Oncol Biol Phys 9:859–865 Thames HD (1989) Repair kinetics in tissues: alternative models. Radiother Oncol 14:321–327 Thames HD, Ang KK, Stewart FA, van der Schueren E (1988) Does incomplete repair explain the apparent failure of the basic LQ model to predict spinal cord and kidney responses to low doses per fraction? Int J Radiat Biol 54:13–19 van den Brenk HAS, Richter W, Hurley RH (1968) Radiosensitivity of the human oxygenated cervical spinal cord based on analysis of 357 cases receiving 4 MeV X- rays in hyperbaric oxygen. Br J Radiol 41:205–214 van der Kogel AJ (1974) Late effects of spinal cord irradiation with 300 kV X-Rays and 15 MeV neutrons. Br J Radiol 45:393–398 van der Kogel AJ (1977) Radiation tolerance of the rat spinal cord: time-dose relationships. Radiology 122:505–509 van der Kogel AJ (1979) Late effects of radiation on the spinal cord. Dose-effect relationships and pathogenesis.

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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 NCI CTCAE

RTOG CHART EORTC V. Bar Ad (&) M. Werner-Wasik Department of Radiation Oncology, Kimmel Cancer Center of Jefferson Medical College, Thomas Jefferson University Hospital, 111 South 11th Street, Philadelphia, PA 19107, USA e-mail: [email protected]

3DCRT DVHs QUANTEC CT

Lethal dose National Cancer Institute’s Common Terminology Criteria for Adverse Events Radiation Therapy Oncology Group Continuous hyperfractionated accelerated radiation therapy European Organization for Research and Treatment of Cancer Three-dimensional conformal radiation therapy Dose–volume histograms Quantitative analysis of normal tissue effects in the clinic Computed tomography


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V. Bar Ad and M. Werner-Wasik

MTD Vx SBRT TITE-CRM DLTs TD IMRT NTCP CGE CCT

1

Maximal tolerated dose Volume receiving more than x Gy Stereotactic body radiation therapy Time-to-event continual reassessment method Dose-limiting toxicities Tolerance dose Intensity modulated radiation therapy Normal tissue complication probability Cobalt-gray equivalent Concurrent chemotherapy

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 radiotherapy, including proliferating basal cells, regenerating epithelium, and scattered areas of complete esophageal denudation. At 3 weeks, the regeneration of the esophageal lining was complete, and after 4 weeks the appearance of the irradiated esophagus was normal. For fractionated radiotherapy doses, the LD50/28 (or radiotherapy 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).

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 necessarily 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 beverages, 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 acetaminophen; liquid morphine; prolonged action opiate preparations, etc.) to control pain and allow adequate oral nutrition. High-calorie liquid oral nutritional supplements are helpful in maintaining satisfactory caloric intake and minimizing weight loss and anemia. Once adequate oral intake of fluids is impaired (as determined 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 concurrent delivery of chemotherapy. Prolonged neutropenia prevents sufficient healing of the esophageal mucosa.

Radiation Therapy-Related Toxicity: Esophagus

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Table 1 Version 4.0 of National Cancer Institute’s Common Terminology Criteria for Adverse Events Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Dysphagia

Symptomatic, able to eat a regular diet

Symptomatic and altered eating/ swallowing

Severely altered eating/ swallowing; tube feedings or TPN or hospitalization indicated

Life-threatening consequences; urgent intervention indicated

Death

Esophagitis

Asymptomatic; clinical or diagnostic observations only; intervention not indicated

Symptomatic; altered eating/ swallowing; oral supplements indicated

Same as above

Life-threatening consequences; urgent operative intervention indicated

Death

TPN total parenteral nutrition

This is a classic indication for a temporary suspension of radiotherapy and administration of a granulocytestimulating 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 associated 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

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 intervention (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 comprehensive measure of normal tissue toxicity than maximum grade alone. Its calculation requires prospective accumulation of data points of toxicity over time, however, and its applicability may therefore be limited to investigational pursuits. The Radiation Therapy Oncology 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

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Table 2 RTOG/EORTC late esophagitis criteria

Esophagus

Grade 0

Grade 1

Grade 2

Grade 3

Grade 4

No symptoms

Mild fibrosis; slight difficulty in swallowing solids; no pain on swallowing

Unable to take solid food normally; swallowing semi-solid food; dilation may be indicated

Severe fibrosis; able to swallow only liquids; may have pain on swallowing; dilation required

Necrosis/ perforation fistula

RTOG/EORTC Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer

standard radiotherapy developed severe acute esophagitis. When chemotherapy is given concurrently 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 symptomatic esophagitis was 1.4 months in the conventional radiotherapy arm, 1.6 months in the arm given conventional radiotherapy with concurrent carboplatin, 3.2 months in the accelerated radiotherapy arm, and 2.4 months in the arm where accelerated radiotherapy was combined with concurrent carboplatin. With the continuous hyperfractionated accelerated radiation therapy (CHART) regimen, used without chemotherapy for locally advanced nonsmall-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 esophagitis 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 incidence of 52% of severe acute esophagitis (35% Grade 3 and 17% Grade 4 esophagitis) with concurrent gemcitabine and thoracic radiotherapy. Pulsed lowdose paclitaxel (at escalating doses of 15, 20, and 25 mg/m2 infused on Monday, Wednesday, and Friday, 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.


4

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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 irradiated animals) (Michalowski and Hornsey 1986). However, the clinical evidence that esophageal toxicity 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 volumetric 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

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 volumetric data (absolute volume or area, relative volume or area, and circumferential measures), no consensus for definitive dosimetric recommendations has been

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reached. Another confounding factor is the fact that in some studies the entire esophagus was not delineated, making volumetric measurements difficult to interpret (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 anatomic 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–


response relationship. In the currently ongoing RTOG 0617 Phase III comparison of 60 vs. 74 Gy thoracic radiotherapy with concurrent and consolidation paclitaxel, 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 located 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, centrally 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 conventional fractionated radiotherapy regimens using between 30 and 35 fractions. A prospective assessment of the dose–volume parameters related to esophageal toxicity associated with hypofractionated


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 equivalent 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

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volume and essentially zero deep to it. As a result, dose to the tumor can be increased, while the frequency 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 paclitaxel. 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 concurrent 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 swallowing dysfunction measured over time (equivalent of esophagitis index), a decrease in pain after chemoradiotherapy, and diminished weight loss in patients receiving chemoradiation (Sarna et al. 2008). Of note, only 40% of all radiotherapy fractions were ‘‘protected’’ by amifostine infusion in that study, and only 29% of patients received the medication according to the protocol. Further investigation of this agent

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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 randomized trial of 97 patients receiving thoracic radiotherapy (McGinnis et al. 1997). An interesting approach of plasmid/liposome delivery by the human manganese superoxide dismutase transgene has been reported to be successful in prevention of radiation esophagitis in mice receiving carboplatin, paclitaxel, and thoracic radiotherapy (Stickle et al. 1999). Palifermin is a human recombinant keratinocyte growth factor shown to significantly reduce severe oral mucositis in patients with hematological malignancies 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 radiotherapy 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 intensification 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.

References Ahn S, Kahn D, Zhou S et al (2005) Dosimetric and clinical predictors for radiation-induced esophageal injury. Int J Radiat Oncol Biol Phys 61:335–347 Antonadou D, Coliarakis N, Synodinou M et al (2001) Randomized phase II trial of radiation treatment plus/minus amifostine in patients with advanced-stage lung cancer. Int J Radiat Oncol Biol Phys 51:915–922 Ball D, Bishop J, Smith J et al (1995) A phase III study of accelerated radiotherapy with and without carboplatin in non-small cell lung cancer: an interim toxicity analysis of the first 100 patients. Int J Radiat Oncol Biol Phys 31:267– 272 Belderbos J, Heemsbergen W, Hoogeman M, Pengel K, Rossi M, Lebesque J (2005) Acute esophageal toxicity in nonsmall cell lung cancer patients after high dose conformal radiotherapy. Radiother Oncol 75:157–164

V. Bar Ad and M. Werner-Wasik Boal DK, Newburger PE, Teele RL (1979) Esophagitis induced by combined radiation and adriamycin. Am J Radiol 132: 567–570 Bradley J, Graham MV, Winter K et al (2005) Toxicity and outcome results of RTOG 9311: a phase I-II dose escalation study using three-dimensional conformal radiation therapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys 61:318–328 Byhardt RW, Scott C, Sause WT et al (1998) Response, toxicity, failure patterns, and survival in five RTOG trials of sequential and/or concurrent chemotherapy and radiotherapy for locally advanced non-small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 42:469–478 Chang JY, Komaki R, Bucci MK et al (2009) Failure patterns and toxicity of concurrent proton therapy and chemotherapy for stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys 75(3):S446 Chen Y, Pandya KJ, Feins R et al (2008) Toxicity profile and pharmacokinetic study of a phase I low-dose scheduledependent radiosensitizing paclitaxel chemoradiation regimen for inoperable non-small cell lung cancer. Int J Radiat Oncol Biol Phys 71:407–413 Choi GB, Shin JH, Song HY et al (2005) Fluoroscopically guided balloon dilation for patients with esophageal stricture after radiation treatment. J Vasc Interv Radiol 16(12): 1705–1710 Choy H, Safran H (1995) Preliminary analysis of a phase II study of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small cell lung cancer. Semin Oncol 4(Suppl 9):55–57 Choy H, LaPorte K, Knill-Selby E, Mohr P, Shy Y (1999) Esophagitis in combined modality therapy for locally advanced non-small cell lung cancer. Sem Rad Oncol 9: 90–96 Cox JD, Pajak TF, Asbell S et al (1993) Interruptions of highdose radiation therapy decrease long-term survival of favorable patients with unresectable non-small cell carcinoma of the lung: analysis of 1244 cases from 3 RTOG trials. Int J Radiat Oncol Biol Phys 27:493–498 Dieleman EMT, Senan S, Vincent A et al (2007) Fourdimentional computed tomographic analysis of esophageal mobility during normal respiration. Int J Radiat Oncol Biol Phys 67:775–780 Dubray B, Livartowski A, Beuzeboc P, Pouillart P, Cosset JM (1995) Combined chemoradiation for locally advanced nonsmall cell lung cancer. J Infus Chemother 5:195–196 Emami B (1996) Three-dimensional conformal radiation therapy in bronchogenic carcinoma. Semin Radiat Oncol 6:92–97 Gandara DR, Chansky K, Albain KS et al (2003) Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIb non-small cell lung cancer: phase II southwest oncology group study S9504. J Clin Oncol 21(10):2004–2010 Goldstein HM, Rogers LF, Fletcher GH, Dodd GD (1975) Radiological manifestations of radiation-induced injury to the normal upper gastrointestinal tract. Radiology 117: 135–140 Grills IS, Yan D, Martinez AA, Vicini FA, Wong JW, Kestin LL (2003) Potential for reduced toxicity and dose escalation in the treatment of inoperable non-small-cell lung cancer: a comparison of intensity-modulated radiation therapy

Radiation Therapy-Related Toxicity: Esophagus (IMRT), 3D conformal radiation, and elective nodal irradiation. Int J Radiat Oncol Biol Phys 57(3):875–890 Kahn D, Zhou S, Ahn SJ et al (2005) ‘‘Anatomically-correct’’ dosimetric parameters may be better predictors for esophageal toxicity than are traditional CT-based metrics. Int J Radiat Oncol Biol Phys 62(3):645–651 Kim TH, Cho KH, Pyo HR et al (2005) Dose-volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 64(4):995–1002 Komaki R, Lee JS, Milas L et al (2004) Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non-small cell lung cancer: report of a randomized comparative trial. Int J Radiat Oncol Biol Phys 58(5):1369–1377 Langer C, Hsu C, Curran W et al (2001) Do elderly patients with locally advanced non-small cell lung cancer benefit from combined modality treatment? A secondary analysis of RTOG 94–10. Int J Radiat Oncol Biol Phys 51(1 Suppl):20–21 Lepke RA, Libshitz HI (1983) Radiation-induced injury of the esophagus. Radiology 148:375–378 Maguire PD, Sibley GS, Zhou SM et al (1999) Clinical and dosimetric predictors of radiation-induced esophageal toxicity. Int J Radiat Oncol Biol Phys 45(1):97–103 McGinnis WL, Loprinzi CL, Buskirk SJ et al (1997) Placebocontrolled trial of sucralfate for inhibiting radiation-induced esophagitis. J Clin Oncol 15:1239–1243 Michalowski A, Hornsey S (1986) Assays of damage to the alimentary canal. Br J Cancer 53(suppl 7):1–6 Movsas B, Scott C, Langer C et al (2005) Randomized trial of amifostine in locally advanced non-small cell lung cancer receiving chemotherapy and hyperfractionated radiation: radiation therapy oncology group trial 98–01. J Clin Oncol 23(10):2145–2154 Patel AB, Edelman MJ, Kwork Y, Krasna MJ, Suntharalingam M (2004) Predictors of acute esophagitis in patients with non small-cell lung carcinoma treated with concurrent chemotherapy and hyperfractionated radiotherapy followed by surgery. Int J Radiat Oncol Biol Phys 60:1106–1112 Phillips TL, Ross G (1974) Time-dose relationships in the mouse esophagus. Radiology 113:435–440 Rodriguez N, Algara M, Foro P et al (2005) Predictors of acute esophagitis in lung cancer patients treated with concurrent three-dimentional conformal radiotherapy and chemotherapy. Int J Radiat Oncol Biol Phys 73(3):810–817

645 Sarna L, Swann S, Langer C et al (2008) Clinically meaningful differences in patient-reported outcomes with amifostine in combination with chemoradiation for locally advanced nonsmall-cell lung cancer: an analysis of RTOG 98–01. Int J Radiat Oncol Biol Phys 72(5):1378–1384 Saunders MI, Dische S, Barrett A, Harvey A, Gibson D, Parmar M (1997) Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in nonsmall cell lung cancer: a randomized multicenter trial. Lancet 350:161–165 Spielberger R, Stiff P, Bensinger W et al (2004) Palifermin for oral mucositis after intensive therapy for hematological cancers. N Engl J Med 351(25):2590–2598 Stickle RL, Epperly MW, Klein E, Bray J, Greenberger J (1999) Prevention of irradiation-induced esophagitis by plasmid/liposome delivery of the human manganese superoxide dismutase transgene. Radiat Oncol Invest 7: 204–217 Suit H, Goldberg S, Niemierko A et al (2003) Proton beams to replace photon beams in radical dose treatments. Acta Oncol 42(8):800–808 Vokes EE, Herndon JE 2nd, Crawford J et al (2002) Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: cancer and leukemia group B study 9431. J Clin Oncol 20(20):4191–4198 Werner-Wasik M, Pequignot E, Leeper D, Hauck W, Curran W (2000) Predictors of severe esophagitis include use of concurrent chemotherapy, but not the length of irradiated esophagus: a multivariate analysis of patients with lung cancer treated with non-operative therapy. Int J Radiat Oncol Biol Phys 48:689–696 Werner-Wasik M, Axelrod SA, Friedland DP et al (2002) Phase II trial of twice weekly amifostine in patients with nonsmall cell lung cancer treated with chemotherapy. Semin Radiat Oncol 12(suppl 1):34–39 Werner-Wasik M, Yorke E, Deasy J, Nam J, Marks LB (2010) Radiation dose-volume effects in the esophagus. Int J Radiat Oncol Biol Phys 76(3 Suppl):S86–93 Werner-Wasik M, Paulus R, Curran WJ Jr, Byhardt R Acute esophagitis and late lung toxicity in concurrent chemoradiotherapy in patients with locally advanced non-small cell lung cancer: analysis of the radiation therapy oncology group (RTOG) database (in press)

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

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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: [email protected]

Abstract

Since lung cancer generally has a high, stage- and histology-dependent propensity for brain metastases, many patients receive prophylactic or therapeutic 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 continues 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 developing 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.


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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 oncology 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 conformal 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 diffuse microscopic spread, which escapes current imaging technology). Therefore, many patients continue 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 radiationinduced 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 RadiotherapyInduced 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 discuss these historical data, which have been summarized 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

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 important. 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 experimentally 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, reirradiation 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 example, in a description of more and more radiobiologically-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 radiation. Obviously, radiation-induced reactions of the CNS are not limited to reproductive or mitotic cell death in mature parenchymal and vascular cell populations. Apoptosis, induced by sphingomyelinasemediated 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 expression, transcription factor activation and functional changes in basically every cell type examined may develop (Raju et al. 2000). Current models of radiotherapy-induced brain alterations include a cascade of complex and dynamic interactions between parenchymal cells (oligodendrocytes, astrocytes, microglia), stem and progenitor cells and vascular endothelial cells (Tofilon and Fike 2000; Fike et al. 2009). The latent time preceding the clinical manifestation 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 phenomena, such as intellectual decline, memory loss, lethargy, dysphoria, dementia and ataxia, also suggest the possible involvement of neurons in radiotherapyinduced CNS reactions. In vitro studies have demonstrated 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 neurogenesis 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, activation of microglia) (Monje et al. 2002, 2007). CNS radiotherapy induces production of inflammatory 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 mechanisms, 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

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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 oligodendrocytes. Thus, compensation for radiationinduced 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 molecule-1 (ICAM-1) in oligodendrocytes and microvascular 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 further 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 largely-selective irradiation of the vessel walls with BNCT. Nevertheless as with conventional nonselective 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 radiotherapy (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 hyperpermeability, resulting in perivascular edema and consecutive 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 system (Roth et al. 1999). Common therapeutic doses of ionizing radiation lead to functional and, later, to structural vascular damage, such as increased

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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, structural 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 astrocytes 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 alterations were also seen (dilation, wall thickening, reactive hypertrophy of neighboring astrocytes) before the development of white matter necrosis (Hopewell et al. 1989). Rubin et al. performed comprehensive magnetic 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 RadiotherapyInduced Brain Toxicity

As stated in the previous paragraph, acute and subacute 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 demyelination 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 disturbance. 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 progression. Usually they resolve with longer follow-up.

4

Delayed or Chronic RadiotherapyInduced 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 leukoencephalopathy. Necrosis develops for the most part

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after 1–3 years (Keime-Guibert et al. 1998). Symptoms of radionecrosis depend on localization and are comparable to tumor-related symptoms before treatment (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 spectroscopy (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. intergroup 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. Commonly prescribed doses are in the range of 15– 20 Gy, depending on volume, technique of SRS and use of additional WBRT. The risk increases when more than 10 cm3 of the normal brain receives more than 10 Gy. The optic apparatus should not receive more than 8 Gy (Mayo et al. 2010). Varlotto et al. reported the results of SRS in 137 patients with brain metastases who had a minimum follow-up of 1 year after SRS (Varlotto et al. 2003). The median marginal tumor dose was 16 Gy. NSCLC was the underlying primary tumor in 77 patients. Eleven patients developed serious side effects, such as visual loss, hemorrhage and persistent steroid-dependent edema or necrosis necessitating surgical intervention. The actuarial incidence of such adverse events was 4% after 5 years for patients with brain metastases

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Fig. 1 Initial CT scans (top) before whole-brain radiotherapy (30 Gy in 10 fractions of 3 Gy) in a 66 year old man with multiple brain metastases from small cell lung cancer (no previous prophylactic brain irradiation). The lower CT scan was taken 2 years later and shows moderate brain atrophy and white matter changes. In addition periventricular calcifications (white arrow) can be seen. The patient had developed overt neurocognitive decline interfering with activities of daily living

B2 cm3 and 16% for those with larger lesions. Age and additional use of WBRT did not influence the complication rate. Therapeutic intervention with corticosteroids or anticoagulants is sometimes successful (Glantz et al. 1994). Often, surgical resection is the only way to effectively improve the symptoms. Diffuse white matter changes are frequently observed in imaging studies (Figs. 1 and 2). Fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted

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Fig. 2 Initial T2-weighted MRI scan before stereotactic radiosurgery (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. Neuropsychological sequelae typically manifest within 4 years of radiotherapy. Psychometric findings suggest greater vulnerability of white matter and subcortical structures, resulting in reduced processing speed, heightened distractibility and memory impairment. Within

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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/EORTC 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 preexisting 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 clinical symptoms. Previous studies described such correlations for patients treated with PCI and chemotherapy for SCLC (Laukkanen et al. 1988; Johnson et al. 1990). Whether or not clinical symptoms, 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 significant neurocognitive decline (Torres et al. 2003; Duchstein et al. 2003). After WBRT, neuropsychological 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 function (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 MiniMental-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 stabilize spontaneously (van de Pol et al. 1997; Armstrong 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 associated 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 spongiosis 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

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anterior and medial cerebral arteries) have occasionally 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 fraction, 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 preliminary 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 prevention 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

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are currently under investigation. The clinical effectiveness of these putative prevention strategies has yet to be established. The prophylactic use of dexamethasone 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 proliferation (Tanaka et al. 1997). The hyperpermeability of blood vessels could be reduced at all time points after irradiation by application of rh-MnSOD (manganese 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 endothelium (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 protection 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 certain growth factors with antiapoptotic effects that also influence the proliferation of stem cells, neurogenesis and angiogenesis. Pena et al. showed that i.v. injections 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 insulinlike growth factor-1 (IGF-1) can increase the longterm 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 strategies of toxicity prevention. The growing body of evidence linking radiationinduced brain injury with oxidative stress and/or inflammation has provided the rationale for applying proven anti-inflammatory-based interventions to prevent 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) blockers. 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-irradiation. Robbins et al. (2009) hypothesized that blocking the brain RAS with the AT1RA, L-158,809, would prevent or ameliorate radiation-induced cognitive 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 ameliorated 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 progenitor 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 interesting prospects. In another recently published experiment, 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, differentiation, 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 RadiotherapyInduced 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 radiosensitization. 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 intervention 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. Sometimes the symptoms are secondary to hyponatremia or hypomagnesemia. Posterior reversible encephalopathy syndrome can develop after systemic administration of cytotoxic drugs, including gemcitabine, cisplatin,

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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 discontinued. Cerebellar toxicity of 5-FU is rare and mostly found in patients with a deficiency of dihydropyrimidine 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 impairment 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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656 Cicciarello R, D’Avella D, Gagliardi ME et al (1996) Timerelated ultrastructural changes in an experimental model of whole brain irradiation. Neurosurgery 38:772–779 De Angelis LM, Delattre JY, Posner JB (1989) Radiationinduced dementia in patients cured of brain metastases. Neurology 39:789–796 Duchstein S, Gademann G, Peters B (2003) Early and late effects of local high dose radiotherapy of the brain on memory and attention [Article in German]. Strahlenther Onkol 179:441–451 Fike JR, Gobbel GT, Marton LJ, Seilhan TM (1994) Radiation brain injury is reduced by the polyamine inhibitor adifluoromethylornithine. Radiat Res 138:99–106 Fike JR, Rosi S, Limoli CL (2009) Neural precursor cells and central nervous system radiation sensitivity. Semin Radiat Oncol 19:122–132 Glantz MJ, Burger PC, Friedman AH, Radtke RA, Massey EW, Schold SC (1994) Treatment of radiation-induced nervous system injury with heparin and warfarin. Neurology 44:2020–2027 Gobbel GT, Bellinzona M, Vogt AR, Gupta N, Fike JR, Chan PH (1998) Response of postmitotic neurons to x-irradiation: implications for the role of DNA damage in neuronal apoptosis. J Neurosci 18:147–155 Gu C, Casaccia-Bonnefil P, Srinivasan A, Chao MV (1999) Oligodendrocyte apoptosis mediated by caspase activation. J Neurosci 19:3043–3049 Hayakawa K, Borchardt PE, Sakuma S, Ijichi A, Niibe H, Tofilon PJ (1997) Microglial cytokine gene induction after irradiation is affected by morphologic differentiation. Radiat Med 15:405–410 Herbst RS, Madden TL, Tran HT et al (2002) Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors. J Clin Oncol 20:4440–4447 Herskovic AM, Orton CG (1986) Elective brain irradiation for small cell anaplastic lung cancer. Int J Radiat Oncol Biol Phys 12:427–429 Hisahara S, Shoji S, Okano H, Miura M (1997) ICE/CED3 family executes oligodendrocyte apoptosis by tumor necrosis factor. J Neurochem 69:10–20 Hong JH, Chiang CS, Campbell IL, Sun JR, Withers HR, McBride WH (1995) Induction of acute phase gene expression by brain irradiation. Int J Radiat Oncol Biol Phys 33:619–626 Hopewell JW, van der Kogel AJ (1999) Pathophysiological mechanisms leading to the development of late radiationinduced damage to the central nervous system. Front Radiat Ther Oncol 33:265–275 Hopewell JW, Calvo W, Campling D, Reinhold HS, Rezvani M, Yeung TK (1989) Effects of radiation on the microvasculature. Front Radiat Ther Oncol 23:85–95 Hulshof MC, Stark NM, van der Kleij A, Sminia P, Smeding HM, Gonzalez D (2002) Hyperbaric oxygen therapy for cognitive disorders after irradiation of the brain. Strahlenther Onkol 178:192–198 Johnson BE, Patronas N, Hayes W et al (1990) Neurologic, computed cranial tomographic, and magnetic resonance imaging abnormalities in patients with small-cell lung cancer: further follow-up of 6- to 13-year survivors. J Clin Oncol 8:48–56

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Brain Toxicity Mildenberger M, Beach TG, McGeer EG, Ludgate CM (1990) An animal model of prophylactic cranial irradiation: histologic effects at acute, early and delayed stages. Int J Radiat Oncol Biol Phys 18:1051–1060 Monje ML, Mizumatsu S, Fike JR, Palmer TD (2002) Irradiation induces neural precursor-cell dysfunction. Nature Med 8:928–930 Monje ML, Vogel H, Masek M et al (2007) Impaired human hippocampal neurogenesis after treatment for central nervous system malignancies. Ann Neurol 62:515–520 Morris GM, Coderre JA, Bywaters A (1996) Boron neutron capture irradiation of the rat spinal cord: histopathological evidence of a vascular-mediated pathogenesis. Radiat Res 146:313–320 Munley MT, Marks LB, Hardenbergh PH, Bentel GC (2001) Functional imaging of normal tissues with nuclear medicine: applications in radiotherapy. Semin Radiat Oncol 11:28–36 Nakajima T, Kumabe T, Kanamori M et al (2009) Differential diagnosis between radiation necrosis and glioma progression using sequential proton magnetic resonance spectroscopy and methionine positron emission tomography. Neurol Med Chir (Tokyo) 49:394–401 Nieder C, Leicht A, Motaref B, Nestle U, Niewald M, Schnabel K (1999) Late radiation toxicity after whole-brain radiotherapy: the influence of antiepileptic drugs. Am J Clin Oncol 22:573–579 Nieder C, Andratschke N, Astner ST (2007) Experimental concepts for toxicity prevention and tissue restoration after central nervous system irradiation. Radiat Oncol 2:23 Nieder C, Bremnes RM, Andratschke NH (2009) Prognostic scores in patients with brain metastases from non-small cell lung cancer. J Thorac Oncol 4:1337–1341 Pena LA, Fuks Z, Kolesnick RN (2000) Radiation-induced apoptosis of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency. Cancer Res 60:321–327 Penitzka S, Steinvorth S, Sehlleier S, Fuss M, Wannenmacher M, Wenz F (2002) Assessment of cognitive function after preventive and therapeutic whole brain irradiation using neuropsychological testing [Article in German]. Strahlenther Onkol 178:252–258 Perrini P, Scollato A, Cioffi F, Conti R, Di Lorenzo N (2002) Radiation leukoencephalopathy associated with moderate hydrocephalus: intracranial pressure monitoring and results of ventriculoperitoneal shunting. Neurol Sci 23: 237–241 Rajeswaran A, Trojan A, Burnand B, Giannelli M (2008) Efficacy and side effects of cisplatin- and carboplatin-based doublet chemotherapeutic regimens versus non-platinumbased doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: a systematic review of randomized controlled trials. Lung Cancer 59:1–11 Raju U, Gumin GJ, Tofilon PJ (2000) Radiation-induced transcription factor activation in the rat cerebral cortex. Int J Radiat Biol 76:1045–1053 Regine WF, Scott C, Murray K, Curran W (2001) Neurocognitive outcome in brain metastases patients treated with accelerated-fractionation vs. accelerated-hyperfractionated

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Quality of Life Outcomes in Radiotherapy of Lung Cancer M. Salim Siddiqui, Farzan Siddiqui, and Benjamin Movsas

Contents

Abstract

Lung cancer is one of the most common cancers in the world. There has been an increased interest in quality of life (QOL) as a clinically meaningful endpoint in clinical trials for lung cancer. Patientreported outcome (PRO) measurements have allowed oncologists to better understand the impact of cancer therapies on the physical, emotional 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 radiation treatment for lung cancer, is included.

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1 1.1 1.2 1.3 1.4

Introduction.............................................................. What is Quality of Life............................................. How is QOL Measured ............................................. How is QOL Analyzed.............................................. QOL Studies in Lung Cancer ...................................

2


References.......................................................................... 671

1

M. Salim Siddiqui B. Movsas (&) Department of Radiation Oncology, Henry Ford Hospital, 2799 W Grand Boulevard, Detroit, MI 48202, USA e-mail: [email protected] F. Siddiqui Department of Radiation Oncology, Ohio State University, 300 W. 10th Avenue, Columbus, OH 43210, USA

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 recommendations to improve the overall QOL of the patient. Such improvements are even more important when one considers the poor prognosis in the majority of lung cancer patients. In many cases, treatments for lung cancer may be associated with toxicities which could adversely impact QOL. In such settings, assessment of QOL endpoints may help to identify


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significant differences in such treatment-related toxicities, while the traditional endpoints may be equivocal. 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, oxycodone, 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 Division 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, methodology, 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 intrapatient cross-cultural and temporal variability of QOL (Leplege and Hunt 1997). However, application of this construct in the clinic necessitates not

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 satisfaction 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 instruments (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-formulated QOL hypothesis, provide a more meaningful clinical arena to measure such outcomes. Gotay (2004) suggested the following guidelines for inclusion 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). Similarly, 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 consistent 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

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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 sociodemographic 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 considerations have been suggested when selecting the ‘‘best’’ QOL instrument: (1) the underlying hypothesis 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. However, 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

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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-administered 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 truncated 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 Sherbourne 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 QLQC30 assesses various elements of QOL through nine


multi-item scales: five functional scales (physical, role, cognitive, emotional, and social); three symptom 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 medication). The score of each item ranges from 0 to 100 with better functioning indicated by a higher value on the functional scales and increased symptoms 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 wellbeing (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 questionnaire consists of six lung cancer symptoms (i.e. appetite loss, fatigue, cough, dyspnea, hemoptysis, and pain) and three general items (i.e. symptomatic distress, activity status, and overall QOL).


The optional observer portion consists of a questionnaire 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 instrument, 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 sideeffects 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 baseline assessment also determines differences in pretreatment QOL in treatment groups and individuals and allows comparison to post-treatment QOL. During 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

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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 nonresponse’’ 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 informative censoring, which may underestimate or overestimate 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 categorized 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). Certainly, clinical investigators can anticipate and address some of these explanations through adequate infrastructure and logistical support for data collection 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

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and reviewing the QOL questionnaires. Often such responsibilities are performed by data managers or trained research nurses. Centralizing such responsibilities and establishing quality control measures may result in high-compliance rates (Sadura et al. 1992; Langendijk et al. 2000a). Beyond traditional centralized QOL data collection by mail or telephone, real-time tracking software 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 questions 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 questionnaires. 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 consistently 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 proposed 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.


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 relevant. 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 Significance 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 individualfocused (i.e. single-anchor) or population-focused (i.e. multiple-anchor) (Guyatt et al. 2002). The individual-focused method attempts to address the question 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 clinician to consider a change in the patient’s management’’(Guyatt et al. 2002). Osoba et al. (1998) used a series of EORTC QLQ-C30 questionnaires to investigate QOL and a subjective significance questionnaire (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 perception 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 perceived ‘‘no change’’ in their condition. However, if


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 manner, Cella and colleagues used the FACT-L questionnaire 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 multipleanchor, method correlates target measure with multiple 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 distribution 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 suggested 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.

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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 contribute 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 independently 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 clinically meaningful differences. For example, in a double-blinded, palliative study of advanced endocrine-insensitive tumors, Beller et al. (1997) randomized 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’’ nutritional status endpoints did not demonstrate a statistically significant difference, the QOL endpoints demonstrated significant improvement in appetite, mood, and overall QOL in patients receiving MA.

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Even in studies with an expected difference in survival between two study arms, QOL outcome can help weigh the risk/benefits of the various treatments. The challenge remains when QOL outcomes from a necessary treatment indicate an unavoidable detriment to the QOL of the patient. In such a setting, beyond providing a needed awareness of the treatment challenges 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 irradiation 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 fractions 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 regimens (i.e. 17 Gy/2 fractions versus 42 Gy/15 fractions 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, symptom relief, or QOL. As a result, short-term hypo

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, significantly 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 cancer. 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 endof-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 palliative 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


longitudinal studies in such patients undergoing radical 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 cancer 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 symptoms 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 radiationinduced pulmonary changes. Balancing the QOL outcomes with the low incidence of regional recurrence 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 medically inoperable Stage I peripherally located NSCLC tumors treated with stereotactic radiotherapy (i.e. 60 Gy in 3 fractions). They evaluated the dynamics of

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QOL changes during and after radiation treatment using the EORTC QLQ-30 and QLQ-LC13. In contrast 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 increasing 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 chemotherapy 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

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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 QLQLC13 were utilized to collect prospective QOL information. Each arm had comparable baseline demographics. The median survival rates were comparable 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 factors, 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 chemoradiation (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 patientreported pain at 6 weeks of follow-up (versus pretreatment) (p = 0.003). Thus, while there was no significant difference between NCI-CTC physicianreported 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 clinical 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


physician-reported assessments underestimated patient distress, particularly in the case of pain (Basch et al. 2006, 2009; Jensen et al. 2006). This ‘‘disconnect’’ may provide an opportunity for a new approach in adverse symptom reporting. Basch et al. (2009) studied 163 patients with lung cancer receiving chemotherapy and used a time-dependent Cox regression model to compare PROs and physician-reported outcomes 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


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 programs should allow more efficient and real-time QOL data collection and tracking. Hopefully, such programs will improve compliance and minimize data management and resource burdens. Secondly, given the clinical relevance of PROs, the NIH has developed an initiative, Patient-Reported Outcomes Measurement 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


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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M. Salim Siddiqui et al. Leplege A, Hunt S (1997) The problem of quality of life in medicine. Jama 278(1):47–50 Little RJA, Rubin DB (2002) Statistical analysis with missing data. Hoboken, N.J, Wiley Louie AV, Rodrigues G et al (2010) Stereotactic body radiotherapy versus surgery for medically operable Stage I non-small-cell lung cancer: a markov model-based decision analysis. Int J Radiat Oncol Biol Phys. doi:10.1016/ j.ijrobp.2010.06.040 Macbeth FR, Bolger JJ et al (1996) Randomized trial of palliative two-fraction versus more intensive 13 fraction radiotherapy for patients with inoperable non-small cell lung cancer and good performance status. Medical research council lung cancer working party. Clin Oncol (R Coll Radiol) 8(3):167–175 McHorney CA, Ware JE Jr et al (1993) The MOS 36 Item short-form health survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 31(3):247–263 McHorney CA, Ware JE Jr et al (1994) The MOS 36 item short-form health survey (SF-36): III. Tests of data quality, scaling assumptions, and reliability across diverse patient groups. Med Care 32(1):40–66 Miller GA (1956) The magical number seven plus or minus two: Some limits on our capacity for processing information. Psychol Rev 63(2):81–97 Moinpour CM, Feigl P et al (1989) Quality of life end points in cancer clinical trials: Review and recommendations. J Natl Cancer Inst 81(7):485–495 Moinpour CM, Sawyers Triplett J et al (2000) Challenges posed by non-random missing quality of life data in an advanced-stage colorectal cancer clinical trial. Psychooncology 9(4):340–354 Montazeri A, Milroy R et al (2001) Quality of life in lung cancer patients: as an important prognostic factor. Lung Cancer 31(2–3):233–240 Movsas B (2003) Quality of life in oncology trials: a clinical guide. Semin Radiat Oncol 13(3):235–247 Movsas B, Scott C et al (2005) Randomized trial of amifostine in locally advanced non-small-cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: radiation therapy oncology group trial 98–01. J Clin Oncol 23(10):2145–2154 Movsas B, Moughan J et al (2009) Quality of life supersedes the classic prognosticators for long-term survival in locally advanced non-small-cell lung cancer: an analysis of RTOG 9801. J Clin Oncol 27(34):5816–5822 NCI, C. T. C. G. P (1988) Cancer therapy evaluation program: Guidelines. N. C. I. Division of Cancer Treatment, Bethesda, MD Nicklasson M, Bergman B (2007) Validity, reliability and clinical relevance of EORTC QLQ-C30 and LC13 in patients with chest malignancies in a palliative setting. Qual Life Res 16(6):1019–1028 Norman GR, Sloan JA et al (2003) Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care 41(5):582– 592 Nunnaly J, Bernstein I (1994) Psychometric therapy. McGrawHill, Mew York

Quality of Life Outcomes in Radiotherapy of Lung Cancer Osoba D (1996) Rationale for the timing of health-related quality-of-life (HQL) assessments in oncological palliative therapy. Cancer Treat Rev 22(Suppl A):69–73 Osoba D, Rodrigues G et al (1998) Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 16(1):139–144 Pijls-Johannesma M, Houben R et al (2009) High-dose radiotherapy or concurrent chemo-radiation in lung cancer patients only induces a temporary, reversible decline in QoL. Radiother Oncol 91(3):443–448 Qian W, Parmar MK et al (2000) Analysis of messy longitudinal data from a randomized clinical trial. MRC lung cancer working party. Stat Med 19(19):2657–2674 Ribaudo HJ, Thompson SG (2002) The analysis of repeated multivariate binary quality of life data: a hierarchical model approach. Stat Methods Med Res 11(1):69–83 Rubin DB (1997) Estimating causal effects from large data sets using propensity scores. Ann Intern Med 127(8 Pt 2):757– 763 Sadura A, Pater J et al (1992) Quality-of-life assessment: Patient compliance with questionnaire completion. J Natl Cancer Inst 84(13):1023–1026 Sales AE, Plomondon ME et al (2004) Assessing response bias from missing quality of life data: the Heckman method. Health Qual Life Outcomes 2:49 Sarna L, Swann S et al (2008) Clinically meaningful differences in patient-reported outcomes with amifostine in combination with chemoradiation for locally advanced non-smallcell lung cancer: an analysis of RTOG 9801. Int J Radiat Oncol Biol Phys 72(5):1378–1384 Slevin ML, Plant H et al (1988) Who should measure quality of life, the doctor or the patient?. Br J Cancer 57(1): 109–112 Sprangers MA, Sloan JA et al (2009) The establishment of the GENEQOL consortium to investigate the genetic disposition of patient-reported quality-of-life outcomes. Twin Res Hum Genet 12(3):301–311 Stewart AL, Ware JE (1992) Measuring functioning and wellbeing: the medical outcomes study approach. Duke University Press, Durham Strain JJ (1990) The evolution of quality of life evaluations in cancer therapy. Oncology (Williston Park) 4(5):22–26 discussion 27 Sundstrom S, Bremnes R et al (2004) Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22(5):801–810

673 Temel JS, Greer JA et al (2010) Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 363(8):733–742 Testa MA, Simonson DC (1996) Assesment of quality-of-life outcomes. N Engl J Med 334(13):835–840 Troxel AB, Fairclough DL et al (1998) Statistical analysis of quality of life with missing data in cancer clinical trials. Stat Med 17(5–7):653–666 van der Voort van Zyp NC, Prevost JB et al (2010) Quality of life after stereotactic radiotherapy for stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 77(1):31–37 Velikova G, Booth L et al (2004) Measuring quality of life in routine oncology practice improves communication and patient well-being: a randomized controlled trial. J Clin Oncol 22(4):714–724 Ware JE Jr, Sherbourne CD (1992) The MOS 36 item shortform health survey (SF-36). I. Conceptual framework and item selection. Med Care 30(6):473–483 Ware JE, Gandek B et al (1996) Evaluating instruments used cross-nationally: Methods from the IQoLA project. Quality of life and pharmacoeconimics in clinical trials. Raven Press, B. Spilker. New York Watkins-Bruner D, Scott C et al (1995) RTOG’s first quality of life study–RTOG 90–20: a phase II trial of external beam radiation with etanidazole for locally advanced prostate cancer. Int J Radiat Oncol Biol Phys 33(4):901–906 WHO (1996) Quality of life assessment. The WHOQOL group, 1994. What quality of life? The WHOQOL group. World Health Forum. WHO, Geneva 1996 Wyrwich KW (2004) Minimal important difference thresholds and the standard error of measurement: is there a connection?. J Biopharm Stat 14(1):97–110 Wyrwich KW, Nienaber NA et al (1999a) Linking clinical relevance and statistical significance in evaluating intraindividual changes in health-related quality of life. Med Care 37(5):469–478 Wyrwich KW, Tierney WM et al (1999b) Further evidence supporting an SEM-based criterion for identifying meaningful intra-individual changes in health-related quality of life. J Clin Epidemiol 52(9):861–873 Wyrwich KW, Tierney WM et al (2002) Using the standard error of measurement to identify important changes on the Asthma quality of life questionnaire. Qual Life Res 11(1):1–7 Wyrwich KW, Bullinger M et al (2005) Estimating clinically significant differences in quality of life outcomes. Qual Life Res 14(2):285–295 Zee BC (1998) Growth curve model analysis for quality of life data. Stat Med 17(5–7):757–766

Prognostic Factors in Lung Cancer Frank B. Zimmermann

Contents

Abstract

1

Introduction.............................................................. 676

2 2.1 2.2 2.3

Non-Small-Cell Lung Cancer................................. Tumor-Related Factors .............................................. Patient-Related Factors.............................................. Treatment-Related Factors ........................................

676 676 679 681

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

683 683 684 684

Treatment-Related Factors..................................... 684

References.......................................................................... 685

F. B. Zimmermann (&) University Hospital Basel, Basel, Switzerland e-mail: [email protected]

Lung cancer is a heterogeneous clinical entity of non-small-cell and small-cell lung cancer types as well as mixed types, with even different clinical behaviors and prognoses within particular pathological subgroups. Current guidelines for treatment decisions in NSCLC and SCLC are based on tumor extension and certain additional clinico-histophatological parameters only. Besides this, numerous clinical laboratory tests and investigations of the cellular, molecular 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. This knowledge might support the treatment decision, research design and analysis, 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 prognostic 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


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F. B. Zimmermann

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, containing 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 constellation 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 syndromes, 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 clinicohistopathological 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 treatment by the prognosis for each patient. In the previous years, numerous clinical laboratory tests, and, most recently, investigations of the cellular, molecular 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

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 differentiation, and extent of disease. • Patient-related as comorbidities, gender, performance 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). Revisions to the TNM-system were made in 1997 and in 2010, to provide greater specificity for patient subgroups, 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 different 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 radiotherapy (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 prognostic implication of cell subtype, but the majority of retrospective trials have shown an independent superior 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

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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 squamous 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. Nevertheless, 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 factor), regulators of the cell cycle and apoptosis (p53, bcl2, 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 EGFRTKI is not exclusive to patients with EGFR-mutationpositive 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

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argyrophilic nucleolar organizer region, and p185 status have been significantly associated with prognosis 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 question 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 treatment 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, nutrition, 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 statistical 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) apparently being the most important one. The prognostic

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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 circulating 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), hypoxiainducible 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, MMP9) participate in many deregulated signaling pathways that are used by the tumor to promote cancer cell growth, angiogenesis, and apoptosis, especially degradation 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 prospectively 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 polypeptide antigen (TPA), cancer antigen 125, and carcinoembryonic antigen (CEA) have been evaluated as valid prognostic determants, with cytokeratin fragments almost certain. Unfortunately, the data are not homogeneous, and the prognostic capability of CEA was rather weak (Buccheri and Ferrigno 2004).


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 survival 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, radiation 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 radiotherapy would be helpful to better tailor individual cancer treatment especially for elderly (Charlson comorbidity index CCI; cumulative illness rating

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scale for geriatrics CIRS-G) (Charlson et al. 1987; Miller et al. 1992). In several former studies the male sex was discussed 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 adenocarcinoma, 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 Japanese 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 homogeneously 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 marital status (Ou et al. 2008).

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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 studies 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 patientreported 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 performance 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 determinant than pure performance status (Langendijk et al. 2000; Buccheri and Ferrigno 2004). Qualityof-life scores and anxiety and depression assessments may reflect the extent of disease and also the patients’ inherent characteristics or degree of emotional support that may predict better disease outcomes, possibly through psychophysiologic mechanisms.

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Weight loss within the last 6 months before diagnosis 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 pulmonary function has been proven, with the estimation of the absolute and predicted proportional postoperative spirometry value being mostly predictive. These values can be calculated by multiplying the observed preoperative value with the percentage of postoperatively 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 chemotherapy 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 distinctive disease (Kawaguchi et al. 2010).

2.2.3

Laboratory, Hematological and Immunological Factors Hematologic or biochemical markers might be associated with disease extent, and therefore have been evaluated 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 secondary analysis of clinical trial information or after retrospective evaluation of patient data outside of clinical protocols have reached similar conclusions (Paesmans 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


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 specifically 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-analysis (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

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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; Nakamura 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 chemoradiotherapy) 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 systemic 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 recurrencefree survival by 30% in some publications, and no significant influence in others (Quejada and Albain 2004). In marginal resectable situations, preoperative chemotherapy may be considered, with proven prolonged 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 resection in curative intention, although no modern randomized 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 stereotactic 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

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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 radiotherapy compared to conventional fractionation, and when treated with higher doses of conventional radiation 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 reasonable 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 chemotherapy and radiotherapy is still investigational, as is the role of combination chemoradiotherapy in more symptomatic patients (Ginsberg et al. 1999). Nevertheless, 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 manifestations 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


3.1

Tumor-Related Factors

3.1.1 Tumor Stage In contrast to NSCLC, small-cell lung cancer is generally classified into a two-stage system—limited and extensive disease—with limited disease (tumor confined to one hemithorax (Veterans Administration Lung Study Group VALG) or without distant metastases (International Association for the Study of Lung Cancer IASLC), respectively, being tested a definite

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 prognostic 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 infiltration 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 carcinoma 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). Unfortunately, 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 parameters 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.


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 prognostic 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 processes (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

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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 connected 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 numerous and even very large clinical trials the performance status—independent of the schedule used—was confirmed 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 prognostic factor also in small-cell lung cancer (Stanley 1980; Tamura et al. 1998; Bremnes et al. 2003). A more complex determinant predicting the survival 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

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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 independent 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 chemotherapy (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

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 complete 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 aminotransferase 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 threegroup-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 documented 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 pronounced (Tai et al. 2003), but a randomized trial comparing higher dose with hyperfractionated schedule 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 radiochemotherapy has only been evaluated in one randomized


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 1

Introduction.............................................................. 692

2 2.1 2.2 2.3 2.4 2.5

Technical Aspects .................................................... Beam Modification.................................................... Three-Dimensional Conformal Radiation Therapy... Intensity-Modulated Radiation Therapy ................... Intensity-Modulated Arc Therapy............................. Volumetric-Modulated Arc Therapy.........................

3

Potential Advantages of Intensity-Modulated Radiation Therapy and Volumetric-Modulated Arc Therapy: Dose-Escalation and Toxicity Reduction .............. Intensity-Modulated Radiation Therapy versus Three-Dimensional Conformal Radiotherapy........... Intensity-Modulated Radiation Therapy Planning Studies........................................................................ Toxicity and Intensity-Modulated Radiation Therapy ...................................................................... Volumetric-Modulated Arc Therapy Experience .....

3.1 3.2 3.3 3.4

4 Treatment Planning................................................. 4.1 Simulation .................................................................. 4.2 Target Volumes (Gross Tumor Volume, Clinical Target Volume, Planning Target Volume)............... 4.3 Inverse Planning ........................................................ 5 Targeting and Verification ..................................... 5.1 Image-Guided Radiation Therapy............................. 5.2 Biological Targeting with Positron Emission Tomography............................................................... 5.3 Treatment Verification ..............................................

I. S. Grills (&) V. S. Mangona Department of Radiation Oncology, William Beaumont Hospital, 3601 West Thirteen Mile Road, Royal Oak, MI 48073-6769, USA e-mail: [email protected]

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6

Outcomes .................................................................. 705

7

Conclusion ................................................................ 709

References.......................................................................... 709

Abstract

Per 2010 estimates by the American Cancer Society, lung cancer has both the highest incidence and mortality of all malignancies in the United States. Overall, outcomes, though improving, remain poor, and radiation therapy (RT) is an important mainstay of locoregional therapy. The technical challenges of delivering biologically effective doses of RT capable of achieving adequate local control are many and relate to target definition, respiratory tumor motion, tissue heterogeneities and normal tissue tolerance. Advancements over standard two-dimensional RT, including three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), and more recently volumetrically-modulated arc therapy (VMAT), in addition to four-dimensional (4D) CT simulation and planning techniques, using biological targeting via positron emission tomography (PET) and 2 and 3-D image-guided delivery methods 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 3D-CRT with respect to tumor dose escalation and OAR dose, particularly for locally-advanced disease. This, however, is potentially at the cost of longer treatment times, monitor units, and volume of lung receiving low dose, with some concern for


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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 studies 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 combined: 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 primary 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 standardfractionated 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

Michigan group reached doses up to 102.9 Gy for small solitary tumors (Rengan et al. 2004). Across dose-escalation studies, however, the maximum tolerated 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 conformal 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 (pneumonitis). 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) increases the potential for dose-escalation while sparing organs at risk (OARs), but requires advanced technologies to account for respiratory tumor motion such as four-dimensional computed tomography (4D-CT) and is ideally administered using online 3D-image-guidance for proper targeting and margin reduction. In this chapter, we discuss technological advances beyond 3D-CRT, particularly IMRT, intensity-modulated 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

693

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-modulated 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 possible 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

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 manipulated 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 intensitymodulated 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 radiationinduced epilation on the patient’s scalp from corresponding

IMRT beam intensity (left) (From McDermott and Orton, color plate 18, The physics and technology of radiation therapy, 2010)

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)

intensities delivered through multiple beam angles allows dose-escalation to target volumes and subvolumes (e.g. simultaneous integrated boost), organ sparing, and ultimately, ‘‘dose painting’’ (Figs. 6, 7) superior to 3D-CRT (Brahme 1988).

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 openand sub-portals). The IMRT beam is therefore a series of ‘‘beamlets,’’ with each beamlet providing a different discrete intensity. At risk of oversimplification, 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

2.4

Intensity-Modulated Arc Therapy

Yu et al. at William Beaumont Hospital first introduced intensity-modulated arc therapy2 (IMAT) in 1995. This was a rotational radiation therapy delivery technique in which the field shape changed dynamically as the linear accelerator gantry rotated. Gantry rotational speed and dose rate were constant

2

Notably, distinctions for IMAT and VMAT are not universally 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-modulated 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.’’


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 heterogeneous 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. 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 sequencing 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 inadequate for dose calculations at a fine resolution; further, support from linear accelerator control software was lacking (Otto 2008; Ramsey et al. 2001). Achievable dose distributions, however, were considered comparable to helical tomotherapy while using a standard linear accelerator (Cao et al. 2007).

2.5

Fig. 6 The dose distribution in a geometric phantom (square slabs in virtual water) illustrating the power of IMRT. Sevengantry 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 heterogeneous 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

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 dynamicallymodulated during RT delivery. Thus highly conformal 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, substantially 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 modulation 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

3.1

Potential Advantages of Intensity-Modulated Radiation Therapy and VolumetricModulated Arc Therapy: Dose-Escalation and Toxicity Reduction 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 concave 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 scenario 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

(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 benefit 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 treatment-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.


697

Table 1 Comparison of median/mean dose to organs at risk: 3D-CRT versus IMRT and VMAT Organ

Study

N

Patients

Parameters

3DCRT

IMRT

VMAT

Difference

P

Spinal cord

Bedford and Warrington (2009)

10

NR

Dmax

10 Gy

–

9 Gy

-0.5 Gy

NS

Grills et al. (2003)a

9

N0

Dmax+3

mm

24 Gy

30 Gy

–

+5.6 Gy

–


9

N2–N3

Dmax+3

mm

41 Gy

41 Gy

–

-0.6 Gy

–

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


35

N2–N3

V5

55%

45%

–

-10%

\0.0001

Liu et al. (2004)

10

I–IIIB

V5

NR

NR

–

+8.0%

b

Lungs

c

0.007 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


10

NR

V10

40%

–

34%

–5.6%

0.03

10

I–IIIB

V10

NR

NR

–

–1.6%

Liu et al. (2004) c

NS c


21

I

V10

NR

–

NR

2.6% RR

0.01


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


10

NR

V20

21%

–

24%

+2.6%

0.02


9

N0

V20

22%

19%

–

-2.8%

–

a

Grills et al. (2003)

9

N2–N3

V20

29%

26%

–

-3.2%

–


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


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


41

III–IV

Veff

71 Gy

58 Gy

–

-13 Gy

\0.0001


10

NR

MLD

14 Gy

–

14 Gy

+0.1 Gy

NS


9

N0

MLD

13 Gy

12 Gy

–

-1.8 Gy

–


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


41

III–IV

MLD

19 Gy

17 Gy

–

-2 Gy

\0.0001


35

N2–N3

MLD

16 Gy

16 Gy

–

+0.1 Gy

NS


41

III–IV

Integral lung dose

19 Gy

16 Gy

–

-3 Gy

\0.0001


9

N0

NTCP

12%

11%

–

+1.1%

–

a

9

N2–N3

NTCP

21%

17%

–

-3.6%


– (continued)

698


Table 1 (continued) Organ

Study

N

Patients

Parameters

3DCRT

IMRT

VMAT

Difference

P

Esophagus


9

N0

V50

5%

6%

–

+0.6%

–

a


9

N2–N3

V50

26%

19%

–

-7.6%

–


9

N0

Mean dose

12 Gy

12 Gy

–

-0.2 Gy

–


9

N2–N3

Mean dose

27 Gy

24 Gy

–

-2.9 Gy

–


35

N2–N3

Dmax

93 Gy

79 Gy

–

-14 Gy

\0.0001


9

N0

Dmax+3

mm

46 Gy

43 Gy

–

-3.4 Gy

–


9

N2–N3

Dmax+3

mm

76 Gy

74 Gy

–

-1.6 Gy

–

a

Heart

Grills 2003(2003)

9

N0

NTCP

5.2%

2.2%

–

-3.0%

–


9

N2–N3

NTCP

41%

19%

–

-22%

–


10

NR

Mean dose

9.9 Gy

–

9.4 Gy

NS

–


9

N0

D33

8.9 Gy

9.3 Gy

–

+0.4 Gy

–

a


9

N2–N3

D33

19 Gy

20 Gy

–

+0.8 Gy

–


9

N0

D67

5.2 Gy

4.4 Gy

–

-0.8 Gy

–

a


9

N2–N3

D67

7 Gy

8 Gy

–

+1.5 Gy

–


9

N0

D100

0.3 Gy

0.6 Gy

–

+0.3 Gy

–


9

N2–N3

D100

0.9 Gy

1.6 Gy

–

+0.7 Gy

–


9

N0

NTCP

0.1%

0%

–

-0.1%

–

a

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 (%)

27

47

22

4

–

78

16

6

–

–

4

67

18

11

–

23

57

16

2

–

18

49

31

–

–

Early

73

22

6

–

–

Early

98

–

–

2

–

45

44

7

4

–

Esophageal

Early Late

Pulmonary

Early Late Early

Nausea Cardiac Skin

Early

Fatigue

Toxicity was scored using a modified RTOG toxicity scoring system (Cox et al. 1995)


2005; Liu et al. 2004; Grills et al. 2003; Chapet et al. 2005; Murshed et al. 2004). With twice-daily hyperfractionated regimens, severe acute esophageal toxicity 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 linearly 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 dose)[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) calculations, 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 PETpositive 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 IntensityModulated 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 intrathoracic 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, suggesting 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 lowdose 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 volumes (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 optimization 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 delivered (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 writing. 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.

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 previously 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 coverage. 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 limitedsegment 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


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

–

–


CI 95%

1.25

–

1.23

NS


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


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 carboplatin/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 strategies may be preferential to an adaptive imageguidance 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 treatment 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 contoured 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 followed 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-FDGavid, subcentimeter lymph nodes are always excluded. 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

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 adenocarcinomas suggests a margin as small as 1.2 mm from GTV (on lung windows) to CTV may be sufficient 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 projection (MIP) approach, (3) automatic breath-hold, (4) respiratory gating, and (5) fluoroscopy. RTOG 0617 recommends fluoroscopy to assess maximal respiratory excursion when 4D-CT is not available. With the various approaches to account for tumor motion, RTOG 0617 defines minimum CTV-to-PTV expansions 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 generation of a fluence map and segments are done simultaneously considering the predefined constraints of the treatment machine, substantially shortening the required time for IMRT planning. Inverse treatment


703

Table 4 CTV to PTV expansions: RTOG 0617 (Bradley et al. 2007) and Beaumont methods RTOG 0617

Superior– inferior

Beaumont

Freebreathing

Breath-hold/ respiratory gating

ITV

No ITV (cm)

With daily imaging (cm)

No daily bone registration (cm)

C1.5

C1.0

C1.0

ITV

4D-Adaptive online IGRT protocol

With daily bony registration (cm)

With bone or soft tissue registration (cm)

(Includes ITV technique and bone or soft tissue registration)

C0.5

0.5

Superior: variablea Inferior: variablea

Motion: C1.0 Setup: 0.5

Axial

C1.0

C0.5

C1.0

C0.5

0.5

Anterior: variablea Posterior: variablea

Motion: C0.5

Medial: 0.3 cm

Setup: 0.5

Lateral: 0.3 cm

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 distribution 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 treatment 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 clinically 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 imageguidance. 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 4Dtechniques using combinations of 4D-imaging, 4Dplanning, and image-guided radiation therapy (IGRT) with oonboard 4D-conebeam CT (4D-CBCT) using three strategies: (1) 4D-union technique, (2) 4D offline 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


Table 5 Dose constraints to organs at risk

Spinal cord Lungs

Esophagus

RTOG 0617 (Bradley et al. 2007) (60 vs. 74 Gy)

RTOG 0839 (Edelman et al. 2010) (60 Gy)

Beaumont (2.0 Gy/day)

Beaumont (1.5 Gy BID)

Dmax \ 50.5 Gya

Dmax \ 50.5 Gya

Dmax(+3 50 Gya

Dmax(+3 Gya

mm)

B

mm)

B 47

(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

Dmax \ 40 Gy

V50 B 30%

V47 B 30%

Dmean B 25 Gy

Dmean B 23.4 Gy

Dmean \ 34 Gy

b

Dmax(+3 75 Gy

mm)

B

Dmax(+3 70 Gy

mm)

B

Brachial plexus

Dmax \ 66 Gy

Dmax \ 66 Gy

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

Dmax B 66 Gy

Dmax B 63 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

3DCRT

4D-union (%)

4D-offline ART (single correction) (%)

4D-online ART (daily correction) (%)

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 fluoroscopy 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 positron 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


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 (simulation/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-escalation 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 proceed 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 (Mohammed 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 respiratorygated 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 imaging 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 particularly 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 relatively 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 writing). However, IMRT has shown ability to escalate tumor dose while sparing normal tissue. In the retrospective 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%, diseasefree 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).

2009

2008–2010

2008–2010

2008–2010

68

40

24

17

17

17

MD Anderson (Yom et al. 2007)

Belgium (Bral et al. 2010)

Milan (Scorsetti et al. 2010)

Beaumont (abstract) (McGee et al. 2010)



2005–2008

2002–2005

2001–2005

55

MSKCC (Sura et al. 2008)

Time

n

Study

Stage III

Stage III

Stage III

Inoperable Stage III

Inoperable Stage IIIa

Stage IIB–IV

Inoperable Stage I–IIIB

Patients

66 (66–72, 54 preoperative)



1.5 BID

1.5 BID

1.5 BID

2.0

2.35

70.5 (all)

66 (50–66)

1.8–2.0

1.8–2.0

Gpf (Gy)

63 (50.4–76)

69.5 (60–90)

Dose (Gy) mean/median (range)

Table 7 Outcomes in NSCLC treated with IMRT and VMAT

IMRT

IMRT

IMRT

VMAT

Helical TT

IMRT

IMRT

RT Type

Concurrent (100%)

Concurrent (100%)

Concurrent (100%)

None (21%)

Sequential (33%)

Concurrent (46%)

None (18%)

Concurrent (0%)

Sequential (82%)

Concurrent (100%)

Induction (29%)

Concurrent (24%)

Sequential (53%)

Chemotherapy

12 months

12 months

12 months

6 months

14 monthsa

8 months (0–27)

21 months (0–61)

Follow-up median (range)

DM

RR

LR

Response at 3 months (RECIST(Therasse et al. 2000))

LPFS

Locoregional Control

Local Control

Parameter

(continued)

1 year: 31%

1 year: 30%

1 year: 6%

Disease progression: 0%

Stable disease: 22%

PR \ 50%: 22%

PR [ 50%: 56%

2 year: 50%

1 year: 66%

12 months: 55%

6 months: 94%

2 year: 58% (Stage III)

2 year: 50% (Stage I–II)

Outcome

706 I. S. Grills and V. S. Mangona

n

40

68

55

55

68

Study






Table 7 (continued)

2002–2005

2001–2005

2001–2005

2002-2005

2005-2008

Time

Stage IIB–IV



Stage IIB-IV


Patients

63 (50.4–76)

1.8–2.0

1.8–2.0

1.8–2.0

69.5 (60–90)

69.5 (60–90)

1.8–2.0

2.35

Gpf (Gy)

63 (50.4–76)

70.5 (all)


IMRT

IMRT

IMRT

IMRT

Helical TT

RT Type

Concurrent (100%)

Induction (29%)

Concurrent (24%)

Sequential (53%)

Concurrent (24%)

Sequential (53%)

Concurrent (100%)

None (18%)

Concurrent (0%)

Sequential (82%)

Chemotherapy

8 months (0–27)

21 months (0–61)

21 months (0–61)

OS

OS

CSS

DFS

DMFS

14 monthsa

8 months (0–27)

Parameter


(continued)

12 months: 55%

6 months: 79%

2 year: 58% (Stage III)

2 year: 55% (Stage I–II)

2 year: 57%

Median: 25 months

2 year: 63%

12 months: 32%

6 months: 67%

1 year: 43%

Median: 10.6 months

Outcome

Intensity-Modulated Radiation Therapy and Volumetric-Modulated Arc Therapy for Lung Cancer 707

40

17



2008–2010

2005–2008

Time

Stage III


Patients


70.5 (all)


1.5 BID

2.35

Gpf (Gy)

IMRT

Helical TT

RT Type

Concurrent (100%)

12 months

OS

1 year: 92%

2 year: 27%

1 year: 65%

Median: 12 months (IIIB)

Median: 17 months

None (18%)

OS

14 monthsa

Outcome

Median: 21 months (IIIA)

Parameter


Concurrent (0%)

Sequential (82%

Chemotherapy

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

n

Study

Table 7 (continued)

708 I. S. Grills and V. S. Mangona


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 hypofractionated 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 distantmetastasis-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, doseescalation trial for patients with stage IIIA–IIIB NSCLC using online 4D-adaptive CBCT imageguidance. 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, preliminary 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 currently 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.

7

709

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 disease, 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 inverseplanning 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 dosimetric 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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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


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 CyberKnife robotic radiosurgery system, originally designed for frameless intracranial radiosurgery using automated image-guidance, has unique characteristics 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.

References.......................................................................... 723

1

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: [email protected]

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 surgical 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 characteristics that make it well suited for SABR of tumors that move with breathing, including lung tumors. This chapter reviews the qualities of the CyberKnife


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B. W. Loo Jr. and I. C. Gibbs

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 stereotactic radiotherapy system is the seamless integration of fully image-guided stereotactic localization, eliminating 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 computer-controlled robotic manipulator, a pair of orthogonal X-ray sources and imaging panels, infrared light-emitting diodes as external surface markers and an optical camera that monitors their position, and a computer-controlled patient couch (Fig. 1). Equally critical

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 software that analyzes the imaging data acquired during treatment to determine the appropriate corrections to apply to the couch and linac positions to maintain stereotactic 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 calculation 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.

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Fiducial Marker Placement

Dynamic target tracking is an integral part of treating tumors that move with breathing using the CyberKnife. 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 percutaneous needle placement, a bronchoscopic procedure, or even endovascular delivery, prior to the initial simulation (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 suboptimal 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 pneumothorax. The CT-guided percutaneous approach in particular carries the highest risk of pneumothorax, although this is still a risk albeit small using bronchoscopic 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 embolization 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 bronchoscopy 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 percutaneously 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).

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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

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treatment system. Because the CyberKnife relies entirely on image guidance for its accuracy, and because it adapts dynamically to intrafractional changes in the target position, requirements for immobilization 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 system cannot compensate other than by interrupting the treatment. It makes more sense to think in terms of patient position stabilization rather than immobilization, 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 evacuation 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 unnecessary, 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 noncoplanar 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 clearance 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

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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 positioning 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.

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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 guidance 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 permits ‘‘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

scan. During treatment delivery, the robotic manipulator 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 calculate 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 planning 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 substantially different density. The standard dose calculation 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 overestimates 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.


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).

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Treatment Delivery and Image Guidance

Image guidance is in fact the key distinguishing feature 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 images 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

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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 threedimensional 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

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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 coordinates. 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 calculated. 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 correlation 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


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, diaphragm, 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 settings, although early clinical reports of favorable tumor control when using this method provide indirect 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 compensation, 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 automated image analysis, such as fiducial marker extraction, can and do occur, manual inspection of the images displayed during the treatment and interruption 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.

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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 cooperative group trial in a uniform population of medically inoperable patients with peripherally located early


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 mediastinum, 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-institutional 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 specifically, 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 published 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 fraction of 15 Gy (the starting dose level of the Phase I trial). In the early period of this study, motion management 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

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possible treatment-related deaths, all in patients who had received prior or subsequent chemotherapy and two of three in patients who had received prior thoracic radiotherapy. Pulmonary toxicity was encountered 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 pulmonary 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 metastases). 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 preliminary analysis of a tumor volume-adapted dosing strategy in which small tumors (\12 mL) were treated with single fractions of biologically effective dose (BED) \100 Gy and larger tumors (C12 mL) were treated with more dose intensive multi-fraction regimens 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

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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 progression was 22 months and median overall survival

was 24 months. There was a statistically significantly longer time to local progression with the higher dose. University of Pittsburgh investigators are also coordinating 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 radiation 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


(Unger et al. 2010). One patient with gross endobronchial 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 fractions (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.

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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

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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.

References Ahn SH, Han MS, Yoon JH et al (2009) Treatment of stage I non-small cell lung cancer with CyberKnife, image-guided robotic stereotactic radiosurgery. Oncol Rep 21:693–696 Anantham D, Feller-Kopman D, Shanmugham LN et al (2007) Electromagnetic navigation bronchoscopy-guided fiducial placement for robotic stereotactic radiosurgery of lung tumors: a feasibility study. Chest 132:930–935 Baumann P, Nyman J, Hoyer M et al (2009) Outcome in a prospective Phase II trial of medically inoperable Stage I non-small cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 27:3290–3296 Brown JM, Diehn M, Loo BW (2010) Stereotactic ablative radiotherapy should be combined with a hypoxic cell radiosensitizer. Int J Radiat Oncol Biol Phys 78:323–327 Brown WT, Wu X, Amendola B et al (2007a) Treatment of early non-small cell lung cancer, stage IA, by image-guided robotic stereotactic radioablation–CyberKnife. Cancer J 13:87–94 Brown WT, Wu X, Fayad F et al (2007b) CyberKnife radiosurgery for stage I lung cancer: results at 36 months. Clin Lung Cancer 8:488–492 Brown WT, Wu X, Wen BC et al (2007c) Early results of CyberKnife image-guided robotic stereotactic radiosurgery for treatment of lung tumors. Comput Aided Surg 12:253–261 Brown WT, Wu X, Fayad F et al (2009) Application of robotic stereotactic radiotherapy to peripheral stage I non-small cell lung cancer with curative intent. Clin Oncol (R Coll Radiol) 21:623–631 Brown WT, Wu X, Fowler JF et al (2008) Lung metastases treated by CyberKnife image-guided robotic stereotactic radiosurgery at 41 months. South Med J 101:376–382 Chang CN, Zhou LY, MacFarlane G et al (2009) Excellent early local control with tumor volume adapted dosing of stereotactic body radiation therapy for pulmonary tumors. J Thorac Oncol 4:S938–S939 ClinicalTrials.gov (2008) CyberKnife radiosurgical treatment of inoperable early stage non-small cell cancer. http://www. clinicaltrials.gov/show/NCT00643318. Accessed 1 Mar 2011 ClinicalTrials.gov (2009) International randomized study to compare CyberKnife stereotactic radiotherapy with surgical resection in stage I non-small cell lung cancer (STARS). http://www.clinicaltrials.gov/show/NCT00840749. Accessed 1 Mar 2011 Collins BT, Erickson K, Reichner CA et al (2007) Radical stereotactic radiosurgery with real-time tumor motion tracking in the treatment of small peripheral lung tumors. Radiat Oncol 2:39 Collins BT, Vahdat S, Erickson K et al (2009) Radical cyberknife radiosurgery with tumor tracking: an effective treatment for inoperable small peripheral stage I non-small cell lung cancer. J Hematol Oncol 2:1

724 Coon D, Gokhale AS, Burton SA, Heron DE, Ozhasoglu C, Christie N (2008) Fractionated stereotactic body radiation therapy in the treatment of primary, recurrent, and metastatic lung tumors: the role of positron emission tomography/computed tomography-based treatment planning. Clin Lung Cancer 9:217–221 CyberKnife radiosurgical treatment of inoperable early stage non-small cell cancer. Accessed March 1, 2011. http://www. clinicaltrials.gov/show/NCT00643318 Ding C, Chang C-H, Haslam J, Timmerman R, Solberg T (2010) A dosimetric comparison of stereotactic body radiation therapy techniques for lung cancer: robotic versus conventional linac-based systems. J Appl Clin Med Phys/ Am Coll Med Phys 11:3223 Harley DP, Krimsky WS, Sarkar S, Highfield D, Aygun C, Gurses B (2010) Fiducial marker placement using endobronchial ultrasound and navigational bronchoscopy for stereotactic radiosurgery: an alternative strategy. Ann Thorac Surg 89:368–373 Discussion 73-4 Hong JC, Yu Y, Rao AK et al (2010) High retention and safety of percutaneously implanted endovascular embolization coils as fiducial markers for image-guided stereotactic ablative radiotherapy of pulmonary tumors. Int J Radiat Oncol Biol Phys, in press, published online ahead of print August 2010 Hoogeman M, Prévost J-B, Nuyttens J, Pöll J, Levendag P, Heijmen B (2009) Clinical accuracy of the respiratory tumor tracking system of the cyberknife: assessment by analysis of log files. Int J Radiat Oncol Biol Phys 74: 297–303 International randomized study to compare CyberKnife stereotactic radiotherapy with surgical resection in Stage I non-small cell lung cancer (STARS). (Accessed March 1, 2011, at http://www.clinicaltrials.gov/show/NCT00840749.) Kothary N, Heit JJ, Louie JD et al (2009) Safety and efficacy of percutaneous fiducial marker implantation for image-guided radiation therapy. J Vasc Interv Radiol: JVIR 20:235–239 Le Q-T, Loo BW, Ho A et al (2006) Results of a phase I doseescalation study using single-fraction stereotactic radiotherapy for lung tumors. J Thorac Oncol 1:802–809 Muacevic A, Drexler C, Wowra B et al (2007) Technical description, phantom accuracy, and clinical feasibility for single-session lung radiosurgery using robotic image-guided real-time respiratory tumor tracking. Technol Cancer Res Treat 6:321–328 Nuyttens JJ, Prévost J-B, Praag J et al (2006) Lung tumor tracking during stereotactic radiotherapy treatment with the CyberKnife: Marker placement and early results. Acta Oncol 45:961–965 Pennathur A, Luketich JD, Burton S et al (2007) Stereotactic radiosurgery for the treatment of lung neoplasm: initial experience. Ann Thorac Surg 83:1820–1824 discussion 4-5 Pennathur A, Luketich JD, Heron DE et al (2009a) Stereotactic radiosurgery for the treatment of lung neoplasm: experience in 100 consecutive patients. Ann Thorac Surg 88: 1594–1600 discussion 600 Pennathur A, Luketich JD, Heron DE et al (2009b) Stereotactic radiosurgery for the treatment of stage I non-small cell lung cancer in high-risk patients. J Thorac Cardiovasc Surg 137:597–604

B. W. Loo Jr. and I. C. Gibbs Prévost J-BG, Nuyttens JJ, Hoogeman MS, Pöll JJ, van Dijk LC, Pattynama PMT (2008) Endovascular coils as lung tumour markers in real-time tumour tracking stereotactic radiotherapy: preliminary results. Eur Radiol 18:1569–1576 Schroeder C, Hejal R, Linden PA (2010) Coil spring fiducial markers placed safely using navigation bronchoscopy in inoperable patients allows accurate delivery of CyberKnife stereotactic radiosurgery. J Thorac Cardiovasc Surg 140: 1137–1142 Schweikard A, Glosser G, Bodduluri M, Murphy MJ, Adler JR (2000) Robotic motion compensation for respiratory movement during radiosurgery. Comput Aided Surg 5:263–277 Schweikard A, Shiomi H, Adler J (2004) Respiration tracking in radiosurgery. Med Phys 31:2738–2741 Sharma SC, Ott JT, Williams JB, Dickow D (2010) Clinical implications of adopting Monte Carlo treatment planning for CyberKnife. J Appl Clin Med Phys/Amer Coll Med Phys 11:3142 Timmerman R, Paulus R, Galvin J et al (2010) Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303:1070–1076 Trakul N, Harris J, Dieterich S et al (2010) Volume adapted dosing in stereotactic ablative radiotherapy of lung tumors. Int J Radiat Oncol Biol Phys 78(3 suppl 1):S179 Unger K, Ju A, Oermann E, et al. (2010) CyberKnife for hilar lung tumors: report of clinical response and toxicity. J Hematol Oncol 3:39–45 Vahdat S, Oermann EK, Collins SP et al (2010) CyberKnife radiosurgery for inoperable stage IA non-small cell lung cancer: 18F-fluorodeoxyglucose positron emission tomography/computed tomography serial tumor response assessment. J Hematol Oncol 3:6 van der Voort van Zyp NC, Prévost J-B, Hoogeman MS et al (2009) Stereotactic radiotherapy with real-time tumor tracking for non-small cell lung cancer: clinical outcome. Radiother and Oncol J Eur Soc Ther Radiol and Oncol 91:296–300 van der Voort van Zyp NC, Hoogeman MS, van de Water S et al (2010a) Clinical introduction of Monte Carlo treatment planning: a different prescription dose for non-small cell lung cancer according to tumor location and size. Radiother and Oncol J Eur Soc Ther Radiol Oncol 96:55–60 van der Voort van Zyp NC, Prévost J-B, van der Holt B et al (2010b) Quality of life after stereotactic radiotherapy for stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 77:31–37 van der Voort van Zyp NC, van der Holt B, van Klaveren RJ, Pattynama P, Maat A, Nuyttens JJ (2010c) Stereotactic body radiotherapy using real-time tumor tracking in octogenarians with non-small cell lung cancer. Lung Cancer 69: 296–301 Whyte RI, Crownover R, Murphy MJ et al (2003) Stereotactic radiosurgery for lung tumors: preliminary report of a phase I trial. Ann Thorac Surg 75:1097–1101 Wilcox EE, Daskalov GM, Lincoln H, Shumway RC, Kaplan BM, Colasanto JM (2010) Comparison of planned dose distributions calculated by Monte Carlo and Ray-Trace algorithms for the treatment of lung tumors with cyberknife: a preliminary study in 33 patients. Int J Radiat Oncol Biol Phys 77:277–284

Advances in Radiation Oncology of Lung Cancer Deepak Khuntia and Minesh P. Mehta

Contents

Abstract

1 1.1 1.2 1.3

Basics of Tomotherapy............................................ Helical Delivery......................................................... Planning Parameters .................................................. Image Guidance.........................................................

725 725 726 727

2 2.1 2.2 2.3

Clinical Application................................................. Stereotactic Body Radiotherapy for NSCLC ........... Unresectable NSCLC ................................................ Hippocampal Sparing Whole Brain Radiation .........

728 728 728 730

A variety of advanced radiation technologies are currently available that have changed the way we practice Radiation Oncology. In this chapter, the authors will review one such technology, Helical tomotherapy. Basic operations and planning, applications in stereotactic body radiotherapy, and locally advanced lung cancer, as well as developing and future applications in hippocampal sparing whole brain radiation, adaptive radiation, and theragnostic radiation delivery will also be discussed.

3 Future Directions..................................................... 730 3.1 Adaptive Radiotherapy and Real-Time Planning............................................ 730 4

Conclusion ................................................................ 732

References.......................................................................... 732

Disclosures Dr. Khuntia serves on the advisory board of Radion Global and has received the speakers honorarium for Tomotherapy. Dr. Mehta serves as a consultant for Tomotherapy, and holds stock options in Tomotherapy. D. Khuntia (&) Western Radiation Oncology, 125 South Drive, Mountain View, CA 94040, USA e-mail: [email protected] M. P. Mehta Northwestern University, 676 N St. Clair, Suite 1800, Chicago, IL 60611, USA

1

Basics of Tomotherapy

1.1

Helical Delivery

Tomotherapy is the ‘‘slice-by-slice’’ delivery of intensity modulated radiation therapy, originally pioneered by Mark Carol as ‘‘serial tomotherapy’’, and commercialized as the NOMOS system. Helical tomotherapy, which replaces the ‘‘serial slice-by-slice delivery’’ (which requires multiple couch position adjustments), represents a substantial degree of sophisticated refinement over this approach, by utilizing helical delivery on a couch in continuous slow-motion, and is currently commercially available as Tomotherapy Hi-Art and Tomotherapy HD (Tomotherapy, Inc., Madison, WI). This represents just one of several image guided radiotherapy (IGRT) delivery devices available in the market place. Tomotherapy, however, differentiates itself from the other devices wherein it is a dedicated IGRT-IMRT


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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 megavoltage 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 fastmoving, actuator-driven multileaf collimators (MLC). This technology has evolved into what is now known as Tomotherapy Hi-Art and Tomotherapy HD (Helical and Direct). Tomotherapy Direct refers to the ability to deliver radiation with limited or fixed gantry positions 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 which allows incredible modulation of the beam, exceeding any currently available commercially available radiation technology (Figs. 1, 2, 3). The beam delivers radiation through a ring gantry system, similar to a diagnostic helical spiral CT scanner. There are multiple advantages to a ring gantry system, including increased stability, faster rotation, simple coplanar delivery, and no possibility of rotational collisions. Further, because of the intense modulation capable with this system, a single low energy (6 MV) is sufficient. This allows for less neutron contamination and less shielding requirements.

Fig. 3 Multi-leaf collimator within gantry of a Tomotherapy Hi-Art system. Each MLC has an incredibly fast transit time of 20 ms. The rapid rotation and modulations allow for conformal radiation delivery

1.2

Planning Parameters

Each Tomotherapy system includes its own proprietary treatment planning system. The system, as a whole, is one of the most forgiving planning systems and also one of the easiest to learn. Treatment planning is based primarily on three parameters: field width, pitch, and modulation factor. Further, each rotation is divided into 51 separate beam projections with each projection having its own leaf opening and closing pattern which transcends over seven degrees of arc. The first planning parameter is field width. 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 standard 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

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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 tomotherapy is a fully integrated IGRT system, there is considerable advantage in this technology in managing 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).

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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 paradigm in lung cancer, focusing on dose-escalation, including the approach of dose-per-fraction escalation, 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 extremely 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 accomplishes 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

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 database 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 unresectable locally advanced NSCLC that have shown initial promise for this difficult disease. Mehta and colleagues described a hypofractionated dose-perfraction 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 parameters utilized, and as can be seen from Fig. 5, the maximal tumor control probability is likely to be


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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

low doses are realized to the esophagus and lung with this plan (Adkison et al. 2008)

achieved when treatment is delivered over 25 fractions, permitting one to utilize this schedule as a baseline and escalating beyond it by increasing fractional 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 nongemcitabine 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.

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 conjunction with concurrent chemotherapy. The authors reported incredibly high 2-year local control and survival rates of 63 and 56%, respectively. Acute esophagitis 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

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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 completed a study (RTOG 0614) evaluating the drug memantine to preserve cognitive function in patients undergoing WBRT, and results are awaited. A current 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

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 standardize 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 performance 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 hippocampus 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


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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

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

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 proprietary to Tomotherapy. Further, investigations are underway that will allow the use of advanced contouring software using deformable registration algorithms 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, perform 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

situations. Tomotherapy is therefore uniquely qualified to develop adaptive radiation therapy protocols given its image guidance and treatment planning software capabilities. Further, this technology will allow for biologically 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 processes such as cell death, measured at a voxel-level using advanced PET or MR imaging; these alterations 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).

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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 garner a better understanding of the toxicities associated with it, such as chest wall pain, trachea-vascular complications, etc., but also because the recent NCIsponsored 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). Further 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. Technological advances in computer processing, exit beam dosimetry from MVCTs, and software updates in deformable registration will allow for rapid translation of new plans perhaps on a daily basis to deliver the ultimate adaptive radiation delivery.

References Adkison JB, Khuntia D et al (2008) Dose escalated, hypofractionated radiotherapy using helical tomotherapy for inoperable non-small cell lung cancer: preliminary results of a risk-stratified phase I dose escalation study. Technol Cancer Res Treat 7(6):441–447 Aoyama H, Tago M et al (2007) Neurocognitive function of patients with brain metastasis who received either whole

brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys 68(5): 1388–1395 Belderbos JS, Heemsbergen WD et al (2006) Final results of a Phase I/II dose escalation trial in non-small-cell lung cancer using three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 66(1):126–134 Bentzen SM, Gregoire V (2011) Molecular imaging-based dose painting: a novel paradigm for radiation therapy prescription. Semin Radiat Oncol 21(2):101–110 Chang EL, Wefel JS et al (2009) Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10(11):1037–1044 Chi A, Jang SY et al (2011) Feasibility of helical tomotherapy in stereotactic body radiation therapy for centrally located early stage nonsmall-cell lung cancer or lung metastases. Int J Radiat Oncol Biol Phys (Epub ahead of print, Jan 19) Dawson LA, Jaffray DA (2007) Advances in image-guided radiation therapy. J Clin Oncol Official J Am Soc Clin Oncol 25(8):938–946 DeAngelis LM, Delattre JY et al (1989) Radiation-induced dementia in patients cured of brain metastases. Neurology 39(6):789–796 Gondi V, Tolakanahalli R et al (2010a) Hippocampal-sparing whole-brain radiotherapy: a ‘‘how-to’’ technique using helical tomotherapy and linear accelerator-based intensitymodulated radiotherapy. Int J Radiat Oncol Biol Phys 78(4):1244–1252 Gondi V, Tome WA et al (2010b) Estimated risk of perihippocampal disease progression after hippocampal avoidance during whole-brain radiotherapy: safety profile for RTOG 0933. Radiother Oncol J Eur Soc Therap Radiol Oncol 95(3):327–331 Hodge W, Tome WA et al (2006) Feasibility report of image guided stereotactic body radiotherapy (IG-SBRT) with tomotherapy for early stage medically inoperable lung cancer using extreme hypofractionation. Acta Oncol 45(7):890–896 Khuntia D, Brown P et al (2006) Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol Official J Am Soc Clin Oncol 24(8):1295–1304 Kong FM, Ten Haken RK et al (2005) High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys 63(2): 324–333 Mackie TR, Balog J et al (1999) Tomotherapy. Semin Radiat Oncol 9(1):108–117 Mackie TR, Kapatoes J et al (2003) Image guidance for precise conformal radiotherapy. Int J Radiat Oncol Biol Phys 56(1):89–105 Mehta M, Scrimger R et al (2001) A new approach to dose escalation in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 49(1):23–33 Mizumatsu S, Monje ML et al (2003) Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res 63(14):4021–4027 Monje ML, Mizumatsu S et al (2002) Irradiation induces neural precursor-cell dysfunction. Nat Med 8(9):955–962

Advances in Radiation Oncology of Lung Cancer Monje ML, Toda H et al (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302(5651):1760–1765 Nagata Y, Takayama K et al (2005) Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame. Int J Radiat Oncol Biol Phys 63(5):1427–1431 Perez CA, Stanley K et al (1980) A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer 45(11):2744–2753 Schubert LK, Westerly DC et al (2009) A comprehensive assessment by tumor site of patient setup using daily MVCT imaging from more than 3, 800 helical tomotherapy treatments. Int J Radiat Oncol Biol Phys 73(4):1260–1269 Shah AP, Langen KM et al (2008) Patient dose from megavoltage computed tomography imaging. Int J Radiat Oncol Biol Phys 70(5):1579–1587 Siker ML, Tome WA et al (2006) Tumor volume changes on serial imaging with megavoltage CT for non-small-cell lung

733 cancer during intensity-modulated radiotherapy: how reliable, consistent, and meaningful is the effect? Int J Radiat Oncol Biol Phys 66(1):135–141 Song CH, Pyo H et al (2010) Treatment-related pneumonitis and acute esophagitis in non-small-cell lung cancer patients treated with chemotherapy and helical tomotherapy. Int J Radiat Oncol Biol Phys 78(3):651–658 Timmerman R, McGarry R et al (2006) Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol Official J Am Soc Clin Oncol 24(30):4833–4839 Yoon SM, Choi EK et al (2006) Clinical results of stereotactic body frame based fractionated radiation therapy for primary or metastatic thoracic tumors. Acta Oncol 45(8): 1108–1114 Yuan S, Sun X et al (2007) A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III nonsmall cell lung cancer. Am J Clin Oncol 30(3):239–244

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

Abstract

Technological advances in image guidance have led to improvements in outcome for lung cancer patients treated with radiation therapy. In particular advancements 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 doseescalation 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. Imageguidance is an important evolving component of radiation therapy for lung cancer and is an area of intense research interest.

References.......................................................................... 741

1 P. Lee (&) P. Kupelian Department of Radiation Oncology, University of California at Los Angeles, 200 UCLA Medical Plaza, Ste. B265, Los Angeles, CA 90095-6951, USA e-mail: [email protected]

Introduction

The recent technological advances in radiation therapy have dramatically improved outcomes in lung cancer patients treated with radiation. In the era of two-dimensional (2D) radiation therapy, tumor control was poor, and dose was limited due to the


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increased toxicity necessitated by the poor imaging quality during planning and treatment, and the requirement to include a large volume of normal tissue 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 realtime tumor motion. More recently, the use of hypofractionated radiation therapy or stereotactic body radiation therapy (SBRT) using sophisticated imageguidance has drastically reduced the overall treatment time as well as improved the tumor control rates to greater than 90% in medically inoperable stage I nonsmall 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) geographic misses due to tumor motion as a result of respiration during treatment delivery; and (3) inadequate planned radiation dose due to nearby doselimiting 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 volumetric 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 relationship 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 conformal SBRT approaches and IGRT, very high biological 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 CTbased imaging to identify the GTV include variability in window and level settings, motion artifact, indistinct 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, undercontouring 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 radiotherapy planning, there are many unanswered questions 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. Respiratory-induced target motion (also known as intrafraction tumor motion), can add significant amount of

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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 development 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 interfractional 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 examination slice in 21% (75/357) of cases. There were statistically significant differences between lowerlobe

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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 reproducibility 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 respiration-induced motion was along the cranio-caudal direction, which ranged from \0.5 to 3.59 cm. Furthermore, three patients had dissimilar respiratoryinduced 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 translations, rotation, and deformation. The overlap index increased only by 1.1 and 1.4%, respectively, when one accounted for rotation and rotation plus deformation. 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 rotation 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 normal 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

(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 kilovoltage 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 correlate, 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 adjustments can be made. For both Accuray and BrainLab systems, an automated 2D/3D co-registration algorithm 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.


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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 imageguided SBRT

5

Fiducial Markers

For these planar IGRT systems to be able to gate or track the tumor during radiation treatment, radiopaque 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 markerbased system for IGRT is the risk of complications

such as pneumothorax, bleeding, or infection. 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 implantation can be done either transcutaneously or transbronchially. 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 pnemothoraces, six of which required the placement of a chest tube. None of the patients who underwent

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transbronchial implantation developed pneumothorax. The authors concluded that in their patient population with many elderly patients with emphysema, transcutaneous marker implantation led to a high complication 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 implantation 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 limitations 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 operates independent of the treatment allowing image acquisition during treatment, and real-time assessment of target motion in order to compensate for intrafractional tumor and organ motion. Due to the limitations of a marker-based system in planar-based IGRT, groups have evaluated the feasibility 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


superior–inferior direction for intra- and inter-fractional 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 positions 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 fluoroscopic 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 volumetric 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 guidance 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 adequate 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


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Fig. 3 In-room megavoltage CT scan of the chest demonstrating changing tumor size throughout a treatment course

regular basis throughout a treatment course, eliminating 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 transbronchial 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 volumetric imaging. One such important future application 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

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 applications 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.

References Bradley J, Thorstad WL, Mutic S et al (2004) Impact of FDGPET on radiation therapy volume delineation in non-smallcell lung cancer. Int J Radiat Oncol Biol Phys 59:78–86 De Neve W, Van den Heuvel F, De Beukeleer M et al (1992) Routine clinical on-line portal imaging followed by immediate field adjustment using a tele-controlled patient couch. Radiother Oncol 24:45–54 Korreman S, Mostafavi H, Le QT et al (2006) Comparison of respiratory surrogates for gated lung radiotherapy without internal fiducials. Acta Oncol 45:935–942

742 Kothary N, Heit JJ, Louie JD et al (2009) Safety and efficacy of percutaneous fiducial marker implantation for image-guided radiation therapy. J Vasc Interv Radiol 20:235–239 Kupelian PA, Forbes A, Willoughby TR et al (2007) Implantation and stability of metallic fiducials within pulmonary lesions. Int J Radiat Oncol Biol Phys 69:777–785 Liu HH, Balter P, Tutt T et al (2007) Assessing respirationinduced tumor motion and internal target volume using four-dimensional computed tomography for radiotherapy of lung cancer. Int J Radiat Oncol Biol Phys 68:531–540 Mac Manus MP, Hicks RJ (2007) Impact of PET on radiation therapy planning in lung cancer. Radiol Clin North Am 45:627–638 Michalski D, Sontag M, Li F et al (2008) Four-dimensional computed tomography-based interfractional reproducibility study of lung tumor intrafractional motion. Int J Radiat Oncol Biol Phys 71:714–724 Nehmeh SA, Erdi YE, Pan T et al (2004a) Four-dimensional (4D) PET/CT imaging of the thorax. Med Phys 31:3179–3186 Nehmeh SA, Erdi YE, Pan T et al (2004) Quantitation of respiratory motion during 4D-PET/CT acquisition. Med Phys 31:1333–1338 Onishi H, Araki T, Shirato H et al (2004) Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma: clinical outcomes in 245 subjects in a Japanese multiinstitutional study. Cancer 101:1623–1631 Perez CA, Bauer M, Edelstein S et al (1986) Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int J Radiat Oncol Biol Phys 12:539–547

P. Lee and P. Kupelian Prenzel KL, Monig SP, Sinning JM et al (2003) Lymph node size and metastatic infiltration in non-small cell lung cancer. Chest 123:463–467 Richter A, Wilbert J, Baier K et al (2010) Feasibility study for markerless tracking of lung tumors in stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 78: 618–627 Seppenwoolde Y, Shirato H, Kitamura K et al (2002) Precise and real-time measurement of 3D tumor motion in lung due to breathing and heartbeat, measured during radiotherapy. Int J Radiat Oncol Biol Phys 53:822–834 Shimizu S, Shirato H, Kagei K et al (2000) Impact of respiratory movement on the computed tomographic images of small lung tumors in three-dimensional (3D) radiotherapy. Int J Radiat Oncol Biol Phys 46:1127–1133 Shirato H, Shimizu S, Kunieda T et al (2000) Physical aspects of a real-time tumor-tracking system for gated radiotherapy. Int J Radiat Oncol Biol Phys 48:1187–1195 Timmerman R, Paulus R, Galvin J et al (2010) Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303:1070–1076 Wu J, Lei P, Shekhar R et al (2009) Do tumors in the lung deform during normal respiration? An image registration investigation. Int J Radiat Oncol Biol Phys 75: 268–275 Xia T, Li H, Sun Q et al (2006) Promising clinical outcome of stereotactic body radiation therapy for patients with inoperable Stage I/II non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 66:117–125

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 confirms the feasibility of proton radiation for earlystage 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 CGE

D. A. Bush (&) Department of Radiation Medicine, Loma Linda University Medical Center, 11234 Anderson Street, Loma Linda, California 92354, USA e-mail: [email protected]

CTV GTV Gy

Twice-daily treatment (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) Clinical target volume Gross tumor volume Gray, standard radiation dose. A common daily fraction of photon-beam radiation is 2 Gy (or 200 centigray (cGy)); a


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IMPT IMRT NSCLC PTV SBRT

D. A. Bush

30-fraction course of radiation at that dose rate equates to a total dose of 60 Gy Intensity-modulated proton therapy Intensity-modulated radiation therapy Non-small-cell lung cancer Planned target volume Stereotactic body radiation therapy

tissue regions such as the heart, lung, esophagus, and spinal cord. Tumor-control rates with photon radiation therapy, however, continue to be disappointing, in part because of dose-limiting constraints associated with these normal structures.

2 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 prognosis 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 peripherally located T1 or T2 tumors without evidence of nodal or distant metastases (Mountain 1997). More than 80% of patients, however, present with moreadvanced 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 (multiple 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-modulated photon radiotherapy (IMRT) or stereotactic body radiation therapy (SBRT), in which more-complex 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 tumorcontrol within the constraints of surrounding normal-

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 nontargeted 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 physician 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 unacceptable side effects. The ability to reduce or eliminate 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 several 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-threatening 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

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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 possible, 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 following pulmonary irradiation. The temporal relationship between elevation of specific cytokines and histological and biochemical evidence of fibrosis illustrated the continuum of response which, the authors speculated, underlies pulmonary radiation reactions and supports the concept of a perpetual cascade of cytokines, produced immediately after radiotherapy and persisting until expression of pathologic and clinical late effects (Rubin et al. 1995). Proton-beam therapy offers a means to reduce the volume integral dose. Protons demonstrate a Bragg peak: the deposited dose is relatively low upon entrance and increases slowly until reaching the prescribed depth in tissue; there, the bulk of the dose is deposited within the targeted volume and no dose is deposited in distal tissues. The radiation oncologist can spread out the Bragg peak to encompass the target volume while still retaining a relatively low entrance dose and sparing tissues distal to the direction of travel (Fig. 1). In NSCLC, and in contrast to

Fig. 2 Planning comparison of a single lateral field with a Xray (left) and proton-beam (right)

treatment of similar target volumes with photon beams, these properties permit sparing the treated lung, opposite lung, heart, esophagus, and spinal cord, in turn allowing for safe dose escalation. Because local tumor-control rates are generally poor with conventional photon radiation treatment, and because evidence exists to indicate that higher doses may improve tumor-control, investigators have anticipated a role for proton radiation therapy in patients with lung cancer. Fowler (2003), using biological modeling, estimated that significant improvements in local tumor-control and survival are likely to supervene with proton radiotherapy. Because of the

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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 treatment regimens with photons. Accordingly, clinical investigations of proton and other heavy-chargedparticle treatments for lung cancer are being conducted 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 dosimetric circumstances for treating lung cancer with protons; these circumstances differ from those associated with proton therapy elsewhere in the body. For example, lung cancers are invariably surrounded by aerated pulmonary parenchyma, in which an essentially 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 situation that is not typically seen in tumors located in other parts of the body. Additionally, when lung targets 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 movement 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

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 techniques to account for respiratory motion in planning proton treatments. Target expansion utilizing treatment planning in which the planning CT data set includes multiple phases of the respiratory cycle (the fourth dimension of 4D planning) was found to provide the most reliable target coverage. Intrinsic pulmonary 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 radiation 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 accentuated by the proton beam’s energy-deposition sensitivity to variations in density caused by respiratory motion. Even allowing for such factors, however, proton-beam dosimetry improves upon that obtainable 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.


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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

percentage of the total prescribed dose. Dose–volume histogram (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

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 nontarget lung dose when protons where used. The normal 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-

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 normal structures in these presentations.

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Similarly, a study by many of the same investigators (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 scattered 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 individualized 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 compensator 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 unnecessarily 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

lateral, posterior, and posterior oblique beams. Frequently 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 tissues distal to the tumor; this location frequently is at the mediastinal pleural surface, thus completely sparing the mediastinum and contralateral lung. Multiple 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 inconsistent 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 earlystage 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


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Fig. 5 Dose–volume histogram for the total of the irradiated lung associated with the treatment plan shown in Fig. 4 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 weightings 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 function (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

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-smallcell 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 significantly lower survival rate (approximately 16%). Pulmonary toxicity was reported as minimal. A recent report from Nakayama et al. (2010) reaffirms that, in their experience, proton radiation therapy was effective and well tolerated in medically inoperable patients with Stage I NSCLC. Studies now underway at LLUMC utilize protonbeam radiotherapy in conjunction with chemotherapy for treating locally advanced lung cancers. Neo-adjuvant 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 esophageal 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

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identifier: NCT00495170) are evaluating proton radiation in combination with Paclitaxel and Carboplatin. These safety/efficacy studies are similar, yet differ in some details. In the Florida study, the primary 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, progression-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 posttreatment 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 treatment-planning comparisons reveal that proton treatment 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 treatmentrelated 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

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.

References Bonnet RB, Bush D, Cheek GA, Slater JD, Panossian D, Franke C, Slater JM (2001) Effects of proton and combined proton/ photon beam radiation on pulmonary function in patients with resectable but medically inoperable non-small-cell lung cancer. Chest 120:1803–1810 Bush DA, Slater JD, Shin BB, Cheek G, Miller DW, Slater JM (2004) Hypofractionated proton beam radiotherapy for stage I lung cancer. Chest 126:1198–1203 Byhardt RW, Martin L, Pajak TF, Shin KH, Emami B, Cox JD (1993) The influence of field size and other treatment factors on pulmonary toxicity following hyperfractionated irradiation for inoperable non-small cell lung cancer (NSCLC). Analysis of a radiation therapy oncology group (RTOG) protocol. Int J Radiat Oncol Biol Phys 27:537–544 Chang JY, Zhang X, Wang X, Kang Y, Riley B, Bilton S, Mohan R, Komaki R, Cox JD (2006) Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensity-modulated radiation therapy in stage I or stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 65:1087–1096 Engelsman M, Kooy H (2005) Target volume dose considerations in proton beam treatment planning for lung tumors. Med Phys 32:3549–3557 Engelsman M, Rietzel E, Kooy H (2006) Four-dimensional proton treatment planning for lung tumors. Int J Radiat Oncol Biol Phys 64:1589–1595

Proton Therapy for Lung Cancer: State of the Science Fowler JF (2003) What can we expect from dose escalation using proton beams? Clin Oncol 15:S10–S15 Grills IS, Yan D, Martinez AA, Vicini FA, Wong JW, Kestin LL (2003) Potential for reduced toxicity and dose escalation in the treatment of inoperable non-small-cell lung cancer: a comparison of intensity-modulated radiation therapy (IMRT), 3D conformal radiation, and elective nodal irradiation. Int J Radiat Oncol Biol Phys 57:875–890 Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300 Kong FM, Ten Haken RK, Schipper MJ, Sullivan MA, Chen M, Lopez C, Kalemkerian GP, Hayman JA (2005) High dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys 63:324–333 Mountain CF (1997) Revisions in the international system for staging lung cancer. Chest 111:1710–1717 Moyers MF, Miller DW, Bush DA, Slater JD (2001) Methodologies and tools for proton beam design for lung tumors. Int J Radiat Oncol Biol Phys 46:1429–1438 Murshed H, Liu HH, Liao Z, Barker JL, Wang X, Tucker SL, Chandra A, Guerrero T, Stevens C, Chang JY, Jeter M, Cox JD, Komaki R, Mohan R (2004) Dose and volume reduction for normal lung using intensity-modulated radiotherapy for advanced-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 58:1258–1267 Nakayama H, Sugahara S, Tokita M, Satoh H, Tsuboi K, Ishikawa S, Tokuuye K (2010) Proton beam therapy for patients with medically inoperable stage I non-small-cell lung cancer at the University of Tsukuba. Int J Radiat Oncol Biol Phys 78:467–471 Nihei K, Ogino T, Ishikura S, Nishimura H (2006) High dose proton beam therapy for stage I non-small-cell lung cancer. Int J. Radiat Oncol Biol Phys 65:107–111 Register SP, Zhang X, Mohan R, Chang JY (2010) Proton stereotactic body radiation therapy for clinically challenging

751 cases of centrally and superiorly located stage I non-smallcell lung cancer. Int J Radiat Oncol Biol Phys, epub ahead of print, doi: 10.1016/j.ijrobp.2010.03.012 Rosenman JG, Halle JS, Socinski MA, Deschesne K, Moore DT, Johnson H, Fraser R, Morris DE (2002) High-dose conformal radiotherapy for treatment of stage IIIA/IIIB NSCLC: technical issues and results of a phase I/II trial. Int J Radiat Oncol Biol Phys 54:348–356 Rubin P, Casarett GW (1968) Clinical radiation pathology. W. B. Saunders, Philadelphia Rubin P, Cooper RA, Phillips TA (eds) (1978) Radiation biology and radiation pathology syllabus. Am Coll Radiol Pub, Chicago Rubin P, Johnston CJ, Williams JP, McDonald S, Finkelstein JN (1995) A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys 33:99–109 Saunders M, Dische S, Barrett A, Harvey A, Gibson D, Parmar M (1997) Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: a randomized multicentre trial. Lancet 350:161–165 Shioyama Y, Tokuuye K, Okumura T, Kagei K, Sugahara S, Ohara K, Akine Y, Ishikawa S, Satoh H, Sekizawa K (2003) Clinical evaluation of proton radiotherapy for non-smallcell lung cancer. Int J Radiat Oncol Biol Phys 56:7–13 Zhang X, Li Y, Pan X, Xiaoqiang L, Mohan R, Komaki R, Cox JD, Chang JY (2010) Intensity-modulated proton therapy reduces the dose to normal tissue compared with intensity-modulated radiation therapy or passive scattering proton therapy and enables individualized radical radiotherapy for extensive stage IIIB non-small-cell lung cancer: a virtual clinical study. Int J Radiat Oncol Biol Phys 77:357– 366 Zhao L, Sandison GA, Farr JB, Hsi WC, Wu H, Li XA (2007) Patient-specific margins for proton therapy of lung. Australas Phys Eng Sci Med 30:344–348

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

Abstract

1

Introduction.............................................................. 754

2 2.1 2.2 2.3 2.4

Hypo-Fractionation Irradiation ............................. Materials and Methods .............................................. Results........................................................................ Discussion .................................................................. Conclusions................................................................

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3 3.1 3.2 3.3

Single-Dose Irradiation ........................................... Patients and Treatment.............................................. Staging ....................................................................... Results and Discussion..............................................

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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: [email protected]

It has been more than one decade since we started carbon ion radiation therapy (CIRT) for non-smallcell lung cancer (NSCLC) in November 1994. From 1994 to 1999, we conducted a phase I/II clinical trial for stage I NSCLC with CIRT and demonstrated an optimal dose of 90 GyE in 18 fractions over 6 weeks and 72 GyE in 9 fractions over 3 weeks for achieving more than 90% local control with minimal pulmonary damage. In the 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 directions. 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


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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 singledose 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 survival 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.

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

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 pulmonary 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 radiotherapy (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 demonstrated 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 completed in November 1993 (Hirao et al. 1992).

(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 effectiveness 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 determined 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 irradiation 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.

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(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.

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

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 squamous cell carcinomas, 2 large cell carcinomas and 1 adenosquamous cell carcinoma. Medical inoperability stood at 76% (Table 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 2.1.1

Materials and Methods

Carbon Ion Beams, HIMAC and Treatment Systems Carbon ion beams with 290, 350 and 400 MeV/ nucleon energy were generated in the HIMAC synchrotron 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 custom-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 radiographs 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).

2.1.3 Treatment The targets were usually irradiated from four oblique directions without prophylactic elective nodal irradiation (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 extending the target margin in the head and tail directions by

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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

Male

38

54

92

Female

12

25

37

0

0

8

8

1

50

68

118

2

0

3

3

Gender

PS

T factor (stage) T1 (IA)

30

42

72

T2 (IB)

21

38

59

Tumor size (mm)

30.9

32.1

31.5

AD

32

53

85

SQ

19

24

43

Histology

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 prevention 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 squamous 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 nonSquamous 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


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 and Survival rate

Local Control (n=131)& Survival(n=129)

1.0

Local Control (5y) 91.5%

0.8

Cause-specific(5y) 67.7%

0.6

Overall (5y) 45.3%

0.4 0.2 0.0 0

10

20 30 40 Month after treatment

50

126 patients were at grade 1 and 3 patients were at grade 2. No more than grade 3 reactions were observed. The cause of death was assessed. Sixty-two out of 129 patients (48.8%) were dead at that time, with 31 dying of the lung tumor treated with CIRT. Five of the patients died due to primary recurrence and 26 patients due to metastasis and dissemination. For the remaining 31 patients, intercurrent diseases were the cause of death.

60

Fig. 2 Five-year local control (blue), cause-specific (red), and overall (green) survivals in 129 patients with 131 stage I NSCLC after start of CIRT on the following two phase-II regimen combined: the total dose was fixed at 72 GyE in 9 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)

RTOG/EOTRC (late) as shown in Table 3. The early skin reaction was assessed for 131 lesions and the late skin reactions for 128 leisions. In acute reaction 125 lesions were at grade 1 and 6 at grade 2. In late reaction 126 lesions were at grade 1, one at grade 2 and one at grade 3. The lung reaction was clinically assessed for 129 patients. There were 127 patients at grade 0 and 2 patients at grade 2 in early reaction. There were 126 patients who were followed up for late effect. Among them, 7 patients were at grade 0,

2.3

Discussion

In the present study, we used the fixed total dose of 72 GyE in 9 fractions over 3 weeks, and of 52.8 GyE for stage IA and 60 GyE for stage IB 4 fractions over one week. Using this schedule which was optimized in the phase I/II study by CIRT (Miyamoto et al. 2003), we conducted a phase II clinical trial for 129 patients with stage I NSCLC. As a result, the local control, cause-specific, and overall survival rates for 129 patients were 91.5, 67.0, and 45.3%, respectively. And toxicity in skin, lung and bone was of a minimum. Local recurrence out of 131 primary cancers of 129 patients occurred in 9 cases (6.8%). The average recurrence time was 17.2 months in an average

758

T. Miyamoto et al.

Table 3 Adverse effects by CIRT Early reaction (RTOG) Lesion no Skin

Lung

Late reaction (RTOG/EORTC)

0

1

2

3

4B

Lesion no

0

1

2

3

4B

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

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 previous 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 reliable 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 outstanding 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 survival. 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


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 difference in the local control rate for T1 and T2 and near significant for squamous cell carcinoma and nonsquamous 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 survival was less than that of surgery due to high incidence 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 ultrasoundguided 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

T. Miyamoto et al.

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

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

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 distribution 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

by using a drawn-out dose fractionation regimen with few adverse effects. The present standard technique is a fractionation regimen in which the required radiation 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 radiotherapy 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 (n=131)

Local Control and survival rate

at more than 36.0GyE 1 .8 .6

.4 .2

Local control(5 years) : 80.5% Cause-specific (5 years) : 71.5% Over all (5 years) : 52.6%

0 0

1

2

3

4

5

6

Years after treatment

Fig. 4 Five-year local control (blue), cause-specific (red), and overall survivals (green) in 131 patients with 131 stage I NSCLC after start of single-dose CIRT (#2010) with doses more than 36 GyE

result of modern science and we are confident that it will mark the beginning of a new era of radiotherapy for the 21st century. To achieve this goal we will remain committed to further research for various cancers at early stage. Irradiation in our single-dose CIRT is completed within one hour. By reducing the burden on the patient’s mental and physical, it is suitable for outpatient radiation and accordingly economical. Reducing mortality due to lung cancer deaths is the most important issue. As a practical solution we propose a new paradigm for the fight against the lung cancer (Iinuma and Miyamoto 2006). This approach calls for the popularization of lung cancer screening CT to cover over 50% of the entire Japanese population aged between 40 and 84 by 2025 and the treatment of the early-lung cancer thus detected by screening CT with single-dose CIRT. By this means it would be possible to reduce the lung cancer mortality by over 22%. The strategic installation of CIRT facilities exclusively dedicated to the treatment of lung cancer throughout Japan would permit reduction of lung cancer death on a large scale at a lower cost than with current surgery. Fortunately, NCI announced in November 2010 (ACRIN 2010) that a large-scale RCT for lung cancer screening by low-dose CT demonstrated the reduction of lung cancer death by 20% and total death by 7% of for heavy smokers. Our proposal will come true in the near future.

761

Acknowledgments We thank the following doctors who participated in this long-term study: Hideki Nisimura, Masasi Koto, Toshiyuki Sugawara, Tomoyasu Yasiro, Naoki Hirasawa, Kenji Kagei, Mio Nakajima, Toshio Sugane, Kyousan Yosikawa, Susumu Kandatsu, Hidefumi Ezawa and Kennosuke Kadono. We also thank the doctors who constantly supported and advised: Hirohiko Tujii, Jun-etsu Mizoe, Suhou Sakata, Kozo Morita, Takeshi Iinuma, and Toru Matzumoto, and Takehiko Fujisawa of the Working group for lung cancer.

References ACRIN (2010) For immediate release. Screening of people at high-risk for lung cancer with low dose CT significantly reduces lung cancer death Bush DA, Slater JD, Bonnet R et al (1999) Proton-beam radiotherapy for early stage lung cancer. Chest 116:1313–1319 Endo M, Koyama-Ito H, Minohara S et al (1996) Hiplan-a heavy ion treatment planning system at HIMAC. J Jpn Soc Ther Radiol Oncol 8:231–238 Harpole DH, Herndon JE, Yung WG et al (1995) Stage I nonsmall cell lung cancer. A multivariate analysis of treatment methods and patterns of recurrence. Cancer 76:787–796 Hirao Y, Ogawa H, Yamada S et al (1992) Heavy ion synchrotron for medical use—HIMAC project at NIRSJAPAN. Nucl Phys A 538:541c–550c Jeremic B, Classen J, Bamberg M (2002) Radiotherapy alone technically operable, medically inoperable, early-stage (I/II) non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 54:119–130 Kanai T, Furusawa Y, Fukutsu K et al (1997) Irradiation of mixed beam and design of spread out Bragg peak for heavyion radiotherapy. Radiat Res 147:78–85 Kanai T, Endo M, Minohara S et al (1999) Biophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy. Int J Radiat Oncol Biol Phys 44:201–210 Koto M, Miyamoto T, Yamamoto N, et al (2004) Local control and recurrence of stage I non-small cell lung cancer after carbon ion radiotherapy. Radiother Oncol 71:147–156 Ludwig Seitz, Hermann Wintz (1920) Unsere Methode der Rontgen-Tiefentherapie und ihre ihre Erforge. Verlag von Uaban & Schwarzenberg, Berlin N24, Wien I, 1920 Martini N, Bains MS, Burt ME et al (1995) Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109:120–129 Minohara S, Kanai T, Endo M et al (2000) Respiratory gated irradiation system for heavy ion radiotherapy. Int J Radiat Oncol Biol Phys 47:1097–1103 Miyamoto T (2004) Carbon beam therapy for lung cancer. Jpn J Lung Cancer 44:741–751 Miyamoto T, Yamamoto N, Nishimura H et al (2003) Carbon ion radiotherapy for stage I non-small cell lung cancer. Radiother Oncol 66:127–140 Miyamoto T, Baba M, Yamamoto N, Koto M et al (2007a) Curative treatment of stage I non-small cell lung cancer with carbon ion beams using a hypo-fractionated. Int J Radiat. Oncol Biol Phys 67:750–758

762 Miyamoto T, Baba M, Yamamoto N, Sugane T et al (2007b) Carbon ion radiotherapy for stage I non-small cell lung cancer using a regimen of four fraction during 1 week. J Thorac Oncol 2:916–926 Mountain CF (1997) Revisions in the international system for staging lung cancer. Chest 111:1710–1717 Nagata Y, Takayama K, Matuo Y et al (2005) Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame. Int J Radiat Oncol Biol Phys 63:1427–1431 Nakajima T, Yasufuku K, Fujiwara T et al (2008) Endobronchial ultrasound-guided transbronchial needle aspiration for the diagnosis of intrapulmonary lesions. J Thorac Oncol 3(9):985–988 Naruke T, Tsuchiya R, Kondo H et al (2001) Prognosis and survival after resection for bronchogenic carcinoma based on the 1997 TNM-staging classification: the Japanese experience. Ann Thorac Surg 71:1759–1764

T. Miyamoto et al. Onishi H, Araki T, Shirato H et al (2004) Stereotactic hypofractionated high-dose irradiation for stageI nonsmall cell lung carcinoma. Cancer 101:1623–1631 Shioyama Y, Tokuuye K, Okumuma T et al (2003) Clinical evaluation of proton radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 56:7–13 Iinuma T, Miyamoto T (2006) A new paradigm for medical practice for lung cancer: A combination of lung cancer screening by LSCT (lung cancer screening CT) and radiosurgery by single-dose carbon irradiation. JJLC 46:309–314 Yamamoto N, Miyamoto T, Nishimura H et al (2003) Preoperative carbon ion radiotherapy for non-small cell lung cancer with chest wall invasion-pathological findings concerning tum response and radiation induced lung injury in the resected organs. Lung Cancer 42:87–95 Yasukawa T, Yamaguchi Y, Aoyagi H et al (1996) Diagnosis of hilar and mediastinal lymph node metastasis of lung cancer by positoron emission tomography using 11C-methionine. Jpn J Lung Cancer 36:919–926

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

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 chemoradiation 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 adenocarcinoma 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.

References.......................................................................... 770

1 C. J. Langer (&) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA e-mail: [email protected]

Introduction

In fit patients with minimal weight loss (i.e., less than 5–10% from baseline) and intact PS (ECOG PS 0-1), concurrent chemoradiation with a platinumbased combination has emerged as the standard


765

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 tolerate an acute fluid load, the use of the etoposide– cisplatin combination with XRT, both started on day 1, is generally favored. The minimum ‘‘accepted’’ 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 (creatinines 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) investigated 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 standard of MVP with weekly carboplatin in combination with either irinotecan or paclitaxel during XRT; in each arm, those without disease progression or untoward toxicity went on to receive two cycles of fulldose chemotherapy during the ‘‘consolidation’’ period using the same agents administered during XRT. The paclitaxel–carboplatin regimen resulted in less toxicity, fewer dose reductions or omissions, and equivalent, 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-generation 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 pemetrexed 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 firstline treatment in advanced non-squamous NSCLC based on a phase III trial showing a survival advantage for pemetrexed–cisplatin compared to gemcitabine–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 effectiveness, ease of administration, and relatively mild toxicities 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 radiation 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 featured pemetrexed (500 mg/m2) with escalating carboplatin 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 regimen 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 toxicity 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 cooperative 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 randomized 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 platinum 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 histology, 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 cisplatin 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 cisplatin 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 toxicity, 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 justifiably 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 thoracic 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 cisplatin (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 doselimiting toxicities were observed. Median radiation dose was 64 Gy (range, 45–66 Gy). Rates of significant Grade 3/4 hematologic toxicity were 38 and 7%, respectively. One patient experienced Grade 3 acute

768

esophagitis, and two experienced late grade 3 esophageal 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%. Longterm PFS and OS are still pending. The authors concluded 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 chemoradiation (ClinicalTrials.gov. NCT00686959; H3E-MCJMIG). 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 consolidation, with clinician’s choice of either cisplatin/ etoposide, cisplatin/vinorelbine, or carboplatin/paclitaxel. 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 etoposide in the therapy of locally advanced, unresectable NSCLC. Meanwhile, ClinicalTrials.gov. lists at least ten ongoing studies evaluating pemtrexed in combination 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 consolidation cisplatin-pemetrexed (ClinicalTrials.gov. NCT0 0497315). A separate trial orchestrated by the Intergroupe Francophone de Cancerologie Thoracique 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). Eligibility stipulates stage III, non-squamous cell NSCLC and performance status 0–1. An aborted trial conducted the Hoosier Oncology Group grafted singleagent pemetrexed onto standard dose thoracic RT (60 Gy) in poor prognosis patients with compromised PS or >10% baseline weight loss. (ClinicalTrials.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 Lineberger Cancer Center of UNC, led by Stinchcombe and colleagues is assessing concurrent pemetrexed and WBRT in NSCLC patients with newly diagnosed 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 doselimiting 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 steroid 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 cellular transport of nab-paclitaxel differs from that of standard solvent-based paclitaxel. Albumin is transported via a gp60-mediated mechanism into endothelial 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 concentration of paclitaxel following administration of ABI-007compared with an equal dose of cremophorbased 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, pancreatic, renal, and esophageal cancer. Caveolin-1 overexpression has been linked to tumor aggressiveness and poor patient prognosis. Albumin-bound nanoparticles (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 paclitaxel wedded to a cremaphor vehicle. As a consequence, 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 neutropenia. The much shorter infusion schedule also favored abraxane over paclitaxel [10–30 min compared 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 carcinoma (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 versus. 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-sensitization 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 antitumor efficacy against both tumor types and acted as a radiosensitizer. Combined with radiation, nab-paclitaxel 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 nabpaclitaxel 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-paclitaxel 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-paclitaxel, SGVSGHV-nab-paclitaxel,and saline controls. HVGGSSV-nab-paclitaxel treatment induced a significantly greater loss in vasculature in irradiated tumors compared with unirradiated tumors, nabpaclitaxel, 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 combination with 3D conformal radiotherapy or intensitymodulated 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 albuminstabilized 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 erlotinib (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 preclinical 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.

References ABI 007. Drugs RD (2004) 5:155–159 (For more details see doi: 10.1200/JCO.2005.03.7135 Aupérin A, Rolland E, Curran WJ et al (2007) Concomitant radio-chemotherapy (RT-CT) versus sequential RT–CT in locally advanced non-small cell lung cancer (NSCLC): a meta-analysis using individual patient data (IPD) from randomised clinical trials (RCTs): A1-04. J Thorac Oncol 2:S310 Brade A, Bezjak A, MacRae R (2011) Phase I trial of radiation with concurrent and consolidation pemetrexed and cisplatin in patients with unresectable stage IIIA/B non-small cell lung cancer. Int J Radiat Oncol Biol Phys 79(5):1395–1401 [Epub 2010 Jun 3] Choy H, Curran WJ, Scott CB , Bonomi P, Travis P, Haluschak J, Belani CP (2002) Preliminary report of locally advanced multimodality protocol (LAMP): ACR 427: a randomized phase II study of three chemo-radiation regimens with paclitaxel, carboplatin, and thoracic radiation (TRT) for patients with locally advanced non small cell lung cancer (LA-NSCLC). Proc Am Soc Clin Oncol 21 Choy H, Schwartzberg LS, Dakhil SR (2010) Ongoing phase II study of pemetrexed plus carboplatin or cisplatin with concurrent radiation therapy followed by pemetrexed consolidation in patients with favorable-prognosis inoperable stage IIIA/b non-small cell lung cancer: Interim update. J Clin Oncol 28:15s [suppl; abstr 7082] Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B,

Focus on Pemetrexed and Nab-Paclitaxel Pereira JR, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP (2009) Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 374(9699):1432–1440 [Epub 2009 Sep 18. PMID: 19767093] Curran W, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Russell A, Byhardt R, Machtay M, Sause W, Cox JD (2010) Phase III Comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III non-small cell lung cancer (NSCLC): report of radiation therapy oncology group (RTOG) 9410. JNCI (in press) Damascelli B, Cantu G, Mattavelli F et al (2001) Intraarterial chemotherapy with polyoxyethylated castor oil free paclitaxel, incorporated in albumin nanoparticles (ABI-007): phase II study of patients with squamous cell carcinoma of the head and neck and anal canal: preliminary evidence of clinical activity. Cancer 92:2592–2602 Desai N, Trieu V, Yao Z et al (2006) Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albuminbound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res 12:1317–1324 Furuse K et al (1999) Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small cell lung cancer. J Clin Oncol 17(9):2692–2699 Green MR, Manikhas GM, Orlov S et al (2006) Abraxane(R), a novel Cremophor(R)-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small cell lung cancer. Ann Oncol 17:126–138 Govindan R, Bogart J, Wang X et al (2009) Phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small cell lung cancer: CALGB 30407. Program and abstracts of the 45th annual meeting of the American Society of Clinical Oncology, May 29–June 2, Orlando, Florida, Abstract 7505 Gradishar WJ, Tjulandin S, Davidson N et al (2005) Phase III trial of nanoparticle albumin-bound paclitaxel compare with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 23:7794–7803 Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr (2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol 22(9):1589–1597

771 Hariri G, Yan H, Wang H, Han Z, Hallahan DE (2010) Radiation-guided drug delivery to mouse models of lung cancer. Clin Cancer Res 16(20):4968–4977 [Epub 2010 Aug 27] Ibrahim NK, Desai N, Legha S et al (2002) Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res 8:1038–1044 Ibrahim NK, Samuels B, Page R et al (2005) Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel in women with metastatic breast cancer. J Clin Oncol 23:6019–6026 Movsas B, Scott C, Langer C et al (2005) Randomized trial of amifostine in locally advanced non-small cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: radiation therapy oncology group trial 98-01. J Clin Oncol 23(10):2145–2154 Nyman DW, Campbell KJ, Hersh E et al (2005) Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies. J Clin Oncol 23:7785–7793 Scagliotti GV, Parikh P, von Pawel J et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small cell lung cancer. J Clin Oncol 26:3543–3551 Seiwert TY, Connell PP, Mauer AM et al (2007) A phase I study of pemetrexed, carboplatin, and concurrent radiotherapy in patients with locally advanced or metastatic nonsmall cell lung or esophageal cancer. Clin Cancer Res 13:515–522 Socinski MA, Bondarenko IN, Karaseva NA (2010) Results of a randomized, phase III trial of nab-paclitaxel (nab-P) and carboplatin (C) compared with cremophor-based paclitaxel (P) and carboplatin as first-line therapy in advanced nonsmall cell lung cancer (NSCLC). J Clin Oncol 28:18s [suppl; abstr LBA7511] Sparreboom A, Baker SD, Verweij J (2005) Paclitaxel repackaged in an albumin-stabilized nanoparticle: handy or just a dandy? J Clin Oncol 23:7765–7767 Wiedenmann N, Valdecanas D, Hunter N et al (2007) Radiocurability and therapeutic gain 130-nm albuminbound paclitaxel enhances tumor. Clin Cancer Res 13: 1868–1874 Yamamoto N, Nakagawa K, Nishimura Y, Tsujino K, Satouchi M, Kudo S, Hida T, Kawahara M, Takeda K, Katakami N, Sawa T, Yokota S, Seto T, Imamura F, Saka H, Iwamoto Y, Semba H, Chiba Y, Uejima H, Fukuoka M (2010) Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small cell lung cancer: West Japan Thoracic Oncology Group WJTOG0105. J Clin Oncol 28(23):3739–3745 Epub 2010 Jul 12

Novel Targeted Agents and Radiopharmaceuticals in Lung Cancer Martin J. Edelman and Nadia Ijaz

Contents 1

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 responsible for normal cellular growth, maintenance and development have been identified. Derangements of these pathways frequently result in cancer, perpetuate cancer or result in resistance to treatment with chemotherapy and/or radiation. New agents targeting 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 radioisotopes to a moiety that will bind with receptors that are aberrantly expressed in cancer.

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: [email protected]

1

Overview

Many commonly employed antineoplastic agents including the platinums, vinca alkaloids, and taxanes have been incorporated into chemoradiotherapy regimens that have improved the potential for cure in patients with locally advanced (stages IIIa, b) nonsmall cell lung cancer (NSCLC). Platinum and etoposide 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 decades has resulted in numerous new agents with


773

774 Table 1 Novel targets and agents currently under clinical investigation

M. J. Edelman and N. Ijaz Class

Agent(s)

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 IGF-R inhibitors

Crizotinib (PF1066) 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)

775

Class

Agent(s)

Polo-like kinase inhibitors

BI 6727 (Volasertib) TAK 960 NMS-1286937

Aurora kinase inhibitors

AT9283 AS703569 CYC116 PF-03814735 MLN8237 LBH589B SNS 314 AMG900 GSK1070916A

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 malignancies. 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 development 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 investigation 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 (Woodburn 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 consequence of the development of agents targeting the

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), panitumumab 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 specifically to the epidermal growth factor receptor (EGFR, HER1, c ErbB-1) on both normal and tumor

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cells, and competitively inhibits the binding of EGF and other ligands, such as TGFa. Binding of cetuximab to the EGFR blocks phosphorylation and activation 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 currently approved as a single agent in advanced colorectal 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 randomized multicenter phase III trial BMS099 evaluated Cetuximab and first-line taxane/carboplatin chemotherapy 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 randomly 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 progressionfree survival assessed by independent radiologic review committee. The median progression-free survival (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 expression was not specified) and found that the EGFR inhibitor resulted in a significantly improved overall survival (Pirker et al. 2009). One thousand one hundred and twenty five patients were randomly assigned to chemotherapy plus cetuximab (n = 557) or chemotherapy alone (n = 568). The experimental arm demonstrated superior survival (median 11.3 vs. 10.1 months; HR = 0.871; P = 0.044). Recently presented 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 carcinoma 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. Starting 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 oncedaily 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 evaluate cetuximab in combination with chemoradiotherapy 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 toxicity. 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 randomized 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 intracellular domain of the EGFR (Woodburn 1999). Only one agent, erlotinib, is fully approved for the treatment of NSCLC in the United States. Gefitinib, initially 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 randomized 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 antiEGFR agents is the demonstrated benefit of EGFR antibodies in addition to cytotoxic chemotherapy in

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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 progression 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; however, 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 evaluated 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 chemotherapy (Cappuzzo et al. 2010). Since the initial studies versus placebo that demonstrated 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 importantly, 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 activating mutations. Prospective studies have now been accomplished in patients with activating mutations demonstrating unprecedented response rates and

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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 discontinuation 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% incidence 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 treatment. 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 signaling via this pathway is frequently associated with neoangiogenesis in tumors. In NSCLC, high levels of VEGF expression indicate a poor prognosis, suggesting that treatment geared toward this pathway might be effective target for therapy.

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 multiforme, 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 demonstrated improved survival for patients with advanced NSCLC treated with bevacizumab15 mg/kg in combination 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 histology. 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 ‘‘bevacizumabeligible’’ 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 progression-free survival while the trial was in progress. PFS was significantly prolonged; the hazard ratios for progression-free survival were 0.75 (6.7 vs. 6.1 months for placebo; P = 0.003) in the low-dose group and 0.82


(6.5 vs. 6.1 months for placebo; P = 0.03) in the highdose group compared with placebo. Objective response rates were 20.1, 34.1, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab, respectively. 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 bevacizumab is unclear. Though an effect on angiogenesis was the basis of its development, some have postulated that benefit may result from a normalization of vasculature 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 bevacizumab with radiation and chemoradiotherapy in locally advanced lung cancer. The Sarah Cannon group evaluated bevacizumab in combination with chemotherapy in locally advanced NSCLC and limited 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

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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 unlikely 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 concurrent 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/sorafenib 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 prespecified 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 bevacizumab and include hypertension, proteinuria, increased risk of neutropenia, and RPLS. Some carry additional toxicities, such as stomatitits (sunitinib).

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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 transcription, and chromatin architecture. PARP1 is involved in the repair of single-strand breaks. Inhibition of PARP results in double-strand breaks, which normal cells can repair through a process of homologous recombination. In cells with defective homologous recombination, such as those with BRCA1or BRCA2 deficiency, PARP inhibition leads to persistent double-strand breaks, inducing cell death through apoptosis as well as autophagy (Carey and Sharpless 2011). Preclinical work has demonstrated the potentiation of DNA damaging chemotherapy and radiotherapy 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 cytotoxicity due to both apoptosis and autophagy (Albert et al. 2007). In glioma cell lines the PARP inhibitor KU-0059436 increased radiosensitivity in a replication-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

PARP inhibition occur to a similar degree in both oxygenated and hypoxic cells. Phase I studies in combination with DNA damaging 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 randomized 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 Consortium has activated a phase I study combining ABT-888 with low-dose weekly carboplatin/paclitaxel 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 specificity at the catalytic site of the 26S proteasome that degrades ubiquitinated proteins. It blocks the nuclear factor-kappa B (NF-kB), leading to increased apoptosis, 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 proapoptotic factors, leading to programmed cell death in neoplastic cells. Currently, bortezomib is approved for the treatment of multiple myeloma. Its role in other malignancies 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/


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 trimodality 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 mediastinal 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 continuation 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 nonoperative 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 development. Some of these agents are irreversible inhibitors, 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

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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 substrates in addition to histones that are involved in regulation of gene expression, cell proliferation, and mitotic cell death. Inhibition of HDACs cause accumulation 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-containing classes I, II, and IV, but does not affect the NAD (+)-dependent class III, enzymes. Histone deacetylase inhibitors constitute a promising 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 combination 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 vorinostat 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 carboplatin/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).

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7


mTOR Inhibitors

The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase positioned at a fundamental point in many cellular signaling pathways and has been identified as a major culprit in tumorigenesis. Several inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus) have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved in the United States for the treatment of advanced renal cell carcinoma. Everolimus 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) chemoradiotherapy (NCT01063478) are now in progress

at a number of sites. In addition, everolimus is being evaluated in combination with whole brain radiotherapy 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, survival, 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 progression 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 development. Figitumumab (CP-751,871) is a fully human immunoglobin G monoclonal antibody against IGF1R 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 figitumumab (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 discontinued due to excessive deaths but others are still in progress (Jassem et al. 2010). In vitro evidence indicates that inhibition of IGF-1R results in radiosensitization (Cosaceanu et al. 2004). No studies of these agents, either alone with radiation or as part of chemoradiotherapy have been reported to date.


9

Cyclooxygenase-2 Inhibitors

Cyclooxygenase-2 (COX-2) is an enzyme of the arachidonic acid cascade. It is upregulated and overexpressed 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 upregulates 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/paclitaxel 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 improvement 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

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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 pneumonia, 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. Celecoxib 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 multicenter 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-twicedaily 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

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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 PGEM 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 urinary PGE-M suppression. If there is to be a future for COX-2 inhibitors in lung cancer, either in combination 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 lymphoma 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 microtubuleassociated 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 identified in tumor tissue by reverse transcription-polymerase 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 apoptosis 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

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 translocation (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 fatigue, nausea/vomiting, diarrhea, and visual disturbances 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 kinases, polo-like kinases, kinesin spindle proteins, survivin and others. In addition to the function of chromosomal segregation, cytokinesis and other key cellular functions mediated by tubulin are also governed 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 particular (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


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 rationale 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 radiation 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 attention to the timing of administration relative to radiation 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 important 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 differentiation, 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

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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 common 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 harboring mutations associated with activation of the Hh signaling pathway (i.e, basal cell carcinoma, medulloblastoma) (Von Hoff et al. 2009; Rudin et al. 2009). The agent demonstrated a favorable pharmacokinetic profile, with high, sustained, plasma concentrations and a terminal half-life of greater than seven days. No doselimiting 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 terminology for radiopharmaceuticals and some of the characteristics 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 validated for the treatment of B-cell non-Hodgkins lymphoma where two agents (yttrium 90 ibritumomab

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Table 2 Radionuclide terminology and examples Term

Definition

Examples

Half-life

Tissue range (mm)

Energy (mEv)

Alpha particle

2 protons ? 2 neutrons (He nucleus)

Bi211

46 min

0.04–0.1

5.87

212

Beta particle

electrons

Bi

1h

0.04–0.1

6.09

At211

7.2 h

0.04–0.1

5.87

Yt90

2.7days

2.76

2.3

a

17 h

2.43

2.1

a

6.7days

0.4

0.50

a 131

8days

0.28

0.81

Re188 Lu177 I

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 antibody, 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 evaluation 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 radiopharmaceuticals including the ability to image the tumor (which can assist with determining the appropriateness 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

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 determination 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 somatostatin 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 tolerability 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 development 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. Consequently, small cell lung cancer has been a disease of


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 demonstrating considerable activity utilizing the radiolabeled 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 particular 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 chemotherapy agents has only rarely been explored, even in preclinical models.

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790 previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. Ann Oncol 20:1674–1681 Spigel DR, Hainsworth JD, Yardley DA, Raefsky E, Patton J, Peacock N, Farley C, Burris HA 3rd, Greco FA (2010) Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol 28(1):43–48 Epub 2009 November 9 Tao Y, Leteur C, Calderaro J, Girdler F, Zhang P, Frascogna V, Varna M, Opolon P, Castedo M, Bourhis J, Kroemer G, Deutsch E (2009) The aurora-B kinase inhibitor AZD1152 sensitizes cancer cells to fractionated irradiation and induces mitotic catastrophe. Cell Cycle 8(19):3172–3181 Epub 2009 October 4 Tarhini A, Kotsakis A, Gooding W, Shuai Y, Petro D, Friedland D, Belani CP, Dacic S, Argiris A (2010) Phase II study of everolimus (RAD001) in previously treated small cell lung cancer. Clin Cancer Res 16(23):5900–5907 Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK (2004) Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64(11):3731 Vestergaard J, Pedersen MW, Pedersen N, Ensinger C, Tümer Z, Tommerup N, Poulsen HS, Larsen LA (2006) Hedgehog signaling in small-cell lung cancer: frequent in vivo but a rare event in vitro. Lung Cancer 52:281–290

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Translational Research in Lung Cancer Deepinder Singh, Kevin Bylund, and Yuhchyau Chen

Contents 1

Abstract

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 3.1 3.2 3.3

Small Cell Lung Cancer Serum Markers ............ Chromogranin A ........................................................ Neuron-Specific Enolase ........................................... Pro-Gastrin-Releasing Peptide ..................................

801 801 801 801

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: [email protected]

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 research of lung cancer. Molecular predictive tumor markers, such as mutation of epidermal 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-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) have been identified to predict response to molecular targeting agents for nonsmall 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 progastric-releasing peptide (ProGRP) may aid diagnosis, detection of disease progression or recurrence, 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 taxanebased 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


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median survival of 14–17 months after chemoradiation treatments, the outcome of this translational 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 markers, 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 treatment 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

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 triphosphate-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 transduction of growth signals. There are three wellcharacterized members of the ras oncogene family: H-ras, K-ras, and N-ras (Barbacid 1987). The oncogenic 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 adenocarcinoma 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 Kras 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 adenocarcinoma (HR 1.40; 95% CI 1.18–1.65). Notably, investigations of ras using immunohistochemical stain (IHC) showed no prognostic values in the metaanalysis (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

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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). Historically, 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

(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)

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 chemoradiation 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

(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 regulating a G1-S checkpoint before DNA synthesis, through the cyclin- dependent kinase (CDK) pathway (CordonCardo 1995). In response to DNA damage by ionizing radiation and a variety of chemical agents or carcinogens, 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.

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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 missense, 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 overexpression and mutation in adenocarcinoma (36 and 34%, respectively) was lower than that in SCC (54 and 52%, respectively). p53 alteration had a significant 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, treatment, 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 mutation (Schiller et al. 2001).

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2.1.3 Gene Expression Profiles Gene expression profiling of resected lung tumors was made possible by microarray technologies and realtime 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 metagene, 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 distinct 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

2.2.1

Predictive Tumor Markers and Molecular Targets

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


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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 tyrosine 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 fluorescence 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 nonSCC (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

number had any significant influence as an independent 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 number, the somatic mutation of EGFR gene in the tyrosine 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 approximately 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

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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 survival 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 survival 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 former light smokers to receive gefitinib versus carboplatin 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 carboplatin–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

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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 progression-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 survival 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 chemotherapy to receive gefitinib or carboplatin plus paclitaxel. In the planned interim analysis of the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standardchemotherapy 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 survival in advanced NSCLC after treatment with cisplatin-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).


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 implicated 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 lowexpressing 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 therapies, 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 cisplatin-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 protein 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

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prospective randomized clinical trial testing the concept 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 evaluated after being randomized to receive either docetaxel 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 ribonucleotide reductase, which catalyzes the production of deoxyribonucleotides from ribonucleotides preparatory 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 carcinogen-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

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progression of disease. Thus, ERCC1 and RRM1 may both predict patients with early stage tumors that do not require further therapy, and also inform appropriate 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) fusiontype 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 relationship 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.

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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 components in DNA mismatch repair processes for the recognition and replacement of erroneous base pairs. Mismatch repair reduces mutations at DNA replications, 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 nonpolyposis colorectal cancer types 1 (for MSH2) or type 2 (for MLH1), wherein patients carry a high risk for various gastrointestinal, genitourinary, and reproductive 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 inactivation (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


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 chemotherapy-induced defects, this is balanced by a mutagenic phenotype, allowing for phenotypic selection.

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3.1

CgA is a 49 kD acidic-soluble protein ubiquitously present in neuroendocrine tissues and serves as a suitable circulating marker of neoplasms of neuroendocrine origin. The ability of serum CgA to distinguish neuroendocrine and non-neuroendocrine tumors either in situ or by serum level titration has been suggested (Drivsholm et al. 1999).

3.2 2.2.7 Serum Proteomic Profiling Serum proteomic profiling that utilizes the matrixassisted 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 (Meyerson 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-gastrinreleasing peptide (Pro-GRP).

Chromogranin A

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 neoplasias (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%), especially 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

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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 (Holdenrieder et al. 2008; Wójcik et al. 2008). In a large retrospective study examining the single and combined diagnostic value of NSE, ProGRP, serum carcinoembryonic antigen (CEA), and cytokeratin fragment 19 (CYFRA21-1), ProGRP reached the highest diagnostic 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 significantly 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 biomedical 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

trials in the investigation of taxane-based chemoradiation 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 differentials 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/paclitaxel), with or without cetuximab (monoclonal antibody 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 chemoradiation regimens. The two studies targeted chest tumor control and distant micrometastasis control, yielding promising results (Chen et al. 2001, 2003, 2010).


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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

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)

4.2.1

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 radiation 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 toxicity (Chen et al. 2008). This phase I study (U1597) yielded a 100% gross tumor response rate, a threeyear survival of 30%, and low rates of grade 3 or 4 toxicities (Chen et al. 2001, 2003, 2008). The investigators 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

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 docetaxel on the cytotoxic effects versus radiation sensitizing 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-

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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

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)

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 micrometastasis, 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. Therefore, 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 concurrent 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).

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 chemotherapy 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 prospective 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, EML4ALK 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


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 investigation 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 Jeremic´

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

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.

References.......................................................................... 817

1

B. Jeremic´ (&) Institute of Lung Diseases, Sremska Kamenica, Serbia e-mail: [email protected]

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 disease. Radiation therapy remains one of the cornerstones 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


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B. Jeremic´

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’’ irrespective 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 evaluate 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-institutional setting and less within the group setting and even less within the intergroup setting. This, unfortunately, leads to less patients enrolled per study and that, ultimately, leads to poorer (lower) clinical evidence such studies can bring. Therefore, it must be clearly said that this type of approach leads to inferior quality of clinical research and hampers implementation 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.

combined radiochemotherapy in locally advanced nonsmall cell lung cancer, only a few prospective phase III clinical trials have been successfully performed, 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, unfortunately, 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 consolidation 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 technology 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 professional 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 representation 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

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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 identifying a person saying so, an unusual matter in a scientific 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 unconditionally 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 immobilization 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 orientation 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 concurrent 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

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that serves as the cornerstone of the current evidencebased 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 chemotherapy 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’’ regimens may lead to due to larger dose per fractions and less time to fractionated total chemotherapy dose.

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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 particular, this is referred to the time component to use gathered knowledge to optimize future attempts via clinical studies. These failures can broadly be separated 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 various dose-intensification trials, we do not have more clinical studies concentrating on those, rather unfavorable, 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 specifically 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

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’’ character 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 adenocarcinomas 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


followed by radical radiation therapy became standard 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 chemotherapy. 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 (concurrent) 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 subsequently 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 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 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 investigators 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

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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.

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Controversial Issues

They can broadly be divided into pressure from industry (largely discussed above), hospital/departmental 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 failures 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 radiochemotherapy 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 compensation for insufficient start (with chemotherapy).

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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 chemotherapy, 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 protracted 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 waiting 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/department management should prioritize access to radiation 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 threedimensional 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/

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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 hospital/centres) and bring more awareness to non-radiation oncology community about opportunities of modern radiation oncology in the field of lung cancer. Some of the controversial issues are actually personal in nature. We all occasionally witness evidencebased 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 oncologists 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 evidence 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


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 confirmatory trials there may be an obstacle to implement what is already proven. Several years ago, (Langer et al. 2005) report on the chemotherapy characteristics 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. Significantly 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/chemotherapy 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 substantiated 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

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and large non-academic institutions/practicing physicians 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 implementation 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 versus late radiation therapy and chemotherapy, a systematic review by (Fried et al. 2004) showed a somewhat smaller but nevertheless significant advantage for early radiation therapy and chemotherapy (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 reconcile 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 additional insight into this matter. It is, therefore, that, sometimes ‘‘meta-analysis of the meta-analyses’’, may be needed, although this could rightly be criticised as additional example of expert-based medicine! (Jeremic B. 2006). Basically, there are various differences 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

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‘‘distant’’ intrathoracic nodal areas, as well as different radiation therapy and chemotherapy characteristics. 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 included into these analyses, enhancing great heterogeneity among the studies, a usual finding when a metaanalysis is done. Also, although all used meta-analytic approach, there were differences in statistical interventions 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 outcome than ‘‘late’’ radiation therapy and chemotherapy. 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 ‘‘consolidation’’ 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 systematically 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

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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 hyperfractionation 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 optimization of this, superior, approach, but rather on optimization of inferior (currently once-daily radiation therapy) through studies of RTOG/CALGB and EORTC, 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 hyperfractionation 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 fractions in 18 treatment days and concurrent low-dose chemotherapy, as this author successfully implemented 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.


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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 successful 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 mechanistic studies to enlighten the problem of irradiationdrug 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 diseasedriven and being at the same time, technology-adapted. This is the only way we, as a profession, could

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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.

References Akerley W, Herndon JE Jr, Lyss AP, Choy H, Turrisi A, Graziano S, Williams T, Zhang C, Vokes EE, Green MR (2005) Induction paclitaxel/carboplatin followed by concurrent chemoradiation therapy for unresectable stage III non-small-cell lung cancer: a limited-access study–CALGB 9534. Clin Lung Cancer 7:47–53 Belani CP, Wang W, Johnson DH (2005a) Phase III study of the Eastern Cooperative Oncology Group (ECOG 2597): induction chemotherapy followed by either standard thoracic radiotherapy or hyperfractionated accelerated radiotherapy for patients with unresectable stage IIIA and B non-small-cell lung cancer. J Clin Oncol 23:3760–3767 Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, Curran WJ Jr (2005b) Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-smallcell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol 23:5883–5891 Belderbos J, Uitterhoeve L, van Zandwijk N, Belderbos H, Rodrigus P, van de Vaart P, Price A, van Walree N, Legrand C, Dussenne S, Bartelink H, Giaccone G, Koning C (2007) EORT LCGC and RT Group. Randomised trial of sequential versus concurrent chemo-radiotherapy in patients with inoperable non-small cell lung cancer (EORTC 08972– 22973). Eur J Cancer 43:114–121 Clamon G, Herndon J, Cooper R (1999) Radiosensitization with carboplatin for patients with unresectable stage III nonsmall-cell lung cancer: a phase III trial of the Cancer and Leukemia group B and the Eastern Cooperative Oncology Group. J Clin Oncol 17:4–11 Curran WJ Jr, Scott C, Langer C, Komaki R, Lee JS, Hauser S (2000) Phase III comparison of sequential Vs cancer (NSCLC): Initial report of Radiation Therapy Oncology Group concurrent chemoradiation for pts with unresected stage III non small cell lung (RTOG 9410). Proc Am Soc Clin Oncol 19:484a (Abstract 1891) Dillman RO, Seagren SL, Propert KJ, Guerra J, Eaton WL, Perry MC (1990) A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 323:940–945 El Sharouni SY, Kal HB, Battermann JJ (2003) Accelerated regrowth of non-small cell lung tumors after induction chemotherapy. Br J Cancer 89:2184–2189 Fried DB, Morris DE, Poole C et al (2004) Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 22:4785–4793 Gandara DR, Chansky K, Albain KS et al (2006) Long-term survival with concurrent chemoradiation therapy followed by consolidation docetaxel in stage IIIB non-small cell lung

818 cancer: a phase II Southwest Oncology Group study (S9504). Clin Lung Cancer 8:116–121 Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V, Sobin L (2007) International association for the Study of Lung Cancer International Staging Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2:706–714 Hanna N, Neubauer M, Yiannoutsos C, McGarry R, Arseneau J, Ansari R, Reynolds C, Govindan R, Melnyk A, Fisher W, Richards D, Bruetman D, Anderson T, Chowhan N, Nattam S, Mantravadi P, Johnson C, Breen T, White A, Einhorn L, Hoosier Oncology Group;US Oncology (2008) Hoosier Oncology Group; US Oncology. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol 26:5755–5760 Huncharek M, McGarry R (2004) A meta-analysis of the timing of chest irradiation in the combined modality treatment of limited-stage small cell lung cancer. Oncologist 9:665–672 Jeremic B (2006) Timing of concurrent radiotherapy and chemotherapy in limited-disease small-cell lung cancer: meta-analysis of meta-analyses. Int J Radiat Oncol Biol Phys 64:981–982 Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S (1997) Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small cell lung cancer. J Clin Oncol 15:893–900 Jeremic B, Shibamoto Y, Nikolic N, Milicic B, Milisavljevic S, Dagovic A, Aleksandrovic J, Radosavljevic-Asic G (1999) The role of radiation therapy in the combined modality treatment of patients with extensive disease small-cell lung cancer (ED SCLC): a randomized study. J Clin Oncol 17:2092–2099 Langer CJ, Moughan J, Movsas B, Komaki R, Ettinger D, Owen J, Wilson JF (2005) Patterns of care survey (PCS) in lung cancer: how well does current U.S. practice with chemotherapy in the non-metastatic setting follow the literature. Lung Cancer 48:93–102 Lau D, Leigh B, Gandara D, Edelman M, Morgan R, Israel V (2001) Twice-weekly paclitaxel and weekly carboplatin with concurrent thoracic radiation followed by carboplatin/ paclitaxel consolidation for stage III non-small-cell lung cancer: a California cancer consortium phase II trial. J Clin Oncol 19:42–447

B. Jeremic´ Le Chevalier T, Arriagada R, Tarayre M, Lacombe-Terrier MJ, Laplanche A, Quoix W (1992) Significant effect of adjuvant chemotherapy on survival in locally advanced non small cell lung carcinoma. J Natl Cancer Inst 84:58 (letter) Movsas B, Moughan J, Komaki R et al (2003) Radiotherapy patterns of care study in lung carcinoma. J Clin Oncol 21:4553–4559 Pijls-Johannesma MCG, de Ruysscher D, Lambin P et al (2004) Early versus late chest radiotherapy for limited stage small cell lung cancer. Cochrane Database Syst Rev No. 4 Saunders M, Dische S, Barrett A, Harvey A, Griffiths G, Palmar M (1999) Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in nonsmall cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee. Radiother Oncol 52:137–148 Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R (1995) Radiation Therapy Oncology Group 88–08 and Eastern Cooperative Oncology Group 4588: Preliminary results of a phase III trial in regionally advanced, unresectable nonsmall cell lung cancer. J Natl Cancer Inst 87:198–205 Schaake-Koning C, van der Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P (1992) Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med 326:524–530 Sekine I, Nokihara H, Sumi M, Saijo N, Nishiwaki Y, Ishikura S, Mori K, Tsukiyama I, Tamura T (2006) Docetaxel consolidation therapy following cisplatin, vinorelbine, and concurrent thoracic radiotherapy in patients with unresectable stage III non-small cell lung cancer. J Thorac Oncol 1:810–815 Socinski MA, Blackstock AW, Bogart JA, Wang X, Munley M, Rosenman J, Gu L, Masters GA, Ungaro P, Sleeper A, Green M, Miller AA, Vokes EE (2008) Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol 26:2457–2463 Turrisi AT 3rd, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, Wagner H, Aisner S, Johnson DH (1999) Twicedaily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 28(340):265–271 Vokes EE, Herndon JE 2nd, Crawford J, Leopold KA, Perry MC, Miller AA, Green MR (2002) Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non small-cell lung cancer: cancer and leukemia group B study 9431. J Clin Oncol 20:4191–4198

Pitfalls in the Design, Analysis, Presentation, and Interpretation of Randomized Clinical Trials Richard Stephens

Contents

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Has the Result been put into the Context of the Previous Work in this Area? ...................... 825 Conclusions ............................................................... 825

1

Introduction.............................................................. 819

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2

Have all the Randomized Patients been Accounted for? ......................................................... 820

References.......................................................................... 825

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What is the Control Treatment? ........................... 820

Abstract

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Is the Sample Size based on Information that is Sensible and Feasible? ............................................ 821

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Has the Trial been Designed to Answer a Clear, Unconfounded Question?........................................ 822

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Are the Number of Statistical Tests Limited, and if not, Have the Significance Levels been Adjusted Accordingly?............................................ 822

Randomised clinical trials are the gold standard tool for testing new treatments, but need to confirm to certain basic guidelines in order to be considered reliable. Good trial design, analysis, presentation and interpretation and an awareness of the common pitfalls are likely to maximise the relevance and impact of the trial.

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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: [email protected]

1

Introduction

We are in the era of evidence-based medicine, and the foundation for this evidence is the randomized clinical 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 outcomes of the two groups are compared. What could go wrong? Well, in practice, many things, as the design, conduct, analysis, presentation, and interpretation of RCTs can actually be very complex. Therefore the importance of high-quality RCTs cannot 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.


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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 subsequently 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 postrandomization 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 cranial 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

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 indicated above, randomization will ensure that all possible patient characteristics are balanced between the groups, including of course, the number of ineligible patients, and the number of patients who will potentially decide to drop out of the trial. Therefore, for the sake of scientific credibility and complete transparency 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.

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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 pragmatic 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 inappropriate control. A common trick is to compare the new treatment alone with the new treatment in combination 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 equivalent 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) survival 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.

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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

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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 difference) 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 schedule, 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 overoptimistic 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 probability of an inconclusive result. An even greater dilemma occurs with equivalence trials. Taking the same example that the addition of a modality (chemotherapy) improves survival over surgery alone or supportive care by about 5%, what happens when we want to show that a new chemotherapy treatment is as

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effective as the standard? If we compare the new chemotherapy to standard chemotherapy with a trial of 400 patients the result may suggest no difference but actually 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 chemotherapy, where the standard is combination chemotherapy 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 schedule 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

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 performed, 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 performed 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 significant if P B 0.025, or as is often used to accommodate interim analyses, the first is only considered significant if P B 0.001 so that the second can be considered significant if P B 0.049. It is important to be aware of how many statistical tests have been performed and what is claimed to be significant, as there can often be a tendency to trawl the data for interesting 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 highlight the balance (or imbalance) between groups. However, it is illogical to apply a statistical test to show balance or imbalance in this situation. Statistical 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.


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 significance. 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 clinicians 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 annually, 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 significant 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 Monitoring and Ethics Committee (DMEC) members there is knowledge of the disease and treatments and previous 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.

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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 randomization, 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 postoperative 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 betweentreatment 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 protocols, these are simply snapshots of the likely survivals 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 comparison, an HR of 0.85 with a 95% CI of 0.65–1.05

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indicates that our best estimate of the survival difference 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 chemotherapy 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 censored 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 example, a treatment that causes many early treatmentrelated 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 progression-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 misleading 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

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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 firstline treatments and give a false impression of their effectiveness. In such situations, progression-free survival 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 pretreatment 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 example, comparing the survival of responders versus nonresponders 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 chemotherapy received, must be viewed with great caution. Prognostic factor analyses are sometimes run to try and identify the factors most related to survival, but


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 inappropriate as treatment will be a confounding factor, and predictive analyses, which look at the impact of treatment 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 multidimensional, 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 problems 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 inappropriately. 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 predefining QL hypotheses which have the effect of guiding the choice of questionnaire, the choice of administration time points, the sample size calculation 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

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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 picture. We must never lose sight of the fact that lung cancer is a global problem and without global collaboration 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.

References Clarke M, Chalmers I (1998) Discussion sections in reports of controlled trials published in general medical journals: Islands in search of continents? JAMA 280:280–282 Clarke M, Alderson P, Chalmers I (2002) Discussion sections in reports of controlled trial published in general medical journals. JAMA 287:2799–2801 Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR et al (2000) Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol 18:2354–2362 Fukuoka M, Yano S, Giaccone G, Tamura T, Nagagawa K et al (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small cell lung cancer. J Clin Oncol 21:2237–2246 Gatzemeier U, von Pawel J, Gottfried M, ten Velde GPM, Mattson K et al (2000) Phase III comparative study of high dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small cell lung cancer. J Clin Oncol 18:3390–3399 Georgoulias V, Papadakis E, Alexopoulos A, Tsiafaki X, Rapti A et al (2001) Platinum-based and non-platinum-based chemotherapy in advanced non-small cell lung cancer: a randomised multicentre trial. Lancet 357:1478–1484 Gore EM, Bae K, Wong SJ, Sun A, Bonner JA et al (2011) Phase III Comparison of prophylactic cranial irradiation versus observation in patients with locally advanced nonsmall-cell lung cancer: primary analysis of radiation therapy oncology group study RTOG 0214. J Clin Oncol 29: 272–278 Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK et al (2001) Randomized phase III trial of paclitaxel plus

826 carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small cell lung cancer: a southwest oncology group trial. J Clin Oncol 19:3210–3218 Langendijk H, de Jong J, Tjwa M, Muller M, ten Velde G et al (2001) External irradiation versus external irradiation plus endobronchial brachytherapy in inoperable non-small cell lung cancer: a prospective randomized study. Rad Oncol 58:257–268 Lee JJ (2011) Demystify statistical significance—time to move on from the p value to Bayesian analysis. J Natl Cancer 103:2–3 Non-Small Cell Lung Cancer Collaborative Group (1995) Chemotherapy in non-small cell lung cancer: a metaanalysis using updated data on individual patients from 52 randomised clinical trials. BMJ 311:899–909 Pujol J-L, Daures J-P, Riviere A, Quoix E, Westell V et al (2001) Etoposide plus cisplatin with or without the combination of 40 -epidoxorubicin plus cyclophosphamide in treatment of extensive small cell lung cancer: a French Federation of Cancer Institutes multicenter phase III randomized study. J Natl Cancer Inst 93:300–308 Ranson M, Davidson N, Nicolson M, Falk S, Carmichael J et al (2000) Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small cell lung cancer. J Natl Cancer Inst 92:1074–1080 Rosell R, Gomez-Condina J, Camps C, Maestre J, Padilla J et al (1994) A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small cell lung cancer. N Engl J Med 330:153–158 Roszkowski K, Pluzanska A, Krzakowski M, Smith AP, Saigi E et al (2000) A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naïve patients with metastatic or nonresectable localized non-small cell lung cancer (NSCLC). Lung Cancer 27:145–147 Roth JA, Fossella F, Komaki R, Ryan MB, Putnam JB et al (1994) A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIa non-small cell lung cancer. J Natl Cancer Inst 86:673 Sandler AB, Nemunaitis J, Denham C, von Pawel J, Cormier Y et al (2000) Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 18:122–130 Sause W, Kolesar P, Taylor IV S, Johnson D, Livingston R et al (2000) Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer. Chest 117:358–364

R. Stephens Scagliotti GV, Fossati R, Torri V, Crino L, Giaconne G et al (2003) Randomized study of adjuvant chemotherapy for completely resected stage I, II or IIIa non-small cell lung cancer. J Natl Cancer Inst 95:1453–1461 Schiller JH, Harrington D, Belani CP, Langer C, Sandler A et al (2002) Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 346:92–98 Sculier JP, Paesmans M, Lecomte J, van Cutsem O, Lafitte JJ et al (2001) A three-arm phase III randomised trial assessing, in patients with extensive disease small cell lung cancer, accelerated chemotherapy with support of haematological growth factor or oral antibiotics. Br J Cancer 85:1444–1451 Shepherd FA, Giaccone G, Seymour L, Debruyne C, Bezjak A et al (2002) Prospective, randomized, double-blind, placebocontrolled trial of marimastat after response to first-line chemotherapy in patients with small cell lung cancer: a trial of the national Cancer Institute of Canada-Clinical Trials group and the European Organization for Research and Treatment of Cancer. J Clin Oncol 20:4434–4439 Socinski MA, Schell MJ, Peterman A, Bakri K, Yates S et al (2002) Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced stage IIIb/IV non-small cell lung cancer. J Clin Oncol 20:1335–1343 Splinter TA, Sahmoud T, Festen J, van Zandwijk N, Sorenson S et al (1996) Two schedules of teniposide with or without cisplatin in advanced non-small cell lung cancer: a randomized study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 14:127–134 Sundstrom S, Bremnes RM, Kaasa S, Aasebo U, Hatlevoll R et al (2002) Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin and vincristine regimen in small cell lung cancer: results from a randomized phase III trial with 5 years’ follow-up. J Clin Oncol 20:4665–4672 Tada H, Tsuchiya R, Ichinose Y, Koike T, Nishizawa N, Nagai K, Kato H (2004) A randomized trial comparing adjuvant chemotherapy versus surgery alone for completely resected pN2 non-small cell lung cancer (JCOG9304). Lung Cancer 43:167–173 Takada M, Fukuoka M, Kawahara M, Sugiura T, Yokohama A et al (2002) Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited stage small cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20:3054–3060

New Directions in the Evaluation and Presentation of Clinical Research in Lung Cancer Noelle O’Rourke, Fergus Macbeth, and Elinor Thompson

Contents 1

Introduction.............................................................. 827

2

What the Evidence Tells and Does Not Tell Us ...................................................... 828

3

Defining the Gaps in Evidence: Formulating Our Questions .......................................................... 829

4

Harnessing the Information to Make It Work for Us......................................................................... 829

5

Controlled Clinical Trials as a Route to Knowledge............................................................ 830

6

Systematic Reviews and Meta-Analyses ............... 831

7

Cochrane Reviews.................................................... 832

8

Challenge of Novel Technologies ........................... 834

9

Expanding Our Definition of Trial Populations ............................................................... 834

10

Translating Evidence into Practice and the Elephant in the Room............................... 835

11

What We Need to Do Next..................................... 835

References.......................................................................... 836

N. O’Rourke Beatson West of Scotland Cancer Centre, Glasgow, UK F. Macbeth (&) National Institute for Health and Clinical Excellence (NICE), London, UK e-mail: [email protected] E. Thompson Univeristy Pompeu Fabra, Barcelona, Spain

Abstract

In this chapter we summarise the problems in accessing and summarising the vast body of clinical research on lung cancer and outline how research may be made more accessible, efficient and relevant.

1

Introduction

Every lung cancer publication opens with a depressing list of statistics. Globally lung cancer tops the incidence tables—1.61 million cases in 2008 (12.7% total cancer cases), and also tops mortality with a consistently high fatality rate across the world— 1.38 million deaths in 2008, 18.2% of total cancer mortality (Ferlay et al. 2010). Fifty-five percent of new cases now occur in developing countries, a large shift in the past decade, with anticipated continuation of this trend as rates of cigarette smoking continue to rise in newly industrialised countries. Despite important developments in surgery, radiotherapy and chemotherapy over the last 20 years and many hundreds of clinical trials, population-based 5-year survival rates for lung cancer still range from about 5% to, at best, 15%. And importantly, all too little is known and published about any changes (for either better or worse) in the quality of that survival. The challenges for lung cancer research in the decade ahead are to improve outcomes not just in terms of added weeks or months of median survival but to increase long-term survival and also to demonstrate improved quality of life by treatment interventions, especially in the palliative setting where


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survival time is short. The emerging novel technologies 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 limitations 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 structures 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 literature 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 international 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

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 nonsmall-cell lung cancer (NSCLC): • Radical surgery (lobectomy or pneumonectomy) is an effective, potentially curative treatment for early-stage disease. Adjuvant chemotherapy following surgery can improve by a few percent the 5year 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 delivered 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 palliation. 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 symptoms 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 chemotherapy 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 radiotherapy 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 radiotherapy 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 survival 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,

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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 questions we need a streamlined information retrieval strategy that will search all possible resources and integrate the diverse datasets obtained. This developing 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 translational medicine. The magnitude and diversity of data generated from searching across the whole Life Sciences spectrum 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 Biomedical 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 continues to progress rapidly. With new hand-held technologies 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

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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 individual studies. A current search of the Cochrane Central Register of Controlled Clinical Trials identifies 6,309 lung cancer trials and the published literature 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 languages. 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 reporting 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 whether it can be applied to the individual patient or population that the reader is treating.

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 collaboration 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 Controlled 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 Medical Informatics Association, offers a freely accessible repository for clinical trial results which has independent peer-review. (The lack of peer review in some of the sites offering rapid access trial results limits their value).


A specialised trials register is a database of randomised 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 reference-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 searches are undertaken using specially developed search strategies, and citations and/or abstracts of all references 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 published. 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.

6

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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 narrative reviews, which may falsely advertise themselves as ‘systematic’, are characterized by their lack of the essential components of a systematic review: a focussed 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 literature), 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 differences 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 combining 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

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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. Individual patient data analyses are therefore more reliable 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 radiochemotherapy 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 Collaboration 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 conducting qualitative and quantitative analyses of the findings. 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 randomised, controlled trials as the ‘gold-standard’ of scientific investigation (Cochrane 1972). Cochrane reviews are based on pre-defined rigorous 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

Collaborative Review Groups

Fields

Centres

Steering Group

Methods Groups

The Consumer Network

Fig. 1 Cochrane collaboration entities

subject to peer reviewing by experts in both the relevant clinical field and in the methodology of systematic 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 regular intervals into the Cochrane Central Register of Controlled Clinical Trials (CENTRAL). The specialised 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

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Table 1 (continued) 26. Pemetrexed disodium for malignant pleural mesothelioma Published protocols

Published reviews

Non-small-cell lung cancer

Non-small-cell lung cancer

1. Gemcitabine for NSCLC

1. Post-operative radiotherapy (PORT) for NSCLC

2. Optimal duration of chemotherapy for advanced NSCLC

2. Radical radiotherapy for stage I/II medically inoperable NSCLC

3. Erlotinib for advanced NSCLC

3. Chemotherapy for NSCLC

4. Gefitinib for NSCLC 5. Taxane schedules for NSCLC

4. Chemo and supportive care versus supportive care alone in advanced NSCLC

Small-cell lung cancer 6. First-line chemotherapy for synchronous brain mets SCLC

5. Palliative radiotherapy for NSCLC

7. Second-line chemo for SCLC

6. Second-line chemotherapy for NSCLC

General

7. Concurrent chemoradiotherapy in NSCLC

8. Anti-angiogenic therapy for lung cancer

8. Surgery for local and locally-advanced NSCLC 9. Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for NSCLC

9. Particle therapy versus conventional treatment for lung cancer New titles

10. Surgery versus radiosurgery for patients with a solitary brain metastasis

1. Pharmacotherapy for the prevention of radiation-induced pneumonitis

11. Chemotherapy and surgery versus surgery alone in NSCLC

2. Cisplatin-based versus carboplatin-based chemo in NSCLC

12. Second or third additional chemo drug for advanced NSCLC

4. Topotecan for SCLC

13. Palliative endobronchial brachytherapy for NSCLC

3. Topotecan for advanced NSCLC 5. PET-CT for assessing mediastinal lymph nodes involvement 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)

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 registered (see www.cochrane.es/lcg). The scope of the LCG covers all aspects of primary 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 information resource in lung cancer care.

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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 increments 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 radiotherapy or the second malignancy rate, which both require substantially prolonged follow-up. And the whole issue of cost of new technology makes evaluation 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. Factoring cost into an assessment of effectiveness of new technology is further complicated by continuous change as cost decreases over time for new technologies, and the user learning curve means that there is

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 eligible 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 contributing centres and for gathering patient demographics 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 ‘goldstandard’ 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


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 knowledge 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 disseminate 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 methodology 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 recommendations 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

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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 exclusively 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 treatment 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 effectiveness that can be provided by systematic reviews and meta-analyses. A specialised trials register has much to offer in accessing trial information. Systematic reviews of the type promoted and published by the Cochrane Collaboration should be an essential

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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 disorganised 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 worldwide 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


gathering and analysing data on all our clinical activity. If we really want to increase our understanding of the biggest cancer killer of our time, the means are already at our disposal.

References Atkins D, Best D et al (2004) Grading quality of evidence and strength of recommendations. BMJ 328:1490 Auperin A, Le Pechoux C et al (2010) Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small cell lung cancer. J Clin Oncol 28(13):2181–2190 Australian National Health and Medical Research Council Guidelines. www.nhmrc.gov.au/guidelines/health_guidelines.htm Booth A, Clarke M et al (2011) International registry of systematic review protocols. Lancet 377:108–109 Clarke M, Horton R (2001) Bringing it all together: LancetCochrane collaborate on systematic reviews. Lancet 357:1728 Cochrane AL (1972) Effectiveness and efficiency. Random reflections on health services. Nuffield Provincial Hospitals Trust, London Ferlay J, Shin HR et al (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917 NICE lung cancer guideline (2011). www.nice.org.uk/CG121 Sackett DL, Rosenberg WM et al (1996) Evidence based medicine: what it is and what it isn’t. BMJ 312:71–72 SIGN lung cancer guideline (2005). www.sign.ac.uk/ guidelines/fulltext/80/index.html

Index

(TD0/5), 744 (TD5/5), 744 (TD50/5), 744 ‘beam’s eye view, 145 11 C-choline, 182 11 C-methionine, 182 18 F-fluoro-deoxyglucose(FDG), 76 18 F-fluoro-thymidine (FLT), 76 201 Tl, 182 3D conformal RT (3DCRT), 160 3D planning, 145 4D computed tomography (4DCT), 148, 347, 728 4-D imaging, 72 4D-cone beam CT (4DCBCT), 160 4D-imaging, 188 a-difluoromethylornithine (DMFO), 654

A Abraxane, 768 Accelerated fractionation, 132 Accelerated hyperfractionated radiation therapy, 507 Accelerated hyperfractionation, 498 Accelerated repopulation, 144 Acidic fibroblast growth factor (aFGF/FGF-1), 19 Active breathing control (ABC), 148, 347 Acute esophagitis, 638 Acute fatigue, 450 Acute myocardial infarction (AMI), 618 Acute pneumonitis, 611 Adaptive radiotherapy, 730 Adenocarcinoma (ADC), 54 Adenocarcinoma, 446, 812 Adjuvant chemotherapy, 439, 250 Age, 446 AKT Pathway Inhibition, 217 ALK targeted inhibitors, 271, 784 Altered fractionation regimens, 411 Amifostine (Ethyol), 226 Amifostine (WR-2721), 616 Amifostine, 425, 630, 643 Anemia, 600 Angiogenesis, growth factors, 678 Angiogenesis, 18

Angiogenic squamous dysplasia (ASD), 47 Angiopoietin-2, 22 Angiotensin-converting enzyme (ACE), 235 Aortopulmonary window, 95 ARDS, 390 Argon plasma coagulation (APC) catheters, 584 Argon plasma coagulation (APC), 50 Arterial oxygen pressure on room air (PO2), 352 Arterioplasty, 109 Ataxia, 649 Autofluorescence bronchoscopy (AFB), 46 Avalanche photodiodes (APDs), 78 Axitinib, 259, 779

B Balloon Dilatation, 584 Basic fibroblast growth factor (b-FGF), 233 Basic fibroblast growth factor (bFGF/FGF-2), 19 Basic fibroblast growth factor (FGF-2), 654 Batho and equivalent-tissue-air ratio (ETAR) methods, 154 Bcl-2 Inhibitors, 219, 237, 260 Bcl-2, 9 Bevacizumab, 254, 778 Bilobectomy, 109 Biological markers, 676, 677 Biologically effective dose (BED), 516, 566 Bioreductive drugs, 217 Blood–brain barrier, 649 Bone marrow, 598 Bone metastases, 561 Bone scans, 71 Boron neutron capture therapy (BNCT), 649 Bortezomib, 780 Brachytherapy, 477 Bragg peak, 745, 754 Brain metastases, 445, 514, 566, 647 Brain neurotoxicity, 517 Breath-hold techniques, 347 Bronchial artery embolization, 589 Bronchial stenosis, 485 Bronchioloalveolar carcinoma, 55 Bronchoplasty, 109

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

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838

B (cont.) Bronchoscopic balloon dilatation, 51 Brown–Sequard syndrome, 628

C Carbogen, 215 Carbon ion radiation therapy, 754 Carbon monoxide (CO), 612 Carbon-11 (11C), 76 Carboplatin, 276, 292, 776 Carboplatin/paclitaxel, 249 Case controls, 828 Cediranib, 259, 779 Celecoxib, 783 Central airway stenosis (CAO), 46 Cervical Mediastinoscopy, 94 Cetuximab, panitumimab, 775 Cetuximab, 256 Chart, 411 Chartwel, 411 Chasing, 347 Chemical pleurodesis, 586 Chemotherapy, 201, 248, 267, 364, 409, 454, 492, 514, 518, 809 Chest pain, 454 Chest radiographs, 64 Chromogranin A, 801 Chronic lung fibrosis, 611 Chronic obstructive pulmonary disease (COPD), 576, 611 Chronic pulmonary dysfunction, 610 Cisplatin, 249, 276 Cisplatin/etoposide, 492 Clinical target volume (CTV), 146, 188, 202, 348, 749, 755 Clinical trials, 524 Clumsiness, 628 c-MET, 10 CMR (complete metabolic response), 180 c-MYC proto-oncogene, 7 Cognitive dysfunction, 517 Cognitive functioning, 518 Cohort studies, 828 Colony formation method, 120 Combined modality treatment, 434 Computed tomography (CT), 64, 90, 173, 202 Computer aided detection (CAD), 67 Concurrent Radiochemotherapy, 415 Cone beam CT (CBCT) , 736, 346 Consolidation chemotherapy, 420, 810 CONSORT (Consolidated Standards of ReportingTrials), 830 Continuous hyperfractionated accelerated radiation therapy (CHART), 132 Control treatment, 820 Conventional radiation therapy, 316 Convolution-superposition (CS) method, 154 Cough, 454, 518, 551, 575 COX-2 inhibitors, 231, 271 Crizotinib, 259, 784 Cryotherapy, 52, 483, 583 Cryptogenic organizing pneumonia (COP), 122 CT on rails, 346

Index CT staging, 446 CT-based planning, 174 CTV/PTV, 455 CyberKnife image-guided robotic radiosurgery, 715 Cyclooxygenase COX-2-Inhibitors, 219 Cyclooxygenase-2 (COX2), 12 Cyclooxygenase-2 Inhibitors, 783 Cyclopamine, 785 Cytokinesis-block micronucleus (MN) test, 124

D Dampening, 347 Data Monitoring and Ethics Committee (DMEC), 823 Decreased sexual interest, 518 Deep inspiration breath-hold, 347 Dementia, 649 Demyelination, 629, 650 Density-correction algorithms, 154 Depression, 450 Diffusewhite matter changes, 651 Diffusing capacity for carbon monoxide (DLCO), 352 Diffusion capacity (DLCO), 612 Digitally reconstructed radiographs (DRRs), 151 Direct machine parameter optimization (DMPO), 702 DNA Repair Inhibitors, 217 Docetaxel, 251, 302 Dose escalation, 400 Dose intensification, 495 Dose-functional histograms (DFHs), 617 Dose-response, 319 Dose-volume histogram (DVH), 350, 368, 614 Dose-volume relationship, 144 Dynamic and diffusion-weighted (DWI) MRI, 72 Dysphagia, 454, 638 Dysphoria, 649 Dyspnea, 575 Dyspnoea, 450, 454, 551

E Early Stage Non-Small-Cell Lung Cancer, 525 Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion oncogene (EML4-ALK), 6 Echinoderm Microtubule-Associated Protein-Like 4-Anaplastic Lymphom Kinase Translocation, 800 Edema, 650 Efaproxaril, 237 Efaproxiral (RSR-13), 215 Elderly, 524, 812 Elective nodal irradiation, 203 Elective nodal irradiation (ENI), 192 Electrocautery (EC), 49 Electromagnetic navigation (EMN) bronchoscopy, 46, 48 Electronic portal imaging device (EPID), 694 Electronic portal imaging devices (EPIDs), 738 Emotional functioning, 518 En bloc chest wall resection, 109 Endobronchial brachytherapy (EBBT), 52, 556

Index Endobronchial Prosthesis, 580 Endobronchial ultrasonography (EBUS), 71 Endobronchial ultrasound (EBUS), 46, 94 Endoluminal brachytherapy, 477 Endoscopic (esophageal) ultrasound (EUS), 90 Endoscopic ultrasound, 71 Enhancement of tumour response, 268 Epidermal growth factor recepto proto-oncogenes: c-erb-B1, 796 Epidermal growth factor receptor (EGFR), 22, 57, 234, 775 Epidermal growth factor receptor (EGFR; ErbB-1), 11 Equivalent uniform dose (EUD), 699 Equivalent-pathlength (EPL) model, 154 Erlotinib, 252, 775, 777 Erythropoiesis-stimulating agent (ESA), 605 Erythropoietin (EPO), 216 Esophageal Endoscopic Ultrasound (EUS), 94 Esophageal ultrasonography (EUS), 71 Esophagitis index, 639 Etoposid, 260, 276, 773 Everolimus, 782 Evidence-based medicine, 819, 828 Extended cervical mediastinoscopy, 95 Extensive disease small cell lung cancer, 505, 537, 813 Extremity weakness, 628

F FACT-L, 664 FACT-TOI, 664 FDG-PET, 189 Febrile neutropenia (FN), 599 Fibroblast growth factor-3 (FGF-3/ int-2), 19 Fibroblast growth factor-4 (FGF-4/hst/K-FGF), 19 Fiducial markers, 344, 739 Figitumumab, 782 Fine motor coordination, 517 Flavopiridol (alvocidib), 236 Flexible intraoperative template (FIT), 472 FLT, 182 Fluorescence, 374 Forced expiratory volume in one second (FEV1), 352, 612 Forced vital capacity (FVC), 352, 612 Four dimensional computed tomography (4D-CT), 692 Four-dimensional (4D)-CT scanning approach, 196 Four-dimensional radiotherapy (4DRT), 157 Frontal lobe dysfunction, 517 Functional Assessment of Cancer Therapy-General (FACT-G), 664

G Gamma linolenic [omega-6] acid, 653 Gating, 347 Gefitinib, 255, 777 Gemcitabine, 251, 297 Gender, Age and Ethnicity, 679 Gene expression profiles, 796 Genetic tumor factors, 677 Geographic miss, 144 Geriatric assessment, 524

839 Granulocyte colony stimulating factor, 19 Granulocyte-colony stimulating factors (G-CSFs), 603 Gross tumor volume (GTV), 145, 188, 202, 348, 455, 748, 755, 813 GyE (Gray equivalents), 754

H Hazard ratio (HR), 823 HDAC inhibitors, 271, 781 Heavy particle beams, 754 Heavy-charged particle, 746 Hedgehog inhibitors, 260 Hedgehog Pathway Inhibitors, 260, 271, 785 Hematopoietic growth factors, 589 Hematopoietic stem cells, 589 Hemiparesis, 628 Hemoglobin (Hb), 604 Hemoptysis, 454, 485, 551, 575 Hemorrhage, 390 Hepatocyte growth factor, 22 Hepatocyte growth factor/scatter factor (HGF/SF), 19 High linear energy transfer (LET), 754 High-dose chemotherapy, 494 High-dose rate brachytherapy, 477 High-dose rate endobronchial brachytherapy (HDR-EBRT), 52 High-molecular-weight mucin-like antigen KL-6, 120 Histology, 812 Histone deacetylase inhibitors, 781 Histone deacetylases (HDAC), 218 Horners syndrome, 454 Human manganese superoxide dismutase transgene, 644 Human MutS Homologue and Human MutL Homologue 1, 800 Human recombinant keratinocyte growth factor, 644 Hybrid Stents, 582 Hyperbaric oxygen (HBO), 633, 655 Hyperbaric Oxygen, 214 Hyperfractionation, 132, 498 Hypoxia, 184, 214, 576 Hypoxic Cell Radiosensitizers, 216

I Idiopathic interstitial pneumonitis, 120 Ifosfamide, 277 IGF-1R pathway inhibitors, 260 IGF-IR targeting therapies, 271 Interleukin [IL]-1b, 231 Interleukin 1 (IL-1), 120, 613, 629, 649 IL-6, 615 Interleukin-8, 19 Image guided radiotherapy (IGRT), 725, 736 Imaging, 148 Increased vascular permeability, 650 Independent cell kill, 268 Individual patient data meta-analysis (IPD), 831 Induction chemotherapy, 413, 414, 439, 440, 810 Inhibitors to poly(ADP-ribose) polymerase (PARP), 237 Insulin-like growth factor (IGF), 630 Insulinlike growth factor-1 (IGF-1), 654

840

I (cont.) Intellectual decline, 649 Intensity modulated (IMRT), 367 Intensity-modulated radiation therapy (IMRT), 133, 401, 424, 528, 692 Intensity-modulated arc therapy (IMAT), 692 Intensity-modulated proton therapy, 747 Intercellular adhesion molecule-1 (ICAM-1), 649 Internal margin (IM), 755 Internal target volume (ITV), 188, 203 International Commission on Radiation Units (ICRU), 188, 202 International Commission on Radiation Units and Measurements (ICRU), 145 Inter-observer variability, 188 Interstitial brachytherapy, 477 Interventional pulmonology, 45 Intracranial stereotactic radiosurgery (SRS), 716 Intraoperative brachytherapy, 470 Intraoperative interstitial brachytherapy, 477 Intraoperative nodal staging, 92 Intraoperative radiation (IORT), 462 Intrapulmonary recurrence, 545 Intratumoral microvessel density (MVD), 20 Invasive mediastinal staging, 92 Irinotecan, 251, 303 Irradiation volume, 499 Irritability, 518 ITV, 348

K Keratinocyte growth factor (KGF), 233 Kilovoltage EPIDs, 738

L Lack of energy, 518 Large cell carcinoma, 54, 446, 812 Late esophageal damage, 639 Late toxicity, 611 Lethargy, 649 Leukopenia, 599 Lhermitte sign, 628 Light Emitting Diodes (LED), 373 Light initiation interval (DLI), 374 Light source, 372 Limited disease small-cell lung cancer, 533, 492, 815 Limited stage disease, 201 Linear analogue self-assessment [LASA] scales, 667 Linear-quadratic (LQ) formula, 350 Line-of-response (LOR), 76 Linifanib, 259 Liver metastases, 568 Lobectomy, 109, 249, 367, 439 Local control, 144 Locally advanced non-small cell lung cancer (LA-NSCLC), 445 Locally Advanced Nonsmall-Cell Lung Cancer, 409, 529 Locally recurrent lung cancer, 546 Locally recurrent non-small-cell lung cancer, 544

Index Location, 812 Locoregional post-surgical recurrences, 545 Locoregional recurrence of small-cell lung cancer, 556 Low-dose CT screening, 65 Low-dose daily chemotherapy, 507 Lung Cancer Symptom Scale (LCSS), 664 Lung metastases, 568 Lung tumors, 119 Lymph node dissection, 92

M Magnetic resonance imaging(MRI), 90 Malacia, 629 Manganese superoxide dismutase (MnSOD), 238 Markers of cellular adhesion, 677 Markers of DNA Repair, 798 Markers of tumor proliferation, 677 Matrix metalloproteinases, 22 Maximal intensity projection (MIP) approach, 702 Maximum intensity projection (MIP), 165, 197 Maximum tolerated dose (MTD), 402 Mean lung dose, 121 Mediastinal lymph node recurrences, 545 Mediastinal lymph node sampling, 92 Mediastinotomy, 95 Medical Outcomes Study (MOS), 663 Medical Outcomes Study 36 item Short Form Health Survey (MOS SF-36), 664 Megavoltage EPIDs, 738 Memory loss, 649 Meta-Analyses, 515, 831 Metallic Stents, 581 Metastasis, 516 Metastatic Non-Small-Cell Lung Cancer, 532 Metastatic spinal cord compression, 561 Misonidazole, 216 Mitogen-activated protein (MAP) kinase, 218 Mitomycin, 277 Mobile linear accelerator, 464 Molecular markers, 794 MRI (Magnetic Resonance Imaging), 64 M-Staging, 81 mTOR inhibitors, 260, 271, 782 Multileaf collimator (MLC), 149 Multi-leaf collimators (MLCs), 692 MVCT, 728 Myelosuppression, 589

N Nanotechnology, 272 Narrow band imaging bronchoscopy, 46 Nd: YAG laser, 483 Nd:YAG Laser Photoresection, 48 Neo-adjuvant chemotherapy, 250, 447 Neurocognitive Function, 450 Neuron-Specific Enolase, 801 Nimorazole, 216 Nitrogen-13 (13N), 76 Non small-cell lung cancer (NSCLC), 54, 515

Index Non-coplanar beams, 344 Non-small cell carcinoma (NSCLC), 54, 524, 812 Normal lung tissue, 119 Normal tissue complication probability (NTCP), 144, 403 N-stage, 81, 90 Numbness, 628

O Odynophagia, 638 Once-daily thoracic radiation, 498 Organs at risk (OARs), 692 Overall treatment time, 498 Oxygen, 214 Oxygen-enhancement ratio (OER), 214

P p53 Tumor Suppressor Gene, 795 p53, 12 Paclitaxel, 292 Palifermin, 644 Palliative radiation therapy, 533 Palliative radiotherapy, 454 Paraneoplastic syndromes, 492 Paresthesias, 628 PARP inhibitors, 271, 780, 218 Pathological fractures, 561 Patient immobilization, 344 Patient-reported outcomes (PROs), 662 Patient-Reported Outcomes Measurement Information System (PROMIS), 670 Pemetrexed, 251, 304, 766 Pentoxifylline (Trental), 234 Performance Status, 680 Perfusion and ventilation scans, 612 Perioperative high-dose-rate brachytherapy (PHDRB), 471 Permanent interstitial transbronchial implantation, 478 Personalized medicine, 794 PET (Positron Emission Tomography), 64 PET- CT, 64 PET/MR imaging, 77 Photodynamic reaction (PDR), 372 Photodynamic Therapy (PDT), 52, 371, 483, 583 Photomultipliers (PMTs), 77 Photosensitizing agent (PS), 372 Planning target volume (PTV), 146, 188, 203, 348, 748, 755 Platelet-derived growth factor (PDGF), 19, 120, 654 Pleuropneumonectomy, 109 PMD (progressive metabolic disease), 180 PMR (partial metabolic response), 180 Pneumonectomy, 109, 249, 367, 390, 439 Polo-like kinase inhibitors, 271, 784 Poly(ADP-Ribose) Polymerase Inhibitors, 236 Porphyrins, 372 Positron emission tomography (PET), 75, 92, 147, 173, 202 Post-chemotherapy volumes, 190, 499 Postoperative radiation therapy (PORT), 364 Postoperative Radiotherapy, 194

841 Potential doubling time (Tpot), 124 Pre-chemotherapy volume, 190, 499 Pro-Gastrin-Releasing Peptide, 801 Prognostic factors, 327, 676 Proliferative activity, 124 Prophylactic cranial irradiation (PCI), 446, 492, 506, 514, 647 Prostaglandin E2 (PGE2), 231 Protease inhibitors, 271 Proteasome Inhibitors, 780 Protection of normal tissues, 268 Proton-beam dosimetry, 746 Protons, 744 Proto-oncogene KRAS, 8 Pulmonary bronchitis, 485 Pulmonary function tests(PFTs), 612

Q QLQ-LC13, 664 Quality of Life Questionnaire Core 30 (QLQ-C30), 664 Quality of life (QOL), 661, 332, 450 Quality-adjusted life expectancy (QALE), 518 Quality-adjusted survival (QAS), 295

R Radiation induced brain toxicity, 648 Radiation myelopathy, 627 Radiation pneumonitis, 121, 754 Radiation response, 119 Radiation Sensitizers, 213 Radiation therapy, 267, 249, 410, 492, 525, 809 Radiation-induced liver disease (RILD), 569 Radiation-induced lung toxicity, 609 Radiochemotherapy, 410, 529 Radiofrequency ablation, 382 Radiopharmaceuticals, 271, 785 Radioprotectors, 424 Radiosensitivity, 124 Radiosensitizer, 214 Radiosurgery, 568 Radiotherapy planning, 177 Radiotherapy, 439, 454, 514, 518 Radivnecrosis, 651 Randomised controlled trials, 828 Randomized clinical trial (RCT), 819 Ras Oncogenes p21, 794 Recombinant human erythropoietin (r-HuEPO epoietin-alfa), 604 Recombinant interleukin-11 (rIL-11), 234 Recurrence, 544 Reirradiation of Small-Cell Lung Cancer, 556 Reirradiation, 549 Relative mean lung dose (rMLD), 404 Reoperation, 545 Residual volume(RV), 612 Respiratory correlated PET-CT, 347 Respiratory gated therapy, 148 Respiratory Gating, 183

842

R (cont.) rh-MnSOD (manganese superoxide dismutase), 654 Ribonucleotide-Diphosphate Reductase M1, 799

S Search strategy, 830 Segmentectomy, 109 Sequential radiochemotherapy, 412 Serine/threonine kinase 11 (STK 11), 7 Serological Tumor Markers, 678 Serum Proteomic Profiling, 801 Set-up error, 197 Set-up uncertainty, 146 Shortness of breath, 518, 610 Sickness Impact Profile (SIP), 663, 664 Silastic Stents, 580 Simultaneous integrated boost(SIB), 699 Single nucleotide polymorphism (SNP) arrays, 4 Single-photon-emission computed tomography(SPECT), 612 Sleeve resection, 109 Slow CT scanning, 196 Slow CT, 347 Small molecule drugs, 32 Small-cell carcinoma (SCLC), 54, 201, 492, 514, 533 SMD (stable metabolic disease), 180 Sorafenib, 259, 779 Spatial cooperation, 268 SPECT, 182 Squamous carcinoma, 446 Squamous cell carcinomas, 812 Stage, 454, 812 Standard radiation therapy, 411 Standardized uptake (SUV), 180, 190 Stereotactic ablative radiotherapy (SABR), 715, 344 Stereotactic body radiation therapy (SBRT), 344, 569, 692, 715, 728 Stereotactic fractionated radiation therapy, 424 Stereotactic radiation therapy, 528 Stereotactic radiosurgery (SRS), 647 Subjective significance questionnaire (SSQ), 666 Sucralfate, 644 Sunitinib, 259, 779 Superior sulcus tumors, 434 Superior vena cava syndrome, 454 Surgery, 315, 364, 545, 809 Surgical resection, 647 Surgical staging, 89 Symptomatic relief, 549 Syncope, 450 Systematic error, 188 Systematic reviews, 828, 831

T Target volume, 202 Targeted gene therapy, 32 Temozolamide, 780 Temporary implants, 480

Index TGF-b, 613, 615 Therapeutic ratio, 268 Thoracentesis, 585 Thoracic radiation therapy, 506 Thoracic radiotherapy, 201, 364 Thoracoscopy, 585 Thoracotomy, 90 Three-dimensional conformal radiation therapy, 188, 317, 403, 424, 455, 692 Thrombocytopenia, 599 Thrombopoietin (TPO), 605 Thymidine phosphorylase, 22 Thyroid transcription factor 1 (TTF-1), 5 Time-to-event analyses, 823 Tirapazamine, 217 Tiredness, 518 TNF-a PDGF, 613 TNFa, 629 Tomotherapy, 725 Topotecan, 260 Total lung capacity (TLC), 612 Toxicity, 328, 450, 532 Tracheobronchial stents, 51 Tracheoesophageal Fistula, 587 Transbronchial Needle Biopsy (TBNBx), 93 Transesophageal ultrasound, 64 Transforming growth factor-a(TGF-a), 19 Transforming growth factor-b(TGF-b), 19 Translational research, 794 Transthoracic Needle Biopsy (TTNBx), 93 Treated volume, 455 Treatment planning, 144 Treatment Volume, 323 Trial outcome index, 664 Tri-modality approach, 436 T-stage, 90 T-staging, 80, 90 Tumor angiogenesis, 19 Tumor histology, 677 Tumor motion, 148 Tumor necrosis factor a (TNF-a), 19, 231, 649 Tumor size, 322 Tumor stage, 322 Tumorcontrol probability, 144 Tumour size, 454 Twice-daily tho racic radiation, 498 Two-dimensional radiotherapy (2DRT), 454 Type I error, 821 Type II error, 822 Type II pneumocyte, 120 Tyrosine kinase inhibitors (TKIs), 775

V V/Q (Ventilation and Perfusion) Scans, 71 V20, 121 V20, 350 V5, 121 Vandetanib, 259, 779 Vascular disrupting agents, 32

Index Vascular endothelial growth factor (VEGF), 18, 257, 629 Vatalanib, 259 Verbal memory, 517 Video-assisted thoracic surgery (VATS), 90, 95, 112, 249 Vinblastin, 277 Vinorelbine, 249, 297 Vital capacity (VC), 612 Volumetric-modulated arc therapy (VMAT), 692 Vorinostat, 781

843 W Weakness, 450 Wedge resection, 109 Weight loss, 454, 680 White matter necrosis, 629 Whole-brain radiotherapy (WBRT), 566, 647

Z Zileuton, 783

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