Textbook of Lung Cancer, Second Edition

Lung

Hansen

Textbook of

Cancer

Textbook of Lung Cancer, Second Edition, published in association with the European Society for Medical Oncology, is a comprehensive and multidisciplinary text, which examines all aspects of this disease, with contributions from a multinational team of authors on etiology, epidemiology, molecular biology, pathology, smoking, detection and management, clinical features, staging and prognostic factors, surgery, radiotherapy and chemotherapy. It provides essential information and guidance for specialist trainees in oncology, and for the many physicians and specialists involved in

Table of contents Etiology of lung cancer • Epidemiology of lung cancer • Molecular biology of lung cancer • Tobacco policy • Smoking cessation programs • Current status of early lung cancer screening • Histopathology of lung tumors • Clinical diagnosis and basic evaluation • Staging, classification and prognosis • Treatment of non-small cell lung cancer • Treatment of small cell lung cancer • Malignant mesothelioma • Summary of treatment • Therapeutic bronchoscopy for palliation of lung tumors • Complications to lung cancer • Quality of life and supportive care • The cost and cost-effectiveness of lung cancer management • The future • Appendix: Chemotherapy

About the editor Heine Hansen MD FRCP is Professor of Clinical Oncology at the Finsen Center, National University Hospital, Copenhagen, Denmark.

Also available: ESMO Handbook of Cancer Prevention Edited by Schrijvers, Senn, Mellstedt, Zakotnik (ISBN: 9780415390859) ESMO Handbook of Principles of Translational Research Edited by Mellstedt, Schrijvers, Bafaloukos & Greil (ISBN: 9780415410915) Lung Cancer – Translational and Emerging Therapies Edited by Pandya, Brahmer & Hidalgo (ISBN: 9780849390210) Image-Guided Radiotherapy of Lung Cancer Edited by Cox, Chang & Komaki (ISBN: 9780849387838)

Lung Cancer

the field of lung cancer.

Textbook of

Second Edition

Cancer

Second Edition

Edited by

Heine Hansen

Textbook of Surgical Oncology Edited by Poston, Beauchamp & Ruers (ISBN: 9781841845074) Lung Cancer Therapy Annual 6 Edited by Hansen (ISBN 9780415465458)

Second Edition www.informahealthcare.com

Lung Textbook of

Published in association with the European Society for Medical Oncology

Textbook of Lung Cancer

Textbook of Lung Cancer Second Edition Edited by

Heine Hansen MD FRCP Finsen Center National University Hospital Copenhagen Denmark

© 2008 Informa UK Ltd First published in the United Kingdom in 2000 Second edition published in the United Kingdom in 2008 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ. Informa Healthcare is a trading division of Informa UK Ltd. Registered Office: 37/41 Mortimer Street, London W1T 3JH. Registered in England and Wales number 1072954. Tel: +44 (0)20 7017 5000 Fax: +44 (0)20 7017 6699 Website: www.informahealthcare.com All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. The Author has asserted his right under the Copyright, Designs and Patents Act 1988 to be identified as the Author of this Work. Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or for any consequences arising from the use of information contained herein. For detailed prescribing information or instructions on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer. A CIP record for this book is available from the British Library. Library of Congress Cataloguing-in-Publication Data Data available on application ISBN-10: 0 415 38510 5 ISBN-13: 978 0 415 38510 7 Distributed in North and South America by Taylor & Francis 6000 Broken Sound Parkway, NW, (Suite 300) Boca Raton, FL 33487, USA Within Continental USA Tel: 1 (800) 272 7737; Fax: 1 (800) 374 3401 Outside Continental USA Tel: (561) 994 0555; Fax: (561) 361 6018 Email: [email protected] Distributed in the rest of the world by Thomson Publishing Services Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel: +44 (0)1264 332424 Email: [email protected] Composition by Exeter Premedia Services Pvt Ltd., Chennai, India Printed and bound in India by Replika Press Pvt Ltd

Contents

List of Contributors

vii

Preface

xi

Color plate 1. Etiology of lung cancer Aage Haugen, Steen Mollerup

xiii 1

2. Epidemiology of lung cancer: a century of great success and ignominious failure Peter Boyle, Sara Gandini, Nigel Gray

10

3. Molecular biology of lung cancer Thomas Tuxen Poulsen, Hans Skovgaard Poulsen, Helle Pappot

20

4.

35

Tobacco policy Nigel Gray

5. Smoking cessation programs Philip Tønnesen

41

6. Current status of lung cancer screening James L Mulshine

53

7. Histopathology of lung tumors Elisabeth Brambilla, Sylvie Lantuejoul

61

8. Clinical diagnosis and basic evaluation John J Mullon, Eric J Olson

75

9. Staging, classification, and prognosis Michael Dusmet, Peter Goldstraw

97

10. Treatment of non-small cell lung cancer 10.1 Treatment of NSCLC: surgery Robert J Korst

123

10.2 Treatment of NSCLC: radiotherapy Merideth MM Wendland, William T Sause

136

vi Contents

10.3 Treatment of NSCLC: chemotherapy Athanasios G Pallis, Sophia Agelaki, Vassilis Georgoulias

147

11. Treatment of small cell lung cancer

12.

11.1 Treatment of SCLC: surgery Hisao Asamura, Riken Kawachi

170

11.2 Treatment of SCLC: radiotherapy Christopher M Lee, William T Sause

177

11.3 Treatment of SCLC: chemotherapy Heine H Hansen, Morten Sørensen

184

Malignant mesothelioma Bruce Robinson, Anna Nowak, Cleo Robinson, Jenette Creaney

190

13. Summary of treatment Heine H Hansen

207

14. Therapeutic bronchoscopy for palliation of lung tumors Paul WA Kunst, Pieter E Postmus, Thomas G Sutedja

210

15. Complications of lung cancer Vincenzo Minotti, Michele Montedoro, Maurizio Tonato

218

16. Quality of life and supportive care Jean-Paul Sculier, Anne–Pascal Meert, Marianne Paesmans, Thierry Berghmans

236

17. The cost and cost-effectiveness of lung cancer management William K Evans, Christopher J Longo

247

18.

The future Giovanni Selvaggi, Giorgio Vittorio Scagliotti

264

Appendix: Chemotherapy

275

List of drugs

331

Index

333

Contributors

Sophia Agelaki MD Department of Medical Oncology University Hospital of Heraklion Heraklion Greece Hisao Asamura MD Division of Thoracic Surgery National Cancer Center Hospital Tokyo Japan Thierry Berghmans MD Department of Critical Care and Thoracic Oncology Institut Jules Bordet Brussels Belgium Peter Boyle MD International Agency for Research on Cancer Lyon France Elisabeth Brambilla MD PhD Deptartment of Pathology Michallon Hospital CHRU Grenoble National Institute for Health and Medical Research University Fourier Grenoble Grenoble France

Jenette Creaney MD School of Medicine and Parmacology Sir Charles Gairdner Hospital Perth, WA Australia Michael Dusmet MD FMH Department of Thoracic Surgery Royal Brompton Hospital London UK Williams K Evans MD FRCPC Department of Oncology McMaster University Hamilton, Ontario Canada Sara Gandini MD Division of Epidemiology and Biostatics European Institute of Oncology Milan Italy Vassilis Georgoulias MD PhD Department of Medical Oncology University Hospital of Heraklion Heraklion Greece Peter Goldstraw MD Department of Thoracic Surgery Royal Brompton Hospital London UK

viii List of Contributors

Nigel Gray AO MBBS FRACP FRACMA Tobacco Unit International Agency for Research on Cancer Lyon France

Christopher J Longo PhD MSc BA DeGroote School of Business McMaster University Hamilton, Ontario Canada

Heine H Hansen MD The Finsen Center National University Hospital Copenhagen Denmark

Anne–Pascal Meert MD Department of Critical Care and Thoracic Oncology Institut Jules Bordet Brussels Belgium

Aage Haugen PhD Department of Chemical and Biological Working Environment National Institute of Occupational Health Oslo Norway

Vincenzo Minotti MD Department of Medical Oncology Santa Maria Della Misericordia Hospital Perugia Italy

Riken Kawachi MD Division of Thoracic Surgery National Cancer Center Hospital Tokyo Japan

Steen Mollerup PhD Department of Chemical and Biological Working Environment National Institute of Occupational Health Oslo Norway

Robert J korst MD Daniel and Gloria Blumenthal Cancer Center Valley Health System Valley Hospital Paramus, NJ USA

Michele Montedoro MD Department of Medical Oncology Santa Maria Della Misericordia Hospital Perugia Italy

Peter WA Kunst MD PhD Department of Pulmonary Diseases HAGA Hospital The Hague The Netherlands Sylvie Lantuejoul MD PhD Department of Pathology Michallon Hospital CHRU Grenoble National Institute for Health and Medical Research University J. Fourier Grenoble Grenoble France Christopher M Lee MD Department of Radiation Oncology University of Utah School of Medicine Huntsman Cancer Hospital Salt Lake City, UT USA

John J Mullon MD Division of Pulmonary and Critical Care Medicine Mayo Clinic College of Medicine Rochester, MN USA James L Mulshine MD Rush University Medical Center Chicago, IL USA Anna Nowak MD School of Medicine and Pharmacology Sir Charles Gairdner Hospital Perth, WA Australia Eric J Olson MD Division of Pulmonary and Critical Care Medicine Mayo Clinic College of Medicine Rochester, MN USA

List of Contributors ix

Marianne Paesmans MSc Data Center Institut Jules Bordet Brussels Belgium Athanasios G Pallis MD PhD Department of Medical Oncology University Hospital of Heraklion Heraklion Greece Helle Pappot MD Department of Oncology Copenhagen University Hospital Copenhagen Denmark Pieter E Postmus MD PhD Department of Pulmonary Diseases Vrije Universiteit University Medical Center Amsterdam The Netherlands Hans Skovgaard Poulsen MD DMSc Department of Radiation Biology Copenhagen University Hospital Copenhagen Denmark Thomas Tuxen Poulsen MSc Department of Radiation Biology Copenhagen University Hospital Copenhagen Denmark Bruce WS Robinson MBBS MD FRACP FRCP DTM&H FCCP

National Research Centre for Asbestos Related Diseases School of Medicine and Pharmacology Sir Charles Gairdner Hospital Perth, WA Australia Cleo Robinson MD National Research Centre for Asbestos Related Diseases School of Medicine and Pharmacology Sir Charles Gairdner Hospital Perth, WA Australia

William T Sause MD LDS Hospital Radiation Center Salt Lake City, UT USA Giorgio V Scagliotti MD Department of Clinical and Biological Sciences University of Turin Orbassano, Turin Italy Jean-Paul Sculier MD PhD Department of Critical Care and Thoracic Oncology Institut Jules Bordet Brussels Belgium Giovanni Selvaggi MD Department of Clinical and Biological Sciences University of Turin Orbassano, Turin Italy Morten Sørensen MD The Finsen Center National University Hospital Copenhagen Denmark Tom G Sutedja MD PhD Department of Pulmonary Diseases Vrije Universiteit University Medical Center Amsterdam The Netherlands Maurizio Tonato MD Regional Cancer Center Poloclinico Hospital Perugia Italy Philip Tønnesen MD Department of Pulmonary Medicine Gentofte University Hospital Hellerup Denmark Merideth MM Wendland MD Department of Radiation Oncology Huntsman Cancer Hospital University of Utah Salt Lake City, UT USA

Preface

Since the publication of the first issue of this textbook in 2000, the epidemiologic features of smoking have undergone continuous changes and the worldwide intensification of the battle against tobacco consumption is changing the geographic pattern. In the USA, some western European countries, and Australia, the incidence of lung cancer is decreasing among males, while the disease continues to increase among females. In the southern and eastern parts of Europe, lung cancer is on a rapid rise, and a similar pattern is seen in highly populated countries like China, Indonesia, and Japan. Other regions of the world, such as the Middle East, Africa, and South America, show the same dismal picture. Worldwide, the annual number of new cases of lung cancer is estimated at more than one million and is expected to increase to ten million in 2025. Fortunately, the political efforts to reduce the use of tobacco are getting increasing attention in many countries and the statistics are now showing the first positive results.

Among the epidemiologic changes we also see a change in the histopathologic pattern, with a relative decrease in squamous cell carcinoma and a rise in adenocarcinoma. Lately, important new information as regards the biology of lung cancer is emerging, including new treatment approaches. The result is a slow, but steady improvement of the overall management of lung cancer based on an increasing use of combined modality therapy, consisting of surgery, chemotherapy, and radiotherapy applied concurrently or sequentially in early stage disease. Furthermore, new techniques are gaining ground, both within surgery and radiotherapy, and targeted medical therapy is being offered to more and more patients. The textbook brings up-to-date information about lung cancer, based on worldwide experience, for the use of the many physicians involved in this field. Heine H Hansen

Color Plates

(a)

(c)

(b)

Figure 8.5 18F-FDG-PET scan with CT fusion demonstrating a primary adenocarcinoma in the left upper lobe (a), with contralateral hilar metastasis (b). (c) Coronal 18F-FDG-PET without CT fusion, demonstrating no extrathoracic involvement. Transbronchial needle aspirate of the right hilar lymph node confirmed metastatic adenocarcinoma with stage IIIB NSCLC assigned.

xiv Color Plates

(a)

(c)

(b)

Figure 8.6 18F-FDG-PET scan with CT fusion demonstrating a primary adenocarcinoma involving the left upper lobe with ipsilateral mediastinal lymph node metastasis (a), and left adrenal mestastasis (b). (c) Coronal 18F-FDG-PET without CT fusion demonstrating mediastinal and extrathoracic (left adrenal) involvement. CT-guided biopsy of the left adrenal confirmed metastatic adenocarcinoma with stage IV NSCLC assigned.

Color Plates xv

Figure 9.13 The nodal chart established by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC) in 1997.3

Figure 11.2.2 Anterior-posterior digitally reconstructed radiograph (DRR) illustrating a typical radiation portal which includes the primary tumor mass and adjacent hilar/mediastinal lymph nodes.

xvi Color Plates

Figure 11.2.3 Conformal radiotherapy planning techniques allow escalated radiation doses to be delivered safely with simultaneous sparing of surrounding critical structures. In this example, a combination of anterior-posterior and oblique fields (four fields in total) are utilized to decrease radiation dose to the nearby spinal cord.

Figure 11.2.4 Right lateral digitally reconstructed radiograph (DRR) illustrating a typical portal used for prophylactic cranial irradiation.

1

Etiology of lung cancer Aage Haugen, Steen Mollerup Contents Introduction • Carcinogens in tobacco smoke • Environmental tobacco smoke • Air pollution, radon, workplace exposure, and viruses • Genetic susceptibility and lung cancer etiology • Females and lung cancer susceptibilty

INTRODUCTION Lung cancer, which was rare at the beginning of the 20th century, is now a global problem. It is the most frequent cancer in the world.1 Presently, 1.2 million people die of lung cancer each year and the global incidence of lung cancer is increasing. A major contribution to this trend comes from the former socialist economies and developing countries where smoking rates are still high. Consequently, lung cancer will remain a major cause of cancer death worldwide in the 21st century even though the prevalence of tobacco use has declined in many high-income countries. That carcinogens in tobacco smoke play a major role in lung cancer is unquestionable. About 85–90% of lung cancer patients are smokers.2 However, lung cancer also occurs in people who have never smoked, and this implies that factors such as environmental tobacco smoke (ETS), environmental and domestic air pollution, work-related risk factors, radon exposure, and viruses may also have an impact on lung cancer incidence rates. In addition, since fewer than 20% of smokers will develop lung cancer in their lifetime, inherited predisposition may be an important component. CARCINOGENS IN TOBACCO SMOKE Lung carcinogenesis is mediated through an interaction between several putative carcinogens. A smoker inhales gas-phase smoke (so-called ‘mainstream smoke’) as well as particulates (tar). Cigarette smoke is a complex mixture of compounds and more than 4000 compounds have been identified in tobacco mainstream smoke3–7 (Table 1.1). Studies have led to the identification of 60–70 carcinogens: polycyclic aromatic hydrocarbons (PAHs), heterocyclic hydrocarbons, N-nitrosamines, aromatic amines, N-heterocyclic amines, aldehydes, various organic compounds, inorganic compounds such as hydrazine and some metals, and free radical species. Table 1.2 lists likely causative agents for lung cancer.

Available evidence indicates that carcinogenic PAH compounds and the tobacco-specific carcinogen NNK (4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone) are of major importance in lung cancer induction in smokers.8 Most studies on tobacco smoking genotoxicity in the lung have focused on these compounds. They are strong carcinogens and tobacco contains relatively high amounts of PAHs and N-nitrosamines. However, compounds such as aldehydes, butadiene, and benzene, which appear to have lower carcinogenic potential, are found in much higher quantities in tobacco smoke. PAHs are formed by incomplete combustion of tobacco during smoking. PAHs, particularly benzo(a) pyrene, induce tumors of the lung in laboratory animals by various routes of administration. Furthermore, studies have demonstrated that human lung tissue can metabolize PAHs to reactive metabolites that can interact with DNA, forming mutagenic DNA adducts.9 DNA adduct formation is thought to be the primary initiating event in carcinogenesis and may be predictive of lung cancer risk.10,11 PAH–DNA adducts have been detected in human lung samples, and increased levels of PAH–DNA adducts in human lung tissue of smokers and ex-smokers relative to non-smokers have been reported in several studies.9 The major adduct formed by activated benzo(a)pyrene, the (+)-anti-benzo(a) pyrene-guanine adduct, is premutagenic, mispairing with A and generating primarily G-to-T transversions. The role of PAHs in lung cancer is consistent with data on mutational analysis of the TP53 gene with the demonstration of a large number of G-to-T transversions at certain bases (hotspots) in this gene in smokers’ lung tumors.12 In vitro studies have shown a direct molecular link between benzo(a)pyrene and the development of lung cancer. Exposure of human epithelial cell cultures to the reactive diol epoxide metabolites of this carcinogen resulted in the formation of adducts and TP53 hotspot mutations, similar to that observed in lung tumors in smokers.13

2 Textbook of Lung Cancer Table 1.1 Carcinogens in cigarette smoke Agent

Amount in mainstream cigarette smoke

IARC evaluation of carcinogenicity In animals

Polynuclear aromatic hydrocarbons Benzo[a]anthracene 20–70 ng Benzo[b]fluoranthene 4–22 ng Benzo[j]fluoranthene 6–21 ng Benzo[k]fluoranthene 6–12 ng Benzo[a]pyrene 8.5–11.6 nga Dibenz[a,h]anthracene 4 ng Dibenzo[a,i]pyrene 1.7–3.2 ng Dibenzo[a,e]pyrene Present Indeno[1,2,3-cd]pyrene 4–20 ng 5-Methylchrysene ND-0.6 ng Heterocyclic hydrocarbons Furan 20–40 µgb Dibenz(a,h)acridine ND–0.1 ng Dibenz(a,j) acridine ND–10 ng Dibenzo(c,g)carbazole ND–0.7 ng Benzo(b)furan Present N-Nitrosamines N-Nitrosodimethylamine 0.1–180 ngb N-Nitrosoethylmethylamine ND–13 ng N-Nitrosodiethylamine ND–25 ngb N-Nitrosopyrrolidine 1.5–110 ngb N-Nitrosopiperidine ND–9 ng N-Nitrosodiethanolamine ND–36 ngb N′-Nitrosonornicotine 154–196 nga 4-(Methylnitrosamino)110–133 nga 1-(3-pyridyl)-1-butanone Aromatic amines 2-Toluidine 30–200 ngb 2,6-Dimethylaniline 4–50 ng 2-Naphthylamine 1–22 ngb 4-Aminobiphenyl 2–5 ngb N-Heterocyclic amines A-α-C 25–260 ng MeA-α-C 2–37 ng IQ 0.3 ng Trp-P-1 0.3–0.5 ng Trp-P-2 0.8–1.1 ng Glu-P-1 0.37–0.89 ng Glu-P-2 0.25–0.88 ng PhIP 11–23 ng

In humans

IARC group

Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient

2A 2B 2B 2B 2A 2A 2B 2B 2B 2B

Sufficient Sufficient Sufficient Sufficient Sufficient

2B 2B 2B 2B 2B

Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient

2A 2B 2A 2B 2B 2B 2Bc 2Bc

Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient

Limited Sufficient Sufficient

2A 2B 1 1 2B 2B 2A 2B 2B 2B 2B 2B (Continued)

Etiology of lung cancer 3

Table 1.1 Continued Agent

Amount in mainstream cigarette smoke

Aldehydes Formaldehyde 10.3–25 µga Acetaldehyde 770–864 µga Phenolic compounds Catechol 59–81 µga Caffeic acid <3 µg Volatile hydrocarbons 1,3-Butadiene 20–40 µgb Isoprene 450–1000 µg Benzene 12–50 µgb Nitrohydrocarbons Nitromethane 0.5–0.6 µg 2-Nitropropane 0.7–1.2 ngc Nitrobenzene 25 µg Miscellaneous organic compounds Acetamide 38–56 µg Acrylamide Present Acrylonitrile 3–15 µg Vinyl chloride 11–15 ng 1,1-Dimethylhydrazine Present Ethylene oxide 7 µg Propylene oxide 0–100 ng Hydrazine 24–43 ng Urethane 20–38 ngb Metals and metal compounds Arsenic 40–120 ngb Beryllium 0.5 ng Nickel ND–600 ng Chromium (hexavalent) 4–70 ng Cadmium 41–62 ngb Cobalt 0.13–0.20 ng Lead (inorganic) 34–85 ng Radio-isotope polonium-210 0.03–1.0 pCi

IARC evaluation of carcinogenicity In animals

In humans

IARC group

Sufficient Sufficient

Limited

2A 2B

Sufficient Sufficient Sufficient Sufficient Sufficient

2B 2B Limited Sufficient

2A 2B 1

Sufficient Sufficient Sufficient

2B 2B 2B

Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient

2B 2A 2B 1 2B 1 2B 2B 2B

Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient

Sufficient Limited

Sufficient Sufficient Sufficient Sufficient Sufficient Limited

1 1 1 1 1 2B 2A 1

Modified from Hoffmann and Hoffmann,4 this table shows components of unfiltered mainstream cigarette smoke, with amounts given per cigarette. Virtually all these compounds are known carcinogens in experimental animals. In combination with data on cancer in humans and – in some cases – other relevant data, IARC Monograph classifications for these agents have been established as Group 2B (possibly carcinogenic to humans), Group 2A (probably carcinogenic to humans), or Group 1 (carcinogenic to humans). Abbreviations: ND, not detected; A-α-C, 2-amino-9H-pyrido[2,3-b]indole; IQ, 2-amino-3-methylimidazo-[4,5-b]quinoline; Trp-P-1, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole; Trp-P-2, 3-amino-1-methyl-5H-pyrido[4,3-b]indole; Glu-P-1, 2-amino6-methyl[1,2-a:3′2″-d]imidazole; Glu P-2, 2-aminodipyridol[1,2-a:3′,2″-d]imidazole; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; pCi, picoCurie. a Data from Swauger et al (2002) (for ‘full-flavor’ cigarettes).5 b Data from US Department of Health and Human Services (1989).6 c Corrected value (see Fowler and Bates, 2000).7

4 Textbook of Lung Cancer Table 1.2 Causative agents in cigarette smoke Carcinogens

Major risk factors PAHs Nitroso compounds

Tumor promoters/ co-carcinogens

Catechol Phenol Aldehydes Oxidative radicals

Minor risk factors Polonium-210 Aldehydes Butadiene Ni, Cd, Cr Oxidative radicals

The concentration of nitrosamines found in tobacco products is relatively high, and except for some occupational exposure situations, heavy smokers have the highest exposure to N-nitroso compounds. The socalled tobacco-specific N-nitrosamines (TSNAs), principally the nicotine-derived NNK, are the strongest respiratory carcinogens identified in tobacco products. Adenocarcinoma of the lung is the main type of lung cancer induced by NNK, and both benign and malignant tumors are formed in rats, mice, and hamsters.14 Moreover, human lung tissue metabolically activates NNK, although less effectively than rodent lung tissue. This activation is mediated by P450 monooxygenases, cyclooxygenases, and lipooxygenases. Metabolites of NNK have been reported in urine from smokers, and NNK and N′-nitrosonornicotine (NNN)-specific DNA adducts have been reported at increased levels in the lungs of smokers.8,15 A high frequency of G-to-A transitions in the TP53 gene is consistent with the mutational spectrum expected from NNK.12 NNK might also exert its biologic activity through cell surface receptors such as nicotine acetylcholine receptors (nAchRs) and β-adrenergic receptors.16 Adenocarcinoma has now overtaken squamous cell carcinoma as the most common lung cancer type, consistent with the role of NNK in lung carcinogenesis. NNK concentrations in mainstream smoke have increased while those of benzo(a) pyrene have decreased since the 1960s. There are relatively high levels of metals in cigarette smoke (Figure 1.1). At least 30 metals have been identified.3,4 The contribution of these metals to increased lung cancer risk is poorly understood. Experimental evidence indicates that many metals are effective initiators

of the carcinogenic process, but can also be potential promoters during carcinogenesis. This is particular true for tobacco smoke, where exposure to multiple agents occurs. Cigarette smoke contains a substantial amount of chromium, cadmium, and nickel. It is known that chromium accumulates in the lung and tobacco smoking is the main source of cadmium exposure in humans. It has been reported that chromates are carcinogenic in rats, inducing lung tumors after instillation.17 Cadmium chloride aerosols produce lung adenocarcinoma and squamous cell carcinoma in rats,18 and nickel subsulfide yields lung cancer in rats upon inhalation.19 Because of their relatively high levels in cigarette smoke, these metals may play a role in lung carcinogenesis. They are likely to contribute to lung cancer induction by multiple mechanisms such as inducing DNA damage (single strand breaks, cross-linking of DNA and proteins), and they could potentiate the genotoxicity of other DNAdamaging agents and enhance mutagenesis. Many studies have demonstrated that reactive oxygen species are implicated in metal carcinogenesis. Table 1.2 lists other constituents of tobacco-smoke that could be involved in lung cancer induction. However, less importance has been attributed to these compounds in comparison with PAH and NNK. Inhalation studies of formaldehyde and acetaldehyde have demonstrated that they are respiratory carcinogens in the rat.20 These compounds are weak carcinogens, but the levels are relatively high in cigarette smoke. Polonium-210 (210Po) is a natural constituent of cigarette smoke and will deposit in the lungs of smokers, emitting alpha particles.21 The content of several carcinogens in tobacco has been reduced due to changes in tobacco processing methods and new cigarette filters, but this is not the case with the 210Po concentration, neither in tobacco nor in tobacco smoke. Radiation exposure may induce lung cancer both alone and in interaction with other carcinogens in tobacco. Animal studies have shown that 210Po is a strong pulmonary carcinogen in rats and Syrian golden hamsters.22 Cigarette smoke contains large amounts of free radicals and is known to induce oxidative damage. Both gas and particulate phases are highly oxidized, and damage the lung. Alkenes (i.e. unsaturated aliphatic hydrocarbons), nitrosamines, aromatic and heterocyclic hydrocarbons, amines, and catechol and hydroquinone are all well known sources of reactive oxygen species such as hydroxyl radicals, superoxides, and peroxides.23 Damage can also result from the activation of phagocytic cells that generate reactive oxygen species (ROS).24 Cigarette smoke is a strong inflammatory stimulus that induces

Etiology of lung cancer 5 Causative agents in cigarette smoke: PAH, NNK, 210Po, Cr, Cd, Ni, aldehydes, oxidative radicals Phase 1 (activation) Susceptibility: Variation in metabolism and DNA repair Nutrition Immunologic status

P 450

DNA-damaging metabolites

Chronic exposure

DNA repair Days

DNA repair 10–30 years

Excretion

Synergistic effect: Asbestos Chloromethyl ethers Mustard gas Radioactive ore

Preneoplastic cells

Initiated cells

Normal cells

Phase 2 (detoxification)

Progression

Lung cancer

DNA repair Months

Genetic changes: TP53, KRAS, EGFR, inactivation of FHIT/RASSF1/SEMA3B (3p), INK4, RB Activation of CCDN1; MYC1 - amplification LOH (2q, 5q, 9q, 18q, 22q)

Figure 1.1 Lung carcinogenesis.

proinflammatory cytokines and recruits activated macrophages and neutrophils to lung tissue.25 Neutrophils play an important role in the defense of the lung through a variety of activities and generate oxidative radicals when exposed to PAHs and aromatic amines. The oxidative capacity of neutrophils is therefore important as a potential cause of oxidative damage to the lung. Several epidemiologic studies have associated lung inflammatory diseases such as asthma, bronchitis, and chronic obstructive pulmonary disease (COPD) with an increased risk of lung cancer development. DNA is an important target for ROS. In order for ROS to induce DNA damage, a sufficient concentration must be available to overwhelm the antioxidant capacity of the lung. Products that result from oxidative damage to both lipids and DNA have been detected in smokers at higher levels than in non-smokers. Although the direct role of such products in carcinogenesis is unclear, 8-oxoguanine (8-oxo-G), a frequent product of oxidative damage, has miscoding properties associated with the cancer induction process.26 Studies indicate that unrepaired 8-oxo-G gives rise to G-to-T transversions. The most abundant genetic change induced as a consequence of oxidative damage is GC-to-AT transition. Apart from oxidative modification of DNA bases, free radicals are also able to induce single strand breaks.

Nicotine is the agent in tobacco capable of producing addiction, or nicotine dependence, and exists at high concentrations in the blood of smokers. Direct involvement of nicotine in the development of lung cancer has not yet been shown, but nicotine does appear to play an important role and may have multiple sites of action. It is absorbed rapidly when smokers inhale. Specific, high-affinity nAChRs are found on human lung cancer cells of all histologic types as well as in normal lung tissue.27 Chronic exposure to nicotine can lead to the activation of growth-promoting pathways upon its interaction with nAChRs, and may also affect apoptosis and angiogenesis.28

ENVIRONMENTAL TOBACCO SMOKE Environmental tobacco smoke (ETS), or passive smoking, is a mixture of exhaled mainstream smoke and sidestream smoke diluted with ambient air. Cigarettes generate a large amount of ETS and affected individuals are exposed to the same carcinogens as an active smoker. However, the relative proportions of the particular compounds may differ between mainstream and sidestream smoke. For example, due to filters, concentrations of PAHs such as benzo(a)pyrene and benzo(a) anthracene in the sidestream are approximately 10-fold

6 Textbook of Lung Cancer

higher than those in mainstream smoke. Benzene, formaldehyde, hydrazine, butadiene, N-nitrosamines, aniline, 2-naphthylamine, and 4-aminobiphenyl may also be present at higher concentrations in sidestream smoke.29 Many epidemiologic studies, which were evaluated by the IARC in 2004,3 have shown an increased lung cancer risk in never-smokers exposed to ETS. This is particularly true for spouses of active smokers, where ETS-exposed never-smoking females and males have an excess risk of lung cancer in the order of 20 or 30%, respectively. Never-smokers exposed to ETS in the workplace may also be at an increased risk (12–19%). Experimental studies have confirmed the carcinogenic potential of ETS. Thus, concentrations of tobaccosmoke-related compounds adducted to biologic macromolecules such as proteins, and to a lesser extent DNA, have been found to be increased in individuals exposed to ETS.3 Also, lung tumors from ETS-exposed nonsmoking individuals show TP53 and KRAS mutations similar to those found in tumors from smokers, although at a lower frequency.30,31

AIR POLLUTION, RADON, WORKPLACE EXPOSURE, AND VIRUSES The different incidence rates for lung cancer among non-smokers in different countries suggest that environmental agents can modify the risk. Air pollution is a complex mixture of different gaseous and particulate components that may pose a moderate risk factor for lung cancer. Numerous air pollutants resulting from heavy traffic, burning of fossil fuels, and industrial plants are potential contributors to the incidence of lung cancer. These include PAH, formaldehyde, benzene, ethylene oxide, petroleum vapors, and metals. An association between lung cancer and air pollution has been reported in studies from cities. Urban residents with the highest exposure levels seem to have an increase in lung cancer in the range of 1.5 times that of rural residents.32 In a large European prospective study, it was found that residence in proximity to heavy-traffic roads or exposure to NO2 concentrations greater than 30 µg/m3 can increase the risk of lung cancer.33 In the case of NO2, the lung cancer risk ratio has shown an exposure–response relationship.34 In other studies, particulate matter (fine particles), SO2, and black smoke have all been associated with a moderate increase in the risk of lung cancer. However, analysis is complicated due to the fact that air pollution is a complex mixture,

with numerous air pollutants that vary during the year and over time. Since the lung has a large respiratory volume (500–600 liters of air/h) with a large surface area (75–85 m2), and a large blood perfusion, exposure to toxic compounds in the ambient air could lead to lung toxicity and lung cancer development even at low levels. Radon, a naturally reactive but chemically inert gas found ubiquitously in the environment, emanates as a toxic gas from the soil and from building material of terrestrial origin, such as stone, bricks, and concrete. High levels of radon exposure occur in occupational settings, particularly in uranium mines. People are also subjected to residential radon exposure, which may be increasing due to the tendency to reduce ventilation rates in indoor air. The carcinogenicity of radon is attributable mainly to its short-lived, radioactive, alphaemitting daughters, polonium-214 and polonium-218.35 In miners, increasing risk of lung cancer is associated with increasing cumulative exposure to radon.36 There is also compelling evidence that indoor radon is an important contributor to the risk of lung cancer.37 The dose–response relation between residential radon exposure and excess risk of lung cancer appears to be linear with no threshold. Overall estimates have been made that radon may contribute to 9% of all lung cancers, and the available data suggest that the risks of lung cancer from exposure to radon and smoking are at least additive. Workplace exposure plays an important role in the causation of lung cancer. The evidence for lung cancer induction by occupational exposure to metals such as beryllium, chromium, nickel and arsenic is convincing and well documented.38 High exposure to PAH occurs in several occupations, such as those involved in aluminium production, coke production, and coal gasification, iron and steel workers, bus drivers (because of diesel engine exhaust), roofers, and asphalt workers. The lung is the major target organ among PAH-exposed workers.39 Although occupational exposure to asbestos is no longer an issue in most developed countries, in several developing countries exposure is widespread and may be a significant etiologic factor for lung cancer. As in most other exposure scenarios, tobacco smoking is the main cause of lung cancer in asbestos-exposed workers, and the relative risk seems to be higher among non-smokers compared to smokers.40 Crystalline silica, which may be inhaled in occupational settings, has been classified as a lung carcinogen, with an apparent linear dose–response relationship without any threshold.41 It is important to note, however, when assessing the

Etiology of lung cancer 7

etiology of lung cancer associated with occupational exposure, that a significant confounder to be considered is tobacco smoking. Oncogenic viruses may be involved in the etiology of lung cancer. Some evidence has been provided for the involvement of human papilloma viruses, but detection rates of the viruses in bronchial carcinomas are highly variable, ranging from 0 to 100% in different studies.42 Regarding other oncogenic viruses such as Epstein– Barr virus, human cytomegalovirus, human herpes virus-8, and simian virus 40, the evidence is scarce.43

repair genes involved in different repair pathways show associations. There is increasing knowledge of the genetic defects that give rise to the observed variation in, and, more importantly functional significance of these allelic variants. However, there are numerous conflicting reports on the association between different polymorphisms and lung cancer risk. Larger studies are needed in this area.

FEMALES AND LUNG CANCER SUSCEPTIBILITY GENETIC SUSCEPTIBILITY AND LUNG CANCER ETIOLOGY Host factors may influence individual susceptibility to tobacco smoke. This may be illustrated by the fact that only 1 in 10 lifetime smokers will develop lung cancer. Several epidemiologic studies have indicated that there are genetic factors modifying the risk of individuals to lung cancer. Some degree of familial aggregation of lung cancer is evident in most family studies. One study has reported linkage to chromosome 6q in lung cancer families, strongly supporting the existence of a gene for lung cancer.44 The human genome project has resulted in increasing information becoming available on the existence of polymorphisms in human genes. Susceptibility to lung cancer may be modulated by host-specific factors including differences in carcinogen metabolism and detoxification, DNA repair, cell cycle control, cell signaling, apoptosis, and inflammation pathways. Several studies have been designed to evaluate a large number of sequence variants among multiple genes of drug-metabolizing enzymes.45 Procarcinogens in tobacco smoke are activated by several forms of cytochrome P450 (phase I) and detoxified by glutathione S-transferase (GST), NADPH:quinone oxidoreductase (NQO), N-acetyl-transferase (NAT), and others (phase II). Many of these genes exhibit allelism and there is accumulating evidence that some CYP, GST, NQO, and NAT genotypes are associated with an altered risk of lung cancer. The removal and repair of DNA damage plays a key role in protecting the integrity of the genome from the insults of genotoxic agents such as PAH and NNK found in tobacco smoke. Lung cancer patients were reported to have a lower DNA repair capacity, and recent studies have assessed the relationship between single nucleotide polymorphisms (SNPs) in several DNA repair genes and the risk of lung cancer.45–47 Several DNA

The relative lung cancer burden from women is increasing, partly due to their changing smoking habits. Although controversial, the increase in lung cancer among females is possibly also partly due to a higher susceptibility to tobacco smoke carcinogens. Several studies have reported the relative risk of lung cancer among females to exceed that of males by a factor of 1.5 to 2.5.48–50 Although not all epidemiologic studies have been able to confirm that females are at increased risk,51,52 it is clear that biologic factors involved in lung cancer development differ between the sexes. Experimental studies have indicated sex differences in PAH metabolism, DNA repair capacity, and cell proliferation potential that may support this hypothesis. By analyzing the TP53 gene mutational spectra in a large number of lung cancer cases, G:C-to-T:A hotspot mutations were found at a higher frequency among female smokers compared to female never-smokers. Similar differences were not found among males.53 Since G:C-to-T:A transversions are associated with exposure to PAH, this indicates a specific role for PAH in generating this particular signature mutation in women. Women have also been reported to have increased levels of pulmonary tobacco-smoke-induced DNA damage in the form of PAH-related adducts.54 The DNA-adduct level may be a predictor of cancer risk.55 Higher DNA-adduct levels among females coincide with a higher level of expression of the smoking-induced cytochrome P450 1A1 (CYP1A1), which is an important gene in the metabolic activation of PAH.56 Estrogens and their receptors have been hypothesized to be involved in these sex differences by interfering with the transcription-activating activity of the aryl hydrocarbon receptor (AHR). AHR is a ligand-activated transcription factor with high affinity for PAH. In studies with lymphocytes isolated from lung cancer patients, it was found that females might also have a lower capacity to

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repair DNA damage,57 which may result in increased susceptibility to the manifestation of mutations. One report has indicated that pulmonary expression of the gastrin-releasing peptide receptor (GRPR), which is involved in lung development during fetal stages, is more frequent among women than men.58 The GRPR gene is induced by smoking and is located on a region of the X-chromosome that appears to escape X-chromosome inactivation in females. Activation of the GRPR has been associated with an increased proliferative response in human airway epithelial cells. Thus, this represents a model where smoking may induce the gene to a higher extent among women. In summary, tobacco smoking (active smoking or exposure to environmental tobacco smoke) plays a major etiologic role in lung carcinogenesis. More than 60 compounds in tobacco smoke have been identified as carcinogenic. Other etiologic factors of minor, but still significant importance for the disease are air pollution, radon, workplace exposure, and viruses. Genetic differences in susceptibility to lung cancer are apparent and sex differences may be involved. REFERENCES 1. World Cancer Research Fund, American Institute for Cancer Research. Food, nutrition and the prevention of cancer: a global perspective. Washington, DC: American Institute for Cancer Research, 1997: 37–145. 2. Parkin DM, Pisani P, Lopez AD, Masuyer E. At least one in seven cases of cancer is caused by smoking: global estimates for 1985. Int J Cancer 1994; 59: 494–504. 3. International Agency for Research on Cancer. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcin Risk Hum 2004; 83. 4. Hoffmann D, Hoffmann I. The changing cigarette, 1950–1995. J Toxicol Environ Health 1997; 50: 307–64. 5. Swauger JE, Steichen TJ, Murphy PA et al. An analysis of the mainstream smoke chemistry of samples of the US cigarette market acquired between 1995 and 2000. Regul Toxicol Pharmacol 2002; 35: 142–56. 6. US Department of Health and Human Services (DHHS). Reducing the health consequences of smoking: 25 years of progress. A report of the surgeon general, Washington DC: US government printing office, 1989. 7. Fowler J, Bates M. The chemical constituents in cigarettes and cigarette smoke. Priorities for harm reduction. Report to the New Zealand Ministry of Health. Epidemiology and Toxicology group, Porirua, ESR, Kenepura Science Centre. 8. Hecht SS. Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention. Lancet Oncol 2002; 3: 461–9. 9. Phillips DH. Smoking-related DNA and protein adducts in human tissues. Carcinogenesis 2002; 23: 1979–2004.

10. Phillips DH. DNA adducts as markers of exposure and risk. Mutat Res 2005; 577: 284–92. 11. Vineis P, Perera F. DNA adducts as markers of exposure to carcinogens and risk of cancer. Int J Cancer 2000; 88: 325–8. 12. Calvez FL, Mukeria A, Hunt JD et al. TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. Cancer Res 2005; 65: 5076–83. 13. Denissenko MF, Pao A, Tang M, Pfeifer GP. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in p53. Science 1996; 274: 430–2. 14. Hecht SS, Carmella SG, Foiles PG et al. Tobacco-specific nitrosamine adducts: studies in laboratory animals and humans. Environ Health Perspect 1993; 99: 57–63. 15. Hecth SS. Human urinary carcinogen metabolites: biomarkers for investigating tobacco and cancer. Carcinogenesis 2002; 23: 907–22. 16. Schuller HM. Mechanisms of smoking-related lung and pancreatic adenocarcinoma development. Nat Cancer Rev 2002; 2: 455–63. 17. Costa M. Toxicity and carcinogenicity of Cr (VI) in animal models and humans. Crit Rev Toxicol 1997; 27: 431–42. 18. Waalkes MP. Cadmium carcinogenesis. Mutat Res 2003; 533: 107–20. 19. Oller AR, Costa M, Oberdorster G. Carcinogenicity assessment of selected nickel compounds. Toxicol Appl Pharmacol 1997; 143: 152–66. 20. International Agency for Research on Cancer. Formaldehyde. IARC Monogr Eval Carcin Risk Hum 1982; 4: 131–2. 21. Khater AEM. Polonium-210 budget in cigarettes. J Environ Radioactivity 2004; 71: 33–41. 22. Little JB, Kennedy AR, McCandy RB. Effect of dose rate on the induction of experimental lung cancer in hamsters by alpha radiation. Radiat Res 1985; 103: 293–9. 23. Rahman I. Oxidative stress, chromatin remodelling and gene transcription in inflammation and chronic lung disease. Biochem Mol Biol 2003; 36: 95–109. 24. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420: 860–7. 25. Hunninghake GW, Crystal RG. Cigarette smoking and lung destruction: accumulation of neutrophils in the lungs of cigarette smokers. Am Rev Respir Dis 1990; 128: 833–8. 26. Kasai H. Analysis of a form of oxidative DNA-damage, 8-hydroxy-2′-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res 1997; 387: 147–63. 27. Maneckjee R, Minna JD. Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines. Proc Natl Acad Sci USA 1990; 87: 3294–8. 28. Xin M, Deng X. Nicotine inactivation of the propoptotic function of Bax through phosphorylation. J Biol Chem 2005; 280: 10781–9. 29. Dockery DW, Trichopoulos D. Risk of lung cancer from environmental exposures to tobacco smoke. Cancer Causes Control 1997; 8: 333–45. 30. Husgafvel-Pursiainen K, Boffetta P, Kannio A. p53 mutations and exposure to environmental tobacco smoke in a multicenter study on lung cancer. Cancer Res 2000; 60: 2906–11. 31. Vahakangas KH, Bennett WP, Castren K et al. p53 and K-ras mutations in lung cancers from former and never-smoking women. Cancer Res 2001; 61: 4350–6.

Etiology of lung cancer 9 32. Boffetta P. Epidemiology of environmental and occupational cancer. Oncogene 2004; 23: 6392–403. 33. Vineis P, Hoek G, Krzyzanowski M et al. Air pollution and risk of lung cancer in a prospective study in Europe. Int J Cancer 2006; 119: 164–74. 34. Nafstad P, Haheim LL, Oftedal B et al. Lung cancer and air pollution: a 27 year follow up of 16209 Norwegian men. Thorax 2003; 58: 1071–6. 35. Phillips PS, Denman AR. Radon: a human carcinogen. Sci Prog 1997; 80: 317–36. 36. International Agency for Research on Cancer. Ionizing radiation, part 2: some internally deposited radionuclides. IARC Monogr Eval Carcin Risk Hum 2001; 78: 137–66. 37. Darby S, Hill D, Auvinen A, Barros-Dios JM et al. Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies. BMJ 2005; 330: 223. 38. Siemiatycki J, Richardson L, Straif K et al. Listing occupational carcinogens. Environ Health Perspect 2004; 112: 1447–59. 39. Boffetta P, Jourenkova N, Gustafsson P. Cancer risk from occupational exposure to polycyclic aromatic hydrocarbons. Cancer Causes Control 1997; 8: 444–72. 40. Liddell FDK. The interaction of asbestos and smoking in lung cancer. Ann Occup Hyg 2001; 45: 341–56. 41. Steenland K, Mannetje A, Boffetta P et al. Pooled exposure– response analysis and risk assessment for lung cancer in 10 cohorts of silica-exposed workers: an IARC multicentre study. Cancer Causes Control 2001; 12: 773–84. 42. Syrjanen KJ. HPV infections and lung cancer. J Clin Pathol 2002; 55: 885–91. 43. Brouchet L, Valmary S, Dahan M. Detection of oncogenic virus genomes and gene products in lung carcinoma. Br J Cancer 2005; 92: 743–6. 44. Bailey-Wilson JE, Amos CI, Pinney SM et al. A major lung cancer susceptibility locus maps to chromosome 6q23–25. Am J Hum Genet 2004; 75: 460–74. 45. Liu G, Zhou W, Christiani DC. Molecular epidemiology of non-small cell lung cancer. Semin Respir Crit Care Med 2005; 26: 265–72. 46. Wei Q, Cheng L, Hong WK, Spitz MR. Reduced DNA repair capacity in lung cancer patients. Cancer Res 1996; 56: 4103–7.

47. Zienolddiny S, Campa D, Lind H et al. Polymorphisms of DNA repair genes and risk of non-small cell lung cancer. Carcinogenesis 2006; 27: 560–7. 48. Risch HA, Howe GR, Jain M et al. Are female smokers at higher risk for lung cancer than male smokers? A case-control analysis by histologic type. Am J Epidemiol 1993; 138: 281–93. 49. Zang EA, Wynder EL. Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst 1996; 88: 183–92. 50. Henschke CI, Miettinen OS. Women’s susceptibility to tobacco carcinogens. Lung Cancer 2004; 43: 1–5. 51. Kreuzer M, Boffetta P, Whitley E et al. Gender differences in lung cancer risk by smoking: a multicentre case-control study in Germany and Italy. Br J Cancer 2000; 82: 227–33. 52. Bain C, Feskanich D, Speizer FE et al. Lung cancer rates in men and women with comparable histories of smoking. J Natl Cancer Inst 2004; 96: 826–34. 53. Toyooka S, Tsuda T, Gazdar AF. The TP53 gene, tobacco exposure, and lung cancer. Hum Mutat 2003; 21: 229–39. 54. Mollerup S, Ryberg D, Hewer A et al. Sex differences in lung CYP1A1 expression and DNA adduct levels among lung cancer patients. Cancer Res 1999; 59: 3317–20. 55. Veglia F, Matullo G, Vineis P. Bulky DNA adducts and risk of cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2003; 12: 157–60. 56. Mollerup S, Berge G, Bæra R et al. Sex differences in risk of lung cancer: expression of genes in the PAH bioactivation pathway in relation to smoking and bulky DNA adducts. Int J Cancer 2006; 119: 141–4. 57. Wei Q, Cheng L, Amos CI et al. Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiology study. J Natl Cancer Inst 2000; 92: 1764–72. 58. Shriver SP, Bourdeau HA, Gubish CT et al. Sex-specific expression of gastrin-releasing peptide receptor: relationship to smoking history and risk of lung cancer. J Natl Cancer Inst 2000; 92: 24–33.

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Epidemiology of lung cancer: a century of great success and ignominious failure Peter Boyle, Sara Gandini, Nigel Gray Contents Introduction • Phase I: public health success, 1930s onwards • Phase II: understanding etiology, losing ground in incidence and mortality • Phase III: descriptive epidemiology of lung cancer • Phase IV: public health failure, 1960s onwards

INTRODUCTION The present century has witnessed a remarkable epidemic of lung cancer. The words of Adler,1 published in 1912, today make salutary reading: Is it worthwhile to write a monograph on the subject of primary malignant tumours of the lung? In the course of the last two centuries an ever-increasing literature has accumulated around this subject. But this literature is without correlation, much of it buried in dissertations and other out-of-the-way places, and, with but a few notable exceptions, no attempt has been made to study the subject as a whole, either the pathological or the clinical aspect having been emphasised at the expense of the other, according to the special predilection of the author. On one point, however, there is nearly complete consensus of opinion, and that is that primary malignant neoplasms of the lungs are among the rarest forms of the disease. This latter opinion of the extreme rarity of primary tumours has persisted for centuries. Lung cancer is currently the most common form of cancer worldwide. It is the most common cause of cancer death in men in North America and in virtually all European countries, west and east, and it is increasingly common as a cause of death in developing populations in Asia, Latin America, and Africa, although comparable high-quality data are not available from many of these populations. From being virtually an unknown and rare disease at the beginning of the last century, public health has documented the development of a true epidemic of lung cancer through the 20th century, and has failed to alleviate the situation by positive actions. Knowing the cause, which has been the case for

lung cancer since at least the middle of the last century, has been of little value in public health terms, since there has been no real action taken to reduce the impact of this serious disease. In viewing the century of lung cancer epidemiology, there are a number of distinct phases that can be identified. Initially (phase I), there was the great success of epidemiology, the basic science of public health, in establishing the causal link between cigarette smoking and lung cancer risk. Following this period, from the mid1950s onwards, there was a period (phase II) where there was an increasing understanding of the etiology of lung cancer, and simultaneously public health began losing ground as smoking rates led to great increases in the incidence and mortality of the disease, particularly among men in developed countries. The association between tobacco smoking and lung cancer became widely known, and many groups actively took up the movement towards tobacco control. During this period (phase III), the situation stabilized while activists and scientists united to try to bring the adverse effects of tobacco smoking to general attention and thereby to take actions designed to reduce smoking and its harmful side-effects. It quickly became clear that a great deal of ground had been lost, and during phase IV large increases in lung cancer among women became apparent, indicating the great failure of public health to curb the development of the habit among women.

PHASE I: PUBLIC HEALTH SUCCESS, 1930s ONWARDS The association between tobacco smoking and the development of lung cancer appears to have been suggested in the UK in 1927.2 The first interview study on tobacco smoking and lung cancer seems to have been reported from Vienna,3 where lung cancer rates

Epidemiology of lung cancer: a century of great success and ignominious failure 11

had risen dramatically. Fleckseder3 found 51 smokers among 54 patients with lung cancer. Thirty-seven of these smoked between 20 and 90 cigarettes daily, while excessive smoking of pipes, cigars, or both was rarer. The same association was alluded to in a report from the USA4 on a study primarily of a series of 79 patients treated by total pneumonectomy. A report from Cologne followed one year later,5 based on the postmortem records of 96 patients. The patients (or more usually the relatives of fatal cases) were interviewed as to patient’s occupation, tobacco consumption, and exposure to specific ‘inhalants’. Reanalysis of Muller’s5 data shows a relative risk of 3.1 among moderate smokers, 2.7 among heavy smokers, 16.8 among very heavy smokers, and 29.16 among excessive smokers. Within the limitations of the study (e.g. small numbers, especially among non-smoking cases, and possible inaccuracies in elucidation of precise smoking histories), these results were noticeably similar to results obtained from later case–control studies in the USA and, apart from a lack of increase among heavy smokers, there is the possible appearance of a dose–response relationship. A study of smoking habits and occupation based on 195 postmortem records of lung cancer cases from the Pathology Institute at Jena for the years 1930–1941 was reported: usable replies were obtained from relatives of 93 men and 16 women. Of the women, 13 were nonsmokers.6 The authors attempted to collect control information by interviewing 700 men in Jena between the ages of 53 and 54, the average age of the lung cancer patients at death (53.9 years). This was a study performed in Germany towards the end of the Second World War, and only 270 men from Jena responded to the questionnaire. The authors showed great insight in concluding that wartime conditions (particularly the rationing system) may have favored results from non-smokers. They reported a statistically significant difference between non-smokers and heavy smokers among lung cancer patients on the one hand and normal patients on the other. Realizing the possible errors on their material, they concluded that there was a considerable probability that lung cancer was far more frequent among non-smokers than expected. Their data are such that an approximate relative risk can be calculated: the risk relative to non-smokers was 1.90 among light smokers, 9.05 among moderate smokers, and 11.34 among heavy/excessive smokers. Again there appears to be a moderate dose–response relationship. The rapid escalation in lung cancer during the 1940s reached a level that permitted more and larger studies

to be conducted and, in 1950, five major contributions were made to the literature.7–11 The data presented by Wynder and Graham10 are capable of transformation to calculate the relative risks (the concept of which was unknown for a few more years). Setting the risk among non-smokers at 1.0, there is to some extent or other a dose–response relationship with increasing levels of smoking in all age groups. Together with the study of Wynder and Graham,10 the fifth paper published on this subject during the year represented a significant contribution not only to knowledge about smoking and cancer but also to the methodology of retrospective epidemiologic studies.11 This well-planned, controlled, and well-conducted study was initially reported,11 and completed and published more extensively two years later. It is this latter report12 that we shall discuss here. Doll and Hill12 did not discuss cigar smoking, but calculated that use of one ounce of pipe tobacco was the equivalent of 26.5 cigarettes, and one ounce per week was equivalent to smoking four cigarettes per day. Non-smokers were defined as people who had never consistently smoked as much as one cigarette per day for as long as one year.11 The strongest difference between cases and controls (for both males and females) was found to be the average amount smoked daily over the 10 years preceding the patient’s illness. Qualitatively similar results were also obtained using the amount smoked immediately before the patient’s illness, the maximum amount ever smoked regularly, the total smoked since smoking began, and the average amount smoked daily over the 10 years preceding the patient’s illness, over the penultimate 10 years and over the whole of the patient’s life since the age of 15 (even after allowance had been made for recorded changes in smoking habit). Patients who recognized that they inhaled were found no more frequently in the lung cancer group than in the control group, although those cases with growths of central origin inhaled less frequently than normal. It also appeared that lung cancer patients more frequently had a history of preceding pneumonia or chronic bronchitis, while other respiratory illnesses were referred to with approximately equal frequency by the two groups. Doll and Hill’s reports11,12 contained a remarkable amount of information, but the fundamental finding in men was a highly significant difference between the proportions of non-smokers and of smokers in the disease group and in the control group. A less marked series of differences was reported for women. Highly

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significant differences were also shown between the proportions of both groups smoking different average amounts, i.e. between heavy and light smokers, and this result held for males and females. It is apparent from the raw data that there is a dose–response relationship present. Less marked but nevertheless distinct differences were found when the duration of smoking was considered rather than the amount smoked. Lung cancer cases, as a group, began to smoke earlier; they continued to smoke longer and gave up less often and, when they did, did so for shorter periods. In males, all these differences were statistically significant, but, although the differences were in the same direction in women, they did not reach the commonly accepted (5%) level of statistical significance. These five studies,7–11 but mainly the impact of two,10,11 alerted the medical and scientific community to the serious health hazards associated with cigarette smoking. Once alerted, the public response to these studies was a significant, but brief, drop in the per capita consumption of cigarettes in both the USA and the UK.

PHASE II: UNDERSTANDING ETIOLOGY, LOSING GROUND IN INCIDENCE AND MORTALITY Throughout the 1950s, a mass of information was published demonstrating the association between lung cancer and cigarette smoking, using data derived from retrospective studies. Many concentrated on inhalation and, while some studies demonstrated a higher occurrence of inhalation among lung cancer patients than among controls, others failed to detect this association. The US Surgeon General was moved by the weight of evidence associating smoking with cancer of the lung, as well as of other sites, to produce an official statement on ‘Smoking and Health’ on behalf of the US Government.13 This created a worldwide reaction, since it implicated a frightening link between cigarette smoking and a variety of fatal diseases in a document of impeccable scientific authority. This report weighed the available evidence, and considered that it had been established that cigarette smoking was causally related to lung cancer in men, and judged cigarette smoking in the USA a sufficiently important health hazard to warrant remedial action. In the 15 years that passed from that initial report, the body of evidence increased, and extended to include

women,14 in whom lung cancer had increased fivefold in two decades in the USA. The Secretary for Health of the time (Mr Joseph Califano) concluded ‘that smoking is the largest preventable cause of death in America’. An important factor in the causal relationship between smoking and lung cancer is the demonstrated dose– response relationship. In epidemiologic studies, the dose has been measured by: • • • • • • • • •

the number of cigarettes smoked per day at interview; the maximum number of cigarettes smoked per day; the age when smoking commenced; the degree of inhalation of tobacco smoke; the total number of years smoked; the total lifetime number of cigarettes smoked; the tar and nicotine levels of the brand of cigarettes used; the number of puffs per cigarette; the length of the unburned portion of cigarette.

A variety of combinations of these variables can be converted into dosage scores. Lung cancer mortality ratios exhibit an inverse relationship with the age of initiation of the smoking habit. Those who develop the habit at school have a much higher risk of lung cancer than those who begin smoking at age 25+, in whom the risk is only four to five times that of non-smokers. Available data show a strong dose–response relationship between self-reported inhalation of cigarette smoke and lung cancer mortality. Those who inhale deeply have risks double those of smokers who do not. The American Cancer Society 25 State Study15 reported a mortality ratio among non-smokers of 1.0, a mortality ratio of 8.0 among smokers who stated that they did not inhale, and elevations in this risk among those who inhaled slightly (8.9), moderately (13.1) and deeply (17.0). Similar results were reported from a Swedish study:16 although the mortality ratios among nonsmokers (1.0), non-inhalers (3.7), light inhalers (7.8), and deep inhalers (9.2) were smaller in magnitude, the same steady pattern was found. Although it has been suggested for some time that the risk of developing lung cancer increases with the tar and nicotine content of cigarettes there has not been any substantial evidence to suggest that individuals who switch to lower-tar and lower-nicotine cigarettes experience less lung cancer mortality.17 It has been proposed that, if the tar and nicotine contents of tobacco

Epidemiology of lung cancer: a century of great success and ignominious failure 13

were reduced, smokers might increase the number of cigarettes smoked per day and effectively vitiate any benefit. On the other hand, those who switch to low-tar and low-nicotine brands might inhale smoke more deeply than smokers of high-tar and high-nicotine cigarettes, and thus exposure to tar and nicotine might be reduced. The relationship of tar and nicotine was carefully examined with respect to lung cancer in a major study,18 in which 897 825 men and women were classified by levels of tar and nicotine smoked. Brands were considered to be high in nicotine if they contained between 2.0 and 2.7 mg of nicotine and high in tar if they contained between 25.8 and 35.7 mg of tar. The medium levels of tar and nicotine were set at 17.6 and 25.7 mg and at 1.2 and 1.9 mg, respectively. Low tar and nicotine levels were all those below these limits. The risk in the high-tar and high-nicotine group of makes was set at 1.0, and the relative risks in the medium group (risk ratio, RR = 0.95) and low group (RR = 0.81) were appreciably lower. Similar results were found for females: high (RR = 1.0), medium (RR = 0.79), and low (RR = 0.60). These results take into account the daily cigarette consumption. In other words, for men smoking the same number of cigarettes per day, there appears to be an almost 20% reduction in the risk of developing lung cancer with the use of cigarettes low in tar and nicotine. In females, keeping the number of cigarettes smoked per day constant, there appears to be a 40% reduction in risk. The amount of tar and nicotine taken into the body per day obviously depends on the number of cigarettes smoked as well as on the tar and nicotine content of individual cigarettes. Hammond therefore performed a second analysis comparing subjects who smoked 1–19 high-tar and -nicotine cigarettes per day with those who smoked 20–39 low-tar and -nicotine cigarettes per day. Setting the risk to be 1.0 among the high categories of both males and females, Hammond found risks of 1.6 (males) and 2.1 (females) among the groups who smoked 20–39 low-tar and -nicotine cigarettes. He concluded that the number of cigarettes smoked per day was relatively more important than the tar and nicotine content.15,18 All these early observations were regarding forms of cancer and forms of tobacco smoking that were the most common at the period. Cigarette smoking increased heavily in Europe during the last years of Napoleon,19 and the habit spread during the Crimean War, accelerated around 1900 and reached many men, and increasingly women, during the First World War

(1914–1918). In many countries, such as the USA and the UK, women began to reach the same smoking levels as men during the Second World War (1939–1945). Subsequent to this period, cancer was becoming more frequent, and was developing into an international disease that was to become, by the latter part of the 20th century, a significant global public health problem. An increasing number of forms of cancer became linked with cigarette smoking: initially oral cancers, then lung cancer, bladder cancer, laryngeal cancer, esophageal cancer, pancreatic cancer, acute myeloid leukemia, cervical cancer, kidney cancer, and gastric cancer. Several of these are of unusually high frequency in international populations.20

PHASE III: DESCRIPTIVE EPIDEMIOLOGY OF LUNG CANCER The main tobacco-related site is the lung. Lung cancer rates in self-reported non-smokers from various studies are of the order of only 10–15 per 100 000. The IARC monograph Tobacco Smoking21 gave estimates of the proportions of lung cancer deaths attributable to tobacco smoking in five developed countries (Canada, England and Wales, Japan, Sweden, and the USA): these ranged between 83% and 92% for males, and between 57% and 80% for females. The most recent, international, cancer incidence data are available for the period around 1990. The highest incidence rate in men is recorded among the AfroAmerican population of New Orleans in the USA, where the average, annual, age-standardized rate per 100 000 person-years is 110.8 (Table 2.1). Other Afro-American populations in the USA also have remarkably high lung cancer rates in men. Rates are also high among the Maori population of New Zealand, where the incidence rate is 99.7 per 100 000 (Table 2.1). The incidence rate is high in Lower Silesia (Poland) and in the west of Scotland (Table 2.1). There are virtually no regions of the world where the annual incidence rates are low: the lowest incidence rates are reported from a variety of population groups from the developing world (Table 2.2). Among women, the highest rates are found in the Maori population group of New Zealand (72.9 per 100 000) (Table 2.3). High rates are also found among a variety of populations of North America – both AfroAmerican and Caucasian. Notably high rates are reported from the west of Scotland, where incidence rates are high in men as well as in women (Table 2.3).

14 Textbook of Lung Cancer Table 2.1 Highest incidence rates of cancer of the trachea, bronchus and lung in men circa 1990 Registry

Cases

ASRa

USA, New Orleans: Black (1988–1992) USA, Central Louisiana: Black (1988–1992) USA, Detroit: Black (1988–1992) USA, San Francisco: Black (1988–1992) New Zealand: Maori (1988–1992) USA, SEER:b Black (1988–1992) USA, Atlanta: Black (1988–1992) Poland, Lower Silesia (1988–1992) Canada, Northwest Territories (1983–1992) UK, Scotland, west (1988–1992) USA, Los Angeles: Black (1988–1992) USA, Connecticut: Black (1988–1992) Italy, Ferrara (1991–1992) USA, New Orleans: White (1988–1992) Italy, Trieste (1989–1992)

842 172 2263 1003 387 4964 892 7213 126 8877 1925 422 597 1707 897

110.81 105.62 103.23 101.49 99.73 99.11 97.26 95.52 90.26 88.90 88.74 86.15 85.73 84.01 82.73

a

Average, annual, age-standardized rate per 100 000 person-years. Surveillance Epidemiology and End Results Program (National Cancer Institute).

b

Table 2.2 Lowest incidence rates of cancer of the trachea, bronchus and lung in men circa 1990 Registry

Cases

ASRa

India, Karunagappally (1991–1992) Thailand, Kohn Kaen (1990–1993) Peru, Lima (1990–1991) Costa Rica (1988–1992) India, Bombay (1988–1992) Singapore: Indian (1988–1992) India, Madras (1988–1992) Peru, Trujillo (1988–1990) India, Trivandrum (1991–1992) USA, New Mexico: American Indian (1988–1992) Ecuador, Quito (1988–1992) India, Bangalore (1988–1992) Mali, Bamako (1988–1992) Uganda, Kyadondo (1991–1993) India, Barshi, Paranda and Bhum (1988–1992)

58 355 635 686 1867 83 789 47 69 24 172 495 38 20 11

17.04 17.02 15.89 15.63 14.48 14.33 12.64 11.93 10.63 10.32 10.13 8.06 5.28 4.24 1.26

a

Average, annual, age-standardized rate per 100 000 person-years.

The finding of the incidence rate among women in Tianjin, China, among the 15 highest incidence rates recorded, is the first clear indication of the rising epidemic of lung cancer, and other cancers, resulting from the increasing prevalence of cigarette smoking during recent decades (Table 2.3). There are some regions of

the world where the incidence rate among women is still truly low (Table 2.4). In men in all European countries, except Portugal, lung cancer is now the leading cause of cancer death. In the USA (and in all European countries except a few Scandinavian countries), it is also the commonest tumor

Epidemiology of lung cancer: a century of great success and ignominious failure 15

Table 2.3 Highest incidence rates of cancer of the trachea, bronchus and lung in women circa 1990 Registry

Cases

ASRa

New Zealand: Maori (1988–1992) Canada, Northwest Territories (1983–1992) Canada, Yukon (1983–1992) USA, San Francisco: Black (1988–1992) USA, Detroit: Black (1988–1992) USA, New Orleans: White (1988–1992) USA, San Franciso: non-Hispanic White (1988–1992) USA, Detroit: White (1988–1992) USA, Central California: non-Hispanic White (1988–1992) USA, Los Angeles: non-Hispanic White (1988–1992) UK, Scotland, west (1988–1992) USA, SEER:b Black (1988–1992) USA, Hawaii: White (1988–1992) USA, Seattle (1988–1992) China, Tianjin (1988–1992)

326 80 39 562 1213 1115 3906 4772 2267 6674 5086 2558 340 4413 3870

72.93 65.56 47.62 44.33 42.02 41.19 40.42 40.17 39.48 38.58 38.47 38.46 37.94 37.62 37.00

a

Average, annual, age-standardized rate per 100 000 person-years. Surveillance Epidemiology and End Results Program (National Cancer Institute).

b

Table 2.4 Lowest incidence rates of cancer of the trachea, bronchus and lung in women circa 1990 Registry

Cases

Malta (1992–1993) France, La Réunion (1988–1992) France, Tarn (1988–1992) Spain, Albacete (1991–1992) Spain, Tarragona (1988–1992) Algeria, Setif (1990–1993) Spain, Granada (1988–1992) Spain, Zaragoza (1986–1990) India, Karunagappally (1991–1992) India, Madras (1988–1992) India, Trivandrum (1991–1992) India, Bangalore (1988–1992) Mali, Bamako (1988–1992) Uganda, Kyadondo (1991–1993) India, Barshi, Paranda and Bhum (1988–1992)

18 46 60 19 72 33 92 116 10 142 14 103 13 4 3

ASRa

3.35 3.34 3.19 3.14 3.09 2.88 2.71 2.66 2.59 2.37 1.89 1.67 1.53 0.41 0.33

a

Average, annual, age-standardized rate per 100 000 person-years.

in terms of incidence (although the recent inflation of prostate cancer incidence figures with very early detection of cases is taking prostate cancer above lung cancer in terms of the incidence of the disease). The range of geographic variation in lung cancer mortality in Europe is threefold in both sexes – the highest rates being observed in the UK, Belgium, the Netherlands, and the

former Czechoslovakia, and the lowest rates being reported in southern Europe and in Norway and Sweden.22 This overall pattern of age-standardized lung cancer mortality rates does not reveal the important and diverging cohort effects occurring in various countries: for instance, some of the countries in which there are now low rates, such as those in southern Europe

16 Textbook of Lung Cancer

and parts of eastern Europe, experienced a later uptake and spread of tobacco use, and now appear among the most elevated rates in the younger age groups. This suggests that these same countries, including Italy, Greece, France, Spain, and several countries in eastern Europe, will have the highest lung cancer rates in men at the beginning of the next century, in the absence of rapid intervention. The importance of adequate intervention is shown by the low lung cancer rates in Scandinavian countries, which have adopted, since the early 1970s, integrated central and local policies and programs against smoking.23,24 These policies may have been enabled by the limited influence of the tobacco lobby in these countries. The experience in Finland provides convincing evidence of the favorable impact, after a relatively short delay, of well-targeted large-scale interventions on the most common cause of cancer death and of premature mortality in general. With specific reference to women, current rates in most European countries (except the UK and Ireland) are still substantially lower than in the USA, where lung cancer is now the leading cause of cancer death in females. In several countries, including France, Switzerland, Germany, and Italy, where smoking is now becoming commoner in young and middle-aged women, overall national mortality rates are still relatively low, although appreciable upward trends have been registered over the last two decades. This is particularly worrisome in perspective, since smoking prevalence has continued to increase in subsequent generations of young women in these countries. Thus the observation that lung cancer is still relatively rare in women, with smoking at present accounting for only approximately 40–60% of all lung cancer deaths, cannot constitute a reason for delaying efficacious interventions against smoking by women. The currently more favorable situation in Europe compared with the USA, together with the observation that smoking cessation reduces lung cancer risk after a delay of several years, should, in the presence of adequate intervention, enable a major lung cancer epidemic in European women to be avoided. A proportion of lung cancers, varying in various countries and geographic areas, may be due to exposures at work, and a small proportion to atmospheric pollution.25 The effect of atmospheric pollution in increasing lung cancer risk appears to be chiefly confined to smokers. Lung cancer risk is elevated in atomic bomb survivors,26 in patients treated for ankylosing spondylitis,27 and in underground miners whose bron-

chial mucosa was exposed to radon gas and its decay products: this last exposure was reviewed and it was concluded that there was ‘sufficient evidence’ that this occupational exposure caused lung cancer.28 A greater risk of lung cancer is generally seen for individuals who are exposed at an older age. Investigation of the interaction with cigarette smoking among atomic bomb survivors suggests that it is additive,29 but the data from underground miners in Colorado are consistent with a multiplicative effect.30 In conclusion, the overwhelming role of tobacco smoking in the causation of lung cancer has been repeatedly demonstrated over the past 50 years. Current lung cancer rates reflect cigarette smoking habits of men and women over past decades,31–33 but not necessarily current smoking patterns, since there is an interval of several decades between the change in smoking habits in a population and its consequences on lung cancer rates. Over 90% of lung cancer may be avoidable simply through avoidance of cigarette smoking. Rates of lung cancer in central and eastern Europe at present are higher than those ever before recorded elsewhere; lung cancer has increased tenfold in men and eightfold in women in Japan since 1950; there is a worldwide epidemic of smoking among young women,34 which will be translated into increasing rates of tobacco-related disease, including cancer, in the coming decades; there is another epidemic of lung cancer and tobaccorelated deaths building up in China as the cohorts of men in whom tobacco smoking became popular reach ages at which cancer is an important hazard.35 Many solutions have been attempted to reduce cigarette smoking, and increasingly many countries are enacting legislation to curb this habit.36

PHASE IV: PUBLIC HEALTH FAILURE, 1960s ONWARDS Thus it has been clear for the entire second half of the 20th century that cigarette smoking causes lung cancer. Current low levels of smoking among physicians and research scientists in many countries have led many of them unconsciously to overlook tobacco smoking as an important cause of cancer.37 There is, however, a very substantial body of evidence from many sources that indicates the carcinogenicity of tobacco smoking. Not only does cigarette smoking greatly increase the risk of lung cancer in smokers, but the risk of oral cavity cancer, laryngeal cancer, esophageal cancer, bladder cancer, pancreatic cancer, and kidney cancer is also

Epidemiology of lung cancer: a century of great success and ignominious failure 17

increased. The risk of cancer of the cervix and stomach may also be increased, although the evidence for this is much less consistent.38 These forms of cancer can be expected to rise in women as a result of their increased levels of cigarette smoking. There is at present a worldwide epidemic of tobaccorelated disease: not only does smoking cause increased levels of many different common forms of cancer, it also increases the risk of cardiovascular disease. As mentioned in the previous section, deaths from lung cancer, the tumor most strongly linked to cigarette smoking, have increased in Japan by a factor of 10 in men and 8 in women since 1950. In central and eastern Europe, more than 400 000 premature deaths are currently caused each year by tobacco smoking. In young men in all countries of central and eastern Europe, there are current levels of lung cancer that are greater than anything seen before in the Western countries, and these rates are still rising. In Poland – a country severely hit by the tobacco epidemic – the life-expectancy of a 45-year-old man has been falling for over a decade now owing to the increasing premature death rates from tobacco-related cancers and cardiovascular disease.39 Tragically, cigarette smoking is still increasing in central and eastern Europe and also in China, where an epidemic of tobacco-related deaths is building up quickly. Tobacco smoking is also the most easily avoided risk factor for cancer. The most important determinant of risk of lung cancer is the duration of smoking: long-term cigarette smokers have a 100-fold increased risk compared with never-smokers. The content of cigarettes (low tar) produces only a threefold variation in risks between the extremes. (‘Low tar’ is frequently taken to include a number of features, including filter-tips as well as the active tar yield.) Lung cancer is the major tobacco-related tumor and the leading cause of cancer death in men in almost every developed country. Incidence rates are around 10–15 per 100 000 in non-smokers and between 80 and 100 per 100 000 in the highest-incidence population groups such as Afro-Americans, and rates exceeding 200 per 100 000 have been reported in cities of central and eastern Europe. Since lung cancer is frequently fatal, mortality rates are high, and consequently so are the social costs. Women around the world have taken up the cigarette smoking habit with gusto. For many years, it appeared that their lung cancer rates were low and that tobacco was not having the same effect as on men. This complacency, which crept in during the two decades from the mid-1960s especially, is now exposed as false:

nor is there evidence that the effect of cigarette smoking on lung cancer risk is greater in women than in men. The dominance of the effect of duration of smoking means that a long period of time will pass between the exposure (large numbers of women smoking) and the effect (high levels of lung cancer). Lung cancer now exceeds breast cancer as the leading cancer cause of death in women in the USA, Canada, Scotland, and several other countries. In Canada, breast cancer mortality has remained at least constant for nearly four decades, while lung cancer death rates have increased between three- and fourfold during the same period. While the higher case-fatality of lung cancer may be one factor in the mortality rates overtaking breast cancer, there is, increasingly, evidence that there are regions of the world where the gap in the incidence rate is now closing. For example, in Glasgow, an area where lung cancer has been historically high, by 1990 the incidence rate for lung cancer (115 per 100 000) exceeded that for breast cancer (105 per 100 000) in 1990.40 Among international cancer registries, there are some where the incidence of lung cancer now exceeds the incidence of breast cancer, and others where there is still a gap. In the SEER (Surveillance Epidemiology and End Results) Program of the US National Cancer Institute, the incidence of lung cancer in both Black and White women increased by over 90% between 1973–1977 and 1988– 1992: the increase in the incidence of breast cancer was around 25% in both racial groups (comparison made between incidence rates age-adjusted using the 1970 US population). It is a great worry that there does not appear to be any end in sight to this increase in lung cancer risk internationally: it is programmed to continue for several decades to come. Part of the complacency over the effect on women was also due to the strong tendency for women to smoke brands of cigarettes that were lower in tar and nicotine content than those smoked by men: it was assumed that these would have less of a risk for lung cancer than the higher-tar cigarettes that men generally smoked. Marked changes in the rates of the major histologic cell types of lung cancer can now be seen, with particular increases in the risk of adenocarcinoma.41,42 The changes seen are compatible with increased risk of adenocarcinoma due to increasing levels of smoking of ‘light’ cigarettes (low-tar, low-nicotine). It appears that abandoning high-tar cigarettes (15–45 mg tar) may have some impact on reducing squamous-cell carcinoma risk, but this is now being balanced by ‘light’ cigarettes increasing the risk of adenocarcinoma.

18 Textbook of Lung Cancer

Cigarette smoking kills half of all those who adopt the habit, with 50% of these deaths occurring in middle age and each losing an average of 20 years of non-smoker’s life expectancy.43 It kills in over 24 different ways, with the lung being the commonest cancer site.43 Lung cancer rates have been declining in men and increasing in women: cigarette smoking in men has been declining while it has been increasing in women. These two trends are closely related. The move to ‘light’ cigarettes, which is increasingly common, now appears to be linked to increases in adenocarcinoma of the lung, and shows no sign of being linked to a reduced risk overall. There is no such thing as a ‘safe cigarette’. Smokers should be urged and helped to stop smoking; children and young adults should be convinced not to smoke. Tobacco can become an addictive drug: it should be left alone.20

ACKNOWLEDGMENTS It is a pleasure to acknowledge that this work was conducted within the framework of support from the Associazione Intaliana per la Ricerca sul Cancro (Italian Association for Research on Cancer).

REFERENCES 1. Adler I. Primary Malignant Growths of the Lungs and Bronchi: A Pathological and Clinical Study. London: Longmans, Green and Co, 1912. 2. Tylecote FE. Cancer of the lung. Lancet 1927; ii: 256–7. 3. Fleckseder R. Ueber den Bronchialkrebs und einge seiner Entstehungsbedingungen. Munch Med Wochenschr Nr 1936; 36: 1585–93. 4. Ochsner A, Debakey M. Primary pulmonary malignancy. Treatment by total pneumonectomy. Analysis of 79 collected cases and presentation of 7 personal cases. Surg Gynecol Obstet 1939; 68: 435–51. 5. Muller FH. Tabaksmisbrauch und Lungenkarzinom. Z Krebsforsch 1940; 49: 57–85. 6. Schairer E, Schöniger E. Lungenkrebs und Tabaksverbrauch. Z Krebsforsch 1943; 54: 261–9. 7. Schrek R, Baker LA, Ballard GP, Dolgoff S. Tobacco smoking as an etiologic factor in disease. Cancer Res 1950; 10: 49–58. 8. Levin ML, Goldstein H, Gerhardt PR. Cancer and tobacco smoking. JAMA 1950; 143: 336–8. 9. Mills CA, Porter MM. Tobacco smoking habits and cancer of the mouth and respiratory system. Cancer Res 1950; 10: 539–42. 10. Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma. JAMA 1950; 143: 329–36.

11. Doll R, Hill AB. Smoking and carcinoma of the lung. BMJ 1950; ii: 739–48. 12. Doll R, Hill AB. A study of the aetiology of carcinoma of the lung. BMJ 1952; ii: 1271–86. 13. US Public Health Services, Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service. US Department of Health, Education and Welfare, Public Health Service, Center for Disease Control, DHEW Publication 1103: Washington, DC, 1964. 14. United States Surgeon General, Smoking and Health. A Report of the Surgeon General. US Department of Health, Education and Welfare, Public Health Service, DHEW Publication (PHS) 79-50066: Washington, DC, 1979. 15. Hammond EC. Smoking in relation to death rates of one million men and women. Natl Cancer Inst Monogr 1966; 19: 127–204. 16. Cederlof R, Friberg L, Hrubec Z, Lorich U. The Relationship of Smoking and Some Social Covariates to Mortality and Cancer Morbidity. A Ten Year Follow-up in a Probability Sample of 55,000 Swedish Subjects Age 18–69, Parts 1 and 2. Stockholm: Karolinska Institute, 1975. 17. Bross IDJ, Gibson R. Risks of lung cancer in smokers who switch to filter cigarettes. Am J Publ Health 1968; 58: 1396–403. 18. Hammond EC, Garfinkel L, Seidman H, Lew EA. Some recent findings concerning cigarette smoking. In: Hiatt HH, Watson JD, Winsten JA, eds. Origins of Human Cancer. Book A: Incidence of Cancer in Humans. New York: Cold Spring Harbor Laboratory, 1977; 101–12. 19. Bouisson J. Du cancer buccal chez les fumeurs. Montpellier Med 1859; 2: 539–99. 20. Boyle P, Veronesi U, Tubiana M et al. School of Oncology Advisory Report to the European Commission for the ‘Europe Against Cancer Programme’ European Code Against Cancer. Eur J Cancer 1995; 9: 1395–405. 21. IARC (International Agency for Research on Cancer), Monographs on the Evaluation of Carcinogenic Risk to Humans. Vol 38. Tobacco Smoking. Lyon: IARC, 1986. 22. Levi F, Maisonneuve P, Filiberti R et al. Cancer incidence and mortality in Europe. Sozial-Präventivmedizin 1989; 34 (Suppl 2): 1–84. 23. Bjartveit K. Legislation and political activity. In: Zaridze DG, Peto R, eds. Tobacco: A Major International Health Hazard. Lyon: IARC, 1986; 285–98. 24. Della-Vorgia P, Sasco AJ, Skalkidis Y et al. An evaluation of the effectiveness of tobacco-control legislative policies in European Community countries. Scand J Soc Med 1990; 18: 81–9. 25. Tomatis L. Air Pollution and Human Cancer. European School of Oncology Monograph. Berlin: Springer-Verlag, 1990. 26. Shimizu Y, Kato H, Schull WJ et al. Life Span Study Report 11, Part 1: Comparison of Risk Coefficients for Site Specific Cancer Mortality Based on the DS86 and T65DR Shielded Kerma and Organ Doses. Radiation Effects Research Foundation Technical Report 12–87. Hiroshima: Radiation Effects Research Foundation, 1987. 27. Smith PG, Doll R. Mortality among patients with ankylosing spondylitis after a single treatment course with X-rays. BMJ 1982; 284: 449–54. 28. IARC (International Agency for Research on Cancer), Monographs on the Evaluation of Carcinogenic Risk to Humans. Vol 44. Alcohol Drinking. Lyon: IARC, 1988.

Epidemiology of lung cancer: a century of great success and ignominious failure 19 29. Kopecky KJ, Yamamoto T, Fujikura T et al. Lung Cancer, Radiation Exposure and Smoking Among A-Bomb Survivors, Hiroshima and Nagasaki, 1950–1980. Radiation Effects Research Foundation Technical Report 13–86. Hiroshima: Radiation Effects Research Foundation, 1987. 30. Whittemore AS, McMillan A. Lung cancer mortality among US uranium miners: a reappraisal. J Natl Cancer Inst 1983; 71: 489–99. 31. Boyle P, Robertson C. Statistical modelling of lung cancer and laryngeal cancer incidence data in Scotland, 1960–1979. Am J Epidemiol 1987; 125: 731–44. 32. Le Vecchia C, Franceschi S. Italian lung cancer death rates in young males. Lancet 1984; ii: 406. 33. La Vecchia C, Levi F, Decarli A et al. Trends in smoking and lung cancer mortality in Switzerland. Prev Med 1988; 17: 712–24. 34. Chollat-Traquet C. Women and Tobacco. Geneva: World Health Organization, 1992. 35. Boyle P. The hazards of passive and active smoking. N Engl J Med 1993; 328: 1708–9. 36. Roemer R. Legislative Action to Combat the World Tobacco Epidemic. Geneva: World Health Organization, 1993.

37. Boyle P. The hazards of passive and active smoking. N Engl J Med 1993; 329: 1581. 38. Boyle P. Cancer, cigarette smoking and premature death in Europe. A review including the recommendations of European Cancer Experts Consensus Meeting. Helsinki, October 1996. Lung Cancer 1997; 17: 1–60. 39. Zatonski WA, Boyle P. Health transformations in Poland after 1988. J Epidemiol Biol 1996; 1: 183–97. 40. Gillis CR, Hole DJ, Lamont DW et al. The incidences of lung cancer and breast cancer in women in Glasgow. BMJ 1994; 305: 1331. 41. Zheng T, Holford T, Boyle P et al. Time trend and age– period–cohort effect on the incidence of histologic types of lung cancer in Connecticut, 1960–1989. Cancer 1994; 74: 1556. 42. Levi F, Franceschi S, La Vecchia C et al. Lung carcinoma trends by histologic type in Vaud and Neuchatel, Switzerland, 197–1994. Cancer 1997; 79: 906–14. 43. Doll R, Peto R, Wheatley K et al. Mortality in relation to smoking: 40 years’ observations on male British doctors. BMJ 1994; 309: 901–11.

3

Molecular biology of lung cancer Thomas Tuxen Poulsen, Hans Skovgaard Poulsen, Helle Pappot Contents Introduction • Growth signals and lung cancer • Apoptosis in lung cancer • Aberrant anti-growth signaling • Replicative potential and telomerases • Angiogenesis • Tissue invasion and metastasis • Conclusion

INTRODUCTION It becomes more and more important to understand the biology of lung cancer as new therapeutic agents are emerging in the field of clinical oncology. These agents are often referred to as targeted therapy or biologic therapy. New advances in molecular technologies are providing insight into the pathobiology of lung cancer development. It is now known that clinical lung cancers have accumulated numerous clonal genetic and epigenetic alterations as a multistep process.1 In many research laboratories molecular studies are these days performed in an integrated approach with clinical investigators to find new ways for early diagnosis, risk assessment, prevention, and treatment for this frequent and deadly disease. In the following, the spectrum of molecular alterations in lung cancer are described as hallmarks of cancer, subdivided as suggested by Hanahan and Weinberg:2 • • • • • •

abnormalities in self-sufficiency signals; evading apoptosis; insensitivity to anti-growth signals; limitless replicative potential; sustained angiogenesis; tissue invasion and metastasis.

of

growth

GROWTH SIGNALS AND LUNG CANCER In tumor cells, activated (proto)oncogenes often encode molecules involved in aberrant growth factor signaling, either by directly promoting cell growth, by mimicking other growth factors, or by neutralizing growth inhibitory signals. Growth factors are proteins that bind to receptors (usually on the cell surface) and trigger activation of cellular proliferation and/or differentiation.

Normal cells depend on external growth stimulating signals to proceed from quiescence to proliferation and these growth stimuli are often provided by neighboring cells in the immediate microenvironment, for instance by release of diffusible growth factors or expression of cell adhesion molecules. These interrelations between the cell and its environment allow for establishment of normal tissue homeostasis with a tight regulation of tissue modeling, growth, and regeneration. Tumor cells have lost their dependency on growth stimulatory signals from the external environment and are fully capable of proliferating independently. This phenotype of growth autonomy is attained by a variety of molecular changes and gene mutations within the cell, typically characterized by a state of growth factor self-sufficiency, where the cell itself produces the required growth factors and receptors, resulting in a self-stimulatory autocrine signaling loop. Aberrant expression and signaling by a number of growth factors and cognate receptors have been identified, which increase the cellular proliferative potential in lung cancer. In non-small cell lung cancer (NSCLC) these include upregulation/mutation of certain receptor tyrosine kinases (RTKs), in particular the epidermal growth factor receptor (EGFR, ErbB1) and other members of the ErbB RTK family. In small cell lung cancer (SCLC) overexpression of insulin-like growth factor I (IGF-I) and its receptor as well as a number of neuronal growth stimulators is frequently observed. An overview of the changes in expression and signaling of central growth factors and receptors, signal transducers, and transcription factors in lung cancer is presented below and summarized in Table 3.1. The section will conclude with a presentation of related experimental therapeutic strategies developed to target these mediators for future treatment of lung cancer.

Molecular biology of lung cancer 21

Table 3.1 Growth signals and lung cancer Signaling mediators involved in activating growth signaling in lung cancer Aberrant activation/mutation frequency Oncogene

NSCLC (%)

SCLC (%)

References

EGFR HER2-Neu IGF-I C-Kit/C-Met K-ras Neuropeptides C-myc

50–90 ∼30 — — ∼20–30 16–47 up to 50

— — >95 Up to 70 — All 10–40

3, 4 33 9 12, 13 15 17 23, 24

Epidermal growth factor receptor overexpression and signaling in NSCLC Overexpression of EGFR occurs in 50–90% of all NSCLC and is particularly common in squamous cell carcinoma,3,4 whereas EGFR overexpression is rare in SCLC. The receptor is membrane associated and contains three main regions: an extracellular ligand binding domain, a hydrophobic membrane spanning region, and a cytoplasmic part holding the catalytic tyrosine kinase activity. Upon ligand binding, EGFR undergoes a conformational change, leading to dimerization of the receptor and activation of the intracellular catalytic domain by phosphorylation of tyrosine residues. The phosphorylated tyrosine residues serve as binding sites for a number of different downstream signaling molecules and adaptors within the cell. Three major signaling pathways downstream of EGFR are outlined in Figure 3.1. One of the most intensively studied cascades is the Ras/Raf/ERK pathway (the right-hand pathway in Figure 3.1). The effects of this pathway are diverse (for a review see reference 5), with a large number of Ras effectors, but in general Ras signaling upon EGF stimulation has been associated with increased cell growth and proliferation. One of the three ras genes, Kirsten-ras (K-ras, p21-ras), is mutated in ∼30% of NSCLC. The oncogenic impact of this mutation in lung cancer is discussed further below. Another central pathway in EGFR signaling involves activation of PI3-kinase and AKT (PKB). This pathway generally serves to promote cell survival, by inhibition of various cell cycle regulators such as glycogen synthase kinase 3 (GSK3) and the pro-apoptotic protein BAD (Figure 3.1, the middle pathway). A final key pathway activated by EGFR involves the activation of phospholipase C-γ (PLC-γ), resulting

in hydrolyzation of phosphoinositide 4,5-bisphosphate (PIP-2) to generate inositol-3-phosphate (IP3) and diacylglycerol (DAG) (Figure 3.1, the left-hand pathway). This results in the release of calcium ions from intracellular stores, which affects cell motility and migration by interfering with the activity of actin-modulatory proteins. The activation of PLC-γ also activates protein kinase C (PKC), which causes attenuation of EGFR signaling by a negative feedback mechanism. The different pathways by which activated EGFR exerts its proliferative, migratory, and anti-apoptotic effects, and the fact that many of the involved signaling modulators have been found to cross-react between pathways, provide a central, yet complex, role for EGFR in cell transformation. In NSCLC, increased EGFR signaling is obtained by an increased gene copy number and by activating mutations within the EGFR gene.6 One mutated EGFR variant termed EGFRvIII, commonly found in various malignancies including ∼16% of NSCLC, has gained increasing interest in recent years. EGFRvIII lacks the extracellular ligand-binding domain, rendering the receptor incapable of binding any ligands, yet the receptor is constitutively active and fully capable of activating downstream modulators.7 In recent years, novel activating mutations within the tyrosine kinase domain of EGFR have been identified in NSCLC. These mutations have gained massive interest, since they have been found to correlate with increased response to treatment with EGFR tyrosine kinase inhibitors.8 Another member of the ErbB family is HER2-Neu (ErbB2), which is overexpressed in ∼30% of NSCLC. No ligands for Her2-Neu have yet been identified but the receptor is a central dimerization partner for the other RTKs of the ErbB family. To date, results are

22 Textbook of Lung Cancer EGFR dimer

EGF

EGF

Membrane

DAG

PKC

PIP2 Raf

IP3

Ras

PLC-γ TK

TK

PI3K SOS SHC

Ca2+

MEK

GRB2 AKT Ca2+ Ca2+ Ca2+

Cytosol

GSK3

BAD

ERK

Nucleus Altered gene expression

- Increased cell growth and proliferation - Downregulation of apoptotic response - Increased cell motility/migration

Figure 3.1 EGFR signaling. Upon ligand binding EGFR dimerizes, resulting in a complex signaling response within the cell. Oncogenic EGFR signaling occurs through three major pathways: the Ras/ERK (right-hand), the PI3-kinase AKT (middle), and the phospholipase C-γ (left-hand) pathways, resulting in an increased malignant potential of the cells. For further explanation see text.

conflicting with regard to Her2-Neu overexpression and prognosis in NSCLC. Overexpression of other growth factor receptors and ligands The expression level of the mitogen IGF-I is elevated in the majority of SCLC, resulting in a self-stimulatory autocrine loop involving the IGF-I receptor which is commonly co-expressed in this malignancy.9 IGF signaling proceeds through binding of IGF ligands (IGF-I and II) to cell surface RTKs (IGF-IR and -IIR). The biologic activity of the signaling system is modulated by

binding of IGF binding proteins present in the extracellular fluids and serum to the IGF ligands. As for EGFR, activated IGF-IR signaling is complex but primarily occurs through the Ras/Raf/ERK and the PI3-kinase/ AKT pathways. A correlation between significantly elevated IGF-I serum levels and lung cancer risk has been reported, but results of other studies are conflicting.10,11 The RTK c-Kit and its ligand stem cell factor (SCF) is another receptor/ligand system, upregulated in more than 80% of SCLC tumors.12 A study of c-Kit expression in SCLC patients identified c-Kit as a marker for

Molecular biology of lung cancer 23

increased survival13 – an observation which appears contradictory to the oncogenic properties of c-Kit signaling. However, the patients enrolled in this study were receiving chemotherapy targeting actively dividing cells, and since activation of c-Kit induces cell proliferation, the active receptor may render the malignant cells more susceptible to cytotoxic treatment, thereby improving overall survival. c-Met is yet another RTK often overexpressed in SCLC. Signaling through this receptor system has been reported to be associated with tumor growth and metastasis. In contrast to the c-Kit/SCF system, the c-Met ligand hepatocyte growth factor (HGF) is rarely co-expressed with the receptor in SCLC,12 but is expressed and secreted from surrounding normal lung fibroblasts. This observation indicates a paracrine rather than autocrine activating loop of c-Met expression in lung cancer. The importance of paracrine c-Met signaling for lung cancer pathogenesis has been investigated further in a study where c-Met-expressing lung cancer cells were transplanted into HGF-overexpressing mice, resulting in increased metastatic potential of the transplanted cells.14 Activating Ras mutations As mentioned, mutations of the intracellular membraneassociated signaling mediator Ras (Figure 3.1, green pathway) with a high overrepresentation of mutations in the K-ras gene are detected in up to 30% of NSCLC,15 but rarely in SCLC patients. Ras protein becomes activated by the binding of guanine triphosphate (GTP), allowing for transmission of growth stimulatory signals to the cell nucleus. Downregulation of Ras signaling occurs by hydrolysis of GTP to GDP, mediated by the GTPase-activating protein (GAP). In NSCLC and other malignancies, activating point mutations in the K-ras gene result in resistance to GAP activity, thereby trapping the Ras protein in a constitutively active state, capable of continuous growth promoting signaling. Controversy exists as to whether K-Ras mutations serve as a marker for poor prognosis in lung cancer, but a global meta-analysis correlated the presence of pointmutated constitutively active Ras in NSCLC with a poor prognosis.16

G-protein-coupled receptors, resulting in activation of various downstream signaling pathways including PLC, PI3-kinase, and certain kinases, involved in cellular focal adhesion. Gastrin releasing peptide (GRP) signaling via the GRP receptor (GRP-R) has become one of the most intensively studied neuropeptide signaling pathways in SCLC, since different studies have shown that blocking GRP or GRPR activity inhibits SCLC cell growth in vitro and in vivo, whereas GRP addition to SCLC cells induces cell proliferation.18,19 The concentration of the GRP precursor pro-GRP is highly elevated in the majority of SCLC patients and levels decrease upon tumor resection, indicating that proGRP serum levels may serve as a detection and monitoring marker for patients with this disease. Other neuropeptides highly expressed in lung cancer include bradykinin, neuron specific enolase and L-Dopa decarboxylase. Whether these molecules play an oncogenic, growth-promoting role in lung cancer and/or whether they may potentially serve as clinical markers remains controversial. In recent years, the expression of the neuroendocrine transcription factor Achaete–Scute homolog 1 (ASH1) in SCLC has gained increased attention. ASH1 is normally expressed in neuronal progenitor cells during early fetal development of various tissues including the central nervous system and the lung. Expression is virtually absent in the normal adult organism, but ASH1 is reactivated and highly expressed in SCLC and in other lung tumors with a neuroendocrine phenotype, including a minority of large cell and adenocarcinomas. High expression of ASH1 seems to correlate with poor differentiation of these lung tumors, since expression is virtually absent in fully differentiated carcinoid tumors.20 Furthermore, ASH1 expression is tightly linked to classic neuroendocrine markers including L-Dopa decarboxylase. Although future research is clearly necessary to clarify the role of ASH1 in lung cancer pathogenesis, many studies suggest ASH1 expression as a critical pathogenic factor in neuroendocrine lung tumors. The overexpression of ASH1 induces lung tumors and cell hyperplasia in mouse models,21 and one study reported significant inhibition of SCLC cell growth after ASH1 knock out in vitro and in vivo.22

Overexpression of neuropeptides Highly elevated expression of different neuropeptides is a hallmark of SCLC and many of these markers have also been detected in some (mainly poorly differentiated) NSCLC tumors.17 Neuropeptides exert their effect via binding to seven transmembrane (7TM)

Amplification of myc Members of the c-myc, N-myc, and L-myc (proto)oncogene family are commonly amplified in SCLC and NSCLC, resulting in overexpression of Myc transcription factors.23,24 Myc protein competes with other transcription factors to bind Max, resulting in activation

24 Textbook of Lung Cancer

and repression of a number of genes. Although the contributions of myc amplification to lung cancer pathogenesis remain to be elucidated, recent studies point to a role for myc in promoting cell cycle progression by activation of key cell cycle molecules responsible for entry into the S-phase of the cell cycle (for a review of myc signaling in lung cancer see reference 25). In combination with loss of tumor suppressor genes such as Rb (the properties of which will be discussed in a later section), myc has been shown to significantly contribute to decreased cell cycle arrest and deregulated tumor growth.26 Experimental therapeutic targeting of growth factors and oncogenes in lung cancer In the previous sections, a number of different growth factors and oncogenes of importance for lung cancer biology have been presented. Knowledge gained about the properties of these molecules has allowed for the development of novel therapeutics targeting key activating, growth promoting, and tumorigenic pathways. A research area of major focus in recent years has been therapeutic targeting of EGFR in NSCLC. There are two general strategies for inhibiting signaling via EGFR. One is to prevent binding of ligand by blocking the ligand binding site (commonly with a monoclonal antibody) and the other is to directly inhibit receptor signaling by blocking activity of the cytoplasmic tyrosine kinase domain. Belonging to the first group, cetuximab is a humanized monoclonal EGFR antibody, which is presently under development and testing for treatment of NSCLC. The results of a recently published phase I/II clinical trial have shown an effect of cetuximab in combination with chemotherapy of NSCLC,27 and further clinical studies are ongoing at present. The two most clinically advanced RTK inhibitors are erlotinib and gefitinib, and erlotinib recently obtained FDA approval for second-line treatment of NSCLC. As previously mentioned, a number of mutations in the RTK domain of EGFR have been identified in NSCLC.8 Importantly, the presence of RTK mutations seems to correlate positively with the response to treatment with gefitinib, suggesting that these mutations may serve as classifiers for selecting the patients who will benefit from EGFR-RTK inhibiting treatments. As previously mentioned, the gene encoding the growth promoting Ras protein is mutated in up to 30% of NSCLC, making this protein a potential target for therapeutic intervention. Cytoplasmic Ras protein is

inactive and must be associated with the plasma membrane to contribute to cell signaling. For this association to occur, synthesized Ras protein is post-translationally modified by addition of a farnesyl group. Farnesylation is mediated by a specific enzyme – the farnesyl transferase – and targeting this reaction with farnesyl transferase inhibitors has been investigated clinically for treatment of lung cancer and other malignancies. Despite promising preclinical data and reported responses in patients with breast cancer and certain leukemias, the results of the use of farnesyl transferases for treating lung cancer have been disappointing, with lack of tumor regression in all of the clinical studies reported to date.28 The monoclonal antibody imatinib targets a number of RTKs including c-Kit and has been evaluated in two recent phase II studies for treatment of SCLC. Disappointingly, both studies report no inhibitory effect on tumor growth, even in patients with c-Kit-positive tumors.29,30 Apart from the clinical studies reported to date, a number of preclinical investigations have shown promise for anti-growth-signaling targeted therapy of lung cancer. Therapeutic blockade of IGF-I signaling by an IGF-IR-specific tyrosine kinase inhibitor has been reported to enhance the sensitivity of SCLC cells to chemotherapy in vitro, correlating with inhibition of the anti-apoptotic PKB signaling pathway.31 Finally, therapeutics have been developed which target neuronal markers overexpressed in lung cancer, primarily SCLC. However, a phase I clinical trial using an antibody targeting GRP in patients with SCLC reported no significant therapeutic response.32 In contrast, recent pre-clinical data showed growth suppression of SCLC cells after knockout of ASH1 in vitro and in vivo.22

APOPTOSIS IN LUNG CANCER Apoptosis is a morphologically and biochemically distinct form of cell death that occurs under various physiologic and pathologic conditions triggered by extrinsic and intrinsic cellular and molecular damage. It is characterized by the activation of a specific event of molecular processes followed by certain morphologic changes such as shrinkage of the cell, condensation of chromatin, and disintegration of the cell into small fragments. Today many of the key players in cellular apoptosis regulation have been identified and activators and inhibitors have been characterized and can therefore be targeted by therapeutic agents. Apoptosis is activated

Molecular biology of lung cancer 25

by a family of intracellular cysteine proteases called caspases. They are synthesized as zymogens and activated by proteolytic cleavage. They are divided into two distinct classes, initiator caspases, which include caspases P8, P9, and P10, and effector caspases, which include caspases P3, P6, and P7. Current knowledge suggests that there are two separate pathways of caspase activation. One starts with binding of an extracellular ligand to its cell surface receptor. The ligands are TNF, FasL, and Trail, and their respective receptors are TNFRI, FAS, and DR4 and DR5. The ligand binding triggers initiator caspase activation through a death inducing signaling complex (DISC), resulting in caspase-P8 activation of effector caspases, either directly or through BCL-2 interacting domain (BID)-mediated release of cytochrome c from mitochondria (Figure 3.2). The other caspase activation pathway starts with release of cytochrome c from the intermembrane space of mitochondria. Two proapoptotic family members, BAX and BAK, appear to facilitate cytochrome c release by participating in the

Death ligand

Death receptor pathway

Mitochondrial pathway

Membrane

Death receptor

PROCASP 8/10 FADD Mitochondria

BID BID DISC

Cytochrome c CASP 8 (CASP10) PROCASP 9 EXECUTIONER PATHWAY CASP3,6,7

APOPTOSIS

CASP 9

APAF1

Apoptosome

Figure 3.2 Apoptosis. Major pathways to apoptosis: two pathways lead to apoptosis, an extrinsic pathway through death receptors and an intrinsic pathway through the mitochondria. The two pathways overlap and interact.

formation of a pore that releases mitochondrial intermembrane space proteins. After its release, cytochrome c binds to apoptotic protease activating factor-1 (APAF-1). APAF-1 binds to procaspase-9 forming a multiprotein complex, called an apoptosome, which activates effector caspases through caspase-9 (Figure 3.2). Anti-apoptotic factors such as Bcl-2-related proteins antagonize BAX and BAK. In addition, IAP (inhibitor of apoptosis protein) binds and inhibits apoptosomerelated caspases. However, this inhibition can be relieved by the release of another mitochondrial protein, called Smac/Diablo, which binds to the IAP and releases active caspases. The most widely studied IAP is survivin. Activators and inhibitors are influenced by several other proteins including p53, RB, PTEN, Raf-ERK, PI3K-PKB, and Hsp70.33,34 The apoptotic pathways and possible defects have not been studied much in human lung cancer, and therefore only sporadic, non-conclusive data are available. However, recently it has been shown that DR4 and DR5 are upregulated in NSCLC, and overexpression of DR5 correlates with a poor prognosis in patients with NSCLC. Bcl-2 expression is higher in SCLC compared with NSCLC. Furthermore, data have indicated that the BAX:Bcl-2 ratio might be of importance for resistance to apoptosis. Caspase-8 and caspase-10 might be deregulated, and differences in deregulation in SCLC compared with NSCLC especially concerning caspase-8 have been observed, resulting in deregulation of DISC. Others have found that the apoptosome signaling might be blocked. In addition, it has been indicated that downregulation of caspase-3 is correlated with a poor prognosis in patients with NSCLC.33,35 Survivin is increased in most NSCLC and it has been shown that absence of its expression might be associated with improved prognosis. In addition, previously unpublished microarray data show that survivin is upregulated in SCLC in human cell lines, xenografts, and resected tumors from patients (Figure 3.3)36 (Poulsen HS, unpublished data). Targeting apoptotic pathways Treatment with TNF has been undertaken. However, due to pronounced general toxicity, its potential as a therapeutic drug is limited. Recently TRAIL agonists have been approved for clinical trials but no data are presently available. Small molecule inhibitors of Bcl-2 have been developed and are at the moment being tested in preclinical trials. In addition, antisense constructs against survivin have been produced and tested in phase I clinical trials.

26 Textbook of Lung Cancer 250

Microarray signal

200

150

100

50

Normal tissues

SCLC cell lines and xenografts

SCLC tumor 1 SCLC tumor 2 SCLC tumor 3 SCLC tumor 4 SCLC tumor 5 SCLC tumor 6

CPH 54A CPH 54A Xeno CPH 54B CPH 136A Xeno GLC 2 GLC 3 GLC 3 Xeno GLC 14 GLC 14 Xeno GLC 16 GLC 19 GLC 26 GLC 28 DMS 53 DMS 79 DMS 92 DMS 114 DMS 153 DMS 273 DMS 273 Xeno DMS 406 DMS 456 H69 H69 Xeno NCI 417 NCI 417 Xeno MAR H24 MAR H24 Xeno MAR 86H

Fetal brain Brain Adrenal gland Colon Heart Kidney Liver Lung Pancreas Prostate Salivary gland Skeletal muscle Small intestine Spleen Stomach Testes Thyroid Trachea

0

Tumors

Figure 3.3 Survivin in SCLC. Survivin mRNA expression in SCLC cell lines, xenografts, and resected patient tumors compared with normal tissue.

In addition, an adenovirus-based gene therapy approach targeting survivin is under development.37

ABERRANT ANTI-GROWTH SIGNALING

A review of key tumor suppressors, frequently mutated in lung cancer is presented below and summarized in Table 3.2, followed by an update within the field of tumor suppressor reactivation in experimental lung cancer therapy.

Apart from upregulation of growth stimulatory signaling, cancer cells often lack expression of a number of tumor suppressors. In contrast to oncogenes, tumor suppressor genes act to prevent and control cell growth, often via tight control of cell cycle progression. Full inhibition of tumor suppressor activity often requires inactivation of both alleles of a tumor suppressor gene in the cancer cell. This dual inactivation is frequently accomplished by a two-step process, involving a chromosomal translocation or deletion resulting in loss of heterozygosity (LOH), followed by an inactivating point mutation of the remaining allele. In lung cancer cells, LOH of distinct chromosomal regions is frequently detected and many of these regions harbor genes encoding central tumor suppressors, known or speculated to be involved in cancer pathogenesis. Tumor suppressor activity may also be inhibited by dominant negative mutations, which actively inhibit the activity of wildtype protein binding partners within the cell. Finally, epigenetic alterations (i.e. mutation-independent mechanisms) have in recent years gained increased attention in the regulation of tumor suppressor knock-down.

Tp53 mutations The transcription factor p53 is one of the most intensely studied tumor suppressors. The Tp53 gene is located within a region of chromosome 17 (17p13), which is mutated or altered in the majority of lung cancers with a specifically high prevalence in SCLC and squamous cell carcinoma.38,39 The types of Tp53 alterations observed in lung cancer range from gross chromosomal changes such as LOH, homozygous deletions, and DNA rearrangements, to local point mutations,40 all of which contribute to Tp53 malfunction or inactivation. The p53 protein is a key player in the cellular response to stress, acting as a gatekeeper of the cell cycle. Activation of p53 signaling in normal cells generally occurs in response to different types of cellular stress including DNA damage, aberrant oncogenic growth factor signaling, and exposure to extracellular factors such as chemotherapeutics and UV light. The level of p53 protein and activity within the cell is regulated at the level of degradation rather than the level of synthesis and, under normal conditions, the protein is rapidly degraded within the cell. The cellular enzyme

Molecular biology of lung cancer 27

Table 3.2 Aberrant anti-growth signaling Tumor suppressor gene mutations/inactivations and LOH in lung cancer Mutation/inactivation frequency Tumor suppressor gene

Chromosome location

NSCLC (%)

SCLC (%)

References

Tp53 RB p16INK4a TGFbRII LOH 3p

17p13 13q14 9p21 3p22 3p regions

∼50 ∼30 ∼70 ∼44 70–100

∼80 ∼90 ∼10 <75 >90

43 44, 61 45, 61 48, 62 51, 52

MDM2 plays an important role in the downregulation of p53. MDM2 serves as a p53 binding partner, which facilitates the attachment of ubiquitin tags to p53, thereby targeting it for degradation. Furthermore, MDM2-bound p53 activates transcription of the MDM2 gene, resulting in increased MDM2 levels, p53 ubiquitinylation, and degradation. Upon lowering of the p53 concentration, fewer MDM2–p53 complexes are formed, resulting in reduced MDM2 transcription and decreased p53 degradation. As such, the MDM2–p53 interaction generates an oscillating feedback loop of p53 and MDM2 degradation and synthesis within the cell (Figure 3.4). Activation of p53 requires post-translational modifications (such as acetylation, glycosylation, and addition of phosphate groups), some of which may inhibit p53 degradation by inhibiting its binding to MDM2. This is the case upon DNA damage, where activation of different proteins such as ATM-kinase and DNA-dependent kinase facilitates the phosphorylation of p53 at sites involved in the interaction with MDM2, resulting in p53 activation (Figure 3.4). Active p53 regulates transcription of a number of genes involved in cell cycle control (such as cyclindependent kinase inhibitors), resulting in cell cycle arrest, thus allowing for repair of damaged DNA by the cellular repair machinery. Activation of p53 also induces apoptosis via activation of a number of apoptotic mediators (including Bax) and inhibits blood vessel formation by activation of genes encoding anti-angiogenic factors. A frequent observation in lung cancer cells with mutated p53 is accumulation of p53 within the cell, due to increased stability of the mutated protein.41 A number of studies have investigated the prognostic role of p53 mutations in lung cancer patients, and although the results are somewhat conflicting, accumulating evidence suggests that p53 mutations result in a

poorer prognosis in NSCLC. Given the high abundance of p53 mutations in SCLC patients, the limited number of patients with intact p53 signaling limits prognostic studies in this malignancy. For a detailed review of p53 mutations in lung cancer, and the clinical impact of these aberrations, see reference 42. Mutated RB and p16INK4a A central tumor-suppressing signaling cascade, frequently altered in human lung cancer, is the p16INK4a/ CDK-cyclin-D/Rb pathway. The retinoblastoma (RB) tumor suppressor gene located at 13q14 encodes a transcription factor involved in the regulation of G1 to S-phase transition in the cell cycle. The tumorsuppressing activity of Rb depends on its level of phosphorylation. In its hypophosphorylated state, Rb binds to and inhibits the activity of different binding partners, including members of the E2F family of transcription factors. Upon phosphorylation of Rb, E2F is released and activated, resulting in transcription of genes responsible for G1 to S-phase cell cycle progression (Figure 3.5). Consequently, Rb in its hypophosphorylated state serves as a tumor suppressor. Phosphorylation of Rb is mediated by different complexes of cell cycle proteins such as cyclin D and CDK4 and 6. The formation of these complexes is inhibited by p16INK4a, which thereby serves as a tumor suppressor upstream of Rb by indirectly inhibiting its phosphorylation and thereby promoting Rb association with its binding partners (Figure 3.5). Inactivation of the RB gene by LOH and/or mutation is observed in 90% of SCLC tumors,43 whereas the p16INK4a gene is frequently inactivated in NSCLC,44 resulting in lack of activity of the Rb tumor suppressor pathway in virtually all lung cancers. These findings indicate that inactivation of this pathway is a mandatory step in the pathogenesis of pleural malignancies. The p16INK4a gene locus is located at chromosome 9p21,

28 Textbook of Lung Cancer DNA damage p14ARF Decreased p53 activity

MDM2 p53

ATM-kinase/DNA dependent kinase

INCREASED MDM2-SYNTHESIS

MDM2

p14ARF MDM2 ACTIVE p53

Altered gene expression

- Cell cycle arrest - Apoptosis - Anti-angiogenesis`

Figure 3.4 p53 signaling. In normal cells p53 plays a key role in regulation of the cellular response to a number of stress factors, but the p53 protein is frequently mutated in lung cancer and other malignancies. Under normal conditions p53 activity is inhibited by the binding of MDM2 to the protein. Upon cellular exposure to stress, cellular proteins such as p14ARF and specific kinases (i.e. ATM-kinase and DNA-dependent kinase) release p53 from MDM2 inhibition, resulting in activation of p53. This again may result in cell cycle arrest, apoptosis, and anti-angiogenic signaling.

which is a region frequently subjected to LOH in NSCLC.45 Apart from p16INK4a, the same locus also encodes the tumor suppressor p14ARF through an alternative reading frame. The p14ARF protein is known to bind to MDM2, thereby inhibiting ubiquitinylation and degradation of p53 (Figure 3.4). Furthermore, E2Fs are known to activate p14ARF transcription, providing a functional link between the Rb and p53 tumor suppressor pathways. Aberrant TGFβ signaling The transforming growth factor β (TGFβ) receptor system is also commonly altered in lung cancer. In contrast to the growth factor receptor systems described in previous sections, the effects of signaling by TGFβ are mostly associated with inhibited cellular proliferation in many cell types. TGFβ signaling is mediated via serine-threonine-kinase receptors that can be divided into two subgroups termed TGFβRI and II. Lack of response to TGFβ (termed TGFβ resistance) in SCLC has been correlated with lack of TGFβRII,46,47 and this

association was recently confirmed by the introduction of functional TGFβRII into receptor-negative lung cancer cells, resulting in restored sensitivity to TGFβ.48 TGFβ signaling is associated with a number of cellular functions, the best described of which relate to inhibition of the cell cycle. Growth inhibitory effects of TGFβ signaling have been associated with inhibition of expression and assembly of some of the cyclin/CDK components responsible for Rb activation.49 Loss of chromosome 3p and related genes Probably the most frequent chromosomal abnormality in lung cancer is loss of regions within chromosome 3p. LOH at chromosome 3p has been reported in 70–100% of all NSCLC and more than 90% of SCLC.50,51 A number of genes within this region have been suggested as putative tumor suppressors. The loss of the fragile histidine triad (FHIT) gene located at position 3p14.2 is frequent in lung cancer, with more extensive genetic lesions occurring in highergrade tumors compared with low-grade and premalignant lesions.52 Accumulating evidence points to a role of FHIT as a tumor suppressor. Expression of FHIT protein in NSCLC cell lines and mouse xenograft models has been shown to suppress tumor growth and induce apoptosis,53 and recently FHIT has been found to stabilize p53 presumably by interaction with MDM2, which thereby becomes incapable of binding and ubiquitinylating p53.54 This points to a functional role of FHIT in apoptotic signaling, although the exact function of FHIT remains to be fully elucidated. RASSF1A is a different candidate tumor suppressor gene residing at chromosome 3p (position 3p21). This gene is inactivated in virtually all SCLC and more than 60% of NSCLC.55,56 Apart from allelic loss, the RASSF1A gene has been found to be inactivated by epigenetic mechanisms and hypermethylation of distinct regions (so called CpG islands) within the promoter of the RASSF1A gene, which inhibits gene transcription. Reintroduction of RASSF1A has been found to reduce colony formation, suppress anchorage-independent growth, and inhibit tumorigenicity of NSCLC cells in vitro and in nude mice.55 Furthermore, RASSF1A has been shown to associate with microtubules, and recently overexpression of RASSF1A has been reported to inhibit motility of NSCLC cells and increase cell adhesion, suggesting a role for RASSF1A in cell migration and metastasis.57 Several other genes reside at the frequently deleted regions of chromosome 3p but much remains to be learned about the role of these genes in tumor suppression. For a review of candidate tumor suppressor

Molecular biology of lung cancer 29

CDK4/6

CYCLIN D

p16INK4a Rb

E2F

Rb

CDK4/6 CYCLIN D

P

ACTIVE E2F

Altered gene expression

- Cell cycle progression - Cell proliferation - Anti-apoptosis

Figure 3.5 Rb signaling. The Rb–p16INK4a–tumor suppressor pathway, which is frequently mutated in lung cancer, acts by inhibiting the activation of the E2F family of transcription factors responsible for growth promoting and anti-apoptotic signaling within the cell. p16INK4a, which is frequently mutated in NSCLC, acts by inhibition of the cyclin-CDK4/6 complex responsible for release of E2F from Rb inhibition. In SCLC, Rb itself is frequently mutated, rendering the protein incapable of inhibiting E2F signaling. The high frequency of Rb and p16INK4a mutations in SCLC and NSCLC, respectively, suggests that inhibition of this pathway is 0mandatory in the development of pleural malignancies.

genes residing at chromosome 3p which may play a role in lung cancer pathogenesis see reference 58. Experimental treatments: reintroduction of tumor suppressors Since the loss of activity of certain tumor suppressor pathways is a distinctive characteristic of human lung cancer, reintroduction of tumor suppressor activity is an attractive strategy for therapeutic intervention. For this purpose, replacement gene therapy by delivery of lost tumor suppressor genes to cancer cells has become increasingly attractive. Most reports of tumor suppressor replacement gene therapy of lung cancer involve reintroduction of TP53 in NSCLC, where a number of clinical trials have been published. In general, the treatment has been found to be well tolerated and responses have been observed in terms of tumor regression and disease stabilization in some of the enrolled patients. However, the limiting factor of gene therapy today remains poor delivery of the therapeutic gene to the cancer cells. The clinical studies performed

to date have all used modified viruses for gene delivery. Although the delivery rates using viral systems have been improved, a major drawback of using viruses for gene delivery is the induction of immune responses against the virus in the patients. This results in the production of antibodies which target the virus for degradation and limit the efficiency of repeated treatments. Novel non-viral delivery vehicles are being developed, which may in the future provide a potent alternative to viral gene therapy. The status within the field of replacement gene therapy for lung cancer and delivery vector development has recently been reviewed.59 Reintroduction of other tumor suppressor genes in lung cancer has been evaluated in preclinical studies. Co-delivery and expression of FHIT and TP53 have been reported to provide a synergistic tumor-suppressing effect in NSCLC in vitro and in vivo.54 Future studies will be necessary to assess the potential of these strategies for treatment of lung cancer patients.

REPLICATIVE POTENTIAL AND TELOMERASES When cultures of differentiated somatic cells are established in vitro they have a well-defined potential for cell division. After a number of divisions, the cells are predetermined to enter crisis, a state characterized by extensive cell death and chromosomal aberrations. This phenomenon has been termed the mitotic clock and is part of the tight regulation of normal cell growth. In contrast, cancer cells propagated in culture have an unlimited potential for continuous cell division and are said to be immortalized. The molecular explanation for the mitotic clock resides in the chromosomal structure and mechanism of DNA replication. Upon cell division, the cell initiates DNA replication which proceeds to produce new leading and lagging strands from the DNA double helix. Since DNA replication can only proceed in one direction (3′–5′), only the leading strand of the double helix is continuously synthesized, whereas the new lagging strand is assembled by ligation of smaller DNA fragments. The discontinuous replication of the lagging strand results in a gap at the 5′ end of the newly synthesized DNA strand, resulting in loss of chromosomal material during each mitotic cycle. The chromosomal ends are termed telomeres and are composed of six nucleotide repeats. The telomeres are involved in the correct orientation of the chromosomes during cell division. Due to the continuous shortening of telomeric DNA following cell division,

30 Textbook of Lung Cancer

lack of telomere maintenance ultimately results in chromosomal degradation and end-to-end chromosome fusion, exemplified by the massive cell death observed during the crisis state of untransformed cells cultured in vitro. In order to overcome the limitation of telomere shortening, cancer cells activate a program for telomere maintenance, which is normally shut down in fully differentiated normal cells. Most frequently, this is accomplished by activation of an enzyme complex known as telomerase, but a subset of cancer cells lacks telomerase activity and are immortalized by a process known as alternative lengthening of telomeres (ALT). The implications of the telomere-activating machinery in lung cancer and the development of therapeutic strategies targeting telomere maintenance are discussed below. Telomere maintenance in lung cancer The core telomerase enzyme comprises an RNA subunit (hTERC) which provides the template for synthesis of new telomeric DNA facilitated by the catalytic subunit human telomerase reverse transcriptase (hTERT). The RNA component hTERC is ubiquitously expressed in many cells, whereas hTERT expression is normally confined to undifferentiated cells such as germ line cells and bone marrow stem cells, identifying the enzyme moiety as the limiting factor for telomere maintenance. Indeed, the great majority of SCLC and NSCLC expresses the enzyme hTERT,60 whereas hTERT expression and telomerase activity has been found to be repressed in the majority of lung carcinoids, a malignancy which is also associated with a longer-term survival.61 A number of studies have shown that increased telomerase activity and increased levels of hTERT mRNA are mainly found in patients with poorly differentiated tumors (such as SCLC) and advanced disease and correlate with poor survival, suggesting telomerase activity as an important prognostic marker for patients with lung cancer.62,63 A number of alternative splice variants of hTERT mRNA, many of which lack enzymatic activity, have been identified, but the prognostic value and molecular role of these mutations in lung malignancies remain to be clarified. As previously mentioned, a small subset of cancer cells acquires telomere maintenance without activation of telomerase by a process termed ALT. Although this phenomenon remains to be fully elucidated, ALT appears to involve recombination of chromosome ends in a mechanism associated with DNA replication.64 No studies reporting ALT in lung cancer have been published to date, and whether ALT plays a role in lung cancer cell immortalization therefore remains to be elucidated.

Experimental therapeutic targeting of telomerase in lung cancer Due to the central role of telomerase in the transformation of lung cancer cells, and the lack of telomere maintenance in normal tissues, blocking the activity of this enzyme appears an intriguing target for therapeutic intervention. A number of small molecular inhibitors of telomerase activity have been developed and some of these agents have been reported to inhibit the growth of NSCLC cells in vitro, albeit with a delay in growth inhibition of several months after the initiation of treatment.65 The compound GRN136L is a lipid-modified oligonucleotide, which binds to the hTERC subunit of telomerase with high affinity, thereby inhibiting reverse transcription by blocking access of hTERT to its RNA template. GRN136L has recently been reported to successfully inhibit telomerase activity, leading to telomere shortening and resulting in decreased growth of adenocarcinoma cells in vitro and effective prevention of tumor metastasis in a xenograft mouse model.66 Another strategy involves activation of an immune response towards telomerase by administration of a vaccine composed of hTERT-derived peptides. Recently a clinical phase I/II study investigating the effect of treatment with two hTERT peptides in patients with advanced NSCLC was published,67 reporting the treatment to be well tolerated and detecting immune responses towards telomerase in 11 and tumor response to treatment in 2 of 24 patients. A new clinical trial is being planned, aiming to investigate the effect of telomerase immunogenic peptides in combination with chemo- and radiotherapy.

ANGIOGENESIS The vasculature is crucial for cell function and survival in all tissues, since oxygen and nutrients are supplied by the vessels. The growth of new blood vessels, called the process of angiogenesis, is a normal physiologic process taking place under organogenesis, which under these conditions is transitory and carefully regulated.2 In a similar way tumors must develop angiogenic ability to progress. This ability appears by activating the angiogenic switch. The activation is probably a result of the change in the balance of angiogenesis inducers and countervailing inhibitors, e.g. by altered gene transcription. Angiogenesis can be described as a result of a dynamic balance between pro-angiogenic factors and anti-angiogenic factors.68 Once a tumor has activated its

Molecular biology of lung cancer 31

angiogenic switch it becomes able to grow; in the absence of this activation the tumor remains in a dormant state and is unable to grow in size beyond a few millimeters. Angiogenesis, however, involves more components than pro- and anti-angiogenic factors only. For succesfull angiogenesis, interactions between tumor cells, activation of the endothelial cells and mature vessels, degradation of the surrounding basement membrane, and invasion and migration of endothelial cells into the surrounding connective tissue are needed. Hereby tumor-associated neovascularization can take place by establishing continuity with the systemic circulation, allowing tumor survival and growth and, more seriously, facilitating further metastatic spreading. Many different pro- and anti-angiogenic factors have been identified. The angiogenesis-initiating signals are exemplified by vascular endothelial growth factor/ vascular permeability factor (VEGF/VPF) and acidic and basic fibroblast growth factors (FGF1/FGF2), which all bind to transmembrane tyrosine kinase receptors displayed by endothelial cells.69 The typical angiogenesis inhibitor is thrombospondin-1, which binds to CD36, a transmembrane receptor on endothelial cells coupled to intracellular Src-like tyrosine kinases.70 In total there are up to nearly one hundred different proand anti-angiogenic factors. These include platelet-derived endothelial cell growth factor (PE-ECGF), platelet-derived growth factor (PDGF), EGF, angiogenin, angiotensin II, platelet-activating factor (PAF), and the inhibitor angiostatin. Most of the molecules involved in angiogenesis are not specific to vascular endothelial cells, but have a broad spectrum of target cells, except from VEGF, which activates only endothelial cells. VEGF is a heparin-binding glycoprotein, which binds selectively to two high-affinity tyrosine kinase cell surface receptors: VEGFR1 and VEGFR2. These receptors are found in blood vessels within or near tumors, and the expression is found to be upregulated in most cancers including lung cancer. VEGF has been demonstrated to be an important predictor of poorprognosis in NSCLC.71 Targeting angiogenic factors Inhibiting angiogenesis through anti-angiogenic and/or vascular targeting agents seems logical, as new anti-cancer treatment strategies. In particular, much attention has focused on targeting VEGF and VEGFR. Compounds currently under investigation in cancer therapy include anti-VEGF/VEGFR antibodies, small molecule VEGFR tyrosine kinase inhibitors, antisense suppression of VEGF, immunotherapy, viral-directed targeting of

VEGFR signaling, ribozymes, and various toxin conjugates.72 Furthermore, blocking angiogenesis may enhance conventional anti-cancer treatments such as radiation therapy in situations where tumors are unresponsive to current anti-growth factor efforts, and the benefits of combining angiogenic inhibitors with radiation are being explored. Recent clinical trials have shown that the anti-VEGF antibody bevacizumab, combined with standard first-line chemotherapy in NSCLC, provided a statistically and clinically significant survival advantage with tolerable toxicity.73 In addition, more recently tested compounds characterized as antivasculature agents have been shown to be effective against mutiple targets; the efficiency of such compounds is currently being investigated in clinical trials for NSCLC.

TISSUE INVASION AND METASTASIS As mentioned above, cancer cells and tissues often have dysregulation of crucial processes and factors, such as apoptosis, growth factors, angiogenesis, replication potential, sensitivity to anti-growth signaling, and invasion and metastasis. Many of these processes are dependent on proteases, making proteases an interesting target for new anti-cancer treatments. Proteases (proteolytic enzymes) are highly involved in invasion and metastasis by degradation of the extracellular matrix, e.g. basement membranes. Proteases are involved in both extra- and intracellular protein degradation. Under normal conditions proteolysis is a physiologic process leading to, for example, wound healing, but in the malignant tumor proteolysis becomes a harmfull factor enabling tumor cells to move out, invade adjacent tissues, and thence travel to distant sites where they may succeed in founding new colonies, metastases (Figure 3.6), which are the cause of 90% of human cancer deaths.74 Thus, based on the degradation of extracellular proteins and basement membranes by proteolytic enzymes, increased invasion and metastasis can take place in malignant diseases. The major components of the basement membrane and the extracellular matrix are type IV collagen, laminin, fibronectin, vitronectin, and proteoglycans. Tumor cells can produce a number of proteolytic enzymes which can degrade these protein structures, including matrix metalloproteinases (MMPs), collagenases, urokinase plasminogen activator (uPA), plasmin, cathepsins, and others. MMPs are known to play a functional role in the metastatic spread of lung cancer.75 Different MMPs are active in

32 Textbook of Lung Cancer

Extravasation Intravasation

Regional lymph node metastasis

Survival in circulation

Growth in new environment

Figure 3.6 Metastasis. This diagram illustrates the importance of proteolysis in cancer, leading to tissue degradation, invasion, and metastasis.

different steps of the invasive and metastatic process, and a better understanding of the involvement of MMPs in the invasion and regulation of growth of both primary and metastatic tumors may help to implement these as anti-cancer therapy targets. Cathepsins have been demonstrated to have a prognostic value in NSCLC and levels of the receptors for uPA (uPAR) and other components of the plasminogen activation system are associated with survival in NSCLC.76 Targeting proteases and the metastatic process It is expected that inhibition of the metastatic potential of a tumor by interaction with extracellular protein degradation could be an important target, especially during early tumor development. Drugs targeting MMPs have been in clinical trials, but have shown little or no activity in lung cancer. Inhibition of MMPs has especially been focused on targeting MMP-2 and -9. In studies on cell lines and xenografts, the MMP inhibitor batimastat has shown an ability to decrease the invasion of cancer cells and to prolong survival in the treated animals. However, these finding have been most consistent in pancreatic cancer. The efficacies of batimastat and another MMP inhibitor marimastat have been tested in different solid tumor types, but the studies have been limited by toxicity. In the clinical phase I and II studies performed to date, little or no activity has been reported in lung cancer. At the moment new MMP inhibitors such as CP-471,358 are being evaluated in phase I and II studies in a number of malignancies including lung cancer.77 CONCLUSION As is evident from the preceding sections, major advances in molecular biologic research during recent decades

have resulted in a substantial insight into important signaling pathways and mediators contributing to lung cancer pathology. Recently, the first novel therapeutic, which directly targets growth-promoting pathways, was approved for treatment of lung cancer and many other drugs are presently under clinical investigation. However, although some patients respond well to the new treatments, it has become evident that further insight into the mechanism of action of many of these novel agents must be gained, in order to better individualize the targeted treatments to the patients who will benefit. Gaining further knowledge into the complexity of molecular lung cancer biology, correctly applying this knowledge in the development of novel therapeutics, and optimization of presently available agents therefore represent important challenges in lung cancer research and clinics for the years to come. REFERENCES 1. Fong KM, Sekido Y, Gazdar AF et al. Lung cancer. 9: Molecular biology of lung cancer: clinical implications. Thorax 2003; 58: 892–900. 2. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70. 3. Rusch V, Baselga J, Cordon-Cardo C et al. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 1993; 53 (10 Suppl): 2379–85. 4. Selvaggi G, Novello S, Torri V et al. Epidermal growth factor receptor overexpression correlates with a poor prognosis in completely resected non-small-cell lung cancer. Ann Oncol 2004; 15: 28–32. 5. Shields JM, Pruitt K, McFall A et al. Understanding Ras: ‘it ain’t over ‘til it’s over’. Trends Cell Biol 2000; 10: 147–54. 6. Hirsch FR, Witta S. Biomarkers for prediction of sensitivity to EGFR inhibitors in non-small cell lung cancer. Curr Opin Oncol 2005; 17: 118–22.

Molecular biology of lung cancer 33 7. Pedersen MW, Meltorn M, Damstrup L, Poulsen HS. The type III epidermal growth factor receptor mutation. Biological significance and potential target for anti-cancer therapy. Ann Oncol 2001; 12: 745–60. 8. Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497–500. 9. Reeve JG, Payne JA, Bleehen NM. Production of immunoreactive insulin-like growth factor-I (IGF-I) and IGF-I binding proteins by human lung tumours. Br J Cancer 1990; 61: 727–31. 10. Yu H, Spitz MR, Mistry J et al. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis. J Natl Cancer Inst 1999; 91: 151–6. 11. Lukanova A, Toniolo P, Akhmedkhanov A et al. A crosssectional study of IGF-I determinants in women. Eur J Cancer Prev 2001; 10: 443–52. 12. Rygaard K, Nakamura T, Spang-Thomsen M. Expression of the proto-oncogenes c-met and c-kit and their ligands, hepatocyte growth factor/scatter factor and stem cell factor, in SCLC cell lines and xenografts. Br J Cancer 1993; 67: 37–46. 13. Rohr UP, Rehfeld N, Pflugfelder L et al. Expression of the tyrosine kinase c-kit is an independent prognostic factor in patients with small cell lung cancer. Int J Cancer 2004; 111: 259–63. 14. Yu Y, Merlino G. Constitutive c-Met signaling through a nonautocrine mechanism promotes metastasis in a transgenic transplantation model. Cancer Res 2002; 62: 2951–6. 15. Gao HG, Chen JK, Stewart J et al. Distribution of p53 and K-ras mutations in human lung cancer tissues. Carcinogenesis 1997; 18: 473–8. 16. Mascaux C, Iannino N, Martin B et al. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 2005; 92: 131–9. 17. Kiriakogiani-Psaropoulou P, Malamou-Mitsi V, Martinopoulou U et al. The value of neuroendocrine markers in non-small cell lung cancer: a comparative immunohistopathologic study. Lung Cancer 1994; 11: 353–64. 18. Thomas F, Arvelo F, Antoine E et al. Antitumoral activity of bombesin analogues on small cell lung cancer xenografts: relationship with bombesin receptor expression. Cancer Res 1992; 52: 4872–7. 19. Weber S, Zuckerman JE, Bostwick DG et al. Gastrin releasing peptide is a selective mitogen for small cell lung carcinoma in vitro. J Clin Invest 1985; 75: 306–9. 20. Jiang SX, Kameya T, Asamura H et al. hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors. Mod Pathol 2004; 17: 222–9. 21. Linnoila RI, Zhao B, DeMayo JL et al. Constitutive Achaete–Scute homologue-1 promotes airway dysplasia and lung neuroendocrine tumors in transgenic mice. Cancer Res 2000; 60: 4005–9. 22. Osada H, Tatematsu Y, Yatabe Y et al. ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features. Cancer Res 2005; 65: 10680–5. 23. Brennan J, O’Connor T, Makuch RW et al. Myc family DNA amplification in 107 tumors and tumor cell lines from patients with small cell lung cancer treated with different combination chemotherapy regimens. Cancer Res 1991; 51: 1708–12.

24. Broers JL, Viallet J, Jensen SM et al. Expression of c-myc in progenitor cells of the bronchopulmonary epithelium and in a large number of non-small cell lung cancers. Am J Respir Cell Mol Biol 1993; 9: 33–43. 25. Zajac-Kaye M. Myc oncogene: a key component in cell cycle regulation and its implication for lung cancer. Lung Cancer 2001; 34 (Suppl 2): S43–6. 26. Santoni-Rugiu E, Falck J, Mailand N et al. Involvement of Myc activity in a G(1)/S-promoting mechanism parallel to the pRb/ E2F pathway. Mol Cell Biol 2000; 20: 3497–509. 27. Thienelt CD, Bunn PA Jr, Hanna N et al. 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 2005; 23: 8786–93. 28. Johnson BE, Heymach JV. Farnesyl transferase inhibitors for patients with lung cancer. Clin Cancer Res 2004; 10(12 Pt 2): 4254–7s. 29. Dy GK, Miller AA, Mandrekar SJ et al. A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study. Ann Oncol 2005; 16: 1811–16. 30. Krug LM, Crapanzano JP, Azzoli CG et al. Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: a phase II clinical trial. Cancer 2005; 103: 2128–31. 31. Warshamana-Greene GS, Litz J, Buchdunger E et al. The insulin-like growth factor-I receptor kinase inhibitor, NVPADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy. Clin Cancer Res 2005; 11: 1563–71. 32. Chaudhry A, Carrasquillo JA, Avis IL et al. Phase I and imaging trial of a monoclonal antibody directed against gastrin-releasing peptide in patients with lung cancer. Clin Cancer Res 1999; 5: 3385–93. 33. Shivapurkar N, Reddy J, Chaudhary PM, Gazdar AF. Apoptosis and lung cancer: a review. J Cell Biochem 2003; 88: 885–98. 34. Jäättelä M. Multiple cell death pathways as regulators of tumour initiation and progression. Oncogene 2004; 23: 2746–56. 35. Fennell DA. Caspase regulation in non-small cell lung cancer and its potential for therapeutic exploitation. Clin Cancer Res 2005; 11: 2097–105. 36. Pedersen N, Mortensen S, Sorensen SB et al. Transcriptional gene expression profiling of small cell lung cancer cells. Cancer Res 2003; 63: 1943–53. 37. Fischer U, Schulze-Osthoff K. Apoptosis-based therapies and drug targets. Cell Death Differ 2005; 12 (Suppl 1): 942–61. 38. Chmara M, Wozniak A, Ochman K et al. Loss of heterozygosity at chromosomes 3p and 17p in primary non-small cell lung cancer. Anticancer Res 2004; 24: 4259–63. 39. Petersen I, Langreck H, Wolf G et al. Small-cell lung cancer is characterized by a high incidence of deletions on chromosomes 3p, 4q, 5q, 10q, 13q and 17p. Br J Cancer 1997; 75: 79–86. 40. Takahashi T, Nau MM, Chiba I et al. p53: a frequent target for genetic abnormalities in lung cancer. Science 1989; 246: 491–4. 41. Iggo R, Gatter K, Bartek J et al. Increased expression of mutant forms of p53 oncogene in primary lung cancer. Lancet 1990; 335: 675–9. 42. Campling BG, el Deiry WS. Clinical implication of p53 mutation in lung cancer. Mol Biotechnol 2003; 24: 141–56. 43. Hensel CH, Hsieh CL, Gazdar AF et al. Altered structure and expression of the human retinoblastoma susceptibility gene in small cell lung cancer. Cancer Res 1990; 50: 3067–72.

34 Textbook of Lung Cancer 44. Otterson GA, Kratzke RA, Coxon A et al. Absence of p16INK4 protein is restricted to the subset of lung cancer lines that retains wildtype RB. Oncogene 1994; 9: 3375–8. 45. Merlo A, Gabrielson E, Askin F, Sidransky D. Frequent loss of chromosome 9 in human primary non-small cell lung cancer. Cancer Res 1994; 54: 640–2. 46. Norgaard P, Damstrup L, Rygaard K et al. Growth suppression by transforming growth factor beta 1 of human small-cell lung cancer cell lines is associated with expression of the type II receptor. Br J Cancer 1994; 69: 802–8. 47. Hougaard S, Norgaard P, Abrahamsen N et al. Inactivation of the transforming growth factor beta type II receptor in human small cell lung cancer cell lines. Br J Cancer 1999; 79: 1005–11. 48. Anumanthan G, Halder SK, Osada H et al. Restoration of TGFbeta signalling reduces tumorigenicity in human lung cancer cells. Br J Cancer 2005; 93: 1157–67. 49. Laiho M, DeCaprio JA, Ludlow JW et al. Growth inhibition by TGF-beta linked to suppression of retinoblastoma protein phosphorylation. Cell 1990; 62: 175–85. 50. Kok K, Osinga J, Carritt B et al. Deletion of a DNA sequence at the chromosomal region 3p21 in all major types of lung cancer. Nature 1987; 330: 578–81. 51. Naylor SL, Johnson BE, Minna JD, Sakaguchi AY. Loss of heterozygosity of chromosome 3p markers in small-cell lung cancer. Nature 1987; 329: 451–4. 52. Wistuba II, Behrens C, Virmani AK et al. 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 2000; 60: 1949–60. 53. Ji L, Fang B, Yen N et al. Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression. Cancer Res 1999; 59: 3333–9. 54. Nishizaki M, Sasaki J, Fang B et al. Synergistic tumor suppression by coexpression of FHIT and p53 coincides with FHIT-mediated MDM2 inactivation and p53 stabilization in human non-small cell lung cancer cells. Cancer Res 2004; 64: 5745–52. 55. Dammann R, Li C, Yoon JH et al. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet 2000; 25: 315–19. 56. Burbee DG, Forgacs E, Zochbauer-Muller S et al. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst 2001; 93: 691–9. 57. Dallol A, Agathanggelou A, Tommasi S et al. Involvement of the RASSF1A tumor suppressor gene in controlling cell migration. Cancer Res 2005; 65: 7653–9. 58. Zabarovsky ER, Lerman MI, Minna JD. Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Oncogene 2002; 21: 6915–35. 59. Poulsen TT, Pedersen N, Poulsen HS. Replacement and suicide gene therapy for targeted treatment of lung cancer. Clin Lung Cancer 2005; 6: 227–36. 60. Hiyama K, Hiyama E, Ishioka S et al. Telomerase activity in small-cell and non-small-cell lung cancers. J Natl Cancer Inst 1995; 87: 895–902.

61. Gomez-Roman JJ, Romero AF, Castro LS et al. Telomerase activity in pulmonary neuroendocrine tumors: correlation with histologic subtype (MS-0060). Am J Surg Pathol 2000; 24: 417–21. 62. Marchetti A, Bertacca G, Buttitta F et al. Telomerase activity as a prognostic indicator in stage I non-small cell lung cancer. Clin Cancer Res 1999; 5: 2077–81. 63. Lantuejoul S, Soria JC, Moro-Sibilot D et al. Differential expression of telomerase reverse transcriptase (hTERT) in lung tumours. Br J Cancer 2004; 90: 1222–9. 64. Muntoni A, Reddel RR. The first molecular details of ALT in human tumor cells. Hum Mol Genet 2005; 14 (Spec No 2): R191–6. 65. Damm K, Hemmann U, Garin-Chesa P et al. A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J 2001; 20: 6958–68. 66. Dikmen ZG, Gellert GC, Jackson S et al. In vivo inhibition of lung cancer by GRN163L: a novel human telomerase inhibitor. Cancer Res 2005; 65: 7866–73. 67. Brunsvig PF, Aamdal S, Gjertsen MK et al. Telomerase peptide vaccination: a phase I/II study in patients with nonsmall cell lung cancer. Cancer Immunol Immunother 2006; 55: 1553–64. 68. de Castro JG, Puglisi F, de Azambuja E et al. Angiogenesis and cancer: a cross-talk between basic science and clinical trials (the ‘do ut des’ paradigm). Crit Rev Oncol Hematol 2006; 59: 40–50. 69. Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 2000; 60: 203–12. 70. Bull HA, Brickell PM, Dowd PM. Src-related protein tyrosine kinases are physically associated with the surface antigen CD36 in human dermal microvascular endothelial cells. FEBS Lett 1994; 351: 41–4. 71. Imoto H, Osaki T, Taga S et al. Vascular endothelial growth factor expression in non-small-cell lung cancer: prognostic significance in squamous cell carcinoma. J Thorac Cardiovasc Surg 1998; 115: 1007–14. 72. Raben D, Helfrich B. Angiogenesis inhibitors: a rational strategy for radiosensitization in the treatment of non-small-cell lung cancer? Clin Lung Cancer 2004; 6: 48–57. 73. Yano S, Matsumori Y, Ikuta K et al. Current status and perspective of angiogenesis and antivascular therapeutic strategy: non-small cell lung cancer. Int J Clin Oncol 2006; 11: 73–81. 74. Sporn MB. The war on cancer. Lancet 1996; 347: 1377–81. 75. Brown PD, Bloxidge RE, Stuart NS et al. Association between expression of activated 72-kilodalton gelatinase and tumor spread in non-small-cell lung carcinoma. J Natl Cancer Inst 1993; 85: 574–8. 76. Pedersen H, Brunner N, Francis D et al. Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res 1994; 54: 4671–5. 77. Planting A, van der GA, Schoffski P et al. A phase I and pharmacologic study of the matrix metalloproteinase inhibitor CP-471,358 in patients with advanced solid tumors. Cancer Chemother Pharmacol 2005; 55:136–42.

4

Tobacco policy Nigel Gray Contents Introduction • Basic policy • Developing countries • The future

INTRODUCTION The single global public health objective in this field is to reduce consumption of tobacco by all possible means as quickly as possible. Major successes such as the decline in British consumption and mortality are currently matched by the steep ascent of these two indices in developing countries, particularly China,1 which illustrates the urgency of policy action. It is reasonable to assert that implementation of policy lags, sometimes decades, behind policy development, which lags similarly behind the development of knowledge. In a number of sophisticated countries, among which are the UK, Norway, Sweden, Australia, Canada, and the USA, the proportion of the population which continues to smoke has fallen from over a half to about a quarter. Mortality declines have usually followed, but at very different rates. So it is wrong to be pessimistic but important to be impatient. Pressing for activist policies, on the grounds that outcomes take a long time, seems to be an integral part of the duty of the health professions. Comprehensive tobacco policy has been well established and understood since the mid-1970s.2 The recommendations in this chapter are informed by long experience of successful and unsuccessful policies in many diverse countries. Many of the important policy issues and outcomes have never been the subject of refereed articles in the technical press, so the reader must be satisfied with basic references and must be willing to search newspaper archives for historic detail. Tobacco use has been, and is, perhaps the most difficult issue faced by public health workers in the 20th century. Historic diseases such as smallpox, polio, measles, diphtheria, tetanus, whooping cough, rubella, and scarlet fever were conquered in developed countries within a decade or so of the arrival of effective control systems. When vaccines and antibiotics worked, they were used. Failures in developing countries relate to the failure of national and international social organization and rarely to organized opposition. The reappearance

of malaria and tuberculosis, depressing though it is, is partly due to these factors and partly due to the lack of really effective means of control. The singular feature of the tobacco problem is that someone is selling it. No one is selling tuberculosis. To this can be attributed the fact that, five decades after discovering its carcinogenicity, tobacco consumption worldwide is falling very slowly. Comparisons with the other industries selling toxic products are unsatisfactory. There is no pretence that asbestos does not cause asbestosis, nor that drunken driving is merely a pleasurable habit. The international tobacco industry is unique in its stubborn refusal to concede the sideeffects of its product, despite revelations3 which make it clear that the industry knew of the carcinogenic and addictive properties of tobacco some decades ago. Once having retreated into its legal bunker it is now in the difficult position of facing enormous legal and financial consequences if it makes concessions or tells the truth. Thus the forces of public health and the global tobacco industry are locked in continuous warfare and prospects for peace are slight. While no form of tobacco use has been discovered to be safe, the cigarette is the most ubiquitous, widely used, and best-studied product. The myriad forms of tobacco use seen in India and other parts of Asia are carcinogenic in many different ways and, being personally grown or based on cottage industry production, each poses specific individual problems. Certainly it is easier to develop policies to control cigarette smoking than tobacco/betel chewing as the product is factory made, taxed, exported and imported, and often the subject of retail licensing. The unrepentant nature of the global tobacco industry, which is controlled by relatively few major manufacturers, is reflected in the sales statistics. Sales are in decline in the most developed countries and the expected indices follow. Lung cancer in males, especially younger ones, is declining, as is heart disease.1 By contrast, tobacco exports from the USA are climbing and the antique tobacco monopolies of the previously

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communist world are being replaced by modern mass production systems owned by the same people. Marketing measures forbidden in the USA, UK, and Europe are rampant in many developing countries. Consideration of tobacco policy may conveniently focus first on the cigarette. Such consideration should take note that smoking is a learned habit which is initiated by social forces but sustained by the development of addiction in persistent users.

•

BASIC POLICY This is theoretically simple: • • • •

change the cultural background; change the smoker; change the cigarette; protect the children.

Changing the cultural background The cultural background against which tobacco smoking must be considered is a mixture of community law and community norms. Laws usually arise as a result of public opinion at a point in time and are an important reflection of community norms, although they do not always mirror public opinion in those countries where the tobacco industry is strongest. The failed battle to introduce strong tobacco legislation in the USA in 1998 shows the difficulties in the path of lawmakers that are posed by the organized and well-funded opposition of tobacco manufacturers. This situation, while obvious in the USA, arises in most countries when tobacco policy requires lawmaking, although the opposition may be less obvious and behind the scenes. An important element in the interaction between government, parliaments, and popular opinion may be non-government organizations. Policy frequently arises in the non-government sector, as may the drive for legislation. Thus the interactive process of introducing legislation may be an important part of providing a driving force for implementation. Popular laws are more likely to be implemented. Opposition to standard comprehensive laws is to be expected and is routinely led by those with vested interests, supported by the industry, using arguments now outdated and often ugly when exposed to public gaze.

•

•

•

Model legislation • •

Health warnings These should state government policy and the facts. Rotating, explanatory warnings

are the first step. Warnings researched for understandability and offering a telephone number to an information service are better. Warnings with graphic pictures are even better. Packet labeling There is a powerful case for generic packaging as a way of interfering with global brand advertising. Packaging should declare yields of known major carcinogens and other substances, which may be specified as knowledge develops. Packet inserts are a way of providing the sort of comprehensive information that is given with such substances as aspirin. Tobacco industry claims for the right to compete for adult markets are specious as adults and children co-exist in society and measures to protect or attract children often impinge on adults and vice versa. Abolition of promotion – in every form Tobacco brand names need to be forbidden in advertisements for any other product. Direct and indirect advertising needs to be specifically addressed. This issue remains difficult because of the cross-border abilities of satellite media. It should be understood that there is no case which can be made in favor of tobacco promotion as the product is seriously and chronically toxic when used as the manufacturers intend. Evasion of promotional restrictions is the profession of a large number of people, all of whose arguments should be ignored. Even at point of sale, advertisement should be forbidden. Availability Sales to children, defined as 16–18 in most countries, need to be prohibited and the prohibition policed. Such legislation is widespread, but policing is not. Vending machine sales need to be supervised in places inaccessible to children, or forbidden. This policy measure is widely adopted but almost nowhere has policing been tried. Until that experiment is done and shown to fail this issue remains high on the agenda for developing countries. Smoke-free environments These need encouragement for exemplary as well as risk-avoidance reasons. Schools, hospitals, workplaces, and public transport should be smoke-free, as a minimum. Smokers in many countries have been remarkably accepting of this policy. It is an important downward pressure on smoking rates in all age groups, and probably reduces daily dose as well as encouraging quitting. Tax This should be high in the context of individual income and should be regularly increased; a set proportion should be allocated to health purposes

Tobacco policy 37

•

including tobacco education.4 Tobacco tax is among the only taxes demonstrated to be popular. There is good reason why the price of a packet of cigarettes should be several times that of a hamburger. Regulation of the product It is unacceptable that a product as dangerous as tobacco should be unregulated. Additives need to be demonstrated to be non-toxic in both burnt and unburnt form; and upper limits should be set, and continuously reviewed, for major carcinogens and toxins. Public health advisors and departments have been slow to act in this field, possibly because of perceived complexities. However, the establishment of upper limits for cigarette emissions is relatively straightforward and is in need of urgent implementation.

The importance of legislation is underlined by the experience of Norway, the pioneer, in 1975, of comprehensive tobacco legislation. Tobacco consumption peaked in the mid-1970s, having risen by about 25% between the mid-1950s and mid-1970s. Since then it has declined by approximately the same amount. The original legislation in Norway was from a unanimous parliament, but was surrounded by much discussion and public interaction. This early legislation did not include severe workplace and public place restrictions, and Norwegian prices have risen only slightly, in real terms, since the 1980s.5 While it is possible to argue over the potential benefits of more aggressive pricing, public education, and smoking opportunity restrictions, the Norwegian experience is a testimony to the efficacy of good legislation as the basis for a comprehensive anti-tobacco program. Community norms are usually well reflected in public opinion. A comprehensive tobacco policy would include regular surveys of tobacco consumption, public opinion, relevant attitudes among smokers and nonsmokers, and evaluation of education programs. Opinion may move slowly, but it does move with time and in the presence of well-directed education programs. It is both logical and true that parental attitudes and example flow through to youth behavior, so changing the cultural background implies measuring beliefs and recruiting all the potential role models of society as well as removing the tobacco industry’s ability to promote its product. It is also logical to believe that education programs work better without opposition, further underlining the importance of complete eradication of promotion. In summary, changing the cultural background requires an activist and persistent approach to legislation

and community involvement. This means that a wellorganized and co-ordinated anti-smoking movement is a necessary basis. Such movements are not always large; efficiency and co-ordination are the keys. Changing the smoker Changing the smoker to become a non-smoker is a complex multifaceted process requiring analysis of individual society’s smoking patterns. It is accepted that addiction to tobacco is the major force in maintaining smoking status. Progress towards becoming a nonsmoker may be generally and simply summarized: Rational information → dissonance → attempts to quit → success → maintenance Dissonance may be defined as dissatisfaction with one’s own smoking behavior, and affects a majority of smokers in the USA, for example, but probably a minority in less well-informed societies. Clearly dissonance is more likely to occur if the victim/person is well informed, so the place of varied education programs, targeted to the subgroups as well as the totality of smokers, cannot be doubted, but is country-specific, at least to a degree. Other factors can be expected to stimulate dissonance: the smoke-free workplace and public places; peer group and family pressure; negative peer group experiences such as deaths or disease; societal attitudes and levels of information. Such factors reflect the cultural background and vary from country to country. Attempts to quit occur frequently in sophisticated countries and policy should encourage and provide support for smokers who make them. The role of nicotine replacement therapy (NRT) is crucial and in need of considerable development. Its value is well established although results are generally disappointing by comparison to expectations. Better products are needed as is greater availability and more support services. It is bizarre that cigarette content is virtually unregulated while bureaucratic restrictions on alternative sources of clean nicotine are widespread. The general global failure of health professionals, especially physicians, in support of patients and provision of therapy is a disturbing reflection of health priorities, which at least means there is hope for potential improvement. The debate over nicotine addiction6 per se ought not to hold back development of better products and services. Tobacco is a uniquely toxic way of delivering the desired dose of nicotine while NRT appears to be safe or relatively so. Up to this time there is no evidence of

38 Textbook of Lung Cancer

mass addiction to nicotine chewing gum, although the lack of competitive products which will deliver the quick, efficient, ‘fix’ of the cigarette might well explain this. Nevertheless, policy should be aimed at providing support, NRT, and whatever other pharmaceutical aids may be developed, since the status quo is an ongoing disaster which justifies greater effort than it receives. Continuing use of NRT in smokers who cut down but do not abstain is a sensible form of harm reduction, although the obvious goal is abstinence. Policy makers should note that the costs of helping smokers are infinitely less than those of treating them and that, while the most immediate mortality, morbidity, and cost benefits are achieved by attention to longduration heavy smokers, every smoker is at risk sooner or later, and early intervention is always best.

learned in reducing vehicle emissions to the cigarette, and to base regulations upon it. It is known8,9 there is great diversity in the levels of major carcinogens in mainstream smoke yields on the world market, so the evidence that cigarettes with lower carcinogen levels can be made and sold is indisputable – cigarettes low in nitrates and nitrosamines are made and sold. The policy issues then become the following: •

•

• Changing the cigarette The cigarette is a uniquely efficient nicotine delivery device which has so far escaped significant production controls worldwide. This is in contrast to motor vehicles, pharmaceuticals, food, houses, and even sewage systems. While the reasons for this disparity are interesting, as they include corruption on a global scale, there can be no excuse for continuing to allow the tobacco industry alone to decide what will go into the product, and therefore what is present in mainstream smoke. First it is necessary to state that the policy of the 1960s, which favored reduction of tar and nicotine levels over time, has not produced the benefits anticipated. Changes in cigarette design7 have brought about reductions in some carcinogens and increases in others. Mortality benefit, if present, is small, and adenocarcinoma has increased in the USA and elsewhere. Since tar measurement takes no account of the qualitative changes which have occurred in smoke it is misleading. Over the same time, bioavailability of nicotine has been increased and, together with compensatory smoking, means the machine-measured levels of nicotine are also misleading. It can therefore be unequivocally stated that tar and nicotine measures as currently used should be abolished – the policy question is what they should be replaced with? It must be recognized that cigarette design is best understood by the tobacco industry and is clouded by commercial secrecy, and that no governments have applied the necessary research resources to know enough to tell manufacturers how to make their product. However, it is certainly possible to apply the principles

•

•

•

•

Governments must claim power to regulate the content of cigarette smoke – this power exists in some countries. Health authorities require suitable advisory systems involving independent scientists and with mandatory access to industry information. Initially, major carcinogens such as benzo(a)pyrene, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and N-nitrosonornicotine (NNN) should be targeted. Market analysis would show the range of yields. Those cigarettes yielding above the median should be removed from the market, or modified, within a standard period such as 12 months. Over time this process would allow progressive reduction in carcinogens and other toxins, since the starting point is a level found to exist on the market and already achieved by at least some manufacturers. Nicotine needs special treatment. The first essential is a new measurement system. However, a measure which measures smoke content will not accurately reflect what gets into the smoker’s bloodstream, as it cannot control for compensatory smoking practices. Therefore, while control of smoke yield can be exerted by a measure such as nicotine content per liter of smoke, the decision-making process which sets the yield levels needs to be informed by behavioral experiment and analysis. The ultimate policy decision – whether mass weaning of nicotine-dependent populations should be attempted by regulatory reduction of dose per cigarette – cannot be made in the light of knowledge in 2007. However the goal of reduction in the addictiveness of the cigarette is a proper one and should be pursued as a matter of policy. In facing the decision to control nicotine yields, policy makers must understand that the rise of cigarette smoking was a vast unplanned experiment performed by the tobacco industry, initially ignorant of its product’s toxicity. Long-term decisions on nicotine policy will require similarly large

Tobacco policy 39

•

experiments based on sensibly considered probabilities. The decision to reduce tar and nicotine was sensible when conceived but subverted by industry manipulation. This mistake should not be made again but should not prevent innovative regulatory policies. New products containing tobacco ought also to be regulated and only tested in situations similar to those which are used for the testing of new pharmaceuticals. So far the tobacco industry has not produced a successful alternative to the standard cigarette. They should not be discouraged from doing so but should not receive marketing advantages over NRT and other nicotine alternatives.

ongoing smokers need to be related to those of children to a smoke-free and promotion-free environment. Policy is not only about prohibitions and restraints. There is a clear need for experimentally based, expensive, education programs aimed at children. The fact that few of these have been developed outside a few richer countries, and even fewer adequately funded, is not an excuse for failure to change. Every society which spends money on treating sick smokers would be well advised to spend funds of the sort spent on promotion of cola drinks on campaigns aimed at discouraging smoking.

DEVELOPING COUNTRIES Protecting the children As social norms and fashions have changed over time, so have the specific stimuli which trigger or contribute to initiation of the smoking habit. Age of onset of initiation varies around the world, beginning earlier in developed countries. Cultural differences play an important role, as exemplified by the great diversity in smoking rates between men and women in countries such as China. Whereas the factors which contribute to initiation in particular societies differ, the policy question is what can be done to interfere with the pressures toward initiation – or in simple terms, what can be done to protect the children? The first policy approach is to remove or reduce all the pro-smoking pressures which can be controlled. Formal and informal promotion of tobacco has been dealt with above. Nevertheless, it must be re-emphasized that children are extremely sensitive to promotional pressures and that any presentation of a tobacco brand name needs to disappear from the social environment. This has been substantially achieved in a number of countries, but has been subverted to a variable degree by cross-border advertising of events such as motor races and cricket matches sponsored by tobacco interests. Global control of this phenomenon will not be achieved easily, but the battle, slowly being won in developed countries, needs to be fought in developing countries as the industry seeks to source such events from them. Local social pressures need policy attention. The role of parents, siblings, peer groups, and local and international role models should be the subject of education programs and local campaigns, with the specific objective of reducing initiating pressures wherever they exist. What happens in schools, homes, workplaces, and public places needs detailed consideration. The rights of

Tobacco use is already built in to many developing countries and takes many forms. No form of tobacco use has been shown to be free of risk and the fact that snuff use in Sweden is less hazardous than tobacco/ betel chewing in India is not sufficient to allow fantasies of safe tobacco products to intrude on public policy. The principles set out above are applicable to some degree with most forms of tobacco use. However, local cultures in which the many and strange variants of tobacco smoking and chewing persist need to be considered individually. The broad-brush weapons of education, warning labels, taxation, and restriction where relevant can be considered by policy makers, and locally suitable policies developed and tried. The after-effects of tobacco use as known are such that no variant of use can be neglected. The reappearance of the cigar as a social status symbol in the USA should warn against complacency.

THE FUTURE The basic principles of tobacco policy discussed here have been tested and appraised in real societies and shown to work to a greater or lesser degree. The degree usually depends on the enthusiasm with which policies are implemented. The force of the vested interests of the tobacco industry has been able to slow policy implementation, but the fact remains that tobacco use in developed countries had declined substantially and the tobacco industry is now seeking to replace its lost, dying, and dead smokers in developed countries with new users in the poor and developing world. The political battle over the proposed tobacco settlement in the USA in 1998, although seemingly lost at

40 Textbook of Lung Cancer

that time, is a serious and important indication of the degree to which the international tobacco industry has declined in power and influence. It is to be expected that the public health principles espoused here will be applied progressively and more rapidly over the next decade. The result can only minimize the tobacco mortality epidemic already set in train by past events, but while tobacco remains one of the largest causes of avoidable death and disease, it remains one of the major global public health targets for all countries. REFERENCES 1. 2.

Peto R, Lopez AD, Boreham J et al. Mortality from smoking world-wide. Br Med Bull 1996; 52: 12–21. Gray N (ed). Lung Cancer Prevention; Guidelines for Smoking Control. Geneva: Union Internationale Contre le Cancer, 1977.

3. 4.

5.

6. 7. 8.

9.

Glantz SA, Slade J, Bero LA et al. The Cigarette Papers. Berkeley: University of California Press, 1996. Manley M, Glynn TJ, Shopland D. The Impact of Cigarette Excise Taxes on Smoking Among Children and Adults: Summary Report of a National Cancer Institute Expert Panel. Bethesda MD: National Cancer Institute, 1993. Bjartveit K, Lund KE. The Norwegian Ban on Advertising of Tobacco Products. Has it Worked? Oslo: Norwegian Cancer Society, 1996. Benowitz NL, Henningfield JE. Establishing a nicotine threshold for addiction. N Engl J Med 1994; 331: 123–4. Hoffmann D, Hoffmann I. The changing cigarette, 1950–1995. J Toxicol Environ Health 1997; 50: 307–64. Fischer S, Speigelhalder B, Preussmann R. Tobacco specific nitrosamines in commercial cigarettes; possibilities for reducing exposure. Relevance to Human Cancer of NNitroso Compounds, Tobacco Smoke and Mycotoxins. International Agency for Research on Cancer. Monograph 105. Lyon: 1991 489–93. Gray N, Boyle P, Zatonzki W. Tar concentrations in cigarettes and carcinogen content. Lancet 1998; 352: 787–8.

5

Smoking cessation programs Philip Tønnesen Contents Introduction • Clinical approach • Stages of motivation • Carbon monoxide in expired air • Nicotine replacement therapy • Varenicline • BupropionSR • Other drugs • New drugs • Alternative therapies • Smoking reduction • Special considerations for lung cancer patients who smoke • Weight gain • Conclusions

INTRODUCTION This chapter focuses on the proper use of nicotine replacement therapy (NRT), varenicline, and bupropionSR, golden rules in smoking cessation, predictors of success, and the concept of smoking reduction. It should be remembered that cigarette smoking is an addiction, and for that reason smoking cessation cannot be compared with treatment of other medical conditions. NRT will produce low success rates when used without adjunctive behavioral support; however, since most smokers quit on their own and using over-the-counter (OTC) NRT, even these low success rates will have an important influence on public health. The degree of supportive adjunctive behavioral therapy parallels the actual success rate, while the relative success rate (i.e. the odds ratio between NRT and placebo) remains more or less unchanged at around a factor of two.1 As a preventive tool, smoking cessation is very costeffective. Smoking cessation with NRT or bupropionSR is approximately eight times more cost-effective per saved year compared with 300 medical treatments.2 Also, smoking is the most important etiologic factor in the development of lung cancer, accounting for almost 85% of all lung cancer cases, and has been strongly correlated with other cancers, including oral, laryngeal, and bladder cancer. Around one-third of all cancer deaths are attributed to tobacco.3 Also, tobacco use is a major contributor to chronic obstructive pulmonary disease (COPD) and coronary arteriosclerosis – diseases that often prevent lung cancer patients from undergoing curative surgery.

CLINICAL APPROACH When a health care provider, i.e. a physician, nurse, dentist, or pharmacist, meets with a smoking patient,

he or she has a responsibility to interfere and discourage tobacco use.4,5 The first thing is to ask whether or not the patient is a smoker. Already, by asking, one shows to the patient that one cares about smoking and that smoking might be of importance in relation to health. It is important that the patient’s smoking be handled in a neutral way without anger or condemnation. The smoker should be informed about the risks of smoking, and the information should be individualized for the particular patient.

STAGES OF MOTIVATION Some smokers are contented smokers: they do not consider quitting and do not think about the dangers of smoking. But many smokers would like to quit. Motivation to do so can be regarded as a cyclic process of changes, as described by Prochaska and Goldstein.6 However, these stages do not correlate well with success in quitting. It is much more important for patients with smoking-related diseases such as lung cancer to quit compared with ‘healthy smokers’. Continued smoking in lung cancer patients has a negative effect on the outcome of surgery, chemotherapy, and radiation therapy, and increases the risk of secondary primary lung cancers in long-term survivors. The therapist’s approach to the smoker depends on the motivation to quit. Use of the questions in Table 5.1 is an easy and quick way to classify the motivational stage of the individual smoker and then to apply the right treatment approach. If the smoker wants to quit you should support with advice about NRT and the golden rules of smoking cessation, use NRT, varenicline, or bupropionSR, clinician-provided assistance and skills training, and follow-up visits.7 If the smoker is only interested in cutting down, the smoking reduction concept should be applied. Patients who declare

42 Textbook of Lung Cancer Table 5.1 Assessment of motivation to quit smoking or to reduce

1.

Will you participate in a smoking cessation course now? Answer ‘Yes’: Start smoking cessation ‘No’: Continue to 2 2. Will you try to cut down your daily number of cigarettes now? Answer ‘Yes’: Start smoking reduction ‘No’: Recommend cessation and give brochures 3. How motivated are you to quit on a scale from 0 to 10? (0 = not at all motivated; 10 = extremely motivated) Answer _______ score (0–10) 4. How motivated are you to reduce on a scale from 0 to 10? (0 = not at all motivated; 10 = extremely motivated) Answer _______ score (0–10)

no interest in smoking cessation or reduction should receive brochures and other self-help material about smoking or smoking cessation. More detailed guidelines for smoking cessation have been published by the Agency for Health Care Policy and Research in the USA and by NICE in the UK.8,9 However, there are some basic principles related to successfull smoking cessation that are important for the therapist to consider: smokers must stop smoking completely at quit day (even one or two cigarettes per day during the first one or two weeks of cessation are usually followed by relapse): •

• •

• •

the use of NRT, varenicline and bupropionSR lessens withdrawal symptoms and improves cessation outcome; for lung cancer patients aggressive use of NRT, varenicline, or bupropionSR should be used; follow-up should be arranged to prevent relapse (which is highest during the first three to six weeks, then gradually declines, similarly to other addictions); smoking reduction might be a gateway to smoking cessation in smokers low in motivation to quit; if the patient relapses, he or she should be encouraged to make another attempt to quit later on and then receive retreatment (‘recycling’).

CARBON MONOXIDE IN EXPIRED AIR In most smoking cessation studies, sustained abstinence is used as the outcome measure. It consists of the smoker’s statement of not smoking now and not having smoked since the last visit, together with biochemical verification by carbon monoxide (CO) in expired air. CO measurement is an easy and inexpensive way to verify abstinence biochemically. The half-life of CO varies between four and six hours, and the cut-off value between non-smokers and smokers is usually 10 parts per million (ppm). Most non-smokers attain CO values of 1–4 ppm, and some use a cut-off value of 6 ppm. Subjects exposed to passive smoking might attain values of 6–9 ppm. CO levels are most often measured with a portable CO monitor (Bedfont Monitor, Sittingbourne, UK) in expired air after a 15 s breathhold, with a CO value of less than 6–10 ppm verifying abstinence.10 The result is displayed immediately. Calibrations have to be performed at least every six months using a 50 ppm CO test gas. False-positive values might be observed in subjects with lactose malabsorption. Although an ethanol filter is present, high ethanol concentrations in the breath might interfere with measurements. Drifting of the zero-point might be observed if many smokers are tested consecutively. Without CO monitoring, up to 10% of failures might state that they do not smoke. Plasma, saliva, or urinary cotinine levels are another biochemical way to verify smoking abstinence.

NICOTINE REPLACEMENT THERAPY The rationale for nicotine substitution is as follows. When quitting smoking, the administration of nicotine decreases withdrawal symptoms in the first months, thus allowing the subject to cope with the behavioral and psychologic aspects of smoking (Table 5.2).

Table 5.2 The principle of nicotine replacement therapy (NRT)

• • • • •

Principle: quit cigarettes Use NRT to reduce withdrawal Break the psychologic addiction After two to four months, stop NRT Some might need NRT for longer periods

Smoking cessation programs 43

Withdrawal symptoms (craving for cigarettes, irritability, anxiety, depression, drowsiness, difficulty in concentrating, restlessness, headache, hunger, sleep disturbances) are usually assessed on a four-point scale (0 = not at all; 1 = mild; 2 = moderate; 3 = severe).11,12 Withdrawal symptoms often appear four to eight hours after quitting, peak during the first week (days 3–5), and then gradually decline over the next two to four weeks. Nicotine dependence is measured by the Fagerström test of nicotine dependence (FTND), with a possible scoring of 0–10 (most dependent)13 (Table 5.3). With the nicotine replacement products used today, lower nicotine levels are attained compared with smoking

(i.e. the high peak plasma levels of nicotine reached during smoking are not achieved) (Figure 5.1). Patients are weaned off nicotine replacement products (usually over two to six weeks) when withdrawal symptoms are lessened owing to decreased dependence. The average 12-month success rate reported in most studies is about 15–25%.8,9 Predictors that correlate with a lower success rate are higher nicotine addiction, lower age, no previous quit attempts, previous depression, suffering from COPD and cardiovascular disease, a smoking spouse, and low motivation to quit. Nicotine is the drug of choice to assist smoking cessation. Results reported in a Cochrane meta-analysis

Table 5.3 Fagerström test for nicotine dependence (FTND) Item

1.

How soon after you wake up do you smoke your first cigarette?

2.

Do you find it difficult to refrain from smoking in places where it is forbidden, i.e. in church, at the library, in the cinema, etc.? 3. Which cigarette would you most hate most to give up? 4. How many cigarettes per day do you smoke?

Do you smoke more frequently during the first hours after waking than during the rest of the day? 6. Do you smoke if you are so ill that you are in bed most of the day (or absent from work)?

Plasma nicotine concentrations (ng/ml)

5.

35

Answer

Score

Within 5 min 6–30 min 31–60 min 61 min or more Yes No

3 2 1 0 1 0

The first one in the morning Any others 1–10 11–20 21–30 31 or more Yes No Yes No Total score

1 0 0 1 2 3 1 0 1 0 0–10

Figure 5.1 Plasma nicotine levels during cigarette smoking, nicotine nasal spray (NNS) use, and 4-mg nicotine chewing gum use.

30 25 20

Cigarettes

15

NNS 4-mg gum

10 5 0 8

9

12

16

20

Time (hours)

24

4

8

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of 105 trials with 39 503 subjects, who received various forms of NRT (gum, patch, spray, inhaler, and sublingual/lozenge), indicated that NRT almost doubled long-term (6–12 months) quit rates.14 The odds ratio for success of NRT compared with controls was 1.8 (95% confidence interval, CI, 1.7–1.9). The odds ratios for the different nicotine replacement products were 1.6 for gum, 1.8 for patch, 2.4 for nasal spray, 2.1 for inhaler, and 2.1 for sublingual/lozenge (Table 5.4). Overall, there was no statistical difference between the different forms of NRT and this has also been found in comparative studies. The nicotine products described above are self-dosing systems to be used ad libitum, in contrast to the patch, which ‘infuses’ about 1 mg of nicotine per hour at a constant rate. There are six different formulations of nicotine replacement products (Table 5.5) and the determination of the most appropriate product should be according to patient preference, cost, nicotine dependence, and number of daily cigarettes (Tables 5.6–5.9).

Nicotine chewing gum Gum users should only chew a piece five to ten times until they can taste the nicotine, then let the gum rest in the cheek for a few minutes, and then chew again to expose a new surface of the gum. Free nicotine can then be absorbed and reduce side-effects due to swallowed nicotine. The gum can be chewed for about 20–30 minutes. About 0.8–1.2 mg of nicotine is absorbed from a piece of 2-mg nicotine gum, and 1.2–1.5 mg of nicotine from a 4-mg piece15 (Table 5.5). With use of nicotine gum throughout the day, blood levels of one-third (for 2-mg gum) and two-thirds (for 4-mg gum) of the nicotine obtained through smoking are achieved.16,17 A basic advantage of gum is the possibility of self-titrating the dose, in contrast to the patch, which delivers a fixed dose. Thus it is possible to use a piece of

gum whenever it is wanted or needed during the day. The principal disadvantage of gum use is potential

underdosing, which might explain the lack of effect in several trials. The approximate dose equivalent for most nicotine patches is approximately 20 pieces of the 2-mg

Table 5.5 NRT formulations

Gum 2 and 4 mg content: 0.8–1.2 mg and 1.2–1.5 mg absorbed, respectively Patch 15 mg/16 h; 21 mg/24 h Inhaler 10 mg in one container: 4–5 mg released (2–3 mg in clinical use) Nasal spray 0.5 mg/dose in each nostril Sublingual tablet 2 mg content: 0.8–1.2 mg absorbed Lozenge 1 mg and 2 mg content: 0.5 and 0.8–1.2 mg absorbed

Table 5.6 NRT use: 1

1–9 cigarettes/day (not-evidence based) • 2-mg gum • Inhaler • 1-mg lozenge 7–9 cigarettes/day • As above, or • Patch 10-mg/16 h or 7-mg/24 h

Table 5.4 Efficacy of NRT

Table 5.7 NRT use: 2

• • •

10–20 cigarettes/day • Patch: 15-mg/16 h or 14-mg/24 h • Gum 2- or 4-mg • Inhaler • 2-mg lozenge or 2-mg sublingual

• • • • •

Meta-analysis controlled trials Success rates sustained for one year Odds ratio 1.77 (95% CI 1.67–1.89) Gum: 1.66 Patch: 1.81 Nasal spray: 2.35 Inhaler: 2.14 Sublingual/lozenge: 2.05

15–20 cigarettes • As above, or • NNS

Smoking cessation programs 45

Table 5.8 NRT use: 3

21+ cigarettes/day • Patch: 25-mg/16 h or 21-mg/24 h • Gum: 4-mg • NNS • Inhaler • Sublingual 2-mg or lozenge 2-mg • Gum as rescue in relapse situations • NRT as long-term use if needed • Combination of patch and one of the other NRTs • NRT in combination with bupropionSR

Table 5.9 NRT use: 4

• • • • •

Use of NRT in smokers as withdrawal suppressor Meetings, workplaces, travel Few hours: gum, inhaler 6 or more hours: gum, inhaler, patch Instruct smoker to try a piece of gum/inhaler before travel starts

Table 5.10 Varenicline use

10+ cigarettes/day • Varenicline 0.5 mg in morning days 1–3; then 0.5 mg b.i.d. days 4–7 • Quit smoking after 1 (–2) week • Varenicline 1 mg b.i.d. • Duration: 12 weeks • In quitters after 12 weeks eventually continue with varenicline up to 6 months • Side-effects: mild nausea (30%), vomiting (2%) • Contraindications: severe renal failure

gum, whereas the mean number of pieces of gum consumed daily is only around five to six in most studies. Thus underdosing is a plausible explanation for lack of efficacy in several studies.18,19 From these observations, it would be logical to attempt to raise the consumed dose either by increasing the number of pieces of gum chewed or by using the higher-dose (4-mg) gum. In four studies comparing the 4- and 2-mg gums, the 4-mg gum was superior to the 2-mg gum for short-term outcome. Another way to

increase the amount of consumed gum might be to administer it in fixed-dosage schedules as shown by Killen et al.20 Side-effects of gum consist mainly of mild, transient, local symptoms in the mouth, throat, and stomach due to swallowed nicotine (i.e. nausea, vomiting, indigestion, and hiccups). After adequate instruction, most smokers can learn to use the gum properly. However, without instruction many will discontinue use or underdose themselves. In the Lung Health Study, among 3094 smokers who were followed for five years, the use of the 2-mg gum appeared safe and did not produce cardiovascular problems or other adverse events, even in subjects who continued to smoke and still used nicotine gum.21 It is suggested that smokers be instructed to stop smoking completely, use the nicotine gum on a fixed schedule (i.e. every hour, from early morning, for at least 8–10 hours), and to use extra pieces of gum whenever needed. The optimal duration of treatment is not known; however, in most studies, the gum has been used for at least 6–12 weeks and up to one year. Individualization of treatment duration is recommended. Nicotine transdermal patch The nicotine patch is a fixed nicotine delivery system that releases about 1 mg of nicotine per hour for 16 hours (daytime patch) or for 24 hours (24-hour patch). Nicotine substitution is about 50% of the smoking level (21-mg patch/24 h and 15-mg patch/16 h) (Table 5.5). The nicotine curve attained in plasma with patches is flat, without the high peaks attained by cigarette smoking. It is much easier to administer the patch and to use it compared with gum, but it is not possible to self-titrate.22 The recommended treatment duration is 8–12 weeks. In a multicenter smoking cessation trial from the USA, examining the effect of 0, 7-mg, 14-mg, and 21-mg nicotine patches, a dose–response effect of increasing nicotine dosages was reported.23 Two large placebo-controlled trials with 600 and 1686 smokers have been published.24,25 The one-year success rate was 9.3% in the active patch group versus 5.0% in the placebo patch group in the first study,24 and 9.0% versus 6.3% in the other study.25 Among 19 studies examining long-term (i.e. 6–12 months) smoking cessation success, 10 showed a significant outcome in favor of the nicotine patch.22 The pooled success rate was 15.8% for active patches versus 8.8% for placebos (odds ratio 1.98; 95% CI 1.70–2.30).

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Side-effects are mainly mild local skin irritation, occurring in 10–20% of subjects. In only 1.5–2.0% of subjects was the patch terminated owing to more persistent and severe skin irritation at the patch location.22 Because of its ease of use, the patch may be the first choice of nicotine delivery system today. Transdermal nicotine replacement does increase success in smoking cessation with minimal adjunctive support. Nicotine inhaler An inhaler consists of a mouthpiece and a plastic tube with a porous plug impregnated with nicotine, which releases nicotine vapor when air is drawn through the plug. Most of the nicotine is absorbed through the mouth and throat. Each inhaler contains 10 mg of nicotine (Table 5.5). In clinical use, each inhaler releases approximately 2–3 mg of nicotine, and the number of inhalers used daily averages five or six. Thus, nicotine levels comparable to those found during use of the 2-mg nicotine gum are attainable (i.e. relatively low concentrations). Few controlled trials have been conducted with nicotine inhalers. The efficacy and safety of the nicotine inhaler were examined in a double-blind, clinical, smoking cessation trial.26 The first published study was a one-year, randomized, double-blind, placebo-controlled trial that enrolled 286 smokers. The success rates for smoking cessation were 15% and 5% at 12 months (p < 0.001) for active and placebo, respectively. The mean nicotine substitution based on determinations after one to two weeks of therapy was 38–43% of smoking levels. The treatment was well accepted, and no serious adverse events were reported. Three other studies have confirmed the above finding, with odds ratios in favor of active treatment of 1.6, 2.2, and 1.6.27 The inhaler may replace some of the habit patterns associated with smoking (e.g. oral and handling reinforcement), along with providing nicotine replacement. At least four inhalers should be used per day, the optimal number being 4–10 per day and the duration of use three months, with another 3–9 months of use and downtitration if needed. With rapid and frequent puffing, it is possible to increase the dose. Nicotine nasal spray The nicotine nasal spray (NNS) consists of a multidose, hand-driven, pump spray with nicotine solution. Each puff contains 0.5 mg nicotine; thus a 1-mg dose is delivered if both nostrils are sprayed as recommended (Table 5.5). The NNS is a strong and rapid means of delivering nicotine into the body with a pharmacokinetic

profile closer to cigarettes. After a single dose of 1 mg nicotine, the peak level is reached within 5–10 minutes, with average plasma trough levels of 16 ng/ml. Three published studies with the NNS indicate that the one-year success rates for active NNS versus placebo, respectively, were 26% and 10%, 27% and 15%, and 27% and 17%.28,29 This strong spray induces localized side-effects, such as sneezing, nasal secretion and irritation, and congestion, watery eyes, and coughing. Up to 5% of subjects rate these side-effects as unacceptable; however, most symptoms decrease within a few days after the spray is initiated. Highly nicotine-dependent smokers might be the target group for this delivery mode of nicotine. The NNS should be used for three months, but has been used for up to one year in some studies. The dose is from 10 to 40 puffs in each nostril per day. Nicotine sublingual tablet/lozenge The 2-mg sublingual tablet should be placed under the tongue, where it will disintegrate within 20 minutes. The 1-mg and 2-mg lozenges should be sucked at until a strong taste appears, they should then rest in the cheek for a few minutes and then the cycle is repeated for 15–20 minutes. The nicotine released from the tablet will be absorbed through the oral mucous membrane and the dose delivered is comparable with the 2-mg nicotine chewing gum.30 Side-effects are similar to those from the nicotine gum. Many subjects with dentures who cannot use nicotine gum can use tablets or lozenges. The tablet/lozenge should be used for three months, but duration of treatment should be individualized for up to one year or longer. One tablet per hour is the recommended dosage up to 20/day, with a maximum dose up to 40 tablets/day in highly dependent smokers. Combination of two different NRTs Relatively few studies have been published about the combination of two NRT products. A short-term increase in success has been observed in some, and a trend towards a statistically significant 12-month increase has been found in meta-analysis.14 A dose–response effect has been observed with both the nicotine gum and patch. Even 22- and 44-mg patches have been tested with promising results after four weeks of treatment, i.e. success rates of 45% and 68%. In two studies the degree of nicotine substitution was compared to outcome and in both higher success rates were found with increasing degree of substitution.

Smoking cessation programs 47

In the CEASE study comprising 3575 subjects, a higher success rate was achieved with 25-mg 16-hour patches compared with 15-mg nicotine patches.31 Overall, in clinical use the combinations of different NRT administration forms seem safe with few sideeffects. Also, concomitant use of NRT and cigarette smoking seems safe, with nicotine concentrations similar to those found during normal cigarette smoking. VARENICLINE Varenicline affects the central nicotine receptors by binding to the nicotine receptor as an agonist with some antagonist action. This means that varenicline mimicks the effect of nicotine, but also prevents the pleasure from cigarette smoking by preventing nicotine from binding to the receptor. In two studies with 1025 and 1027 smokers with similar design, varenicline 1 mg bid was compared with bupropionSR 150 mg bid versus placebo for three months.32,33 The quit rate after 1 year was 22% and 23% for varenicline, 16.4% and 15% for bupropionSR, and 8.4% and 10.3% for placebo, i.e. there were significantly higher quit rates for varenicline versus placebo and bupropionSR. A relapse prevention study reported that, in subjects who had quit after 3 months, prolongation of varenicline use for another three months resulted in a higher quit rate after one year.34 The major side-effect was nausea in approximately 30% of cases, with 2–3% discontinuing the drug due to nausea and vomiting. However, in most subjects the nausea was not a major problem. No drug interactions have been found, and no significant contraindications have been reported, except severe renal failure. Varenicline has no effect on post-cessation weight gain. Overall, varenicline is a new, effective, and safe agent for smoking cessation. Also, varenicline tends to be more effective than bupropionSR. Varenicline should be considered a first-line drug in lung cancer patients. The dosing should be varenicline 0.5 mg a.m. for 3 days, 0.5 mg bid for another 3 days, then quit cigarettes from day 7 and continue with 1 mg varenicline bid for 12 weeks and, if needed, up to six months.

of 19 placebo-controlled studies reported a doubling of quit rates with an odds ratio of 2.06 (95% CI 1.8–2.4) in favor of bupropionSR.35 The recommended dosing for bupropionSR is 150 mg a.m. for one week prior to the quit date, in order to establish adequate blood levels. Therapy should then continue with 150 mg bid for 7–12 weeks. Common adverse events from bupropionSR are insomnia (up to 40%) and dry mouth. These sideeffects usually decline during the first week of therapy. In clinical trials the treatment was stopped due to adverse events in 10–12% of subjects. The most serious adverse event was epileptic seizures, which were reported in 0.1% of patients, and allergic reactions (1–2%), with 0.1% cases of serious hypersensitivity.35,36 The formulation is slow release to prevent high peak concentrations as seizures are concentration-dependent. BupropionSR is contraindicated in individuals with an increased risk of seizures (e.g. epilepsy, earlier head trauma, anorexia nervosa). A reduced dose – that is, one tablet daily – is recommended in patients with severe liver impairment. As bupropionSR is metabolized in the liver, interactions occur with several drugs. Similarly, it is important not to increase the dose above 300 mg, and to administer the daily dose in divided form, with an interval of at least eight hours. The last dose should not be taken later than 6 p.m. if insomnia is a problem. Post-cessation weight gain is reduced by 2–3 kg during the drug treatment period. There are few studies comparing bupropionSR with NRT or looking at the combination effect; however, the combination seems safe and is recommended for hard-core smokers such as lung cancer patients. BupropionSR is of similar efficacy to NRT and is generally well tolerated in smoking cessation. As bupropionSR has a more severe side-effect profile, more contraindications, and is only available on prescription, I regard NRT as first-line medication and bupropionSR as a second-line drug, but this is a matter of personal judgment and in most guidelines bupropionSR is a first-line medication. The dosing should be bupropionSR 150 mg a.m. for 6 days, then quit cigarettes from day 7 and continue with 150 mg bid for 7–12 weeks and, if needed, up to six months (see Table 5.11).

BUPROPIONSR OTHER DRUGS BupropionSR, an amino-ketone, is an antidepressant that differs from tricyclic antidepressants and serotonin reuptake inhibitors, and the effect on smoking is not coupled to the antidepressive effect per se. A meta-analysis

Nortriptyline, a tricyclic antidepressant, has been shown to be as effective as NRT and bupropionSR in smoking cessation. A meta-analysis of four trials found an odds

48 Textbook of Lung Cancer Table 5.11 BupropionSR use

10+ cigarettes/day • BupropionSR 150 mg in the morning for 7 days • Quit smoking after 7 days • Increase dose: bupropionSR 150 mg b.i.d. • Duration: 7–12 weeks • Side-effects: sleep disturbances, seizures in 1:2000 • Contraindications: epilepsy, increased risk of seizures, impaired liver function

It might be used as a secondary drug, especially in smokers afraid of or not accepting weight gain. Rimonabant has been marketed as a weight-reducing agent due to the low efficacy in smoking cessation. Several nicotine vaccines are under development. The principle is to produce antibodies in the blood that prevent most of the inhaled nicotine from cigarettes from reaching the brain. Phase II studies have found that it is possible to induce a long-term antibody level in humans with a safe vaccine and that high antibody response is associated with smoking cessation.40

ALTERNATIVE THERAPIES ratio of 2.8 (1.7–4.6) for one-year quit rates for nortriptyline versus placebo at a dose of 50–75 mg daily.37 There are contraindications, common anticholinergic side-effects, and particularly cardiac conduction disturbances and a decrease in orthostatic blood pressure. However, at the relatively low dose used for smoking cessation, nortriptyline seems to be relatively well tolerated and is a second-line agent or even first-line agent, especially in countries that cannot afford the more expensive first-line drugs or where they are not marketed. Several other antidepressants including selective serotonin re-uptake inhibitors have not been found to be effective in smoking cessation, e.g. doxepin, fluoxetine, sertraline, moclobemide, and venlafaxine. Clonidine, an α2-noradrenergic agonist, has been used as a smoking cessation agent. Six studies were included in a meta-analysis comprising 722 subjects, and the odds ratio of success with clonidine versus placebo was 1.89 (95% CI 1.30–2.74).38 However, a high incidence of adverse effects (median 71%) occurred (e.g. dry mouth, sedation, dizziness, and symptomatic postural hypotension). In my opinion – due to the high incidence of adverse events – clonidine is an obsolete drug in this area.

NEW DRUGS Rimonabant is a cannabinoid type 1 receptor antagonist with a central action and has been tested in smoking cessation trials. Preliminary results showed an increased three month quit rate with rimonabant, with relatively low absolute abstinence rates.39 Rimonabant more or less prevents post-cessation weight gain; however, when the drug is ceased weight increases. The role of rimonabant in smoking cessation has to be defined.

Other ‘popular’ interventions often used are acupuncture and hypnosis. However, there is no evidence to support an effect from hypnosis or other alternative therapies. A meta-analysis comparing active versus control acupuncture found that acupuncture was no more effective than placebo.41 One study reported no effect for laser therapy in 320 adolescents.42

SMOKING REDUCTION Many smokers would prefer to reduce the number of cigarettes smoked daily instead of quitting completely. The aim of smoking reduction is to widen access to cessation by including smokers not currently able or willing to stop abruptly, wanting to reduce smoking, or unable or unwilling to quit. As shown below, by the concept of smoking reduction it is possible to recruit a new segment of smokers who are not interested in abrupt cessation. The reduction process should be looked at as a gateway to complete cessation. The definition of smoking reduction is a decrease in the number of cigarettes (or tobacco) smoked daily. A 50% reduction or more in daily cigarettes has been chosen arbitrarily in most studies.43,44 Several randomized controlled trials have been published. In eight studies, two using nicotine inhalers and six using nicotine chewing gum for half to one year, comprising 2424 smokers, a reduction (>50%) was reported in 15.9% of smokers using nicotine products compared with a reduction in 6.7% of placebo users.45 Surprisingly, after one year a smoking cessation rate of 8.4% was found among nicotine users versus 4.1% in placebo users. A reduction of more than 50% after 3–4 months had a strong predictive value for quitting at one year. Also, participation in reduction

Smoking cessation programs 49

trials increased the motivation to quit smoking, thus not undermining the motivation to stop smoking completely. Another way to attain smoking reduction and reduce the harm of smoking could be through tobacco product modification.46 For the group of smokers not motivated to quit smoking a less hazardous cigarette might be an advantage. Also, smokeless tobacco (chewing tobacco and snuff) might be an alternative with tobacco smoking, with fewer health risks compared with smoking.47 Epidemiologic studies in Sweden have found much less harm in snuff users compared with cigarette smokers.48 The smoking reduction concept should be offered to smokers who are not motivated to quit. They should be prescribed NRT – nicotine gum or inhaler – for three months and recommended to reduce the number of cigarettes by at least 50% during the first 1–2 weeks and then to try to reduce further. If the smoker has not reduced by more than 50% after three months, NRT should be stopped as the chance of quitting then is low. In smokers who have reduced by more than 50%, NRT should be continued for up to one year, and after six months they should be recommended to try to stop smoking completely. In summary, smoking reduction seems to have a role for smokers not motivated or able to quit, as a gateway to complete cessation. There is limited evidence that smoking reduction is followed by an improvement in health, in contrast to the use of smokeless tobacco products.

SPECIAL CONSIDERATIONS FOR LUNG CANCER PATIENTS WHO SMOKE In this group of patients as many as 80% quit smoking during the time of diagnosis.49 However, up to 50% of patients undergoing curative surgery for lung cancer relapse and smoke after five years, thus increasing the risk of a secondary primary lung cancer.50,51 In healthy smokers a high relapse rate is observed during the first month after quit day, in contrast to cancer patients where most relapses occur between one and six months after quit day.52,53 An increasing proportion of lung cancer patients undergo chemotherapy and this proportion will probably further increase during the next decade due to increased public focus on this disease. Thus, in the future most patients will undergo treatment with surgery and/or chemotherapy. The importance of smoking cessation is due to a decreased complication rate after

surgery and during chemotherapy and radiation therapy if the patient has stopped smoking. The period of diagnosis and therapy might elicit depressive reactions and put a heavy strain on the patient’s and family’s mental and social situations. Many family members of lung cancer patients are often smokers and do not quit spontaneously during this period.54 It might also be that lung cancer patients are more nicotine dependent.55 Overall, this calls for a more intensive and aggressive effort to get these patients to successfully quit smoking. A nurse-managed program reported an abstinence rate of 40% after six weeks.54 A combination of nicotine patch with another NRT product should be the rule, and also a longer duration of treatment with the possibility to continue long term with NRT. A combination of NRT and bupropionSR might also be an option. However, as many of these smokers have tried NRT previously, varenicline might be the right option for these dependent smokers. Scheduled visits with smoking cessation counseling and support are important, to be combined eventually with telephone calls. In healthy smokers higher quit rates have been obtained if spouses are also enrolled in the same program and quit smoking, and this might also prove to be the case for lung cancer patients. For the small fraction of lung cancer patients with the lowest performance status, where only supportive therapy is prescribed and who have an expected short survival time, I would not actively suggest smoking cessation. The clinics involved with the diagnostics and therapy of lung cancer should be able to cover smoking cessation, and the health-care workers should have an adequate knowledge about smoking cessation.52 It is important that a specific budget is allocated to each clinic for a smoking cessation service.

WEIGHT GAIN A weight gain of 3 to 6 kg for abstainers after one year is found in most studies.56,57 In 10% of males and 13% of females the weight increase is more than 14 kg, i.e. they are ‘supergainers’. About half of the participants are afraid of gaining weight and it may be a more significant problem for females. Weight gain can be regarded as a withdrawal symptom due to increased hunger and increased caloric intake. NRT products are only partially able to reduce the post-cessation weight gain while bupropionSR has a slightly greater effect, i.e. a reduction in post-cessation weight gain of 2–3 kg.57

50 Textbook of Lung Cancer

For lung cancer patients the increase in weight might be an advantage if they are underweight. The increase in appetite might also be an advantage for patients with decreased appetite.

CONCLUSIONS In summary, NRT, varenicline, and bupropionSR almost double the one-year cessation outcome, and, combined with counseling and behavioral strategies, are important adjuncts for maintaining long-term smoking cessation. Nicotine gum, patch, and inhaler are first line drugs, while NNS nasal spray is for the more heavily dependent smokers. The patch might not be the first choice for heavily dependent smokers. The duration of NRT treatment is approximately three months, with individual variations. NRT is a very cost-effective treatment compared with several other medical treatments, and should be much more widely implemented in the future. If the smoker has failed using NRT, varenicline or bupropionSR is the choice. As lung cancer patients might be more nicotinedependent and have more difficulty in stopping smoking, a more aggressive therapeutic approach should be used, i.e. higher doses of NRT, a combination of two NRT formulations, varenicline, bupropionSR plus NRT, a longer duration of therapy (6–12 months), and more support visits. Family members who smoke should also be enrolled in a cessation program. Most lung cancer patients have used NRT previously, varenicline seems to be the drug of choice as it seems more effective than bupropionSR, with fewer adverse effects and almost no contraindications or interactions. Also, varenicline tends to be more effective when compared with bupropionSR. Physicians and other health-care providers have an obligation to discourage tobacco use in their patients and to deliver up-to-date assistance in smoking cessation.

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3. Peto R, Lopez AD, Boreham J et al. Mortality from tobacco in developed countries 1950–2000. Oxford: Oxford University Press, 1994. 4. World Health Organisation (WHO). European partnership to reduce tobacco dependence: WHO evidence based recommendations on the treatment of tobacco dependence. Geneva: WHO, 2001. 5. IASLC Workshop. Prevention and early detection of lung cancer. Clinical aspects. Proceedings. Elsinore, Denmark, 1996. 6. Prochaska JO, Goldstein MG. Process of smoking cessation. Implications for clinicians. Clin Chest Med 1991; 12: 727–35. 7. American College of Chest Physicians, American Thoracic Society, Asia Pacific Society of Respirology, Canadian Thoracic Society, European Respiratory Society International Union Against Tuberculosis and Lung Diseases. Smoking and health: a physician’s responsibility. A statement of the joint committee on smoking and health. Eur Respir J 1995; 8: 1808–11. 8. USDHHS. Tobacco and the Clinician: Interventions for Medical and Dental Practice. NCI 94-3693. Rockville, MD: US Department of Health and Human Services, Public Health Service, National Institutes of Health, 1994. 9. National Institute for Clinical Excellence (NICE). Guidance on the use of nicotine replacement therapy (NRT) and bupropionSR for smoking cessation. National Institute for Clinical Excellence Technology Appraisal Guidance No 39, 2002. Available from URL:www.nice.org.uk. 10. Jarvis MJ, Russell MA, Saloojee Y. Expired air carbon monoxide: a simple breath test of tobacco smoke intake. BMJ 1980; 281: 484–5. 11. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders–IV. Washington, DC: APA, 1994. 12. Hughes JR, Gust SW, Skoog K et al. Symptoms of tobacco withdrawal. A replication and extension. Arch Gen Psychiatry 1991; 48: 52–9. 13. Fagerström KO, Heatherton TF, Kozlowski LT. Nicotine addiction and its assessment. Ear Nose Throat J 1991; 69: 763–8. 14. Silagy C, Lancaster T, Stead L et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2004; 3: CD000146. 15. McNabb ME, Ebert RV, McCusker K. Plasma nicotine levels produced by chewing nicotine gum. JAMA 1982; 248: 865–8. 16. McNabb ME. Chewing nicotine gum for 3 months: What happens to plasma nicotine levels? Can Med Assoc J 1984; 131: 589–92. 17. Tønnesen P, Fryd V, Hansen M et al. Two and four mg nicotine chewing gum and group counseling in smoking cessation: an open, randomized, controlled trial with a 22 month follow-up. Addict Behav 1988; 13: 17–27. 18. Tønnesen P, Fryd V, Hansen M et al. Effect of nicotine chewing gum in combination with group counseling on the cessation of smoking. N Engl J Med 1988; 318: 15–18. 19. Puska P, Bjorkqvist S, Koskela K. Nicotine containing chewing gum in smoking cessation: a double-blind trial with half year follow-up. Addict Behav 1979; 4: 141–6.

Smoking cessation programs 51 20. Killen JD, Fortmann SP, Newman B, Varady A. Evaluation of a treatment approach combining nicotine gum with selfguided behavioral treatments for smoking relapse prevention. J Consult Clin Psychol 1990; 58: 85–92. 21. Murray RP, Bailey WC, Daniels K et al. Safety of nicotine polacrilex gum used by 3,094 participants in the Lung Health Study. Chest 1996; 109: 438–45. 22. Fagerström KO, Säwe U, Tønnesen P. Therapeutic use of nicotine patches: efficacy and safety. J Smok Relat Dis 1992; 3: 247–61. 23. Transdermal Nicotine Study Group. Transdermal nicotine for smoking cessation. JAMA 1991; 22: 3133–8. 24. Russell MAH, Stableton JA, Feyerabend C et al. Targeting heavy smokers in general practice: randomized controlled trial of transdermal nicotine patches. BMJ 1993; 306: 1308–12. 25. Imperial Cancer Research Fund General Practice Research Group. Effectiveness of a nicotine patch in helping people to stop smoking: results of a randomized trial in general practice. BMJ 1993; 306: 1304–8. 26. Tønnesen P, Nørregaard J, Mikkelsen K et al. A double-blind trial of a nicotine inhaler for smoking cessation. JAMA 1993; 269: 1268–71. 27. Schneider NG, Olmstead R, Nilsson F et al. Efficacy of a nicotine inhaler in smoking cessation: a double-blind, placebocontrolled trial. Addiction 1996; 91: 1293–306. 28. Sutherland G, Stapleton JA, Russell MAH et al. Randomised controlled trial of a nasal nicotine spray in smoking cessation. Lancet 1992; 340: 324–9. 29. Blondal T, Franzon M, Westin A et al. Controlled trial of nicotine nasal spray with long term follow-up. ARRD 1993; 147: A806. 30. Wallström M, Nilsson F, Hirch JM. A randomized, doubleblind, placebo-controlled clinical evaluation of a nicotine sublingual tablet in smoking cessation. Addiction 2000; 95: 1161–71. 31. Tønnesen P, Paoletti P, Gustavsson G et al. Higher dosage nicotine patches increase one-year smoking cessation rates: results from the European CEASE trial. Eur Respir J 1999; 13: 238–46. 32. Gonzales D, Rennard SI, Nides M et al. Varenicline, an α4, β2 nicotinic acetylcholine receptor partial agonist, vs sustainedrelease bupropionSR and placebo for smoking cessation. JAMA 2006; 296: 47–55. 33. Jorgenby DE, Hays T, Rigotti NA et al. Efficacy of varenicline, an α4, β2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropionSR for smoking cessation. JAMA 2006; 296: 56–63. 34. Tonstad S, Tønnesen P, Hajek P et al. Effect of maintenance therapy with varenicline on smoking cessation. JAMA 2006; 296: 64–71. 35. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev 2004; 4: CD000031. 36. Tønnesen P, Tonstad S, Hjalmarson A et al. A multicentre, randomised, double-blind, placebo-controlled, 1-year study of bupropionSR for smoking cessation. J Intern Med 2003; 254: 184–92. 37. Wagena EJ, Knipschild P, Zeegers MPA. Should nortriptyline be used as a first-line aid to help smokers quit? Results from a

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systematic review and meta-analysis. Addiction 2005; 100: 317–26. Glourlay SG, Stead LF, Benowitz NL. Meta-analysis of clonidine for smoking cessation. Cochrane Database Syst Rev 2004; 3: CD000058. Cox SL. Rimonabant hydrochloride: an investigational agent for the management of cardiovascular risk factors. Drugs Today (Barc) 2005; 41: 499–508. Hatsukami DK, Rennard S, Jorenby D et al. Safety and immunogenicity of a nicotine conjugate vaccine in current smokers. Clin Pharmacol Ther 2005; 78: 456–67. White AR, Rampes H, Earnst E. Acupuncture for smoking cessation. Cochrane Database Syst Rev 2002; 2: CD000009. Yiming C, Changxin Z, Ung WS et al. Laser acupunture for adolescent smokers – a randomised, double-blind controlled trial. Am J Chin Med 2000; 28: 443–9. Bolliger CT, Zellweger JP, Danielsson T et al. Smoking reduction with oral nicotine inhalers: double blind, randomised clinical trial of efficacy and safety. BMJ 2000; 321: 329–33. Wennike P, Danielsson T, Landfeldt T et al. Smoking reduction promotes smoking cessation: results from a double blind, randomized, placebo-controlled trial of nicotine gum with 2-year follow-up. Addiction 2003; 98: 1395–402. Tonnesen P, Danielsson T. Cutting down smoking then stopping with nicotine replacement therapy: an innovative approach to smoking cessation. Thorax 2005; 60 (Suppl II): ii36. Bates C, McNeill A, Jarvis M, Gray N. The future of tobacco product regulation and labelling in Europe: implications for the forthcoming European Union directive. Tob Control 1999; 8: 225–35. Kozlowski LT, O’Connor RJ, Edwards BQ, Flaherty BP. Most smokeless tobacco use is not a casual gateway to cigarettes: using order of product use to evaluate causation in a national US sample. Addiction 2003; 98: 1077–85. Henley SJ, Thun MJ, Connell C, Calle EE. Two large prospective studies of mortality among men who use snuff or chewing tobacco. Cancer Causes Control 2005; 16: 347–58. Sanderson Cox L, Sloan JA, Patten CA et al. Smoking behavior of 226 patients with diagnosis of stage IIIA/IIIB non-small cell lung cancer. Psychooncology 2002; 11: 472–8. Richardson GE, Tucker MA, Venzon DJ et al. Smoking cessation after successful treatment of small-cell lung cancer is associated with fewer smoking-related second primary cancers. Ann Intern Med 1993; 119: 383–90. Kawahara M, Ushijima S, Kamimori T et al. Second primary tumours in more than 2-year disease-free survivors of small-cell lung cancer in Japan: the role of smoking cessation. Br J Cancer 1998; 78: 409–12. Gritz ER. Facilating smoking cessation in cancer patients. Tobacco Control 2000; 9 (Suppl I): i50. Wewers ME, Jenkins L, Mignery T. A nurse-managed smoking cessation intervention during diagnostic testing in lung cancer. Oncol Nurs Forum 1997; 24: 1419–22. Solak ZA, Goksel T, Telli CG, Erdinc E. Success of a smoking cessation program among smoking relatives of patients with serious smoking-related pulmonary disorders. Eur Addict Res 2005; 11: 57–61.

52 Textbook of Lung Cancer 55. Schnoll RA, Rothman RL, Newman H et al. Characteristics of cancer patients entering a smoking cessation program and correlates of quit motivation: implications for the development of tobacco control programs for cancer patients. Psychooncology 2004; 13: 346–58. 56. Klesges RC, Winders SE, Meyers AW. How much weight gain occurs following smoking cessation? A comparison of weight

gain using both continuous and point prevalence abstainers. J Consult Clin Psychol 1997; 65: 286–91. 57. Hays JT, Hurt RD, Rigelli NA. Sustained-release bupropionSR for pharmacological relapse prevention after smoking cessation, a randomised, controlled trial. Ann Intern Med 2001; 135: 423–33.

6

Current status of lung cancer screening James L Mulshine Contents Introduction • Current evidence • Technical innovations with CT imaging • Recommendations from professional societies • Recent developments • Conclusion

INTRODUCTION Lung cancer screening is the crucible where providing an expensive new service with the potential for harm in vast numbers of variably at-risk individuals collides with the consequences of the world’s most lethal cancer. With over 160 000 annual deaths, lung cancer accounts for 30% of cancer deaths in the USA.1 Regional or distant metastatic spread is evident in at least threequarters of lung cancer cases at time of initial diagnosis resulting in a 5-year survival rate of 15%. For surgically resected cancer, the 5-year survival rate exceeds 60%. By comparison, localized breast and prostate cancer are detected at rates of 63 and 82%, so correspondingly their 5-year survival rates are much better at 87 and 98%, respectively. For women, there has been a 600% increase in the frequency in lung cancer over the last eighty years, and lung cancer death rates in United States women are the least favorable in the world.2 Unlike cardiovascular disease, the risk of developing lung cancer remains elevated after smoking cessation.3–5 Lung cancers are being diagnosed at least as frequently in the over 45 million former smokers as in current smokers,3 and smoking cessation strategies are of no utility in the growing cohort of former smokers. The progress in cardiovascular disease has not been matched in lung cancer outcomes, so this cancer has recently emerged as the dominant cause of death in tobaccoexposed individuals.6 Tobacco-related diseases are the leading cause of premature death and account for half of health-care costs in our society, so better approaches to lung cancer management are critical.7 Promising reports with high-resolution computed tomography (CT) detection have renewed interest in early lung cancer screening.4,8–11 No major lung cancer screening trial has been completed here in decades and the recent United States Preventive Services Task Force (USPSTF) analysis acknowledges the methodologic limitations of the previous chest X-ray screening trials.12–14 Lingering debate about those earlier trials has fostered

concern about CT-based lung cancer detection being not only prohibitively expensive but possibly dangerous.15–17 Against this charged back drop, it is timely to review the status of early lung cancer detection.

CURRENT EVIDENCE A number of CT screening pilot studies have been reported over the last few years (Table 6.1). While there are different eligibility criteria and case work-up approaches, these single-arm studies have been consistent for several critical parameters. Frequency of stage I detection with CT screening is about 80%, which is considerably higher than the national experience of 17%.1 This published experience is too recent to have long-term clinical outcomes except for a recently presented Japanese series. From 1975–1993, the Anti-lung Cancer Association performed 26 338 screening chest X-rays,18 and in the detected cases 42% were stage I lung cancer with an average primary size of 3 cm and 33% were stage III/IV. During 1993, this group began using CT and, by 2002, 15 342 scans had been performed. With CT screening, 78% of the detected cases were stage I with a mean diameter of 1.5 cm and the rate of detection for stage III/VI disease had decreased to 14%. With this transition, the overall 5-year survival improved from 49% with chest X-ray-detected cases to 84% with CT-detected cases. This experience is consistent with the early reports from the International-Early Lung Cancer Action Project (I-ELCAP), whose screening experience with current and former smokers was presented with prevalence evaluation of over 26 000 subjects and follow-up incidence data from 19 700 subjects.19,20 The critical endpoint of a randomized trial is significant cancer-related mortality reduction in the screened population compared to a control population. The randomized trial design addresses the potentially confounding influence of overdiagnosis. The term

54 Textbook of Lung Cancer Table 6.1 Distillation of the pilot CT screening results for non-small cell lung cancer No of subjects

Prevalence cohorts8,37,38,67,71 Incidence cohorts33,37,38,67,71

Number of CT-detected lung cancers tumors

Mean size of primary (mm)

Percent stage I cancers

13 122

112

16.5

79

9 401

54

14.8

81

‘overdiagnosis’ refers to clinical outcome events not adjusted for disease that would remain clinically covert until death from other causes. If there is considerable overdiagnosis, an apparently favorable screening result in regard to stage or 5-year survival would not lead to a significant lung cancer mortality reduction in the screened arm. With current information it is not possible to establish a reliable estimate of the magnitude of overdiagnosis, but emerging clinical and biologic information suggests that these small screen-detected lung cancers may behave like symptom-detected lung cancers.21,22 Furthermore, the term ‘overdiagnosis’ is used loosely and may be construed to include the situation where a clinically aggressive lung cancer is detected by CT screening. However, in certain situations overdiagnosis also refers to the patient who expires first of a co-morbid condition related to tobacco yeast. In the decades since the last major NCI-sponsored lung cancer screening trials, the influence of competing risks has diminished related to both improved coronary artery disease outcomes and the increasing number of former smokers perhaps mitigating the influence of overdiagnosis.6,23–25 Finally, overdiagnosis could also be construed as cases where lethal iatrogenic complications occur in the course of clinical management of screen-detected lesions.26 Overtreatment refers to the use of an intervention that may entail greater morbidity than benefit of screening that may be accrued to an individual choosing to undergo lung cancer screening. The best clinical management for small CT-detected primary cancers is emerging to be different from the standard management recommended for a chest X-raydetected lung cancer.27,28 For example, an anatomic lobectomy with mediastinal dissection is the appropriate operation to manage a chest X-ray-detected lung cancer, but is it the best way to remove a 7 mm peripheral primary lung cancer? Since even with subcentimeter screen-detected primary cancers, the frequency of regional nodal involvement remains around 10%, the

optimal size range for finding lung cancers before lymphatic dissemination must be even smaller. Nevertheless, the evidence for more favorable outcomes in managing smaller primary lung cancers is growing.29–36 From the experience in Tokyo, Rochester (MN), New York City, and Milan, it is evident that centers of excellence can deliver high-quality lung cancer screening care and measures reducing the number of invasive diagnostic procedures improve cost efficiencies.8,33,37–40 Professional groups such as the Society for Thoracic Surgery have developed national registries as a tool for improving quality outcomes in thoracic surgery (http://www.sts.org/doc/8406), and these measures may allow favorable management outcomes to become more generalized.4,41 Currently, the best approach to reducing overtreatment, and with it the morbidity and mortality of screening case management, is an area of uncertainty, but clear research opportunities exist and preliminary studies in this regard are being undertaken.42–45 An important finding at both Mayo Clinic and Cornell is that smoking cessation counseling in the setting of lung cancer screening is associated with favorable quit rates.46,47 Tobacco control has been the dominant public health response for improving lung cancer outcomes.48 Linking smoking cessation with early detection research efforts may improve the cost economy of lung cancer screening. In light of the reports suggesting spiral CT can detect small, early lung cancer, the NCI rapidly initiated the National Lung Cancer Screening Trial (NLST) to evaluate whether CT screening leads to a significant improvement in lung cancer-related mortality. This urgency was heightened by the concern that widespread ad hoc CT screening, despite being a non-reimbursed service, could preempt the opportunity for conducting a formal randomized trial. Based on favorable initial data, many people believe that lung cancer screening will be a sensitive test for early disease. While this may be true for many individuals, from a public health policy perspective it is also necessary to place emphasis on the

Current status of lung cancer screening 55

specificity of a screening test. The specificity of the screening test will affect the resultant costs to society, in terms of morbidity and dollars, in regard to overdiagnosis, overtreatment, false positives, and adverse events associated with appropriate treatment. Conventional wisdom is that these factors can only be assessed in a prospective, randomized trial with a control group and a lung cancer mortality endpoint. The NLST, which has already completed full accrual, uses multi-detector-row scanners (at least four rows) for the 25 000 volunteers on the CT arm of that trial. The control group of 25 000 receives annual chest X-ray screening. The NLST subjects will receive annual screening for three years, and follow-up will continue for a few years until a mortality endpoint is reached. The Dutch national randomized CT screening trial will use 16-detector scanners and computer-assisted-detection (CAD) tools for their entire study population and compare outcomes with a standard care control arm. Other European trials including studies in France and Italy are coming online. Investigators from the American and European trials will have periodic meetings to standardize elements of data acquisition so that comparison of results from the various trials may be more productive. While breast cancer screening trials were conducted over several decades with relative stability of the imaging detection tool,49 the dynamic pace of innovation with spiral CT and its consequences have imposed an unprecedented challenge to the randomized trial design concept.50,51 Thoughtful analysis of the relative utility of different trial designs, large databases, and other resources in permitting adaptive public health progress is a profound strategic challenge, but one that merits more serious attention.19,41

TECHNICAL INNOVATIONS WITH CT IMAGING Over the last decade, there have been substantial improvements in the speed and quality of CT imaging. Ten years ago, a typical single-detector CT scanner acquiring one centimeter thick views (slices) along the entire axial length of the thorax took several minutes and consequently the respiratory motion of chest structures seriously compromised image resolution. Since then there have been several generations of multi-detector CT scanners; the latest 64-detector-row scanners will image the entire thorax using 0.625 mm slice thicknesses in several seconds. This thinner slice thickness may allow for markedly better image resolution, but the

amount of data generated in this process is daunting. Currently, the average size of incident primary cancers detected at one center is under 1.0 cm.27,52,53 The gap between the technical capabilities of the hardware in acquiring vast amounts of imaging data and the availability of validated software to harness this improved imaging capability highlights the importance of research into CAD for early cancers. A potential benefit of higher-resolution imaging is that the evaluation may be more sensitive in finding smaller primary cancers. This size reduction may further decrease the frequency of metastatic disease as well as interval-detected cancer.27– 32 A particular problem in this regard is the reliable detection of curable small cell lung cancer cases. CAD has not had a major clinical impact on breast cancer imaging,54 but this is a two-dimensional data situation. With the anatomically more precise, three-dimensional spiral CT, this situation could be different for lung cancer. The additional information provided by the third dimension greatly improves the precision of measurement and of volume comparisons across time.55–57 If CT screening is validated to be effective, many more lung CT scans will be performed. Even with screening high-risk cohorts, the frequency of cancer in a high-risk population will typically be about 1% or less, so software to allow efficient work flow is essential to leveraging the productivity of thoracic radiologists. However, to reliably establish clinically relevant features such as the irregular boundary of small pulmonary lesions abutting normal adjacent structures, the amount of imaging information required by a CAD system may exceed the amount of imaging information that it is reasonable to expect a radiologist to review. This disconnection will be most evident when CAD is being applied to evaluate very small lesions, where human vision has limited capabilities and determining the ‘ground truth’ will be problematic. Therefore, developing and validating CAD applications for cancer screening are great challenges, but standardized image evaluation tools may prove essential in moving population-based lung cancer screening into routine care settings.54,58–60 For this reason, the NCI developed the Lung Image Database Consortium (LIDC) to accelerate the maturation of image-processing tools for CAD. The key aspect of this cooperative group is to create a large, well-characterized database of images and clinical outcomes data for CAD algorithm research and validation. This resource could expedite such projects as the utility of volumetrically determined growth rates for identifying potential cancerous pulmonary nodules53,61 or studies on the natural history of newly reported

56 Textbook of Lung Cancer

ground-glass opacities (or non-solid nodules).39,42,62 Rapid progress with CT-based imaging is expected to continue. To extract clinically significant information from such a detail-rich image, computer-assisted tools will be crucial. The further pragmatic issues encountered in the breast cancer screening efforts in regard to radiologists’ workload, reimbursement, and professional liability may also be ameliorated if validated computer-aided diagnosis methods are developed.63,64 A major concern about widespread CT screening relates to its cost, especially in light of one study which projected enormous costs from models assembled using assumptions based on early screening reports.15 More extensive use of non-invasive imaging techniques in the work-up of screen-detected lesions may explain why the cost features of some screening management approaches are less expensive.65 Only 13% of the screened cases require further follow-up, with most of those cases evaluated by serial CT imaging for nodule growth rate.52,53,61 Further potential for cost savings and morbidity reductions can be achieved by carefully

defining the risk features of the screened cohort,66 by reducing the screening intensity in following up screen-negative populations,67 as well as from further innovation with the imaging technology.

RECOMMENDATIONS FROM PROFESSIONAL SOCIETIES The American Cancer Society (ACS) updated its statement on testing for early lung cancer and recommended against testing for early lung cancer in the asymptomatic population of at-risk individuals.68 However, this revised statement recommends that individuals at high risk for lung cancer, due to significant exposure to tobacco smoke or occupational exposure, should discuss with their physician the potential benefits and harm to inform their testing decision. ACS further recommends that such testing be done only in experienced centers linked to multidisciplinary specialty groups for diagnosis and follow-up.69

Table 6.2 Points to consider for clinicians in discussing lung cancer screening and its implications with individuals considering spiral CT screening

• • • •

• • •

• • • •

The risk and benefits of lung cancer screening should be discussed, including potential morbidity, mortality, and associated medical costs No data are available from the two randomized trials evaluating for improvement in lung cancer-related mortality and results are expected in several years Results from observational studies of CT screening among high-risk patients (i.e. those with a history of heavy smoking) indicate a high rate of diagnosis of lung cancer in stage I (a relatively curable stage) The risk:benefit issues around lung cancer screening may be different for current smokers compared to former smokers. • For current smokers, smoking cessation remains the single most important measure to improve one’s overall but especially cardiovascular health prospects • For former smokers, the elevated risk of developing lung cancers persists for the rest of their lives CT screening reveals many non-calcified nodules, only a fraction of which will be found to be lung cancer The approach to diagnostic evaluation of suspicious nodules should be refined to maximize information yield from non-invasive procedures while minimizing iatrogenic risk Referral to a facility that is experienced and committed to providing high-quality integrated screening care is essential. At such a facility there would be experienced and credentialed clinicians from multidisciplinary fields (including thoracic surgeon, pathologist, pulmonologist) The surgeon selected to perform the lung cancer operation should not only be specifically trained to provide such care but should also perform lung cancer operations frequently Facilities providing lung cancer screening care should provide objective information about the quality of their outcomes There is a persistent increased risk of subsequent lung cancers after curative resection of lung cancer, so ongoing surveillance is essential Participation in research to optimize CT screening management should be strongly encouraged

Current status of lung cancer screening 57

The conclusions from the USPSTF analysis, based on a review of the literature published as of January 2003, (http://www.ahrq.gov/clinic/uspstf/uspslung.htm) are as follows: The USPSTF recommends neither for nor against using chest x-ray, computed tomography (CT scan), or sputum cytological examination to look for lung cancer in people who have no symptoms to suggest the disease. If screening is being considered, doctors and patients should discuss the pros and cons of screening before going ahead with x-ray, CT scan, or sputum cytologic examination to screen for lung cancer. Patients should be aware that there are no studies showing that screening helps people live longer. They should also know that false-positive test results are common and can lead to unnecessary worry, testing, and surgery.12 This statement represents a change from their previous recommendation against screening and this reflects the accumulation of more persuasive though not yet definitive data regarding the utility of lung cancer screening. As a reflection of the extraordinary pace of this field, a number of relevant reports have been published since the completion of the USPSTF literature review on new cohorts,18,38,39 efficiency of the diagnostic work-up,27,53,70 outcomes,72,73 and cost-effectiveness.45,65 In this dynamic setting, clinicians have a major challenge in staying abreast to provide current information to their patients. Issues to consider in discussion with a patient who may be considering lung cancer screening are complex. In light of recent reports about health literacy there is a major communications challenge in responsibly educating about lung cancer screening (see http://www.iom.edu/report.asp?id=19723 and http:// www.ahrq.gov/clinic/epcsums/litsum.htm). Since the clinical management for lung cancer screening has a higher probability of morbid and mortal complications than cancer screening for other organs, a mortality reduction benefit found by the NLST may not result in improved national outcomes with lung cancer if screening care delivery systems for early lung cancer are not in place.41 The choice is between organized screenings, where screening services are provided in centers committed to excellence in early cancer management, or ad hoc screening, where the specifics of screening care are left to be refined by market forces. We recently tried to organize a series of issues that should help physicians organize their dialog with subjects considering lung cancer screening.72

RECENT DEVELOPMENTS The New England Journal of Medicine recently published a landmark experience in using spiral CT in over 31 000 individuals at risk for lung cancers from 38 institutions across three continents.73 Over the last 15 years, the group at Cornell, together with their collaborators, has systematically explored the best approach to finding and operating on early lung cancer. In a series of peerreviewed publications they have defined innovative uses of spiral CT, image processing techniques, and internet-based clinical trial co-ordination, driving progress in the detection and management of early lung cancer. There is controversy about the benefit of CTbased screening for lung cancer, but there should be no argument about the core strategy of attempting to improve our ability to routinely find early, localized lung cancer. In community-based populations, finding early lung cancer is a daunting process since disease prevalence is relatively low. Finding economic approaches to detect and confirm the occurrence of lung cancer in this setting is a critical public health challenge. The Cornell group has described a successful approach to this and has integrated minimally invasive diagnostic and surgical techniques as feasible for early lung cancer management. In addition, they have worked with a number of the most respected thoracic pathologists in the world (mostly from IASLC) to review these cases and, in their recent publication, reported that the cases found by CT screening fulfill standard criteria for fully fledged aggressive lung cancers.74 This supports recent tumor biology information suggesting that these screen-detected tumors behave like routinely detected lung cancers.22 Of the more than 400 cancers recently reported in the Cornell study, 85% of the detected cases were stage I. The 10-year survival analysis, after three years of median follow-up, shows that over 90% of the people undergoing operations were projected to be alive and lung cancer free. All eight individuals who for personal reasons declined surgery died of lung cancer. A key enabler of this large study consortium was the use of a web-based early lung cancer management system developed by the Cornell group which allowed research to go on in the setting of clinical care. The current I-ELCAP results convincingly demonstrate that systematic efforts to find early lung cancer can be associated with very favorable outcomes and their organizational process accelerates early lung cancer research. A challenging debate is proceeding about the sufficiency

58 Textbook of Lung Cancer

of the I-ELCAP data to change national health-care policy on lung cancer screening. This is a profoundly important scientific, medical, and political process. However, the IASLC could play a pivotal role in generating the research data to inform the process. There are many steps in moving to responsible management of early lung cancer and we need better information about all of them. How do we identify the optimal cohort, how do we do the diagnostic work-up, how do we do the most appropriate removal of the primary cancer, how frequently do we do follow-up CT scans to find synchronous primaries, etc. These and many more issues need to be addressed with research using stateof-the-art imaging tools. Since the progress in improving imaging tools is moving so fast, it is a major challenge for our research processes. This is a part of the discussion about early detection research that merits much more serious and urgent research attention. The contentious discussion surrounding screening trial design has distracted us from a profound emerging opportunity to much more successfully manage lung cancer.

CONCLUSION CT screening for lung cancer detection has considerable promise. Yet many individuals seeking lung cancer screening services, such as the lower-risk subject outlined in the introductory vignette, may have a greater chance of iatrogenic harm that screening benefit. While definitive trials are in progress, the opportunity should not be lost to conduct further essential research to generalize a potential mortality reduction benefit evident in a lung cancer screening trial to routine care settings. REFERENCES 1. Jemal A, Tiwari RC, Murray T et al. Cancer statistics, 2004. CA Cancer J Clin 2004; 54: 8–29. 2. Patel JD, Bach PB, Kris MG. Lung cancer in US women: a contemporary epidemic. JAMA 2004; 291: 1763–8. 3. Tong L, Spitz MR, Fueger JJ, Amos CA. Lung carcinoma in former smokers. Cancer 1996; 78: 1004–10. 4. Warner EE, Mulshine JL. System engineering lung cancer screening with spiral CT: how could it work? Oncology 2004; 18: 564–75. 5. Enstrom JE, Heath CW Jr. Smoking cessation and mortality trends among 118 000 Californians, 1960–1997. Epidemiology 1999; 10: 500–12. 6. CDC. Annual smoking-attributable mortality, years of potential life lost and economic cost – United States 1995–1999. MMWR 2002; 51: 300–3.

7. Leaf C. Why we’re losing the war on cancer and how to win it. Fortune 2004; 149: 76–96. 8. Henschke CI, McCauley DI, Yankelevitz DF et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999; 354: 99–105. 9. Henschke CI, Yankelevitz DF, McCauley DI et al. Guidelines for the use of spiral computed tomography in screening for lung cancer. Eur Respir J Suppl 2003; 39: 45s–51s. 10. Kaneko M, Kusumoto M, Kobayashi T et al. Computed tomography screening for lung carcinoma in Japan. Cancer 2000; 89: 2485–8. 11. Mulshine J. Screening for lung cancer: in pursuit of pre-metastatic disease. Nature Rev Cancer 2003; 3: 65–73. 12. Humphrey LL, Teutsch S, Johnson M. Lung cancer screening with sputum cytological examination, chest radiography and computer tomography: an update for the U.S. Preventive Task Force. Ann Intern Med 2004; 140: 740–53. 13. Strauss G, Dominioni L. Varese meeting report. Lung Cancer 1999; 23: 171–2. 14. Fontana RS, Sanderson DR, Woolner LB et al. Screening for lung cancer. A critique of the Mayo Lung Project. Cancer 1991; 67: 1155–64. 15. Mahadevia PJ, Fleisher LA, Frick KD et al. Lung cancer screening with helical computed tomography in older adult smokers: a decision and cost-effectiveness analysis. JAMA 2003; 289: 313–22. 16. Swensen SJ, Jett JR, Midthun DE, Hartman TE. Computer tomographic screening for lung cancer: home run or foul ball? Mayo Clin Proc 2003; 78: 1187–8. 17. Brenner DJ. Radiation risks potentially associated with lowdose CT screening of adult smokers for lung cancer. Radiology 2004; 231: 440–5. 18. Kakinuma R. Low-dose helical CT screening for lung cancer: the Japanese experience and perspective. Proc IASLC Workshop 2003: 18. 19. Henschke CI, Yankelevitz D. Lung cancer screening with spiral CT: how can it work: reviewed. Oncology 2004; 18: 584–7. 20. Wisnivesky JP, Mushlin AI, Sicherman N et al. The cost-effectiveness of low-dose CT screening for lung cancer: preliminary results of baseline screening. Chest 2003; 124: 614–21. 21. Bianchi F, Hu J, Pelosi G et al. Screening spiral CT-detected lung cancers have a malignant phenotype by cDNA microarray analysis. Clin Cancer Res 2004; 10: 6023–8. 22. Mulshine JL, Weinstein JN. Is the gene expression pattern different in lung cancer detected by screening spiral CT rather due to symptoms? Clin Cancer Res 2004; 10: 5973–4. 23. CDC. Cigarette smoking among adults – United States 2000. MMWR 2002; 51: 642–5. 24. Lenfant C. Shattuck lecture – clinical research to clinical practice – lost in translation? N Engl J Med 2003; 349: 868–74. 25. Ambrogi V, Pompeo E, Elia S et al. The impact of cardiovascular comorbidity on the outcome of surgery for stage I and II non-small-cell lung cancer. Eur J Cardio-Thorac Surg 2003; 23: 811–17. 26. Warner EE, Mulshine JL. Surgical considerations with lung cancer screening. J Surg Oncol 2003; 84: 1–6. 27. Henschke CI, Yankelevitz DF, Naidich DP et al. CT Screening for lung cancer: suspiciousness of nodules according to size on baseline scans. Radiology 2004; 231: 164–8.

Current status of lung cancer screening 59 28. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995; 60: 615–22; discussion 622–3. 29. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111: 1710–17. 30. Mountain CF. Staging classification of lung cancer. A critical evaluation. Clin Chest Med 2002; 23: 103–21. 31. Martini N, Bains MS, Burt ME et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 1995; 109: 120–9. 32. Martini N, Rusch VW, Bains MS et al. Factors influencing tenyear survival in resected stages I to IIIa non-small cell lung cancer. J Thorac Cardiovasc Surg 1999; 117: 32–6; discussion 37–8. 33. Henschke CI, Naidich DP, Yankelevitz DF et al. Early lung cancer action project: initial findings on repeat screenings. Cancer 2001; 92: 153–9. 34. Gajra A, Newman N, Gamble GP et al. Impact of tumor size on survival in stage IA non-small cell lung cancer: a case for subdividing stage IA disease. Lung Cancer 2003; 42: 51–7. 35. Fang D, Zhang D, Huang G et al. Results of surgical resection of patients with primary lung cancer: a retrospective analysis of 1,905 cases. Ann Thorac Surg 2001; 72: 1155–9. 36. Konaka C, Ikeda N, Hiyoshi T et al. Peripheral non-small cell lung cancers 2.0 cm or less in diameter: proposed criteria for limited pulmonary resection based upon clinicopathological presentation. Lung Cancer 1998; 21: 185–91. 37. Swensen SJ, Jett JR, Hartman TE et al. Lung cancer screening with CT: Mayo Clinic experience. Radiology 2003; 226: 756–1. 38. Pastorino U, Bellomi M, Landoni C et al. Early lung-cancer detection with spiral CT and positron emission tomography in heavy smokers: 2-year results. Lancet 2003; 362: 593–7. 39. Kakinuma R, Ohmatsu H, Kaneko M et al. Progression of focal pure ground-glass opacity detected by low-dose helical computed tomography screening for lung cancer. J Comput Assist Tomogr 2004; 28: 17–23. 40. Geraghty PR, Kee ST, McFarlane G et al. CT-guided transthoracic needle aspiration biopsy of pulmonary nodules: needle size and pneumothorax rate. Radiology 2003; 229: 475–81. 41. Smith RA. Lung cancer screening with spiral CT: how can it work, reviewed. Oncology 2004; 18: 578–3. 42. Asamura H, Suzuki K, Watanabe S et al. A clinicopathological study of resected subcentimeter lung cancers: a favorable prognosis for ground glass opacity lesions. Ann Thorac Surg 2003; 76: 1016–22. 43. Okada M, Yoshikawa K, Hatta T, Tsubota N. Is segmentectomy with lymph node assessment an alternative to lobectomy for non-small cell lung cancer of 2 cm or smaller? Ann Thorac Surg 2001; 71: 956–60; discussion 961. 44. Sugarbaker DJ, Strauss GM. Extent of surgery and survival in early lung carcinoma: implications for overdiagnosis in stage IA nonsmall cell lung carcinoma. Cancer 2000; 89: 2432–7. 45. Tsushima Y, Endo K. Analysis models to assess cost effectiveness of the four strategies for the work-up of solitary pulmonary nodules. Med Sci Monit 2004; 10: MT65–72. 46. Ostroff JS, Buckshee N, Mancuso CA et al. Smoking cessation following CT screening for early detection of lung cancer. Prev Med 2001; 33: 613–21.

47. Cox LS, Clark MM, Jett JR et al. Change in smoking status after spiral chest computed tomography scan screening. Cancer 2003; 98: 2495–501. 48. Peto R, Chen ZM, Boreham J. Tobacco – the growing epidemic. Nat Med 1999; 5: 15–17. 49. Shapiro S. Screening: assessment of current studies. Cancer 1994; 74: 231–8. 50. Sackett DL, Wennberg JE. Choosing the best research design for each question. BMJ 1997; 315: 1636. 51. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000; 342: 1887–92. 52. Kostis WJ, Reeves AP, Yankelevitz DF, Henschke CI. Threedimensional segmentation and growth-rate estimation of small pulmonary nodules in helical CT images. IEEE Trans Med Imaging 2003; 22: 1259–74. 53. Kostis WJ, Yankelevitz DF, Reeves AP et al. Small pulmonary nodules: reproducibility of three-dimensional volumetric measurement and estimation of time to follow-up CT. Radiology 2004; 231: 446–52. 54. Gur D, Sumkin JH, Rockette HE et al. Changes in breast cancer detection and mammography recall rates after the introduction of a computer-aided detection system. J Natl Cancer Inst 2004; 96: 185–90. 55. Ambrose J, Hounsfield G. Computerized transverse axial tomography. Br J Radiol 1973; 46: 148–9. 56. Wormanns D, Fiebich M, Saidi M et al. Automatic detection of pulmonary nodules at spiral CT: clinical application of a computer-aided diagnosis system. Eur Radiol 2002; 12: 1052–7. 57. Reeves AP, Kostis WJ. Computer-aided diagnosis for lung cancer. Radiol Clin North Am 2000; 38: 497–509. 58. Beam CA, Layde PM, Sullivan DC. Variability in the interpretation of screening mammograms by US radiologists. Findings from a national sample. Arch Intern Med 1996; 156: 209–13. 59. Elmore JG, Carney PA. Computer-aided detection of breast cancer: has promise outstripped performance? J Natl Cancer Inst 2004; 96: 162–3. 60. Bassett LW, Monsees BS, Smith RA et al. Survey of radiology residents: breast imaging training and attitudes. Radiology 2003; 227: 862–9. 61. Yankelevitz DF, Reeves AP, Kostis WJ et al. Small pulmonary nodules: volumetrically determined growth rates based on CT evaluation. Radiology 2000; 217: 251–6. 62. Henschke CI, Yankelevitz DF, Mirtcheva R et al. CT screening for lung cancer: frequency and significance of part-solid and nonsolid nodules. Am J Roentgenol 2002; 178: 1053–7. 63. Enzmann DR, Anglada PM, Haviley C, Venta LA. Providing professional mammography services: financial analysis. Radiology 2001; 219: 467–73. 64. Kopans DB. Mammography screening is saving thousands of lives, but will it survive medical malpractice? Radiology 2004; 230: 20–4. 65. Wisnivesky JP, Mushlin AI, Sicherman N, Henschke C. The cost-effectiveness of low-dose CT screening for lung cancer: preliminary results of baseline screening. Chest 2003; 124: 614–21. 66. van Klaveren RJ, de Koning HJ, Mulshine J, Hirsch FR. Lung cancer screening by spiral CT. What is the optimal target population for screening trials? Lung Cancer 2002; 38: 243–52.

60 Textbook of Lung Cancer 67. Nawa T, Nakagawa T, Kusano S et al. Lung Cancer Screening Using Low-Dose Spiral CT: results of baseline and 1-year follow-up studies. Chest 2002; 122: 15–20. 68. Smith RA, Cokkinides V, Eyre HJ. American Cancer Society Guidelines for the Early Detection of Cancer, 2003. CA Cancer J Clin 2003; 53: 27–43. 69. Smith RA, Cokkinides V, Eyre HJ. American Cancer Society Guidelines for the Early Detection of Cancer, 2004. CA Cancer J Clin 2004; 54: 41–52. 70. Libby DM, Smith JP, Altorki NK et al. Managing the small pulmonary nodule discovered by CT. Chest 2004; 125: 1522–9.

71. Sobue T, Moriyama N, Kaneko M et al. Screening for lung cancer with low-dose helical computed tomography: anti-lung cancer association project. J Clin Oncol 2002; 20: 911–20. 72. Mulshine JL, Sullivan DC. Clinical practice. Lung cancer screening. N Engl J Med 2005; 352: 2714–20. 73. International–Early Lung Cancer Action Program Investigators. Survival of patients with Stage I lung cancer detected on CT screening. N Engl J Med 2006; 355: 1763–71. 74. Flieder DB, Vazque M, Carter D. Pathological findings of lung tumors diagnosed on baseline CT screening. Am J Surg Pathol 2006; 30: 606–13.

7

Histopathology of lung tumors Elisabeth Brambilla, Sylvie Lantuejoul Contents Introduction • Squamous cell carcinoma • Adenocarcinoma • Small cell carcinoma • Large cell carcinoma • Adenosquamous carcinoma • Sarcomatoid carcinoma • Typical and atypical carcinoid • Conclusions

INTRODUCTION With 169 500 new cases per year in the United States and 182 000 new cases per year in Europe, lung cancer is the most common worldwide diagnosed cancer and the major cause of mortality,1 with157 400 cancer deaths2 in the USA and 190 000 cancer deaths in the European Union in 2001. Although cancer incidence began to decline in men in the USA from 1980,3 its rate is increasing in women,2 as a consequence of the increasing proportion of women who smoke. The international standard for histologic classification of lung tumors is that proposed by the World Health Organization (WHO) and the International Association for the Study of Lung Cancer (IASLC; Table 7.1).4 The four major histologic types of lung cancer are squamous cell carcinoma, adenocarcinoma, the incidence of which is increasing at the expense of squamous cell carcinoma, small cell carcinoma (SCLC), and large cell carcinoma. These major types have been subclassified into subtypes, the clinical significance of which might be extremely important, such as the bronchioloalveolar carcinoma (BAC) as a variant of adenocarcinoma.4 Although lung cancer can be divided into many subtypes, the most important distinction is between SCLC and non-small cell lung carcinoma (NSCLC). Clinical importance has been given to this distinction because of the major clinical differences in presentation, metastatic spread, and response to therapy of SCLC. However, this is an extremely simplistic means of distinction between these subtypes which is not recommended because it may override the clinical significance of specific subtypes like BAC. Histologic heterogeneity is an important feature of the pathology of lung cancer, which consists of a mixture of histologic types that represent a derivation of lung cancer from a pluripotent stem cell.5–10 This histologic heterogeneity is apparent on light microscopic examination in at least 30% of

lung cancers, and is even more frequently seen by electron microscopy.

SQUAMOUS CELL CARCINOMA A malignant epithelial tumor showing keratinization and/or intercellular bridges that arises from bronchial epithelium.11 Squamous cell carcinoma (SCC) accounts for approximately 30% of all lung cancers in the United States12 and 45% in Europe. Twenty years ago it was the most frequent histologic type of lung cancer in Europe, and it has progressively decreased, while adenocarcinoma has increased in incidence. Over 90% of SCC occurs in cigarette smokers. Two-thirds of SCCs present as central tumors, whereas one-third present as peripheral tumors, although the primary bronchial site may be easily detected at histology.13,14 The morphologic features that characterize squamous differentiation include intercellular bridging and keratinization (or individual cell keratinization or squamous pearl formation). These differentiated features are readily apparent in well-differentiated tumors, and are difficult to detect in poorly differentiated ones.15 However, this spectrum of differentiation has not been demonstrated to correlate with prognosis in lung SCC. Segmental bronchi more often than lobar and mainstem bronchi are the primary site of SCC.16 Variants described in the WHO classification include papillary, clear cell, small cell,17 and basaloid subtypes.4 This last variant has a dismal prognosis as compared to poorly differentiated SCC.18,19 In a recent evaluation of a large series of cases where basaloid carcinoma appeared to have a shorter survival than other types of NSCLC (p = 0.005) the basaloid variant of SCC did not differ from pure basaloid cases with regard to survival.20 Papillary SCC often shows a pattern of exophytic endobronchial growth.21,22

62 Textbook of Lung Cancer Table 7.1 WHO histologic classification of tumors of the lung

Table 7.1 Continued

Malignant epithelial tumors Squamous cell carcinoma Papillary Clear cell Small cell Basaloid

8070/3 8052/3 8084/3 8073/3 8083/3

Small cell carcinoma Combined small cell carcinoma

8041/3 8045/3

Adenocarcinoma Adenocarcinoma, mixed subtype Acinar adenocarcinoma Papillary adenocarcinoma Bronchioloalveolar carcinoma Non-mucinous Mucinous Mixed non-mucinous and mucinous or indeterminate Solid adenocarcinoma with mucin production Fetal adenocarcinoma Mucinous (‘colloid’) carcinoma Mucinous cystadenocarcinoma Signet ring adenocarcinoma Clear cell adenocarcinoma

8140/3 8255/3 8550/3 8260/3 8250/3 8252/3 8253/3 8254/3

Large cell carcinoma Large cell neuroendocrine carcinoma Combined large cell neuroendocrine carcinoma Basaloid carcinoma Lymphoepithelioma-like carcinoma Clear cell carcinoma Large cell carcinoma with rhabdoid phenotype

8012/3 8013/3 8013/3

Adenosquamous carcinoma

8560/3

Sarcomatoid carcinoma Pleomorphic carcinoma Spindle cell carcinoma Giant cell carcinoma Carcinosarcoma Pulmonary blastoma

8033/3 8022/3 8032/3 8031/3 8980/3 8972/3

Carcinoid tumor Typical carcinoid Atypical carcinoid

8240/3 8240/3 8249/3

8230/3 8333/3 8480/3 8470/3 8490/3 8310/3

8123/3 8082/3 8310/3 8014/3

(Continued)

Salivary gland tumors Mucoepidermoid carcinoma Adenoid cystic carcinoma Epithelial-myoepithelial carcinoma Preinvasive lesions Squamous carcinoma in situ Atypical adenomatous hyperplasia Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia Mesenchymal tumors Epithelioid hemangioendothelioma Angiosarcoma Pleuropulmonary blastoma Chondroma Congenial peribronchial myofibroblastic tumor Diffuse pulmonary lymphangiomatosis Inflammatory myofibroblastic tumor Lymphangioleiomyomatosis Synovial sarcoma Monophasic Biphasic Pulmonary artery sarcoma Pulmonary vein sarcoma Benign epithelial tumors Papillomas Squamous cell papilloma Exophytic Inverted Glandular papilloma Mixed squamous cell and glandular papilloma Adenomas Alveolar adenoma Papillary adenoma Adenomas of the salivary gland type Ta Mucous gland adenoma Pleomorphic adenoma Others Mucinous cystadenoma Lymphoproliferative tumors Marginal zone B-cell lymphoma of the MALT type Diffuse large B-cell lymphoma

8430/3 8200/3 8562/3 8070/2

9133/1 9120/3 8973/3 9220/0 8827/1

8825/1 9174/1 9040/3 9041/3 9043/3 8800/3 8800/3

8052/0 8052/0 8053/0 8260/0 8560/0

8251/0 8260/0 8140/0 8940/0 8470/0 9699/3 9680/3 (Continued)

Histopathology of lung tumors 63

Table 7.1 Continued

Lymphomatoid granulomatosis Langerhans cell histiocytosis Miscellaneous tumors Harmatoma Sclerosing hemangioma Clear cell tumor Germ cell tumors Teratoma, mature Immature Other germ cell tumors Intrapulmonary thymoma Melanoma Metastatic tumors

9766/1 9751/1

8832/0 8005/0 9080/0 9080/3 8580/1 8720/3

From WHO Classification of Tumors, 2004. Behavior is coded /0 for benign tumors, /3 for malignant tumors, and /1 for borderline or uncertain behavior.

ADENOCARCINOMA A malignant epithelial tumor with glandular differentiation or mucin production, showing acinar, papillary, bronchioloalveolar, or solid with mucin growth patterns, or a mixture of these patterns. Adenocarcinoma can be classified into: • • • •

• • • • •

adenocarcinoma mixed subtype; acinar adenocarcinoma; papillary adenocarcinoma; bronchioloalveolar carcinoma; – non-mucinous – mucinous – mixed non-mucinous and mucinous – solid adenocarcinoma with mucin production. Variants are: fetal adenocarcinoma; mucinous (‘colloid’) carcinoma; mucinous cystadenocarcinoma; signet ring adenocarcinoma; clear cell adenocarcinoma.

Adenocarcinomas account for about 30% of lung cancers in Europe and the USA.12 Most primary pulmonary adenocarcinomas, in contrast with metastases, are highly heterogeneous and consist of a mixture of histologic subtypes. Most adenocarcinomas are histologically heterogeneous, consisting of two or more of the histologic subtypes and whilst a majority of the lung adenocarcinomas diagnosed are classified today into

the mixed subtype. For this reason the adenocarcinoma mixed subtype was moved to the top of the list of adenocarcinoma subtypes in the 2004 WHO classification, although it was not recognized in the 1981 WHO classification.23 The acinar and papillary subtypes are recognized by their architectural pattern of tumor cell growth and invasion. A substantially different definition has been given to bronchioloalveolar carcinoma (BAC subtype), which should be restricted to tumors that grow in a purely lepidic fashion without invasion of stroma, blood vessels, or pleura. The solid type is a poorly differentiated carcinoma presenting intracytoplasmic mucins that should be of at least five mucin droplets in two different high-power fields. Mucin stains recommended are PAS (periodic acid–Schiff) with diastase digestion and Kreyberg staining with alcian blue. Several additional unusual variants have also been recognized, such as well-differentiated fetal adenocarcinoma,24 mucinous (‘colloid’) adenocarcinoma,25 mucinous cystadenocarcinoma,26–28 signet ring carcinoma,29 and clear cell adenocarcinoma.4 Two unusual gross patterns of adenocarcinoma include the endobronchial polypoid adenocarcinoma30 and pseudomesotheliomatous adenocarcinoma.31–33 Bronchioloalveolar carcinoma is uncommon, and probably restricted to fewer than 5% of all lung malignancies.12 In the new 1999 WHO/IASLC classification, BAC is defined as a tumor showing lepidic growth along pre-existing alveolar septa with intact elastic and basal lamina frames, without invasive growth. It should be noticed that some increased fibrotic collagen deposit of alveolar walls is accepted, as long as no myofibroblastic proliferation is visible. The lack of invasive growth is added as an essential criterion4 based on clinico-pathologic data indicating that in patients with less than a 2 cm tumor, BAC may be curable by economic surgical resection.34 As a result of the narrow criteria for BAC, the term ‘adenocarcinoma, mixed subtype’ is used for tumors that have BAC and an invasive component. In such cases the invasive patterns present (acinar, papillary, or solid) should be mentioned. It is common to observe central scars in pulmonary adenocarcinoma that contain invasive components and a focal BAC-like pattern at the periphery of the tumor. As a consequence of this revised definition of BAC, the literature dealing with these tumors need complete re-evaluation. Indeed, previous to the last classification, BAC included tumors with obvious invasive growth.23,35,36 More than 50% of tumors previously classified as BACs presented focal central desmoplastic scarring tissue or

64 Textbook of Lung Cancer

intra-alveolar complex papillary growth while the lepidic growth started around the edge of the scar.37 For tumors showing malignant tumor cell nests in a desmoplastic stromal reaction, the diagnosis is adenocarcinoma mixed subtype and the various subtypes present should be mentioned (such as acinar, papillary, or BAC). These are no longer considered as pure BAC.13,37 In addition, filling of alveolar lumens by papillary or micropapillary structures is considered to be papillary adenocarcinoma, but not bronchioloalveolar carcinoma. BAC has two major cytologic subtypes, non-mucinous and mucinous,4 and are rarely mixed, consisting of an association of mucinous and non-mucinous cells.4 The majority of BACs are mucin-producing, followed by the non-mucinous type, while about 12% are a mixture of both.37,38 Non-mucinous BACs consist of Clara cells and type II pneumocytes; the latter cell type is a common stem cell for distal bronchioles and alveoli identified in fetal lung and is nowadays considered as the lung adenocarcinoma stem cell.39 The non-mucinous BACs are more likely to be solitary38 than the mucinous type. These tumors are composed of cuboidal cells proliferating along alveolar septa and showing a hobnail appearance. Specific nuclear inclusions are patent in half of the nonmucinous tumor cells that are stained with diastasedigested PAS and immunohistochemically for surfactant apoprotein. On electron microscopy, these inclusions form a network of 40-nm diameter microtubules.40,41 The mucin-producing BACs tend to be more multicentric and characteristically have mucin production.38 They may cause lobar consolidation resembling pneumonia on gross examination. Histologically, these tumors consist of tall columnar cells with abundant apical cytoplasmic mucin and small, basally oriented, regular bland nuclei lining thin alveolar septa. Alveolar and bronchiolar spaces are filled with abundant mucin. According to the 1999 WHO/IASLC classification, a final diagnosis of BAC can only be achieved on examination of a surgical resection specimen. Small biopsies obtained by bronchoscopy or fine needle sampling may show a lepidic growth pattern suggesting the possibility of BAC, but are not sufficient to exclude the presence of an invasive growth. Pathoradiologic correlations There are several growth presentations for the most common adenocarcinoma mixed subtype with BAC: • •

a solitary nodule; multiple nodules;

• •

lobar consolidation; diffuse (pseudopneumonic) consolidation pattern.

The typical radiologic appearance of BAC (pure BAC or BAC component) is the ground glass pattern by CT and an ill-defined, aerated, spongy density on gross examination. In contrast, a grossly circumscribed nodule at growth examination and a pure solid appearance on CT is typical of purely invasive adenocarcinoma (acinar, papillary, solid). In between, a mixture of these growths and CT appearances is seen in mixed subtype adenocarcinoma with both invasive (often centrally located) components and BAC component (often peripheral). When BAC and other adenocarcinomas present with multiple nodules they can be unilateral or bilateral. Unilateral nodules are classified as T4 by the TNM classification and multiple nodules in another lobe are classified as M1. Lobar consolidation and diffuse pseudopneumonic condensation patterns are difficult to distinguish grossly or radiologically from infective pneumonia. All cases of adenocarcinoma presenting with a diffuse or pseudopneumonic consolidation pattern have been shown to correspond to mixed subtype adenocarcinoma with BAC component. They are more frequently of the mucinous cell type, with varying amounts of acinar, papillary, and solid components. Prognostic correlations with solitary small peripheral lung nodules Several important clinico-pathologic studies have shown the clinical significance of BAC.34,42,43 Noguchi et al34 reported that, in a large series of 236 peripheral lung adenocarcinomas less than 2 cm in size, the patients achieved 100% 5-year survival. These were pure BACs, in contrast to patients with ‘invasive BAC’ who experienced higher mortality and a 5-year survival of 75%, while the purely invasive form had a 5-year survival of 52%. Suzuki et al42 demonstrated that the size of the fibrotic scar was correlated with survival in a series of 100 peripheral adenocarcinomas less that 3 cm in size: a 5-year survival of 100% was recorded for patients with a scar size of 5 mm or less, in contrast to 70% for patients with scars 5 to 15 mm in size and 40% for patients with a central scar greater than 15 mm. In this study, the size of central fibrosis was an independent prognostic factor on multivariate analysis (p = 0.01), as significant as vascular invasion (p = 0.024) and lymph node metastasis (p = 0.024). Yokose et al43 studied multiple pathologic factors for prognostic assessment in 200 patients: 100% 5-year

Histopathology of lung tumors 65

survival was associated with at least one of the following features: • • •

a pattern of lepidic growth of more than 75%; a central scar measuring 5 mm or less; lack of destruction of the elastic fiber framework by tumor cells.43

The most significant determinants of shorter survival in the multivariate analysis were vascular invasion (p < 0.001) and more than 25% papillary or invasive growth (p = 0.043). Size and grade/pattern of stromal invasion44,45 also influence survival. This has practical consequences: all small (≤3 cm) tumors with a predominant BAC component should be entirely sampled serially, and included so that potential foci of invasion are detected. BAC is not a unique feature for lung adenocarcinoma since about 15% of digestive mucinous carcinoma metastases might mimic the histologic appearance of BAC. Thyroid transcription factor-1 (TTF-1) immunostaining restricted to primary lung adenocarcinoma is of great help in this distinction.

SMALL CELL CARCINOMA A malignant epithelial tumor consisting of small cells with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli. The cells are round, oval, and spindle-shaped. SCLC accounts for 25% of all lung cancers in the USA as well as in Europe.12 Two-thirds of SCLCs are proximal and present as a perihilar tumor. They occur in a bronchial location, infiltrating the bronchial submucosa and subsequently leading to bronchial obstruction by circumferential compression. SCLCs are not commonly observed on a surgical specimen since extensive lymph node metastasis is common and the tumor is not surgically curable. Macroscopically the tumor is soft, friable, white-tan, and extensively necrotic. Extensive lymph node metastasis is very frequent and less than 5% of cases present as a solitary coin lesion.46,47 The 1999 WHO/IASLC classification presents only two types of SCLC: SCLC (with pure SCLC histology) and combined SCLC (combined with any non-small cell type) (see Table 7.1).4 The two subtypes oat cell carcinoma and intermediate cell type, that were proposed in the 1981 WHO classification, as well as the category of mixed small cell, large cell, proposed in 1988 by the IASLC, were discarded from the new classification

because of difficulties in reproducibility of these subtypes and lack of confirmation that these patients have a different prognosis.48,49 SCLC has a distinctive histologic appearance. The tumor cells have a small size, not exceeding that of three lymphocytes. They have a round or fusiform shape, scant cytoplasm with a nuclear to cytoplasmic ratio of 9 to 10, a finely granular nuclear chromatin (‘salt and pepper’ appearance), and absent or inconspicuous nucleoli.4 Owing to the scarcity of cytoplasm, nuclear molding and smearing of nuclear chromatin is frequent, caused by crush artifacts. There is usually extensive necrosis and a mitotic rate exceeding 20 and reaching 100 mitoses per 2 mm2 area. Most often, the growth pattern consists of diffuse sheets, although endocrine differentiations with rosettes, palisading, ribbons, and organoid nesting might be seen.50 Basophilic encrustation of vessel walls is known as the Azzopardi effect in necrotic areas.50 Depending on the biopsy specimens, the tumor cell size of SCLC might appear larger, which is often the case in well-fixed open biopsies. Fine needle aspiration (FNA) biopsy and core biopsy may provide excellent material for assessment of the diagnosis of SCLC, essentially because cytologic features of SCLC have a high diagnostic value and the architecture is not critical for the diagnosis. The small cell proliferation, with nuclear moulding, the very high nuclear to cytoplasmic ratio, and the ‘salt and pepper’ quality of chromatin are extremely useful for this diagnosis on FNA. The diagnostic markers (NE markers, TTF-1, absence of CK34βE12 expression) are of primary help in the diagnosis of SCLC. There is an excellent yield of these markers on FNA and/or biopsy. Combined small cell lung cancer The frequency of combined SCLC depends on the extent of histologic sampling, and the extent of the associated component. Combined SCLC represents about 10%49 of SCLC if small biopsies are considered. However, in a recent study on surgically treated SCLC, using a conservative estimate of 10% of tumors showing associated NSCLC for subclassifying a tumor as a combined variant of SCLC, 28% of the cases of SCLC showed a combination with NSCLC, more commonly with large cell lung carcinoma followed by adenocarcinoma and squamous cell carcinoma.48,49,51–53 SCLC can also be associated, although rarely, with spindle cell carcinoma,54,55 giant cell carcinoma,54 and carcinosarcoma.56 Immunohistochemistry might help to differentiate associated components, such as cytokeratin antibody

66 Textbook of Lung Cancer

cocktails, which tend to stain NSCLC components, a good example of which is cytokeratin 1, 5, 10, 14 recognized by 34βE12.57 However, evidence is lacking that pure and combined SCLC behaves differently with regard to prognosis and response to therapy.51 Following chemotherapy, a mixture of large cells, squamous cells, adenocarcinoma or giant cells with SCLC may be seen in 15 to 45% of the cases.52,58–60 Differential diagnosis Because SCLC has distinctive clinical properties with an aggressive clinical course, frequent widespread metastasis of presentation, common paraneoplastic syndrome, and responsiveness to chemotherapy, histologic classification of lung cancer often is simplified into SCLC versus NSCLC. A constellation of criteria is applied for the distinction between SCLC and large cell neuroendocrine carcinoma (LCNEC) including cell size, nucleoli, nuclear-to-cytoplasmic ratio, nuclear chromatin pattern, nuclear molding, cell shape (fusiform versus polygonal), and Azzopardi phenomenon (Table 7.2).4,23,61,62 Disagreement among expert lung cancer pathologists over this distinction occurs in up to 10% of cases,10,63 owing to the fact that sometimes LCNEC may adopt the nuclear features of SCLC. With the new description of LCNEC, the main differential resides in the distinction

of SCLC from LCNEC (Table 7.2). Crush artifact is common in small biopsy specimens owing to scarcity of stromal protection; this can also be seen in carcinoid tumors, lymphocytic infiltrates, or poorly differentiated NSCLC. In these cases, cytology specimens might be helpful because the morphology may be more diagnostic than on a small biopsy specimen. Immunohistochemistry for neuroendocrine differentiation, keratins, and common leukocyte antigen (lymphoid marker) can be useful in marking SCLC versus lymphoid cells, respectively.64 TTF-1 has been shown to be of great help in distinguishing between SCLCs, which are 85% positive for TTF-1 nuclear staining, and other proliferating small cells such as the small cell variant of squamous cell carcinoma and basaloid carcinoma, both of which are always TTF-1 negative.57,65 The most useful and specific neuroendocrine markers for distinction of SCLC in formalin-fixed, paraffin-embedded tissue sections are chromogranin A, synaptophysin, and neural cell adhesion molecule, especially the 123C3 clone and CD56.61,66–70 Keratin (AE1/AE3) and epithelial membrane antigen (EMA) as well as TTF-1 stain virtually all SCLCs in open lung biopsy and transbronchial biopsy specimens.57,61,65,66 In contrast, a specific set of cytokeratins never expressed in neuroendocrine proliferations (CK 1, 5, 10, 14) called 34βE12 is always absent in pure SCLC. In the cases where common cytokeratins

Table 7.2 Light microscopic features for distinguishing small cell carcinoma and large cell neuroendocrine carcinomaa Histologic feature

Small cell carcinoma

Large cell neuroendocrine carcinoma

Cell size

Larger

Nuclear/cytoplasmic ratio Nuclear chromatin

Smaller (less than diameter of 3 lymphocytes) Higher Finely granular, uniform

Nucleoli

Absent or faint

Nuclear molding Fusiform shape Polygonal shape with ample pink cytoplasm Nuclear smear Basophilic staining of vessels and stroma

Characteristic Common Uncharacteristic

Lower Coarsely granular or vesicular, less uniform Often (not always) present, may be prominent or faint Less prominent Uncommon Characteristic

Frequent Occasional

Uncommon Rare

a

From Travis WD, Linnoila RI, Tsokos MG, et al.61 Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 15: 529–533, 1991; with permission.

Histopathology of lung tumors 67

Table 7.3 Histochemical differential diagnosis between small cell lung carcinoma (SCLC), basaloid carcinoma, and large cell neuroendocrine carcinoma (LCNEC)

SCLC Basaloid carcinoma LCNEC

NE markers

TTF-1

Cytokeratins 1, 5, 10, 14

+ −

+ −

− +

+

+/−

−

are negative in a suspected SCLC, the pathologist should exclude other possibilities such as chronic inflammation, lymphoma (CD45 positive), primitive neuroectodermal tumor, or small cell round sarcoma. One difficulty resides in the fact that about 25% of SCLCs express the antigen CD99/MIC-2, as do primitive neuroectodermal tumors and small round cell sarcoma. It is important to recognize that this distinction is based primarily on light microscopy (Table 7.2).4 Since no single monoclonal antibody can reliably distinguish SCLC from NSCLC,70,71 a set of reliable markers should be considered (Table 7.3).

LARGE CELL CARCINOMA Large cell carcinoma is a tumor that shows no differentiation pattern to allow classification into squamous cell carcinoma, adenocarcinoma, or small cell carcinoma. These poorly differentiated tumors most often arise in the lung periphery, although they may be located centrally. They frequently appear at gross examination as large, necrotic tumors. Histologically, these consist of sheets or nests of large polygonal cells with vesicular nuclei and prominent nucleoli.23 Although they are undifferentiated by light microscopy, features of squamous cell or adenocarcinoma might be found on electron microscopy examination.6,7,72 There are several variants of large cell carcinoma, some of which have high clinical significance, recognized in the new WHO/IASLC histologic classification of lung cancer (Table 7.1).4 These include LCNEC,4,61,73 basaloid carcinoma,18,19,74 lymphoepithelial-like carcinoma,75–77 clear cell carcinoma,78 and large cell carcinoma with rhabdoid phenotype.79 Lymphoepithelial-like carcinoma is described as an EBV (Epstein–Barr virus) dependent epithelial proliferation more commonly seen in the upper respiratory tract.

Because lung cancers are classified according to the best differentiated component, areas of large cell carcinoma are frequently observed in poorly differentiated adenocarcinoma or squamous cell carcinoma, and due to the common heterogeneity of these cancers it is difficult to specifically and appropriately classify many lung cancers in which only small pieces of tissue are available. In such cases, the best diagnosis might be ‘non-small cell carcinoma’ and specification of the most obvious component.5,80,81 Large cell neuroendocrine carcinoma LCNEC is a variant of large cell carcinoma. It is a highgrade non-small cell neuroendocrine carcinoma that differs from atypical carcinoid and small cell carcinoma. Histologic criteria include: (1) neuroendocrine morphology (organoid, palisading, trabecular, or rosette-like growth patterns; (2) non-small cell cytologic features (large size, polygonal shape, low nuclear to cytoplasmic (N/C) ratio, coarse or vesicular nuclear chromatin, and obvious nucleoli); (3) high mitotic rate (≥11 per 2 mm2) with a mean of 60 mitoses per 2 mm2; (4) frequent necrosis; and (5) at least one positive neuroendocrine immunohistochemical specific marker or neuroendocrine granules by electron microscopy.4,61 It is difficult to diagnose LCNEC based on small biopsy specimens because of frequent lack of neuroendocrine morphology without a substantial sampling of the tumors. Some criteria have been proposed based on cytology.82 The term combined LCNEC is used for tumors associated with other histologic types of NSCLC, such as adenocarcinoma or squamous cell carcinoma (Table 7.1).4 Any combination of LCNEC with SCLC is diagnosed as SCLC combined.4 A variety of criteria must be used to separate SCLC from LCNEC (Table 7.2). Differential diagnosis In 10% of the cases of NSCLC lacking neuroendocrine morphology, immunohistochemical neuroendocrine markers or neuroendocrine granules by electron microscopy can be demonstrated. Such tumors are called nonsmall cell carcinomas (adenocarcinoma, squamous cell carcinoma, or large cell carcinoma) with neuroendocrine differentiation (NSCLC-NED).4,61 Although Iyoda et al83 found that the tumor size of large cell carcinoma with

68 Textbook of Lung Cancer

neuroendocrine differentiation was significantly larger than that for LCNEC, the survival was not different in this series from patients with LCNEC. At the present time, the clinical significance of the diagnosis of NSCLCNED is not known. Whether these tumors are responsive to SCLC chemotherapy regimens84–86 or whether expression of neuroendocrine markers may be an unfavorable prognostic factor87–94 remains to be determined.

show no staining in small cell, large cell and LNEC whereas it stains quite all basaloid carcinoma. TTF-1 is never present in basaloid carcinoma, but is present in the majority of SCLC and LCNEC (Table 7.3).57,95 p63 is expressed in most cells of all basaloid carcinomas.

Basaloid carcinoma Basaloid carcinoma is the most prominent variant of large cell carcinoma after LCNEC.4,18,74 Basaloid carcinoma represents 3 to 4% of NSCLCs in Europe, almost always occurs in males, and most of these tumors develop in proximal bronchi where they frequently have an endobronchial component. Two-thirds of these tumors arise from long areas on the bronchial mucosa and show prolonged and laterally extended in situ carcinoma. About half of the tumors present with a pure basaloid pattern that belongs to a variant of large cell carcinoma. The remaining cases have minor (less than 50%) components of squamous cell carcinoma or, more rarely, adenocarcinoma and are thus classified as squamous cell carcinoma (basaloid variant) or adenocarcinoma, respectively. These tumors consist of a lobular, trabecular, or palisading gross pattern of relatively small monomorphic cuboidal to fusiform cells with moderately hyperchromatic nuclei, finely granular chromatin, absent or only focally conspicuous nucleoli, scant cytoplasm but a nuclear to cytoplasmic ratio lower than that of SCLC, and a high mitotic rate from 20 to 100 mitoses per 2 mm2. Neither intercellular bridges nor individual cell keratinization are present which allows them to be distinguished from poorly differentiated squamous cell carcinoma. Patients with basaloid carcinoma have a significantly shorter survival than those with poorly differentiated squamous cell carcinoma which deserves this differential diagnosis.18,19,74

Adenosquamous carcinoma accounts for 0.6 to 2.3% of all lung cancers96–100 and is defined as a lung carcinoma having at least 10% of squamous cell or adenocarcinoma components.4 Adenosquamous carcinoma should not be confused with mucoepidermoid carcinoma, a malignant epithelial tumor characterized by the presence of squamoid cells, mucin-secreting cells, and cells having intermediate type, identical to the same tumors encountered in the salivary glands. Mucoepidermoid carcinoma of high-grade malignancy is differentiated from adenocarcinoma by a variety of features including a mixture of mucin-containing cells and squamoid cells, transition areas from classic low-grade mucoepidermoid carcinoma, and lack of keratinization.

Differential diagnosis Since comedo type necrosis is common, palisading is a characteristic feature of basaloid carcinoma, and rosettes can be identified in about one-third of cases, the main differential diagnosis resides in separation from LCNEC. Immunohistochemical stains for neuroendocrine markers are negative in basaloid carcinoma and positive in LCNEC. No secretory granules have been seen by electron microscopy in basaloid carcinoma. Two antibodies are helpful to make the distinction on small biopsies between basaloid carcinoma, SCLC, and LCNEC. The specific cytokeratins 1, 5, 10, 14 recognized by 34βE12

ADENOSQUAMOUS CARCINOMA

SARCOMATOID CARCINOMA This group of lung carcinomas is poorly differentiated and expresses a spectrum of pleomorphic, sarcomatoid, and sarcomatous elements. They express the features and the biological behavior of epithelial cells that adopt an epithelial to mesenchymal transition in certain conditions of culture in vitro. Pleomorphic carcinomas tend to be large peripheral tumors invading bronchial lumens, forming endobronchial growth. They often invade the chest wall and are associated with a poor prognosis.54 Because of the characteristic histologic heterogeneity of this tumor, adequate sampling is required and should consist of at least one section per centimeter of the tumor diameter. To enter in this category a pleomorphic carcinoma should have at least a 10% component of spindle or giant cells associated with, but distinctly identifiable from, other histologic types such as adenocarcinoma or squamous cell carcinoma.4 A few giant cells disseminated in an otherwise recognizable squamous cell adenocarcinoma or SCLC have no value for classification in the category of sarcomatoid carcinoma. Rarely carcinomas present with a pure giant cell or spindle cell pattern and deserve the terms giant cell or spindle cell carcinoma. Giant cell carcinoma consists of

Histopathology of lung tumors 69

huge, bizarre, pleomorphic and multinucleated tumor cells that engulf numerous inflammatory cells, particularly polymorphonuclear leukocytes, in their cytoplasm.101– 103 They are discohesive and separated by significant infiltration of inflammatory cells. This tumor is defined as a carcinoma by light microscopy, but immunohistochemical and epithelial markers such as keratins are also quite helpful in confirming their epithelial nature.4 Carcinosarcoma Carcinosarcoma is a tumor composed of a mixture of carcinoma and sarcoma. A heterologous component should be demonstrated such as cartilage, bone, or skeletal muscle – heterologous elements which do not display cytokeratin staining.4 Experience proves that these cases are extremely rare while observations of pseudochondromatous or pseudo-osseous patterns in sarcomatoid carcinoma are frequent: in these cases the pseudosarcomatous components also express keratins. Pulmonary blastoma Pulmonary blastomas are defined as biphasic tumors consisting of an association of a glandular component that resembles well-differentiated fetal adenocarcinoma and a primitive sarcomatous or mesenchymal component.4 Well-differentiated fetal adenocarcinoma is no longer regarded as the epithelial pattern of monophasic pulmonary blastoma but, rather, as a variant of adenocarcinoma.4

TYPICAL AND ATYPICAL CARCINOID Carcinoid tumors accounts for 1 to 2% of all invasive lung malignancies.12 The majority of patients are asymptomatic at presentation.104 Symptoms include hemoptysis, postobstructive pneumonitis, dyspnea, paraneoplastic syndromes including carcinoid, Cushing’s syndrome,104–106 and acromegaly.107 There is no gender predilection.104,108 There is no association with smoking since 40% of patients with carcinoid are non-smokers, which is the proportion within the normal population. The mean age is 55 years, with a range up to 82 years.104 This is the most common lung tumor in childhood.109 The treatment of choice of pulmonary carcinoids is surgical resection.104,110 Patients with typical carcinoid (TC) have an excellent prognosis and rarely die from their tumors.104,111 However, metastases do not disqualify the diagnosis of typical carcinoid. Five to ten percent of TCs have regional lymph node involvement that does

not affect their clinical outcome.13 Compared with TC, atypical carcinoid (AC) presents with a larger tumor size, higher rate of metastases, and a significantly reduced survival. Most series where the diagnosis was based on actual accepted criteria reported a mortality of 27 to 47%.104,112–114 Carcinoid tumors are most often centrally located with a polypoid endobronchial obstructive component. When peripheral carcinoids occur they are more often of the spindle cell type. Both TC and AC are characterized histologically by an endocrinoid, organoid growth pattern and uniform cytologic features, consisting of moderate eosinophilic, finely granular cytoplasm, a nucleus with a finely granular chromatin (Table 7.4), and inconspicuous nucleoli that can be discretely more prominent in AC. A variety of histologic patterns may occur in AC and TC, including trabecular, palisading, rosette-like, papillary, sclerosing papillary, glandular, paragangliomatous, spindle cell, and follicular patterns.61 More rarely, the tumor cells of pulmonary carcinoid tumors may have oncocytic, acinic cell-like, signet ring, mucin-producing, or melanocytic features.61 The most distinguishing feature between typical carcinoid and atypical carcinoid is the rate of mitosis and the presence or absence of necrosis. Typical carcinoids show less than 2 mitoses per 2 mm2 area of viable tumor (per 10 high power field) and no necrosis. The presence of between 2 and 10 mitoses per 2 mm2 or necrosis73 defines the diagnosis of atypical carcinoids. The presence of features such as cell pleomorphism, vascular invasion, and increased cellularity are of no help in separating TC from AC and in allowing stratification of patients for prediction of survival.73 TC may well show focal cytologic pleomorphism, as do paragangliomas in the head and neck area.61,112 The necrosis in AC usually consists of small foci centrally located within organoid nests of tumor cells. Immunohistochemistry Nearly 80% of TC and AC stain for pancytokeratins and, as other pulmonary neuroendocrine tumors, they always express cytokeratins 8, 18, and 19.115 From a more practical standpoint, expression of cytokeratins 1, 5, 10, and 14 has never been observed along the whole spectrum of neuroendocrine tumors of the lung.116 Neuroendocrine markers are present in all carcinoids. Chromogranin A is present in neurosecretory granules and synaptophysin is contained in synaptic vesicles.68 They all express CD 56/NCAM, which belong to the immunoglobulin superfamily of transmembrane

70 Textbook of Lung Cancer Table 7.4 Typical and atypical carcinoid: distinguishing features Histologic or clinical feature

Typical carcinoid

Atypical carcinoid

Histologic patterns: organoid, trabecular, palisading, and spindle cell Mitoses

Characteristic

Characteristic

Absent or <2 per 2 mm2 area of viable tumor (10 high power fields on some microscopes) Absent

2–10 per 2 mm2 or area of viable tumor (10 high power fields on some microscopes) Characteristic, usually focal or punctate Often present

Necrosis Nuclear pleomorphism, hyperchromatism Regional lymph node metastases at presentation Distant metastases at presentation Survival at 5 years

Usually absent, not sufficient by itself for diagnosis of AC 5–15%

Disease-free survival at 10 years

40–48%

Rare

20%

90–95%

58%

90–95%

35%

adhesion molecules, and to date, as for other neuroendocrine tumors of the lung, NCAM remains the most useful immunohistochemical marker, even on crushed biopsies or small specimens, in the differential diagnosis with papillary adenocarcinoma and sclerosing hemangioma. In contrast, as widely reported, NSE immunostaining is of little help in the diagnosis of neuroendocrine tumors in general because of its lack of specificity.69,117 TTF-1 expression was demonstrated to be negative in the spectrum of neuroendocrine hyperplasia, tumorlets, and typical and carcinoid tumors.118 However, other authors have reported some TTF-1 expression in nearly one-third of TC and AC,119,120 predominantly in a peripheral location.121 This discrepancy could be related to differences in immunohistochemical techniques or in assessing the threshold of positivity. TTF-1 expression has not been demonstrated in cDNA expression profiling, whereas it is in high-grade NE tumors of poor prognosis.122 Concerning the proliferation antigen Ki 67 in carcinoids, staining is observed in less than 10%, and an index higher than 4%, more frequently observed in AC, seems to be related to a shorter survival.123,124 Differential diagnosis Carcinoids differ from tumorlets by the size of the latter, which do not exceed 5 mm in diameter. Sclerosing

hemangiomas may resemble carcinoids, especially with a papillary or pseudoglandular pattern. The demonstration of neuroendocrine markers and absence of TTF-1 expression distinguish carcinoids from sclerosing hemangiomas.124 Carcinoids may be confused with paragangliomas, but this lesion remains very rare in the lung, and the lack of cytokeratin expression in the latter has a discriminative feature. Glomus tumors and other smooth muscle tumors may mimic carcinoids, from which they are distinguished by the presence of smooth muscle actin and the absence of neuroendocrine markers. Adenocarcinoma enters the differential diagnosis because a gland-like pattern occurs in carcinoids. Mucin production is not a definitive distinguishing feature since carcinoids may disclose mucin formation. TTF-1 expression and the absence of neuroendocrine markers in adenocarcinoma are of great help. The solid type adenoid cystic carcinoma may be mistaken for carcinoid, but is negative for neuroendocrine markers.

CONCLUSIONS Histologic subclassification of lung tumors is essentially based on light microscopy in order to achieve the widest application through the world and assume comparability and consistency of data. However, techniques including immunohistochemistry, electron microscopy,

Histopathology of lung tumors 71

tissue culture, and molecular biology might provide valuable information on carcinogenesis, histogenesis, and differentiation. It is well recognized that immunohistochemistry and electron microscopy may detect differentiation, specifically regarding the histologic heterogeneity of lung cancer, that cannot be seen by routine light microscopy. However, these techniques are occasionally required for precise classification. An example of this is LCNEC and malignant mesothelioma, which require appropriate immunohistochemical and/or electron microscopic findings to confirm the diagnosis.

15.

16.

17.

18.

19.

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Histopathology of lung tumors 73 70. Brambilla E, Veale D, Moro D et al. Neuro-endocrine phenotype in lung cancers:comparison of immunochemistry with biochemical determination of enolase isoenzymes. Am J Clin Pathol 1992; 98: 88–97. 71. Tome Y, Hirohashi S, Noguchi M et al. Preservation of cluster 1 small cell lung cancer antigen in zinc-formalin fixative and its application to immunohistological diagnosis. Histopathology 1990; 16: 469–74. 72. Kodama T, Shimosato Y, Koide T et al. Large cell carcinoma of the lung – ultrastructural and immunohistochemical studies. Jpn J Clin Oncol 1985; 15: 431–41. 73. Travis WD, Rush W, Flieder DB et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 1998; 22: 934–44. 74. Brambilla E. Basaloid of the lung. In: Corrin B, ed. Pathology of Lung Tumors. New York, Edinburgh, London, Melbourne, San Francisco and Tokyo: Churchill Livingstone, 1997. 75. Butler AE, Colby TV, Weiss L et al. Lymphoepithelioma-like carcinoma of the lung. Am J Surg Pathol 1989; 13: 632–9. 76. Chan JK, Hui PK, Tsang WY et al. Primary lymphoepithelioma-like carcinoma of the lung. A clinicopathologic study of 11 cases. Cancer 1995; 76: 413–22. 77. Pittaluga S, Wong MP, Chung LP et al. Clonal Epstein–Barr virus in lymphoepithelioma-like carcinoma of the lung. Am J Surg Pathol 1993; 17: 678–82. 78. Katzenstein AL, Prioleau PG, Askin FB. The histologic spectrum and significance of clear-cell change in lung carcinoma. Cancer 1980; 45: 943–7. 79. Cavazza A, Colby TV, Tsokos M et al. Lung tumors with a rhabdoid phenotype. Am J Clin Pathol 1996; 105: 182–8. 80. Chuang MT, Marchevsky A, Teirstein AS et al. Diagnosis of lung cancer by fibreoptic bronchoscopy: problems in the histological classification of non-small cell carcinomas. Thorax 1984; 39: 175–8. 81. Haratake J, Horie A, Tokudome S et al. Inter- and intra-pathologist variability in histologic diagnoses of lung cancer. Acta Pathol Jpn 1987; 37: 1053–60. 82. Wiatrowska BA, Krol J, Zakowski MF. Large-cell neuroendocrine carcinoma of the lung: proposed criteria for cytologic diagnosis. Diagn Cytopathol 2001; 24: 58–64. 83. Iyoda A, Hiroshima K, Toyozaki T et al. Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology. Cancer 2001; 91: 1992–2000. 84. Gazdar AF, Kadoyama C, Venzon D et al. Association between histological type and neuroendocrine differentiation on drug sensitivity of lung cancer cell lines. Monogr Natl Cancer Inst 1992; 191–6. 85. Graziano SL, Mazid R, Newman N et al. The use of neuroendocrine immunoperoxidase markers to predict chemotherapy response in patients with non-small-cell lung cancer. J Clin Oncol 1989; 7: 1398–406. 86. Linnoila RI, Jensen SM et al. Neuroendocrine (NE) differentiation in non-small cell lung cancer (NSCLC) correlates with favorable response to chemotherapy. Proce Am Soc Clin Oncol 1989; 8: 248. 87. Berendsen HH, de Leij L, Poppema S et al. Clinical characterization of non-small-cell lung cancer tumors showing

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74 Textbook of Lung Cancer 105. Pass HI, Doppman JL, Nieman L et al. Management of the ectopic ACTH syndrome due to thoracic carcinoids. Ann Thorac Surg 1990; 50: 52–7. 106. Ricci C, Patrassi N, Massa R et al. Carcinoid syndrome in bronchial adenoma. Am J Surg 1973; 126: 671–7. 107. Scheithauer BW, Carpenter PC, Bloch B et al. Ectopic secretion of a growth hormone-releasing factor. Report of a case of acromegaly with bronchial carcinoid tumor. Am J Med 1984; 76: 605–16. 108. el-Naggar AK, Ballance W, Karim FW et al. Typical and atypical bronchopulmonary carcinoids. A clinicopathologic and flow cytometric study. Am J Clin Pathol 1991; 95: 828–34. 109. Lack EE, Harris GB, Eraklis AJ et al. Primary bronchial tumors in childhood. A clinicopathologic study of six cases. Cancer 1983; 51: 492–7. 110. Stamatis G, Freitag L, Greschuchna D. Limited and radical resection for tracheal and bronchopulmonary carcinoid tumour. Report on 227 cases. Eur J Cardiothorac Surg 1990; 4: 527–32. 111. Warren WH, Gould VE. Long-term follow-up of classical bronchial carcinoid tumors. Clinicopathologic observations. Scand J Thorac Cardiovasc Surg 1990; 24: 125–30. 112. Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg 1972; 64: 413–21. 113. Bonato M, Cerati M, Pagani A et al. Differential diagnostic patterns of lung neuroendocrine tumours. A clinico-pathological and immunohistochemical study of 122 cases. Virchows Arch A Pathol Anat Histopathol 1992; 420: 201–11. 114. Paladugu RR, Benfield JR, Pak HY et al. Bronchopulmonary Kulchitzky cell carcinomas. A new classification scheme for typical and atypical carcinoids. Cancer 1985; 55: 1303–11. 115. Brambilla E, Brambilla C. Hétérogénéité des cancers bronchiques. Problèmes d’histogénèse. Rev Mal Resp 1986; 5: 235–45. 116. Sturm N, Rossi G, Lantuejoul S et al. 34β E12 expression along the whole spectrum of neuroendocrine proliferations of

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8

Clinical diagnosis and basic evaluation John J Mullon, Eric J Olson Contents Introduction • History • Physical examination • Imaging • Diagnostic techniques • Overview of basic evaluation • Future developments

INTRODUCTION

HISTORY

Lung cancer is the most lethal of all malignant diseases worldwide and remains the leading cause of cancerrelated death in the United States.1 Lung cancer is responsible for the overall increase in cancer mortality noted over the second half of the 20th century in the USA, which since 1999 has exceeded heart disease as the leading cause of death in those less than 85 years of age.1 Although the overall death rates due to lung cancer have decreased in the USA and western Europe since 1991, largely due to reductions in tobacco smoking,2,3 global lung cancer incidence and mortality rates are expected to continue to rise as a result of the ongoing tobacco use in countries with developing or transitional economies.4 Three- to five-year diseasefree rates for resected stage I lung cancer as high as 60 to 90% are reported, but less than 20% of all lung cancers are stage I at the time of diagnosis and five-year survival rates for all stages of lung cancer remain approximately 15%.1 It is imperative that clinicians be familiar with the evaluation of lung cancer given its tremendous worldwide public health impact and the prognostic importance of early cancer detection. Lung cancer outcome depends on the cell type and stage of disease at presentation based on the TNM classification. Accordingly, the essential aspects of lung cancer evaluation are the histologic distinction of small cell (SCLC) and non-small cell (NSCLC) types and accurate determination of the extent of disease so that appropriate treatment can be initiated. The evaluation of lung cancer begins with a careful history and physical exam, followed by testing to obtain a tissue diagnosis and stage the extent of disease. This chapter will review aspects of clinical presentation, imaging, and diagnostic testing for bronchogenic carcinoma. Details regarding staging are discussed elsewhere in this text.

Lung cancers are clinically silent for the majority of time as they theoretically grow from a single malignant cell to a potentially detectable lesion. The vast majority of patients diagnosed with lung cancer are symptomatic at the time of diagnosis. In only about 10% of cases is lung cancer discovered incidentally in an asymptomatic patient, for instance as a solitary pulmonary nodule on a routine chest radiograph. Smoking history,5 concurrent chronic obstructive pulmonary disease (COPD),6 and previous exposures to certain environmental and occupational carcinogens,7 including environmental tobacco smoke,8 predict a higher risk for bronchogenic carcinoma. Ethnic and racial differences also contribute to the smoking-related risk of lung cancer, with African Americans and native Hawaiians within the USA at higher risk.9 Local tumor growth, regional extension, metastases, paraneoplastic phenomenon, or a combination of mechanisms may cause tumor-associated symptoms (Table 8.1). There are no characteristics of clinical presentation which absolutely distinguish NSCLC and SCLC. Local effects The most common initial symptom of lung cancer is cough, which occurs in 45–75% of patients,10 and may be productive in up to 27%.11 Bronchorrhea, the expectoration of large-volume, thin, mucoid secretions, may be seen with advanced bronchioloalveolar carcinoma (BAC), but is rare. Due to the location of vagal afferent cough receptors, which principally line the airway mucosa, cancer types with a predilection for central airway involvement (notably SCLC or NSCLC in the form of squamous cell carcinoma) may cause cough earlier in their course, whereas peripherally located tumors such as adenocarcinoma or large cell carcinoma may only cause cough as a late symptom. In addition to bronchial mucosa tumor invasion, causes of cough may include

76 Textbook of Lung Cancer Table 8.1 Aspects of lung cancer presentation

Asymptomatic Symptomatic Effects of local tumor growth Cough Bronchorrhea Fever, chills, purulent sputum production (postobstructive pneumonitis) Dyspnea Hemoptysis Chest pain Wheeze Stridor Effects of regional tumor extension Hemidiaphragm paralysis Hoarseness Dysphagia Bronchoesophageal fistula Pericardial effusion/tamponade/ tachyarrhythmias Lymphangitic carcinomatosis Pulmonary nodules Tumor microembolism Pleural effusion Superior vena cava syndrome Pancoast syndrome Metastatic effects Adrenal Liver Central nervous system Bone Paraneoplastic effects See Table 8.2

postobstructive pneumonitis/atelectasis, tumor cavitation, or pleural effusion. Although cough is a nonspecific symptom frequently present in patients with co-existent smoking-related airways disease, a change in the character of a chronic cough, such as new hemoptysis or co-existent fever and chills, should raise suspicion of an additional process such as lung cancer. Lung cancer is overall an unusual cause of chronic cough, occurring in less than 2% of patients,12 and is even less likely in the setting of a normal chest radiograph.13 One-third to one-half of patients initially report dyspnea that may arise from large airway obstruction, postobstructive pneumonitis/atelectasis, pleural effusion, lymphangitic metastases, pericardial effusion, or concurrent illnesses such as COPD. Dyspnea in a lung

cancer patient with a normal chest X-ray may be due to pulmonary thromboembolism or, less commonly, tumor microembolism. Lung cancer presents with hemoptysis in many patients as a result of tumor necrosis, mucosal ulceration, tumor erosion into pulmonary vasculature, postobstructive pneumonia, and pulmonary thromboembolism. Retrospective studies reveal that bronchogenic carcinoma accounts for 19–29% of cases of hemoptysis.14,15 In patients with a normal chest radiograph and hemoptysis, only 2–9% are subsequently found to have lung cancer.16 Hemoptysis is commonly blood-streaked sputum, although large central tumors may lead to massive hemoptysis that can result in death by asphyxiation. Tumor involvement of the parietal pleura, chest wall, and mediastinum leads to chest pain as an initial complaint in 25–50% of patients.17 Other causes of pain include rib cage metastases, pulmonary embolism, and postobstructive pneumonitis. Pneumothorax is a rare cause of chest pain and dyspnea in lung cancer patients. Regional extension effects Direct mediastinal extension by lung cancer or metastases to mediastinal lymph nodes can lead to a variety of presentations due to the diversity of adjacent structures. Phrenic nerve involvement by tumor may cause ipsilateral diaphragmatic paralysis demonstrated on chest X-ray by hemidiaphragm elevation often in the setting of a centrally located mass. If lung cancer is not initially identified as the etiology of diaphragm paralysis, it is unlikely to become the explanation over time.18 Hoarseness, a finding at presentation in 5–18% of lung cancer patients,17 is usually attributable to unilateral left vocal paralysis resulting from damage to the left recurrent laryngeal nerve anywhere along its intrathoracic course. Extrinsic esophageal compression by tumor or metastatic lymph nodes may cause dysphagia. Postprandial coughing raises the possibility of bronchoesophageal fistula. Pericardial involvement, which may be present in 20% of patients,17 occurs by hematogenous, lymphatic, or direct extension routes, and may cause asymptomatic pericardial fluid/thickening detected radiographically, tachyarrhythmias, or pericardial tamponade. In addition to its characteristic tendency to spread to hilar and mediastinal lymph nodes, lung cancer may metastasize within the lung in several patterns. One type is lymphangitic carcinomatosis, which usually appears on chest radiography as focal or diffuse reticular or reticulonodular interstitial infiltrates and Kerley B lines, possibly combined with central adenopathy and

Clinical diagnosis and basic evaluation 77

pleural effusions. By high-resolution chest computed tomography (CT), this process characteristically appears as irregular nodular thickening along bronchovascular bundles and interlobular septa, consistent with the role of lymphatics in this form of dissemination.19 Intrapulmonary metastases may also appear as single or multiple nodules/masses in one or both hemithoraces. A management dilemma occurs in patients with otherwise resectable lung cancer who have one or more radiographically indeterminate lung nodules. The differential diagnosis is broad, but includes synchronous lung cancers, granulomatous processes, silicotic nodules, metastatic extrapulmonary malignancies, Wegener’s granulomatosis, and others. An individualized approach to these situations is generally recommended. Lung cancer microembolism to the pulmonary arterial system, a rare form of intrathoracic metastasis, produces dyspnea and is very difficult to diagnose antemortem. Diagnosis has been occasionally accomplished by cytologic examination of blood drawn through a wedged pulmonary artery catheter. Pleural effusion Ten percent of all lung cancers metastasize to the pleura, with adenocarcinoma being the most common.17,20 Malignant pleural effusions due to lung cancer are generally on the same side as the main tumor. They may be moderate to large in size, bloody, and recurrent following thoracentesis. Pleural effusions develop in the setting of malignancy from local effects of the tumor (pleural metastases, lymphatic obstruction, bronchial obstruction with pneumonia or atelectasis, chylothorax), systemic effects (pulmonary thromboembolism, hypoalbuminemia), or as complications of therapy. The main mechanism for malignant pleural effusion formation is altered lymphatic drainage. Metastatic tumor implants on the pleural surface may alter capillary permeability and further increase pleural fluid formation. In most cases, metastatic involvement of the pleura is thought to begin with hematogenous seeding of the visceral pleura followed by subsequent movement and attachment of tumor cells to the parietal pleural surface. Malignant effusions are usually exudative (effusion meets at least one of the following criteria: pleural fluid/ serum total protein ratio >0.5, pleural fluid/serum lactate dehydrogenase [LDH] ratio >0.6, or pleural fluid LDH > two-thirds of the upper limits of normal of the serum). The fluid may appear serous, serosanguinous, or frankly bloody. The initial thoracentesis of a malignant effusion reveals malignant cells 50% of the time.

The cytologic yield increases to 65% and 70% on the second and third attempts, respectively. Pleural fluid cytology is more sensitive than closed pleural biopsy, primarily because pleural metastases tend to be focal and percutaneous biopysy is performed blindly. Pleural biopsy adds very little to the overall diagnostic yield when combined with cytology.21 Therefore, a second thoracentesis is usually performed rather than closed pleural biopsy if malignant effusion is suspected. Low pleural fluid pH (<7.30) and glucose (<60 mg/dl) values predict higher pleural fluid cytology yields, but also predict poor response to pleurodesis and short survival time.22 Malignant cells in pleural fluid indicate T4 or stage IIIB disease in NSCLC and this eliminates further consideration of surgical resection. It is important to remember, however, that the mere presence of a pleural effusion does not categorically preclude surgery for NSCLC. Other conditions that can cause pleural fluid without direct tumor involvement of the pleura include postobstructive pneumonitis/atelectasis, pulmonary embolism, or illnesses unrelated to the tumor, such as congestive heart failure, non-obstructive pneumonia, and cirrhosis. Therefore, the physician must thoroughly evaluate pleural effusion in NSCLC patients with otherwise potentially resectable disease. Unfortunately, series have demonstrated that only 5–10% of lung cancer patients with cytologically negative pleural effusions are ultimately found to have operable disease.23 Superior vena cava syndrome Several well-known syndromes result from regional growth of lung cancer. Obstructed venous flow due to extrinsic compression of the superior vena cava (SVC) by adjacent bronchogenic carcinoma causes the SVC syndrome.24 Overall, approximately 2–4% of patients suffering from bronchogenic carcinoma will develop the SVC syndrome;25 however occurrence is as high as 20% in those with SCLC due to its propensity to develop in the central airways.26 Clinical manifestations result from venous hypertension above the level of the obstruction. Symptoms and signs typically include headache and facial fullness (which may be worse in the recumbent position), swelling and ruddiness of the face, neck, and upper extremities, distended neck veins, and prominent/tortuous collateral venous drainage over the upper torso (Figure 8.1). Chest radiography may reveal mediastinal widening or a right perihilar mass. The differential diagnosis also includes lymphoma, metastatic extrathoracic malignancies, granulomatous mediastinal inflammation/fibrosis, postirradiation fibrosis, and aortic

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Figure 8.1 Tortuous, prominent, collateral venous drainage over the upper torso in superior vena cava syndrome. (Courtesy of JH Ryu MD, Mayo Clinic, Rochester, MN.)

imaging (MRI) in staging is recommended and is superior to CT in determining the extent of local invasion.33 A magnetic resonance angiogram (MRA) is likewise superior to both MRI and CT in assessing vascular involvement.34 The majority of cases of Pancoast’s syndrome are due to NSCLC, but SCLC, metastatic extrapulmonary cancer, and infectious conditions (bacterial, mycobacterial, and fungal) have also been implicated. Tissue diagnosis is recommended and transthoracic needle aspiration is frequently and successfully employed in this regard. Pancoast’s tumors are generally found to be stage IIB, IIIA, or IIIB lesions.

aneurysms. Although the treatment goal remains prompt initiation of palliative chemotherapy or radiation, SVC syndrome is no longer regarded as a medical emergency.27 Diagnostic studies can be safely executed and a tissue diagnosis should be obtained before starting therapy. Overall treatment with radiation and/or chemotherapy is effective in approximately 60% of cases of SVC syndrome due to NSCLC; however recurrence occurs in almost 20%.28 The presence of SVC syndrome is a poor Prognostic indicator for patients with NSCLC, with a median survival of five months.29

Metastatic effects Approximately 40–50% of NSCLC patients present with metastatic disease that precludes surgical resection. SCLC has an even greater propensity to metastasize earlier in its course. Consequently, SCLC is considered a systemic disease at time of diagnosis, even if it appears limited to the chest. Lung cancer dissemination may occur via lymphatic, hematogenous, or interalveolar routes. Metastases to nearly every organ have been described, but the most common sites of involvement are the lung, adrenals, liver, central nervous system, and bone. Clinical manifestations depend upon the extent of specific organ dysfunction induced by metastases. Quoted frequencies of metastases differ depending upon whether initial presentation or autopsy series are cited.

Pancoast’s syndrome Pancoast’s syndrome is characterized by a tumor situated in the extreme apical region of the hemithorax called the superior sulcus, in conjunction with ipsilateral shoulder and medial scapular discomfort. Pancoast initially described the syndrome of shoulder and arm pain in the distribution of the eighth cervical and first and second thoracic nerve trunks, Horner’s syndrome, and ipsilateral hand atrophy and weakness associated with superior pulmonary sulcus tumors.30 Most patients do not have all of these signs and symptoms until late in the course of the disease. Tumor invasion of the adjacent chest wall, brachial plexus, and sympathetic ganglion is the cause for the clinical manifestations. The clinical findings vary depending on the extent to which the adjacent structures are involved. Shoulder pain is the most common symptom, occurring in up to 88% of patients, with arm weakness noted in 40% and Horner’s syndrome in 30%.31 Superior sulcus tumors may manifest on chest radiography as unilateral apical thickening (>5 mm), an apical mass (Figure 8.2), or bony destruction.32 The use of magnetic resonance

Adrenal Adrenal metastases are common in lung cancer. They are usually asymptomatic and initially detected as unilateral adrenal gland enlargement on staging chest CT extended to the upper abdomen. In two series totaling 576 NSCLC patients, 4–7.5% were found to have an isolated unilateral adrenal mass, and approximately 30–40% of the adrenal lesions were found to be malignant.35,36 Adrenal adenomas occur in 2–10% of the general population and typically appear on CT as homogeneous, low attenuation (due to fat content), well-circumscribed lesions <3 cm in diameter.37 The differential diagnosis for benign adrenal enlargement includes adrenal adenomas, nodular hyperplasia, and hemorrhagic cyst. Chemical shift MRI has been shown to be 96% sensitive and 100% specific for distinguishing adenomas,38 and more recently 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET) has been shown to be 93% sensitive and 90% specific for detecting adrenal metastases in patients with known lung cancer.39 A positive result on 18F-FDG-PET, although highly suspicious, does not confirm the presence of adrenal

Clinical diagnosis and basic evaluation 79 (a)

(b)

Figure 8.2 (a) Posteroanterior and (b) lateral chest radiographs, and (c) CT appearance of a large right superior sulcus tumor in a 52-year-old smoker who presented with right shoulder pain. Transthoracic needle aspiration revealed squamous cell carcinoma.

(c)

metastasis, which must be further proven by CT or endoscopic ultrasound-guided needle biopsy before withholding potentially curative resection. Liver Metastatic involvement of the liver is common and usually clinically silent early in the course of disease. Liver metastases are particularly common with SCLC. History and physical exam do not dependably detect liver metastases. Liver involvement may be suggested by abnormalities on the initial staging CT or by elevated liver test values. Advanced liver involvement may be associated with systemic symptoms, such as anorexia, weight loss, and jaundice. Central nervous system Lung cancer is the most common cause for brain metastases, accounting for approximately 70% of cases.40 Clinical and autopsy data indicate that approximately 40% of lung cancer patients will develop brain metastases.17 Small cell and adenocarcinoma are the most common histologic

types of lung cancer to cause brain metastases. Although occasionally asymptomatic, brain metastases usually cause either non-focal symptoms, such as headache (most common), nausea, and vomiting, or focal abnormalities, including seizures, hemi-sensorimotor changes, and cranial nerve deficits. Neurologic symptoms precede lung cancer symptoms in most patients with concurrent disease. Metastases develop more commonly in the cerebral hemispheres, particularly in the parietal and frontal lobes, than in the cerebellum.41 Metastatic lesions are detected by CT or MRI. Central nervous system metastases signal stage IV disease and generally herald an ominous prognosis, but neuro- and radiosurgical advances have resulted in successful treatment of brain metastases leading to improvements in neurologic status and survival.41,42 In SCLC the brain is a common site of relapse and prophylactic cranial irradiation is shown to confer a significant 3-year survival benefit to those patients who experience a complete initial response.43 Other forms of central nervous involvement by metastatic lung cancer include spinal cord metastases and

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leptomeningeal carcinomatosis. Intraspinal lesions usually cause back pain that is worsened by movement, straining, and supine positioning. Neurologic deficits from spinal cord compression, such as sensory defects at or below the level of the lesion, paraparesis or paraplegia, and bowel/bladder incontinence tend to develop quickly, progress rapidly, and be irreversible. In this event, spinal metastases become a medical emergency for which steroids should be starting pending definitive therapy. Leptomeningeal carcinomatosis is uncommon and uniformly predicts a short survival time. Neurologic symptoms may also result from a number of paraneoplastic syndromes, which are discussed below. Bone Skeletal metastases occur in approximately 25–30% of lung cancer patients and are typically found as osteolytic lesions in the vertebral bodies, ribs, and long bones of the arms and legs.17 These lesions usually produce pain or elevations of calcium or alkaline phosphatase.37 Twenty percent of SCLC patients may also have bone marrow involvement, which may not initially be accompanied by clinical or laboratory abnormalities. Bony metastases may be detectable on plain radiographs. If these are negative or non-diagnostic, a planar bone scan, single photon emission computed tomogram (SPECT), or 18F-FDG-PET scan should be obtained. Of these three, 18F-FDG-PET is the most sensitive, but is associated with greatest expense and is not universally available.44,45 Directed MRI of the culprit region remains an alternative as MRI is highly sensitive and specific for bony metastasis, although it has not yet been systematically compared to 18F-FDG-PET in this regard. Paraneoplastic effects Bronchogenic carcinomas are associated with paraneoplastic syndromes more than any other tumor. Ten to twenty percent of lung cancer patients will develop paraneoplastic syndromes.46 These diverse phenomena, most of which are more common with SCLC, result from effects of lung cancer on other organ systems beyond those related to the physical presence of the primary or metastatic lesions. The clinical manifestations are frequently non-specific and are mediated by the ectopic production of biologically active peptides, cytokines, and antibodies. An awareness of the paraneoplastic syndromes is important since they may be the presenting feature of an otherwise difficult to detect lung cancer in its earlier or recurrent stages. With the clinically frustrating exception of the neurologic syn-

dromes, the course of most paraneoplastic syndromes is analogous to that of the underlying lung cancer. Table 8.2 lists the paraneoplastic syndromes associated with lung cancer. The most common paraneoplastic syndromes are discussed below. Hypercalcemia Hypercalcemia is the most frequently encountered paraneoplastic syndrome, occurring in up to 12.5% of patients with lung cancer.47 Lung cancer is the most commonly responsible malignancy, with squamous cell the usual histologic type. Hypercalcemia generally results from tumor production of parathyroid hormone-related peptide (PTHrP).48 Rarely, hypercalcemia is due to osteolytic bony metastases or aberrant elaboration of other cytokines. PTHrP mimics the actions of endogenous parathyroid hormone (PTH), so hypercalcemia results from heightened osteoclastic bone breakdown, decreased bone formation, and decreased renal calcium excretion. The manifestations of hypercalcemia are malaise, weakness, fatigue, abdominal pain, constipation, anorexia, polydipsia, polyuria, confusion, hyporeflexia, and shortened QT interval on electrocardiogram. Coma and death are late manifestations. Diagnosis is made by demonstrating a combination of increased serum ionized calcium level (or disproportionate increase in total serum calcium relative to the serum albumin), normal or low PTH level by immunoassay (to rule out primary hyperparathyroidism), and exclusion of other causes of hypercalcemia (granulomatous disorders such as sarcoidosis, hyperthyroidism, adrenal insufficiency, acute renal failure, Paget’s disease, and medications such as thiazide diuretics and vitamin D). It is also very important to rule out bony metastases. PTHrP is detectable by radioimmunoassay. Treatment strategies are volume repletion with normal saline, increased urinary calcium excretion with a loop diuretic such as furosemide, decreased bony resorption with bisphosphanates, calcitonin, or gallium, and treatment of the underlying malignancy. A novel therapeutic approach inhibiting osteoclast activity through the use of an immunologically mediated tumor necrosis factor receptor blockade has effectively inhibited hypercalcemia in a murine model.49 This therapeutic approach has yet to be fully investigated. Hypercalcemia in the setting of lung cancer is generally a late complication occurring in the setting of advanced disease. The median survival after onset of hypercalcemia is two to three months. Syndrome of inappropriate antidiuretic hormone The cardinal manifestation of the syndrome of inappropriate antidiuretic hormone (SIADH) is hyponatremia

Clinical diagnosis and basic evaluation 81

Table 8.2 Paraneoplastic syndromes associated with lung cancer

Endocrine/metabolic Hypercalcemia Syndrome of inappropriate antidiuretic hormone Cushing’s syndrome Gynecomastia Galactorrhea Acromegaly Carcinoid syndrome Hyperthyroidism Hypercalcitoninemia Hyperglycemia Hypoglycemia Hypouricemia Cachexia/anorexia Cutaneous Clubbing/hypertrophic osteoarthropathy Dermatomyositis Acanthosis nigricans Erythema gyratum repens Hyperpigmentation Urticaria Vasculitis Pruritis Basex’s syndrome (acrokeratosis) Tylosis Erythroderma Acquired ichthyosis Erythema annulare centrifugum Sign of Leser–Trelat Musculoskeletal Polymyositis Myopathy Neurologic Lambert–Eaton myasthenic syndrome Peripheral neuropathy Cerebellar degeneration Limbic encephalitis Polyradiculopathy Myelopathy Opsoclonus/myoclonus Dysautonomia Retinopathy (Continued)

Table 8.2 Continued

Hematologic Anemia Polycythemia Hypercoagulable state Migratory thrombophlebitis Disseminated intravascular coagulation Non-bacterial thrombotic endocarditis Leukocytosis/leukemoid reaction Dysproteinemia Eosinophilia Thrombocytopenia purpura Renal Glomerulonephritis Tubulointerstitial disorders Nephrotic syndrome Modified from references 37 and 46.

due to the inappropriately sustained ectopic production of arginine vasopressin (AVP; antidiuretic hormone), which acts on the distal renal tubule to promote free-water conservation. Small cell is almost always the underlying lung cancer histologic type.50 SIADH can occur with equal frequency in limited and extensive SCLC and may produce symptoms in 5% of patients.46 What, if any, prognostic significance SIADH may have is unclear, although a recent study suggested a slightly worse survival in those patients with limited stage SCLC and SIADH when compared with those without SIADH.51 This is in contrast to earlier studies that found no difference in responsiveness to chemotherapy or survival in patients with SCLC and SIADH in comparison to those without SIADH.50,52 Clinical manifestations of hyponatremia are due to cerebral edema and occur more in relation to the rate of fall of the serum sodium rather than to the absolute serum sodium level. Because the hyponatremia usually develops slowly in SIADH, many patients are asymptomatic at presentation. Early symptoms include fatigue, weakness, nausea, and anorexia. The diagnostic criteria for SIADH are hyponatremia, serum hypoosmolality (<275 mosm/kg), inappropriately increased urine osmolality (>200 mosm/kg), natriuresis (urine sodium >20 mEq/l), clinical euvolemia, and the absence of renal, adrenal, and thyroid dysfunction. Central nervous system disorders, other pulmonary lesions (notably pneumonia), and drugs (including cyclophosphamide, tricyclic antidepressants, thiazide diuretics, morphine, and vincristine) can also cause SIADH.

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Asymptomatic or mildly symptomatic patients may be treated with restriction of water intake to less than 1 liter per day (although sustained compliance is difficult) and demeclocycline (which gradually blocks the action of AVP on the kidney). More serious symptoms, such as seizures, cognitive decline, and mental status changes, or more profound hyponatremia (serum sodium <120 mEq/l), should be treated with normal (0.9%) saline and a loop diuretic. Use of normal saline alone may actually decrease the serum sodium concentration so a loop diuretic must be added. The use of hypertonic (3%) saline is rarely indicated. The goal should be to raise the serum sodium at a maximum rate of 2 mEq/l/hour (maximum 20 mEq/l/day) to a target of 120–125 mEq/l. More aggressive sodium correction may theoretically result in central pontine myelinolysis, a devastating central neurologic insult usually resulting in death. Ectopic adrenocorticotropic hormone syndrome Cushing’s syndrome describes a constellation of findings due to excess glucocorticoid production. Approximately 80% of adrenocorticotropic hormone (ACTH)-dependent cases of Cushing’s syndrome are due to Cushing’s disease – an ACTH-secreting tumor of pituitary origin. The remaining cases are due primarily to ectopic ACTH or corticotropin-releasing hormone (CRH) production, usually by bronchial carcinoid tumors, but also occurring as a result of thymic carcinoid, gastrinoma, pheochromocytoma, and small cell carcinoma.53 Ectopically produced ACTH directly stimulates adrenal glucocorticoid release, while CRH triggers ACTH release from the pituitary. Slowly growing carcinoid tumors may be accompanied by the classic features of Cushing’s syndrome, including truncal weight gain, moon facies, hypertension, purplish cutaneous striae, hirsutism, glucose intolerance, and proximal muscle weakness. Cushing’s manifestations in more rapidly growing SCLC are usually limited to weight loss, hypertension, edema, weakness, poor skin integrity, hypokalemic alkalosis, and glucose intolerance. Overall, less than 5% of SCLC patients develop Cushing’s syndrome46 and its occurrence predicts a shorter survival time, perhaps due to the co-morbidities induced by glucocorticoid excess. An elevated 24-hour urinary free cortisol level (four or more times the upper limit of normal) and failure to suppress cortisol during lowdose dexamethasone challenge generally confirm the presence of Cushing’s syndrome. Late-night salivary cortisol levels have been shown to have high diagnostic sensitivity and specificity for Cushing’s syndrome and

may in the future replace urinary free cortisol or lowdose dexamethasone suppression as a first-line screening test.54 The diagnosis is at times problematic as tumors responsible for Cushing’s syndrome may have variable secretory activity and, especially pulmonary carcinoids, may be suppressible with low-dose dexamethasone. Treatment options include resection (carcinoidtumors),chemotherapy(SCLC),bilateraladrenalectomy, or medical suppression of adrenal glucocorticoid production with ketoconazole, aminoglutethimide, etomidate, or metyrapone. Neurologic syndromes There are several stereotypic neurodegenerative syndromes that occur primarily in SCLC patients. These paraneoplastic syndromes are distinct from the nonfocal neurologic dysfunction induced by systemic effects of cancer. They are felt to be sequelae of autoimmune phenomena that can involve any level(s) of the nervous sytem (brain, cranial nerves, spinal cord, peripheral nerves, neuromuscular junction, and muscle). The proposed pathogenetic sequence begins with the ectopic expression by tumor cells of antigens similar to those normally expressed in the nervous system. The shared antigen is sensed as foreign and an immune response ensues, causing nervous system injury and clinical deficits.55,56 In support of this mechanism are the observations that these syndromes are associated with specific detectable antibodies, nervous system injuries are strikingly limited to specific cell types, deposits of immunoglobulin have been demonstrated in areas of neuronal cell loss, and the characteristic antibodies are made in the central nervous system by autoreactive lymphocytes. The prototypic process of the autoantibody pathogenetic mechanism is the Lambert–Eaton myasthenic syndrome (LEMS). However, not all patients with clinically similar syndromes have detectable autoantibodies, attempts to induce similar syndromes in animals with passive immunoglobulin transfer or immunization with the culprit antigen have been largely unsuccessful, and immunosuppressants are not usually effective treatments. Our understanding of these syndromes continues to evolve. Lambert–Eaton myasthenic syndrome Proximal muscle weakness, hyporeflexia, and autonomic dysfunction (dry mouth, erectile dysfunction, constipation, blurred vision) characterize LEMS. The pathognomonic electromyographic finding is a marked increase of the compound muscle action potential following high rates of nerve stimulation. Similarly, augmented strength and reflexes can be demonstrated on

Clinical diagnosis and basic evaluation 83

physical exam after maximal contraction of the involved muscle groups. Clinical manifestations are due to antibodies to P/Q type voltage-gated calcium channels expressed on the presynaptic cholinergic synapses of peripheral nerves that interfere with the release of acetylcholine.57 These voltage-gated calcium channels also appear on SCLC cells. Treatments of potential benefit include 3,4-diaminopyridine (increases presynaptic calcium influx), pyridostigmine (inhibits acetylcholinesterase), oral immunosuppressive agents such as corticosteroids, plasma exchange, intravenous immunoglobulin, and treatment of the underlying tumor. Approximately one-third to one-half of LEMS patients will improve with treatment of the underlying SCLC. However, not all patients with LEMS have an identifiable underlying malignancy. Antineuronal nuclear autoantibodies-1-associated (ANNA-1) syndromes ANNA-1, also known as anti-Hu antibodies, are IgG antibodies that recognize a family of nuclear mRNA binding proteins expressed in SCLC cells and neurons of the central and peripheral nervous systems. These antibodies are distinct from the autoantibodies of systemic lupus erythematosis, and whether ANNA-1 antibodies have a pathogenetic role in the neurologic manifestations remains unclear. Seropositivity for ANNA-1 is associated with a diverse set of neurologic disorders that can occur in varying combinations.58 Lucchinetti and colleagues59 reported on the wide spectrum of neurologic and oncologic findings in 162 ANNA-1 seropositive patients. Twice as many women were afflicted as men. By the end of follow-up, a malignancy had been detected in 142 patients (88%), with 81% having SCLC. Of the patients with SCLC, 17 developed at least one other malignancy. Neurologic signs associated with ANNA-1, in decreasing frequency, were neuropathy (sensory > mixed somatic > autonomic > motor), cerebellar ataxia, limbic encephalitis (neurocognitive and neurobehavioral deficits), polyradiculopathy, LEMS, myopathy, myelopathy, opsoclonus/ myoclonus, motor neuronopathy, brachial plexopathy, and aphasia. Gastrointestinal dysmotility occurred in 38 (28%) patients, as manifested primarily by gastroparesis and intestinal pseudoobstruction due to involvement of the myenteric plexus. The neurologic manifestations preceded the cancer diagnosis in 96% of patients, and usually progressed in a subacute manner. None of the 49 patients who received immunosuppressant therapy (steroids, plasma exchange, intravenous immunoglobulin, or cyclophosphamide) experienced

neurologic improvement. Somewhat ironically, ANNA-1 seropositivity is associated with more limited stage SCLC at presentation, higher complete tumor response to chemotherapy, and longer survival.60 Patients with unexplained neurologic findings, ANNA-I positivity, and a history of smoking should undergo a thorough search for SCLC, including a chest CT with contrast. If evidence of SCLC is not clearly identified by CT the addition of an 18F-FDG-PET scan should be considered as the combination of CT and 18F-FDG-PET has been shown in one small series to be 100% sensitive for tumor detection.61 Five to fifteen percent of SCLC patients may be ANNA-1 seropositive without neurologic findings. Other neurologic paraneoplastic syndromes Type 2 antineuronal nuclear autoantibodies (ANNA-2), also known as anti-Ri antibodies, are linked with opsoclonus/myoclonus (opsoclonus are involuntary, conjugate, arrhythmic high-amplitude, saccadic eye movements) in breast cancer. Paraneoplastic cerebellar degeneration is associated with a specific anti-Purkinje cell antibody called anti-Yo (PCA 1) in females with breast and gynecologic malignancies. Similar syndromes can occur in SCLC and NSCLC, but lung cancer patients are typically, although not always, ANNA-2 or anti-Yo seronegative. Cancer-associated retinopathy is a rare complication of SCLC, felt to be due to detectable antibodies directed at the retinal photoreceptor layer or ganglion cells. SCLC is also strongly associated with other antineuronal autoantibodies such as collapsing response-mediating protein-5 (CRMP-5), which has yet to be directly associated with a discrete clinical syndrome. It has been suggested that abnormalities identified on autoantibody paraneoplastic panels may serve best to predict the underlying neoplasm rather than a specific neurologic syndrome.62 Other paraneoplastic syndromes Clubbing of the fingers and toes is characterized by loss of the angle between the base of the nail bed and cuticle, rounded nails, and enlargement of the digit tips. Hypertrophic osteoarthropathy (HPO) is a painful, proliferative periostitis that classically involves long bones of the arms and legs. The affected bones reveal periosteal new bone formation on plain radiographs and increased, symmetric uptake on radionuclide studies. Clubbing and HPO are rare entities that can occur together or as isolated findings. The cause(s) remains unknown; however recent data suggest that platelet microthrombi with subsequent release of platelet-derived and vascular

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endothelial growth factors may play a role in the development of clubbing.63 Clubbing and HPO can occur in conjunction with bronchogenic carcinoma, as well as a variety of cardiopulmonary suppurative processes (bronchiectasis, cystic fibrosis, empyema, subacute bacterial endocarditis), usual interstitial pneumonitis/ idiopathic pulmonary fibrosis, pulmonary arteriovenous malformations, congential cyanotic heart disease, inflammatory bowel disease, and cirrhosis. The potential association between the inflammatory myopathies and lung cancer remains to be fully defined.64 Similarly, it is unclear how thoroughly the physician should search for malignancy in patients with unexplained venous thromboembolism. A prospective randomized trial of 201 patients with idiopathic venous thromboembolism65 identified a 10% incidence of occult malignancy in the extensively screened cohort. Over a two-year follow-up, 9.8% of patients in the control group subsequently developed symptomatic malignancy. Overall malignancies were detected earlier and at an earlier stage in the extensively screened group, although a significant survival benefit could not be demonstrated. Currently no professional organization recommends extensive screening for malignancy in the setting of idiopathic venous thromboembolism. A prudent strategy may be to maintain a low threshold of suspicion for malignancy when venous thromboembolism develops without conventional risk factors, and to proceed with additional testing as directed by history, physical exam, and routine initial investigation.

PHYSICAL EXAMINATION A careful physical exam is a vital component of the lung cancer evaluation as it may provide important diagnostic, prognostic, and staging clues. General appearance may be normal or may reveal debilitation, cachexia, lethargy, pallor, jaundice, fever, or significant comorbidities. Blood pressure irregularities can be seen in conjunction with neurologic or adrenal paraneoplastic phenomena. Hoarseness suggests recurrent laryngeal nerve compromise. Respiratory system examination should be conducted in an orderly manner. On inspection, tachypnea may signal painful rib metastases, pleural effusions, or postobstructive pneumonia, while expiratory prolongation is consistent with underlying COPD. Signs of venous hypertension limited to the head, neck, and arms are seen with SVC syndrome, while jugular venous hypertension and pulsus paradoxus are signs of pericardial

tamponade from metastatic disease. Pain may cause the patient to favor the upper extremity ipsilateral to a superior sulcus tumor. Neck palpation may yield evidence of spread to supraclavicular lymph nodes. Focal rib tenderness implies metastases. Direct extension of lung cancer to the chest wall is rarely palpable. The combination of percussible dullness, diminished breath sounds, and reduced fremitus suggests pleural effusion, hemidiaphragm dysfunction due to phrenic nerve entrapment, or postobstructive pneumonitis/atelectasis. Bronchial breath sounds and increased fremitus indicate consolidation with patent proximal airways. Focal wheezing is detected with central airway compromise by an endobronchial tumor or extrinsic compression, generalized wheezing with COPD. Concurrent interstitial lung diseases, such as asbestosis, may be heralded by characteristic Velcro-type inspiratory crackles. Depending on their distribution, rubs may be due to venous thromboembolic events or metastatic pericardial or pleural involvement. The remainder of the exam is equally important. Pertinent skin findings include cutaneous metastases, typically over the torso and scalp, and Basex’s syndrome, which is hyperkeratosis of the acral regions. Acanthosis nigricans, brown velvety plaques of the groin, back of neck and axillae, may be paraneoplastic phenomena, but are more commonly seen with obesity and diabetes. The differential diagnosis for bony pain in the cancer setting includes skeletal metastases and HPO. Liver metastases may be palpable. A thorough nervous system examination is crucial, especially in patients with headache, sensorimotor complaints, and back pain. Unilateral lower extremity swelling, tenderness, and erythema may accompany deep venous thromboses. The history and physical exam findings can be combined to estimate general health status, such as by the Karnofsky (Table 8.3) or Eastern Cooperative Oncology Group (ECOG, Table 8.4) performance scores.66,67 These clinical indices provide a convenient framework to rate the impact of the lung cancer and comorbidities on the patient. Performance status has been reproducibly shown to be an important prognostic variable in NSCLC and SCLC, and usually influences treatment decision-making.

IMAGING Standard chest radiograph The standard posteroanterior and lateral chest radiograph is usually the first test to suggest bronchogenic

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Table 8.3 Karnofsky Performance Scale (modified from Mor et al66) Definition

Percent

Able to carry on normal activity and to work; no special care needed

100 90 80

Unable to work; able to live at home; cares for most personal needs; a varying amount of assistance is needed

70 60 50

Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly

40 30 20 10

Criteria

Normal; no complaints; no evidence of disease Able to carry on normal activity; minor signs or symptoms of disease Normal activity with effort; some signs or symptoms of disease Cares for self; unable to carry on normal activity or to do active work Requires occasional assistance but is able to care for most of needs Requires considerable assistance and frequent medical care Disabled; requires special care and assistance Severely disabled; hospitalization is indicated, although death may not be imminent Very sick; hospitalization necessary; active supportive treatment necessary Moribund; fatal processes progressing rapidly

Table 8.4 Eastern Cooperative Oncology Group Performance Scale (from Oken et al67) Performance status

Definition

0 1

Fully active; no performance restrictions Strenuous physical activity restricted; fully ambulatory and able to carry out light work Capable of all selfcare but unable to carry out any work activities. Up and about >50% of waking hours Capable of only limited selfcare; confined to bed or chair >50% of waking hours Completely disabled; cannot carry out any selfcare; totally confined to bed or chair

2 3 4

carcinoma, and it helps to assess the intrathoracic extent of cancer, guides subsequent work-up, and identifies simultaneous thoracic disease.68 The spectrum of possible findings is broad, but the most common are a localized opacity (nodule or mass), pleural effusion, infiltrate, atelectasis, and adenopathy. Certain radiographic appearances may suggest histologic types of lung cancer, but these generalizations are not absolute. Squamous cell carcinoma usually presents as a large mass centered at or near the hilum, that may cavitate. Due to the central airway origin, up to 50% of patients with squamous cell carcinoma will present with endobronchial obstruction with postobstructive pneumonia or atelectasis.69 SCLC may also present as a rapidly enlarging central mass with contiguous hilar and mediastinal involvement. Only 5–10% of SCLCs present as peripheral lung lesions. Adenocarcinoma typically arises

peripherally as a solitary nodule or mass. Large cell carcinoma is characteristically a large peripheral mass. BAC may appear as a nodule or an alveolar infiltrate that can be diffuse. The drawbacks of plain chest radiography include lack of specificity and resolution limitations. Lesions smaller than 2–3 mm are not reliably detectable and the miss rate for lesions less than 2 cm may exceed 50%.70 Regions obscured by the heart, clavicles, and diaphragm may be particularly difficult to interpret. Estimates are that chest radiography is 70–80% accurate in the overall detection of lung cancer, 50–60% sensitive in the detection of hilar adenopathy, and less than 50% sensitive in the detection of mediastinal adenopathy.71 Studies using commercially available computer-aided diagnostic software to improve the sensitivity of digital chest radiographs show modest improvements in nodule detection.72

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Computed tomography CT greatly enhances the imaging of bronchogenic carcinoma by providing further definition of the primary lesion’s appearance, detecting concurrent parenchymal or pleural disease missed by plain chest radiography, demonstrating lymphangitic spread of malignancy, guiding diagnostic maneuvers, and evaluating hilar and mediastinal lymph node metastases. CT also helps in the evaluation of distant metastases by the routine practice of extending the examination to include the liver and adrenals. The delineation by CT of the relation of bronchogenic carcinoma to surrounding structures is particularly important since these findings significantly influence prognosis and, in the case of NSCLC, surgical options. However, the resolution limitations of CT in this regard must be acknowledged. Consensus calls for intrathoracic lymph nodes larger than 1 cm in the short axis dimension to be considered abnormal by CT; however, using this criterion CT is only 57% sensitive and 82% specific in identifying hilar and mediastinal lymph metastases.73 The sensitivity of CT suffers from microscopic lymph node metastases, while the specificity is influenced by benign causes for lymphadenopathy, such as reactive hyperplasia, granulomatous inflammation, and anthracosis. CT also has difficulties in accurately diagnosing chest wall or mediastinal structure invasion, detecting endobronchial lesions, and differentiating tumor from adjacent atelectasis or pneumonia. Hence, CT is not a substitute for histologic information and patients must not be denied surgery for NSCLC simply on CT findings without tissue confirmation. Solitary pulmonary nodule Solitary pulmonary nodule (SPN) is a common clinical radiologic dilemma. Defined as a singular rounded lesion entirely surrounded by normal lung parenchyma and without associated lymphadenopathy, an SPN may be caused by malignant and benign processes (Table 8.5).74 The majority of SPNs are benign. Most malignant SPNs are clinical stage I bronchogenic carcinomas. SPNs are usually incidental findings on plain chest radiographs or CTs obtained for other purposes. The questions become whether the SPN is benign or malignant, and whether it should be observed, biopsied, or removed. The evaluation begins, if possible, with review of previous chest radiographs. A nodule that has been radiographically stable for at least two years is by definition benign, and no further maneuvers are necessary. A steadily growing nodule is considered malignant and should be immediately resected. When

Table 8.5 Causes of solitary pulmonary nodules (from Midthun et al74)

Infectious granuloma Tuberculosis Histoplasmosis Coccidiomycosis Bronchogenic carcinoma Metastatic cancer Breast Head and neck Colon Renal cell Sarcoma Germ cell Bronchial carcinoid Hamartoma Organizing pneumonia/abscess Wegener’s granulomatosis Rheumatoid nodule Arteriovenous malformation Pulmonary infarction Bronchogenic cyst Lipoma Amyloidoma

comparison studies are insufficient, the next step is to assess for calcification in the nodule with CT. Central, concentric, or popcorn calcification patterns are reliable indicators of their benign nature. Eccentric calcification does not rule out malignancy. Thin-section CT images may also detect fat within the nodule, indicative of a hamartoma, which is always benign. Taking advantage of the differences in vascular supply between benign and malignant nodules, Swensen and colleagues75 demonstrated that the level of nodule enhancement detected by thin-section CT after injection of intravenous contrast reliably differentiated benign versus malignant lesions (Figure 8.3). Using 15 Hounsfield units as the threshold for enhancement, sensitivity of this technique for malignancy was 98%. Specificity was just 58%, since some inflammatory and infectious lesions may enhance. The negative predictive value was 96% – if a nodule does not enhance, it is almost always benign. Recently 18F-FDG-PET was compared to nodule enhancement CT and found to have similar sensitivity and superior specificity in differentiating malignant from benign pulmonary nodules, although noduleenhancement demonstrated a negative predictive value

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Figure 8.3 CT images demonstrating enhancement of 87 Hounsfield units (HU) of a left lung nodule after injection of iodinated contrast (31 HU on the precontrast image versus 118 HU on the postcontrast image). The circle within the nodule circumscribes the region used to measure enhancement.

(b)

HU= 31

of 100%.76 The authors concluded that 18F-FDG-PET is preferable to nodule-enhancement CT in evaluating indeterminate pulmonary nodules; however noduleenhancement CT remains a useful tool due to its very high negative predictive value, convenience, and lower cost. If radiologic studies are inconclusive, clinical factors which predict a higher risk of malignancy include advanced age of the patient, smoking history, prior malignancies, and larger nodule size. The patient’s wishes must be considered in the decision-making process. Lesions ≥3 cm in size are malignant in over 90% of cases and should not be observed. If a lesion is not removed and is indeterminate, then it must be observed. Observation typically involves obtaining serial chest CT scans every three months for the first six months, and then every six months for the remainder of two years.77 Serial plain chest radiographs do not reliably detect enlargement of small nodules. If the nodule grows, it must be resected. If the nodule is stable for two years, it is safe to assume that it is benign. With the introduction of helical and multi-detector row CTs the detection of nodules as small as 1–2 mm is becoming common. The Mayo Clinic CT Screening Trial demonstrated that less than 1% of nodules <5 mm in size in patients without a history of cancer proved to be malignant.78 Henschke and colleagues79 further demonstrated that the follow-up interval for nodules <5 mm in size at initial detection could safely be extended to 12 months. The likelihood that an incidentally detected nodule is malignant also depends on known risk factors such as cigarette smoking, as well as radiographic characteristics such as density. With this in mind the Fleischner Society80 has endorsed a statement recommending variable follow-up of small nodules (<8 mm) identified incidentally based on patient risk factors and nodule size at the time of detection. Included in this is a provision for no follow-up of incidentally detected nodules less than or equal to 4 mm in size in low-risk patients.

HU= 118

Ground-glass opacities Recent advances in CT screening for lung cancer (discussed below) have led to increased detection of focal ground-glass opacities (GGOs). A GGO is defined as a hazy area of increased lung attenuation with preserved bronchial and vascular margins (Figure 8.4).81 These features may be the result of interstitial thickening, air space filling or partial collapse, or increased capillary blood flow; alternatively they may be seen as a feature of normal exhalation. As such, GGO is a non-specific finding which may be caused by a variety of infectious, inflammatory, and neoplastic processes.82,83 A recent series84 demonstrated that GGOs with no concomitant solid component will represent malignancy approximately 20% of the time; however with serial follow-up almost 40% will regress or disappear spontaneously. In the same series, GGOs with a concomitant solid component represented malignancy approximately 30% of the time; however up to 50% regressed or disappeared spontaneously. Regression, when present, occurred within the first 90 days of follow-up in the vast majority of cases. Malignant and premalignant lesions are most commonly BAC, adenocarcinoma, and atypical adenomatous hyperplasia.85 Female gender, spiculated border, a concomitant solid component, and size greater than 1 cm appear to be risk factors for malignancy, whereas an elevated serum eosinophil count may predict a benign etiology. When malignant, tumor doubling times vary widely and may be as long as 1486 days for some BACs.86 Frequent spontaneous regression, relatively high malignancy rates, and long doubling times all make management decisions for GGOs problematic, and currently no specific guidelines exist for the follow-up or management of GGOs. Based on available data it may be reasonable to biopsy GGOs that persist beyond 90 days and are greater than 1 cm in size or have other concerning characteristics. Serial follow-up, if elected, should continue beyond five years before determining that an identified GGO does not represent malignancy.

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Figure 8.4 Chest CT demonstrating a ground-glass opacity measuring 12 × 7 mm (circled). Note the preservation of underlying vascular and interstitial structures.

CT lung cancer screening Five-year survival for stage I lung cancer approaches 70%; however <20% of lung cancers are detected at this early stage. That the vast majority of these early stage lung cancers are asymptomatic and identified incidentally on a radiograph or CT obtained for other purposes has raised tremendous interest in devising a rational method to screen for lung cancer radiographically, similar to the way a mammogram is used to screen for breast cancer. Early screening trials conducted in the 1970s using chest radiography and sputum cytology demonstrated a higher incidence rate, resectability, and survivorship among the intensively screened group, but failed to show a mortality benefit (summarized in reference 87). A number of more recent studies investigating the use of low-dose CT have shown an ability to detect earlier stage cancers; however, they have also shown high false-positive rates with indeterminate nodules identified in up to 70% of participants.88,89 Recent five-year prospective data collected on over 1500 highrisk participants suggest that overdiagnosis rather than earlier diagnosis may be playing a role in the use of CT screening, and did not demonstrate a mortality benefit.90 Conversely, a recently reported multicenter study91 enrolling over 31 000 patients over ten years identified 484 lung cancers, 85% of which were stage I. For those patients diagnosed at stage I, the estimated ten-year survival rate was 88%, and 92% for those who underwent surgical resection within one month of diagnosis. At this time no professional organization recommends screening for lung cancer.

F-fluoro-2-deoxy-D-glucose positron emission tomography Accurate staging of NSCLC is essential to determine appropriate therapy and estimate prognosis. Evaluation of mediastinal nodal disease and extrathoracic metastasis is crucial in this regard due to their impact on operative candidacy and potential surgical cure. As discussed above, the accuracy of CT for predicting mediastinal nodal metastasis is not ideal. 18F-FDG-PET is a radionuclide test that involves injection of the radioisotope 18 F-fluorodeoxyglucose (18F-FDG). Tissues with high metabolic activity, such as high-grade neoplasms, demonstrate increased glucose uptake relative to normal tissues and will show increased isotope deposition. A meta-analysis of 18 studies found 18F-FDG-PET to have a sensitivity of 84% and specificity of 89% when investigating the mediastinum for metastases (Figure 8.5).73 In lymph nodes smaller than 1 cm specificity may be as high as 95%, although sensitivity is lower.92 18F-FDG-PET also increases detection of extrathoracic metastases (Figure 8.6), identifying unsuspected distant metastases in as many as 28% of patients with stage III disease in one series,93 and reducing by 20% non-therapeutic thoracotomies in a series enrolling patients with stages IA–IIIA NSCLC.94 18F-FDG-PET imaging has been shown to be superior to conventional imaging for identifying tumor recurrence.95 False-positive results may be seen with various inflammatory and infectious processes such as sarcoidosis, pulmonary Langerhans cell histiocytosis, and mycobacterial and fungal diseases. False-negative results may occur with low-grade neoplastic processes such as BAC and bronchial carcinoid tumors. Because of the occasional false-positive findings potentially metastatic sites should be proven by biopsy when clinically and technically feasible.96 Magnetic resonance imaging MRI does not have a routine role in the evaluation of lung cancer. However, its superiority over CT in distinguishing tumor abutment versus invasion of chest wall, vertebral, and mediastinal structures makes MRI a useful adjunct in situations such as superior sulcus tumors and possible neuroforaminal encroachment. The magnetic resonance angiogram (MRA) is the study of choice to investigate vascular invasion. Other nuclear medicine studies In NSCLC patients with marginal pulmonary function, quantitative ventilation-perfusion (V/Q) lung scans can be used to assess candidacy for lung resection.

Clinical diagnosis and basic evaluation 89 (a)

(c)

Figure 8.5 18F-FDG-PET scan with CT fusion demonstrating a primary adenocarcinoma in the left upper lobe (a), with contralateral hilar metastasis (b). (c) Coronal 18F-FDG-PET without CT fusion, demonstrating no extrathoracic involvement. Transbronchial needle aspirate of the right hilar lymph node confirmed metastatic adenocarcinoma with stage IIIB NSCLC assigned. (See color plate section, page xiii)

(b)

The fraction of total ventilation or perfusion from the contralateral lung is multiplied by the preoperative forced expiratory volume in 1 second (FEV1) to predict postoperative FEV1 for patients undergoing pneumonectomy. A postoperative FEV1 of 40% of predicted suggests the patient should tolerate resection from a pulmonary perspective.97 Bone scan and 18F-FDG-PET are useful in investigating bony metastases in patients with bone pain, hypercalcemia, increased alkaline phosphatase, and/or pathologic fractures. Of these three techniques, 18F-FDG-PET is the most sensitive and has the additional advantage of identifying other areas of intra- and extrathoracic metastases. Abnormalities identified with these techniques will require further

evaluation by plain radiography or MRI, and, under appropriate clinical circumstances, biopsy.

DIAGNOSTIC TECHNIQUES An accurate tissue diagnosis is an essential early step in the management of lung cancer because of its therapeutic and prognostic import. Biopsy procedures are not always required before surgical therapy, but are conducted in most patients suspected of lung cancer since clinical and radiographic findings are not uniquely assigned to SCLC or NSCLC. Various techniques are available to obtain tissue for cytologic and histopathologic analysis.

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(c)

Figure 8.6 18F-FDG-PET scan with CT fusion demonstrating a primary adenocarcinoma involving the left upper lobe with ipsilateral mediastinal lymph node metastasis (a), and left adrenal mestastasis (b). (c) Coronal 18F-FDG-PET without CT fusion demonstrating mediastinal and extrathoracic (left adrenal) involvement. CT-guided biopsy of the left adrenal confirmed metastatic adenocarcinoma with stage IV NSCLC assigned. (See color plate section, page xiv)

(b)

Sputum examination Sputum cytology Sputum cytology is a non-invasive method to obtain a diagnosis in appropriate situations.98 The yield depends on the ability of the patient to produce acceptable sputum, tumor size, location of the tumor in relation to major central airways, and the skills of the cytopathologist. The average sensitivity is approximately 65%, with sensitivities ranging from 22 to 98% reported.99 Most studies, although not all, show decreased sensitivity for the diagnosis of peripherally based nodules and masses, with an overall sensitivity of 71% for central and 49% for peripheral lesions.99 The appropriate number of specimens to collect remains unclear, but one to three

consecutive early morning samples or a three-day pooled sputum specimen are generally recommended.100 A sputum sample can be obtained spontaneously or induced, and is considered representative if bronchial epithelial cells or alveolar macrophages are present. Overall diagnostic yield appears highest with specimens collected spontaneously, except in the setting of peripherally based cancers where induced specimens appear more informative.101,102 Abnormal findings may also result from concurrent pulmonary infections (false-positives) or unsuspected head and neck cancers. Sputum cytometry Recent data suggest that the yield of sputum cytology may be improved through the use of molecular, genetic,

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and immunocytochemical markers of malignancy. Studies evaluating archived sputum specimens collected as part of lung cancer screening programs have shown that abnormal cells may be identified as early as twenty months prior to the diagnosis of lung cancer using these techniques. Xing and colleagues103 further demonstrated a twenty-fold improvement in sensitivity over sputum cytology alone using automated cytometric techniques. They were able as well to detect severe dysplasia/carcinoma in situ lesions and correctly identified over 70% of peripherally based cancers. A sensitivity of 75% and specificity of 98% has been shown for semiautomated sputum cytometry in the diagnosis of lung cancer in a multinational study.104 These results have sparked interest in the implementation of this technique as part of a co-ordinated lung cancer screening process.

specimens. TBNA should be obtained before sampling other endoscopically visible lesions to avoid false-positive results. Bleeding is a very infrequent complication of TBNA. Autofluorescence bronchoscopy exploits the difference in fluorescence properties between normal bronchial mucosa and that of invasive and pre-invasive disease. The best-known device uses a helium-cadmium laser (442-nm wavelength) and an optical multichannel analyzer in place of the standard white light source, with normal mucosal surfaces having a green coloration whereas premalignant and malignant lesions appear reddish in color. A prospective, multicenter trial demonstrated an increase in the detection of preinvasive disease with the use of autofluorescence by a factor of 2.1 when compared to white light bronchoscopy alone.110 Bronchoscopy in COPD patients confers only a slightly increased risk if obstruction is severe.

Flexible fiberoptic bronchoscopy Flexible fiberoptic bronchoscopy is commonly used for diagnostic and staging purposes. Endoscopically visible abnormalities are approached with traditional biopsy forceps, brushings, and washings. Transbronchial needle aspirations (TBNAs) may also be performed on submucosal tumors or those causing extrinsic bronchial compression. The yield from an endoscopically visible lesion should be in excess of 80%. Peripheral lesions are sampled with fluoroscopically guided transbronchial biopsies, brushings, and washings. Lesion size is the primary determinant of outcome, with yields of 25% reported for malignant lesions under 2 cm, 60–70% for lesions >2cm, and 80% for lesions >4 cm.105 Yield, particularly for lesions <2 cm, may be increased with the use of electromagnetic navigation bronchoscopy, with a recent study demonstrating 74% diagnostic yield for peripheral lesions in this size range.106 Transbronchial lung biopsies should detect lymphangitic spread of malignancy. For staging purposes, bronchoscopy may occasionally detect synchronous lesions, assess proximal extent of tumor, and facilitate sampling of paratracheal, subcarinal, and hilar lymph nodes by TBNA. Traditional TBNA sensitivity is 50%, with a specificity of 90% for mediastinal staging.107 However, guidance using endobronchial ultrasound (EBUS) increased the sensitivity to 94% in one study of 500 patients.108 EBUS also appears superior to CT in differentiating airway tumor infiltration from extrinsic compression.109 Chest CT should be obtained before TBNA to help guide the attempts. Use of 19-gauge needles improves sensitivity by allowing procurement of cytologic and histologic

Transthoracic needle aspiration Peripheral lesions or those with extension to the mediastinum, chest wall, or pleura may also be sampled by fluoroscopically or CT-guided transthoracic needle aspiration (TTNA). Suspicious peripheral lesions are sometimes directly resected for diagnosis and treatment if surgery would be the anticipated maneuver regardless of TTNA results. However, TTNA may be applied when a tissue diagnosis is needed but the patient cannot or will not undergo surgery, the patient is undecided about surgery pending tissue confirmation of cancer, or fiberoptic bronchoscopy was non-diagnostic. Yields above 90% have been reported.111,112 Pneumothorax is the main complication, occurring in up to 30% of cases, yet less than 15% typically require a chest tube. Tumor seeding of the biopsy tract is a very rare complication. Increased risk situations for TTNA include bullous emphysema in the region to be biopsied, lesions located away from the pleural surface, a poorly cooperative patient, and underlying lung disease whose impact would significantly increase if pneumothorax developed. There is a substantial false-negative rate (20–30% of patients with a negative TTNA may have a malignant lesion)37 so indeterminate or negative TTNA results must not be interpreted as a diagnostic endpoint. A repeat TTNA is diagnostic in 35–65% of cases.37 Percutaneous radiologic-guided needle aspiration is used to confirm metastases to liver, bone, and adrenals. Endoscopic ultrasound The linear array echoendoscope was introduced in the mid-1990s and is gaining popularity due to its ability to

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permit fine-needle aspiration of mediastinal abnormalities from a transesophageal approach that are not easily accessed by bronchoscopy or mediastinoscopy. Endoscopic ultrasound (EUS) easily identifies vascular structures and is useful in sampling tissue from inferior and posterior mediastinal (station 8, 9), aortopulmonary window (station 5, 6), and subcarinal (station 7) lymph nodes. Lobar (station 12), interlobar (station 11), and anterior tracheal nodes (station 3) are not well evaluated by EUS. In a study of 26 patients undergoing transesophageal biopsy performed with EUS and fineneedle aspiration the overall sensitivity for the diagnosis of malignancy was 89% and the specificity was 83%, with a positive predictive value of 100% and a negative predictive value of 75%.113 Recent studies further suggest that EUS may be superior to CT and PET in establishing mediastinal staging of NSCLC,114,115 and may be superior to mediastinoscopy in sampling paratracheal and subcarinal nodes.116 Thoracic surgery techniques Cervical mediastinoscopy and anterior mediastinotomy have been the traditional routes by which histologic verification of mediastinal metastases has been obtained. These are safe procedures whose findings may obviate the need for further surgery in NSCLC patients. Cervical mediastinoscopy allows sampling of the right paratracheal and subcarinal nodes, while anterior mediastinotomy accesses the left paratracheal, supra-aortic, and aortopulmonary window nodes.37 It remains controversial whether mediastinal sampling should be routinely performed before all surgery for NSCLC. Many surgeons may forego mediastinoscopy in patients with radiographic T1N0 disease due the relatively low prevalence (5–15%) of nodal metastases in this group. 18F-FDG-PET may have a role in these patients, allowing those without evidence of mediastinal involvement to avoid mediastinal lymph node sampling, although PET combined with CT may still miss up to 5% of mediastinal micrometastases.117 Video-assisted thoracoscopic surgery (VATS) is a more recent, less invasive technique for sampling of indeterminate peripheral nodules, pleural thickening and effusions, and mediastinal/hilar lymph nodes. Scalene or supraclavicular lymph node biopsy is an appropriate diagnostic and staging procedure in the setting of clinically significant enlargement. The patient with a suspicious lesion (enlarging or spiculated nodule) without evidence of metastatic disease may go directly to thoracotomy for definitive diagnosis and treatment.

OVERVIEW OF BASIC EVALUATION The purpose of the basic evaluation is to efficiently and accurately establish the diagnosis and initial extent of lung cancer. Aspects of this process are influenced by local practice biases. The core elements include a careful history and physical exam, posteroanterior and lateral chest radiographs, and basic blood tests, including complete blood count and chemistry profile (especially electrolytes, serum calcium, alkaline phosphatase, glutamic-oxaloacetic transaminase, albumin, total bilirubin, and creatinine).36 While the cost-effectiveness of the blood tests can be debated, they may suggest metastatic disease, paraneoplastic phenomena, or co-morbidities. Chest CT with extension to upper abdominal CT is routinely obtained to define the primary lesion and locoregional extent of disease. 18F-FDG-PET scanning plays an additive role in addressing the solitary pulmonary nodule and should be included when investigating mediastinal and extrathoracic metastases from a known NSCLC. Testing for extrathoracic metastases is pursued as directed by the initial information. Biopsy of suspected metastases may allow simultaneous diagnosis and staging. For peripheral chest lesions the diagnostic options are TTNA, bronchoscopy, VATS, or thoracotomy. It is unclear whether TTNA or bronchoscopy is the better initial choice. TTNA may enjoy a higher yield for smaller lesions, but also a higher complication rate. Bronchoscopy allows for endobronchial visualization and would still be performed at the time of thoracotomy if TTNA were positive. For central lesions or hemoptysis with negative chest film, sputum cytology is also an option, and bronchoscopy is usually favored over TTNA. Additional pulmonary testing may be necessary if surgical resection is considered. Given the common etiologic thread of smoking, it is not surprising that 80–90% of lung cancer patients also have COPD, 20–30% with severe disease.118 Lung resection, incisional pain, medical appliances, and postoperative use of sedatives and analgesics impact negatively on lung function and defense. Preoperative spirometry and diffusing capacity (DLCO) should be obtained. Patients with FEV1 >1.5–2 l, maximal voluntary ventilation (MVV) >50% predicted, and DLCO >60% predicted can proceed to thoracotomy. Patients below these values may need to undergo a more thorough examination that includes quantitative V/Q lung scanning and/or exercise testing with evaluation of maximum oxygen uptake. Although no value categorically precludes surgery, predicted postoperative FEV1 <40% of predicted, hypercapnia (PCO2 >45), or maximal oxygen consumption <10 ml/

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kg/min during exercise testing predicts significant postoperative problems.119 The use of VATS and limited resections have dramatically changed the definition of inoperability due to pulmonary limitations.

FUTURE DEVELOPMENTS Given the dramatic differences in overall lung cancer survival versus those enjoyed with resectable stage I disease, interest will continue to focus on methods of earlier lung cancer detection and more accurate staging. The recent use of spiral CT scanners allows for extremely rapid thoracic imaging at a reduced radiation dose, thereby imparting the benefits of CT sensitivity with the speed and radiation levels of more traditional radiographic imaging. Whether CT screening, alone or in concert with other screening modalities, results in earlier detection and decreased mortality from lung cancer remains to be demonstrated and the results of the National Lung Screening Trial will determine to a great extent whether CT screening is adopted as a viable standard screening modality. Sputum cytometry and autofluorescence bronchoscopy additionally show promise as methods to identify cancerous and precancerous lesions within the central airways early, when directed therapy or resection is most successful. Their role in standardized screening warrants further investigation. In 2007 a five-year randomized surveillance study funded by Cancer Research UK incorporating combined techniques of sputum cytology/cytometry, CT scanning, and autofluorescence bronchoscopy began enrollment and have helped define the role of these techniques in screening for lung cancer. Early reports of serum proteomic patterns being able to distinguish patients with ovarian and prostate cancer from normal controls are exciting, although preliminary. What, if any, role proteomic patterns may play in the detection and diagnosis of lung cancer is one of the most intriguing new areas of investigation in early detection. It is hoped that these new techniques combined with greater participation of patients in prospective clinical trials (currently only 1% of lung cancer patients in the USA are enrolled) will result in improved lung cancer survival rates. REFERENCES 1. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2006. CA Cancer J Clin 2006; 56: 106–30.

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43. Ausperin A, Arriagada R, Pignon JP et al. Prophylactic cranial irradiation for patients with small cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999; 341: 476–84. 44. Hetzel M, Arslandemir C, Konig H et al. F-18 NaF PET for detection of bone metastases in lung cancer: accuracy, costeffectiveness, and impact on patient management. J Bone Min Res 2003; 18: 2206–14. 45. Schirrmeister H, Glatting G, Hetzel J et al. Prospective evaluation of the clinical value of planar bone scans, SPECT, and (18)F-labeled NaF PET in newly diagnosed lung cancer. J Nucl Med 2001; 42: 1800–4. 46. Patel AM, Davila DG, Peters SG et al. Paraneoplastic syndromes associated with lung cancer. Mayo Clin Proc 1993; 68: 278–87. 47. Burtis WJ. Parathyroid hormone-related protein: structure, function, and measurement. Clin Chem 1986; 4: 1191–8. 48. Bender RA, Hansen H. Hypercalcemia in bronchogenic carcinoma: a prospective study of 200 patients. Ann Intern Med 1974; 80: 205–8. 49. Oyajjobi BO, Anderson DM, Traianedes K et al. Therapeutic efficacy of a soluble receptor activator of nuclear factor KBIgG Fc fusion protein in suppressing bone resorption and hypercalcemia in a model of humoral hypercalcemia of malignancy. Cancer Res 2001; 61: 2572–8. 50. List AF, Hainsworth JD, Davis BW et al. The syndrome of inappropriate secretion of anti-diuretic hormone in small cell lung cancer. J Clin Oncol 1986; 4: 1191–8. 51. Tai P, Yu E, Jones K et al. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) in patients with limited stage small cell lung cancer. Lung Cancer 2006; 53: 211–15. 52. Hainsworth JD, Workman R, Greco A. Management of the syndrome of inappropriate antidiuretic hormone secretion in small cell lung cancer. Cancer 1983; 51: 161–5. 53. Ilias I, Torpy DJ, Pacak K et al. Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab 2005; 90: 4955–62. 54. Arnaldi G, Angeli A, Atkinson AB et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2003; 88: 5593–5602. 55. Dalmau J, Posner JB. Paraneoplastic syndromes affecting the nervous system. Semin Oncol 1997; 24: 318–28. 56. Rosenfeld MR, Eichen JG, Wade DF et al. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol 2001; 50: 339–48. 57. Lennon VA, Kryzer TJ, Griesmann GE et al. Calcium-channel antibodies in the Lambert–Eaton syndrome and other paraneoplastic syndromes. N Engl J Med 1995; 332: 1467–74. 58. Graus F, Keime-Guilbert F, Rene R et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001; 124: 1138–48. 59. Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type I antineuronal nuclear autoantibodies. Neurology 1998; 50: 652–7. 60. Graus F, Dalmau J, Rene R et al. Anti-Hu antibodies with small-cell lung cancer: association with complete response to therapy and improved survival. J Clin Oncol 1997; 15: 2866–72.

Clinical diagnosis and basic evaluation 95 61. Linke R, Schroeder M, Helmberger T et al. Antibody-positive paraneoplastic syndromes: value of CT and PET for tumor diagnosis. Neurology 2004; 63: 282–6. 62. Pittock SJ, Kryzer TJ, Lennon VA et al. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol 2004; 56: 609–10. 63. Atkinson S, Fox SB. Vascular endothelial growth factor (VEGF)-A and platelet-derived growth factor (PDGF) play a central role in the pathogenesis of digital clubbing. J Pathol 2004; 203: 721–8. 64. Dalakas MC. Polymyositis and dermatomyositis. Lancet 2003; 362: 971–82. 65. Piccioli A, Lensing AWA, Prins MH et al. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. J Thromb Haemost 2004; 2: 884–9. 66. Mor V, Laliberte L, Morris JN et al. The Karnofsky Performance Status Scale: an examination of its reliability and validity in a research setting. Cancer 1984; 53: 2002–7. 67. Oken MM, Creech RH, Torney DC et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649–55. 68. Karsell PR, McDougall JC. Diagnostic tests for lung cancer. Mayo Clin Proc 1993; 68: 288–96. 69. Midthun D, Jett J. Lung tumors. In: Albert R, Spiro S, Jett J, eds. Comprehensive Respiratory Medicine. London: Mosby, 2004. 70. Quenkel G, Kessels A, Goei R, van Engelshoven J. Miss rate of lung cancer on chest radiograph in clinical practice. Chest 1999; 115: 720–4. 71. Swensen SJ, Brown LR. Conventional radiology of the hilum and mediastinum in bronchogenic carcinoma. Radiol Clin North Am 1990; 28: 521–38. 72. Kakeda S, Moriya J, Sato H et al. Improved detection of lung nodules on chest radiographs using a commercial computer-aided diagnosis system. Am J Roentgenol 2004; 182: 505–10. 73. Toloza EM, Harpole L, McCrory DC. Noninvasive staging of non-small cell lung cancer. Chest 2003; 123: 137–46S. 74. Midthun DE, Swensen SJ, Jett JR. Approach to the solitary pulmonary nodule. Mayo Clin Proc 1993; 68: 378–85. 75. Swensen S, Viggiano R, Midthun D et al. Lung nodule enhancement at CT: multicenter study. Radiology 2000; 214: 73–80. 76. Christensen JA, Nathan MA, Mullan BP et al. Characterization of the solitary pulmonary nodule: 18F-FDG-PET versus nodule-enhancement CT. Am J Roentgenol 2006; 187: 1361–7. 77. Ost D, Fein AM, Feinsilver SH. The solitary pulmonary nodule. N Engl J Med 2003; 348: 2535–42. 78. Midthun DE, Swensen SJ, Jett JR et al. Evaluation of nodules detected by screening for lung cancer with low dose spiral computed tomography. Lung Cancer 2003; 41 (Suppl 2): S40. 79. Henschke CI, Yankelevitz DF, Naidich DP et al. CT screening for lung cancer: suspiciousness of nodules according to size on baseline scans. Radiology 2004; 231: 164–8. 80. McMahon H, Austin JH, Gamsu G et al. Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology 2005; 237: 395–400.

81. Austin JH, Muller NL, Friedman PJ et al. Glossary of terms for CT of the lungs: recommendations of the Nomenclature Committee of the Fleischner Society. Radiology 1996; 200: 327–31. 82. Nagajima R, Yokose T, Kakinuma R et al. Localized pure ground-glass opacity on high resolution CT: histologic characteristics. J Comput Assist Tomogr 2002; 26: 323–9. 83. Collins J, Stern EJ. Ground-glass opacity at CT: the ABCs. Am J Roentgenol 1997; 169: 355–67. 84. Oh J-Y, Kwon S-Y, Yoon H-I et al. Clinical significance of a solitary ground-glass opacity (GGO) lesion of the lung detected by chest CT. Lung Cancer 2007; 55: 73–6. 85. Nakata M, Saeki H, Takata I et al. Focal ground-glass opacity detected by low-dose helical CT. Chest 2002; 121: 1464–7. 86. Aoki T, Nakata H, Watanabe K et al. Evolution of peripheral lung adenocarcinomas: CT findings correlated with histology and tumor doubling time. Am J Roentgenol R 2000; 174: 763–8. 87. Bach PB, Kelley MJ, Tata RC, McCrory DC. Screening for lung cancer: a review of the current literature. Chest 2003; 123: 72–82S. 88. Henschke CI, McCauley DI, Yankelevitz DF et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999; 354: 99–105. 89. Swensen SJ, Jett JR, Hartman TE, Midthun DE et al. Lung cancer screening with CT: Mayo Clinic experience. Radiology 2003; 226: 756–61. 90. Swensen SJ, Jett JR, Hartman TE et al. CT screening for lung cancer: five-year prospective experience. Radiology 2005; 235: 259–65. 91. International Early Lung Cancer Action Program Investigators; Henschke CI, Yankelevitz DF, Libby DM et al. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006; 355: 1763–71. 92. Gupta N, Graeber G, Bishop H. Comparative efficacy of positron emission tomography with fluorodeoxyglucose in evaluation of small (< 1 cm), intermediate (1–3 cm), and large (> 3 cm) lymph node lesions. Chest 2000; 117: 773–8. 93. Eschmann SM, Friedel G, Paulsen F et al. FDG PET for staging of advanced non-small cell lung cancer prior to neoadjuvant radio-chemotherapy. Eur J Nucl Med Mol Imaging 2002; 29: 804–8. 94. Reed CE, Harpole DH, Posther KE et al. Results of the American College of Surgeons Oncology Group Z0050 Trial: the utility of positron emission tomography in staging potentially operable non-small cell lung cancer. J Thorac Cardiovasc Surg 2003; 126: 1943–51. 95. Bury T, Corhay JL, Duysinx B et al. Value of FDG-PET in detecting residual or recurrent nonsmall cell lung cancer. Eur Respir J 1999; 14: 1376–80. 96. Pieterman R, van Putten J, Meuzelaar J et al. Pre-operative staging of non-small cell lung cancer with positron-emission tomography. N Engl J Med 2000; 343: 254–61. 97. Kaza AK, Mitchell JD. Preoperative pulmonary evaluation of the thoracic surgical patient. Thorac Surg Clin 2005; 15: 297–304. 98. Mehta AC, Marty JJ, Lee FYW. Sputum cytology. Clin Chest Med 1993; 14: 87–98.

96 Textbook of Lung Cancer 99. Schreiber G, McCrory DC. Performance characteristics of different modalities for diagnosis of suspected lung cancer: summary of published evidence. Chest 2003; 123: 115–28. 100. Ng AB, Horak GC. Factors significant in the diagnostic accuracy of lung cytology in bronchial washing and sputum samples. II. Sputum samples. Acta Cytol 1983; 27: 397–402. 101. Kennedy TC, Proudfoot SP, Piantadosi S et al. Efficacy of two sputum collection techniques in patients with air flow obstruction. Acta Cytol 1999; 43: 630–6. 102. Agusti C, Xaubet A, Monton C et al. Induced sputum in the diagnosis of peripheral lung cancer not visible endoscopically. Resp Med 2001; 95: 822–8. 103. Xing S, Khanavkar B, Nakhosteen JA et al. Predictive value of image cytometry for diagnosis of lung cancer in heavy smokers. Eur Resp J 2005; 25: 956–63. 104. Marek W, Kotschy-Lang N, Muti A et al. Can semi-automated image cytometry on induced sputum become a screening tool for lung cancer? Evaluation of quantitative semi-automated sputum cytometry on radon and uranium workers. Eur Resp J 2001; 18: 942–50. 105. Arroliga AC, Matthay RA. The role of bronchoscopy in lung cancer. Clin Chest Med 1993; 14: 87–98. 106. Gildea TR, Mazzone PJ, Karnak D et al. Electromagnetic navigation diagnostic bronchoscopy: a prospective study. Am J Resp Crit Care Med 2006; 174: 982–9. 107. Harrow EM, Wang KP. The staging of lung cancer by bronchoscopic transbronchial needle aspiration. Surg Clin North Am 1996; 6: 223–35. 108. Herth FJ, Eberhardt R, Vilmann P et al. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling of mediastinal lymph nodes. Thorax 2006; 61: 795–8. 109. Herth F, Ernst A, Schultz M et al. Endobronchial ultrasound reliably differentiates between airway infiltration and compression by tumor. Chest 2003; 123: 458–62. 110. Haussinger K, Becker H, Stanzel F et al. Autofluorescence bronchoscopy with white light bronchoscopy compared with

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9

Staging, classification, and prognosis Michael Dusmet, Peter Goldstraw Contents Introduction • The staging system • The staging process • The staging tests • Restaging after induction chemotherapy • Other prognostic indicators • Prognosis

INTRODUCTION It is logical that this chapter should fall between the preceding one on diagnosis and evaluation and those that follow on the treatment modalities for non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). At its most simplistic, ‘staging’ is the process by which the clinician examines and describes the local, regional, and distant extent of the cancer. This precise information is then used to determine the appropriate therapy for a patient diagnosed to have lung cancer. However, staging should not be thought of as a set of investigations that are performed between diagnosis and treatment. Many of the tests that are undertaken to establish the diagnosis, such as chest radiography, bronchoscopy, and pleural aspiration cytology, provide valuable information as to stage. Often the choice of test by which to establish the diagnosis will be made on the basis of the clinician’s assessment of the probable stage of the disease. In this context, obviously taking into account the financial cost and the potential morbidity of every procedure, it is desirable to undertake first the test that will prove the highest stage. For example, if a patient has a lung lesion and a probable adrenal metastasis, biopsy of the adrenal will, if positive, provide both a tissue diagnosis of cancer and the stage (M1).Tests undertaken to decide stage proceed in parallel with those required to establish the diagnosis and others to assess patient fitness for possible treatment options, often interweaving and providing information across these categories. Tests may have to be repeated if undertaken without sufficient foresight to look beyond the diagnosis and consider the consequential issues of treatment. Sometimes treatment may be recommended after staging and before a firm diagnosis. A surgeon may ‘stage’ a patient and recommend thoracotomy with only the strong clinical–radiographic suspicion of lung cancer and without pursuing the diagnosis to a cytologic or histologic conclusion. In such circumstances the surgeon will establish the diagnosis as the

first step at thoracotomy using rapid, ‘frozen section’ histology prior to proceeding with treatment by pulmonary resection. Thus staging has several objectives, some patient orientated and some disease centered. Precise staging will allow the clinician to offer the individual patient the best treatment, on the basis of the understanding of prognosis that derives from the stage. Staging allows clinicians to evaluate the results of different treatment regimens and to exchange and compare them between different centers. This also allows new treatment strategies to be assessed. Finally it allows us to evaluate in an on-going manner the results of staging modalities. We will consider the separate aspects of staging: the ‘staging system’, the ‘staging process’, and the ‘staging tests’.

THE STAGING SYSTEM The International Staging System (ISS) for lung cancer is the TNM Classification of Malignant Tumors, administered by the International Union Against Cancer (UICC).1 This provides a recognized shorthand to describe the extent of the disease, in which the T descriptor indicates the extent of the primary tumor, the N descriptor the extent of lymph node involvement, and the M descriptor the presence or absence of distant metastases. For each descriptor, advancing numeric subscripts are allocated for progressively advancing disease. The latest revision of the ISS was published in 1997,2,3 and integrated into the sixth edition of the UICC TNM Classification of Malignant Tumors manual in 2002.4 The next revision of the staging system is due to be published early in 2009. The descriptors as presently defined are listed in Table 9.1. A more precise definition of the boundaries and definitions can be found in another article by Dr Mountain.5 The definition of the great vessels includes the aorta, the vena cava,

98 Textbook of Lung Cancer Table 9.1 TNM descriptorsa

Primary tumor (T) TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumour ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchusb (i.e. not in the main bronchus) T2 Tumor with any of the following features of size or extent: • >3 cm in greatest dimension • involves main bronchus, ≥2 cm distal to the carina • invades the visceral pleura • associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung. T3 Tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or tumor in the main bronchus <2 cm distal to the carina, but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; or tumor with a malignant pleural or pericardial effusion,c or with satellite tumor nodule(s) within the ipsilateral primary-tumor lobe of the lung Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes involved by direct extension of the primary tumor N2 Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s) N3 Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) Distant metastasis (M) MX Presence of distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis presentd a

Reproduced with kind permission of Dr CF Mountain and the Editor of Chest.2 The uncommon superficial tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified T1. c Most pleural effusions associated with lung cancer are due to tumor. However, there are a few patients in whom multiple cytopathologic examinations of pleural fluid show no tumor. In these cases, the fluid is non-bloody and is not an exudate. When these elements and clinical judgement dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient’s disease should be staged T1, T2, or T3. Pericardial effusion is classified according to the same rules. d Separate metastatic tumor nodule(s) in the ipsilateral non-primary-tumor lobe(s) of the lung are also classified M1. b

and their main intrathoracic branches and tributaries. The point at which the pulmonary vessels become great vessels (a T4 descriptor) is the pericardium: the intrapericardial portions of these vessels are considered to be great vessels. As an example, a tumor of 5 cm in diameter, involving the ipsilateral mediastinal lymph glands and with an additional pulmonary nodule, believed to be malignant, in the contralateral lung would be described as T2N2M1.

For convenience, TNM subsets with similar survival prospects and for which treatment options would be similar are combined into stage groups (Table 9.2) and the example given above would be assigned to stage IV. Staging is done at various time points during the patient’s journey through preliminary investigations and then treatment. It is important to know when staging is done so as to compare like with like when

Staging, classification, and prognosis 99

Table 9.2 Stage

0 IA IB IIA IIB IIIA

IIIB

IV

Stage grouping: TNM subsetsa,b TNM subset

Carcinoma in situ T1N0M0 T2N0M0 T1N1M0 T2N1M0 T3N0M0 T3N1M0 T1N2M0 T2N2M0 T3N2M0 T4N0M0 T4N1M0 T4N2M0 T1N3M0 T2N3M0 T3N3M0 T4N3M0 Any T Any N M1

a

Staging is not relevant for occult carcinoma, designated TXN0M0. Reproduced with the kind permission of Dr CF Mountain and the Editor of Chest.2 b

evaluating different treatment regimens. The initial, pretreatment, stage is the clinical/evaluative stage, or cTNM. This may integrate the information obtained from imaging and bronchoscopy as well as, for example, the histopathology from a fine needle aspiration biopsy (FNAB) of a distant metastasis. Obviously, with the addition of information obtained at surgery and the pathologic examination of the resection specimen, the postsurgical/pathologic stage known as the pTNM will be more accurate. (See comments later on ‘stage migration’.) The ‘y’ prefix is used when the patient is restaged after induction or neo-adjuvant therapy (induction therapy being a treatment modality aimed at rendering an inoperable stage tumor operable; the goal of neoadjuvant therapy is to improve the survival rate of an operable tumor). This can be used in conjunction with the ‘c’ and ‘p’ prefixes. Thus ycTNM would reflect the clinical restaging after induction or neo-adjuvant therapy and ypTNM the pathologic (i.e. postsurgical) stage after similar presurgical chemo- and/or radiotherapy. The ‘r’ prefix is used for the staging of recurrent tumors and the ‘a’ prefix for autopsy findings.4 It is important to understand the principle differences the fifth edition of the TNM Classification of

Malignant Tumors brought to the staging system for lung cancer in 1997 as many studies on induction/ neo-adjuvant therapy were designed and/or implemented before that year. The four main differences are: (1) that stages I and II were subdivided, respectively, into stages IA, IB and IIA, IIB; these reflect the increase in size of the tumor from T1 to T2 (i.e. ≤ or >3cm in diameter); (2) stage T3N0M0 was moved from stage IIIA to IIB as the five-year survival is more akin to this latter stage; (3) separate nodules within the same lobe were assigned to the T4 category; and (4) separate nodules in other, ipsilateral lobes and the contralateral lung were included in M1 disease. Many clinicians feel that such detailed staging is irrelevant for SCLC, and consider that a cruder division into ‘limited’ and ‘extensive’ disease allows clinical decisions to be made on treatment.6 There are two definitions: from the Veterans Administration Lung Study Group (VALG) and from the International Association for the Study of Lung Cancer (IASLC). In the former, limited disease (LD) is defined as tumor which is restricted to one hemithorax, often including the ipsilateral supraclavicular fossa, basically a single radiotherapy field, whilst any wider-spread disease, including distant metastases, is considered as extensive disease. In the IASLC staging system all patients without distant metastases are considered to have LD, including those with a malignant pleural effusion and all patients with contralateral mediastinal and/or supraclavicular lymph node metastases to be included in the LD category. It has been shown that the IASLC staging system is a better discriminator of survival.7 Whilst this distinction is certainly sufficient for the vast majority of sufferers with this cell type the TNM stage remains relevant for the fortunate patient with unusually localized disease (stage I essentially, possibly stage IIA) for whom surgical therapy or multimodality therapy should be considered.5,8

THE STAGING PROCESS The clinician is confronted with a bewildering array of tests which may, when used appropriately, provide information as to the extent of disease and therefore permit one to stage the patient and advise on therapy. The value and place of each test will be discussed in the

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next section. The clinician may utilize any and all such tests to construct a clinical/evaluative TNM stage (cTNM). Such tests may include surgical exploration such as mediastinoscopy and video-assisted thoracoscopy (VATS) undertaken prior to a decision to recommend treatment. It is as well to remember that as one proceeds with this information-gathering exercise, the tests become increasingly costly and more invasive. Once sufficient information has been collected as to permit a decision regarding treatment, then further tests become obtrusive and unwarranted. The difficulty for the clinician is to know where to draw the line and to decide that the evidence is sufficiently reliable as to make the case for a particular treatment. There can be no rigid protocol for staging and the clinician will decide the next step based upon the overall picture as it emerges as each step provides additional information. For most clinicians the critical point in the staging process is reached once the patient’s disease has been shown to be too extensive to permit surgical treatment. The oncologist or radiotherapist might still consider other staging tests to be important in defining the most appropriate regimen. If the patient comes through the assessment of the clinician and is still considered operable, the surgeon may wish to define the stage more precisely before making a final decision to operate. As this frequently involves a decision as to the probable extent of resection, and the use of surgical investigations such as mediastinoscopy, this step should be left to the surgeon. The issue as to which tests are considered the minimum necessary to establish cTNM has been considered by the IASLC, and is one that is regularly updated at their workshops.9,10 The American Thoracic Society and the European Respiratory Society have accepted similar recommendations.11 More recent guidelines have been published by the American College of Chest Physicians (ACCP) in 2003,12 and by the National Institute for Health and Clinical Excellence (NICE) in the UK in 2005.13 A summary of these recommendations is shown in Table 9.3. Once a decision has been made as to treatment, the cTNM assigned to that patient should not be changed in the records. As alluded to above, additional information will accumulate if the patient proceeds to thoracotomy and pulmonary resection. This will allow the pTNM to be established. This should be recorded separately, and does not replace the cTNM. The UICC4 allows and recommends that a record be made of the assessment of residual disease after treatment. This is also the recommendation in the

Manual for Staging of Cancer, produced by the American Joint Committee on Cancer Staging and End Results Reporting.15 This is most usually done after surgical resection. The designation R is used to define this. RX indicates that it is not possible to evaluate the presence of residual disease. R0 indicates that no residual disease remains, i.e. that there was a complete resection with all resection margins through normal, non-tumoral tissues. R1 indicates that microscopic residual tumor remains and R2 signifies that there is macroscopic residual tumor after what must be considered an incomplete resection. Most workers interpret the R1 status as applying to the case where the resection margins are unexpectedly positive on subsequent histologic examination of the resection specimen. Honest surgeons will also use this descriptor when tumor tissue has been cleaved off remaining structures. This classification is not part of the staging system but represents good practice. The 2005 IASLC guidelines define the requirements of complete resection.16 These require histologically proven free resection margins, complete lymph node clearance (vide infra) with no extracapsular spread in the nodes, and disease-free highest mediastinal node. We believe that at least six lymph node stations (three N1 and three N2) need to be completely resected (as opposed to sampled) to qualify as lymph node clearance, as specified in the European Society of Thoracic Surgeons (ESTS) guidelines for intraoperative staging.17 When the resection margins are free but all of these criteria are not met, or if there is carcinoma in situ at the bronchial resection margin, or if the pleural lavage cytology is positive, then the term ‘uncertain resection’ should be used. As time passes the disease may recur or progress and additional tests may be indicated to establish a retreatment or rTNM. Some would consider that our ultimate insight into the extent of disease is realized at autopsy, when a TNM can be created. However, time is the ultimate test and our understanding of disease progression is curtailed by death, preventing the development of clinically relevant disease that could be overlooked at autopsy. In summary, the first step in the evaluation of a patient with suspected lung cancer is to take a very careful history and perform a thorough physical examination. Chest radiographs and computerized tomographic (CT) scans (chest and abdomen to include the entire liver and both adrenals) are then obtained. Bronchoscopy will usually be performed at this time, especially if the tumor is centrally located. If there is a suspicion of brain metastases appropriate imaging will

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Table 9.3 Pretreatment minimal staging6,9,11,12

Step 1 Investigation Clinical history

Weight loss and performance status

Patient group All patients

Clinical examination Chest radiographs

All patients PA All patients Lateral Blood tests Hb All patients Alk phosphatase Transaminase Lactate dehydrogenase If still thought suitable for curative therapy proceed to Step II Step II Investigation Bronchoscopy

Patient group All patients with central tumors or those in whom central extension is suspected All patients if available

Confirmatory tests As appropriate As appropriate Aspiration of any effusion (considered positive if cytology malignant) As for high-risk patients in Step II

Confirmatory tests The features of proximal, extrinsic compression are unreliable and require further evaluation of the mediastinum by CT and/or mediastinal exploration Dubious findings confirmed (not necessarily histologic)

CT chest and upper abdomen (to lower pole of kidneys with iv contrast enhancement of mediastinal vessels) Liver ultrasound High risk groupa if CT of abdomen not available Brain assessment by Advisable in high risk groupa MRI (or CT if MRI not available) a High risk patients are those having non-specific features identified by Hooper et al.14 • Unexplained anaemia (Hb <11%) • Unexplained weight loss (>8 lb (3 kg) in 6 months) • Abnormal alk phosphatase, or transaminase • Where any clinical suspicion of metastatic disease exists • Patients with stage III disease If still thought suitable for curative treatment proceed to Step III Step III Investigation (a) PET-CT (b) Bone scan only if PET not available (c) Bronchoscopy if not previously undertaken (d) Thoracoscopy (video-assisted)

Patient group All patients Skeletal X-rays ± CT/MRI of bone if dubious positive result All patients If pleural effusion present and cytology negative but clinical suspicion remains, do a pleural biopsy (Continued)

102 Textbook of Lung Cancer Table 9.3 Continued

(e) Mediastinal exploration • It is recommended that this is performed pre-operatively by: • Transtracheal or transesophageal aspiration

Patients in whom CT suggests mediastinal invasion or if CT shows aspiration nodes >1.0 cm in Short axis diameter • Cervical mediastinoscopy Same • Additional evaluation of the The above groups with tumors of the left upper subaortic fossa by left anterior lobe or left main bronchus if suspicion of station mediastinotomy or VATS 5 or 6 metastases on CT or PET • This must be performed All patients – including those whose intra-operatively mediastinum has been assessed preoperatively • Palpation insufficient • Careful and extensive mediastinal dissection (‘systematic nodal dissection’) • Separate labeling as per Naruke or ATS of excised nodes for subsequent histologic examination (only N1 nodes on resection specimen) • Re-evaluation of T stage: completion of intra-operative staging of tumor and pleural space Proceed with definitive therapy, which will be surgical resection in all but the most unusual circumstances

be obtained (preferably magnetic resonance imaging (MRI) – vide infra). If the patient is a candidate for radical (i.e. ‘curative’) therapy then a positron emission tomography (PET)-CT should be obtained.13 While this staging process is being undertaken the functional evaluation of the patient can be carried out so that at the end of this process a treatment decision can be made. If the treatment decision is to give the patient induction therapy this process will need to be repeated at the term of the induction therapy so as to determine the logical next step. THE STAGING TESTS Lung cancer is dealt with nowadays by teams which comprise pulmonary physicians, surgeons, oncologists, radiotherapists, palliative care physicians, radiologists, pathologists, and numerous support staff. In the UK this is known as the multidisciplinary team (MDT). In an age of technologic progress it is often necessary to

remind ourselves of the importance of good clinical acumen. All of our elaborate scans have to be directed by clinical assessment and interpreted in the light of this. Clinical history and examination These remain the most basic and most cost-effective assessments of disease extent. The clinician, whilst enquiring as to symptoms of the primary tumor, will be looking to assess performance status and co-morbid conditions. Watching the patient come into the consultation room and careful enquiry into his/her functional status and exercise tolerance will determine the patient’s ability to undergo aggressive treatment, be it surgery, chemotherapy, or radiotherapy. Investigations may be curtailed in a very unfit patient because their results will not influence treatment choices. The performance status (Table 9.4) of every patient should be recorded at the first clinical visit. A few questions are critical to assess stage. The presence of chest wall pain is more accurate at determining

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Table 9.4 ECOG performance status142 Grade

ECOG performance status

0

Fully active, able to carry on all predisease performance without restriction Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light house work, office work Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours Capable of only limited self-care, confined to bed or chair more than 50% of waking hours Completely disabled; cannot carry out any self-care; totally confined to bed or chair Dead

1

2

3

4 5

chest wall invasion than a CT scan. The presence of unexplained weight loss should alert the clinician to the increased possibility of disseminated disease in such patients. A patient may well dismiss weight loss as attributable to changes in diet and a deliberate attempt at weight reduction. Further enquiry may show that repeated previous attempts at weight reduction have failed without the assistance of disseminated malignancy! The patient coming to see a chest specialist will not volunteer the recent onset of bone pain, assuming it to be degenerative or traumatic in nature, and may assume that hoarseness is due to the trauma of coughing. Similarly, patients and their relatives may rationalize the change in personality as due to anxiety after hearing the diagnosis and dismiss neurologic symptoms as due to minor nerve damage. A careful examination should focus upon any questions raised in the history and also routinely examine for cervical lymphadenopathy and hepatomegaly. One’s ability to detect enlarged neck nodes improves with practice and this important examination should not be designated to the most junior member of the team. Examination of the supra-clavicular fossa with ultrasound (US)-guided FNAB is becoming increasingly popular and does detect a number of otherwise unsuspected lymph node metastases, which are very important as they are an N3 determinant (stage IIIB). When reading the literature on routine US screening of the supra-clavicular fossa it is important to determine the prevalence of nodal disease, which will be related to

the inclusion criteria for the study (patients with ‘operable’ NSCLC vs all patients with suspected or proven NSCLC vs patients with suspected N2 disease) as this has an obvious impact on the incidence of N3 disease detected by this investigation. Thus in one study of ‘operable’ patients with NSCLC this technique proved N3 disease by virtue of supra-clavicular lymph node metastases in 8% of patients, but this led to upstaging of only 4%.19 In a study of patients with lung cancer at any stage, 31% were found to have supra-clavicular lymph node metastases in non-palpable nodes.20 This was the same frequency as probable or proven adrenal metastases and the supra-clavicular lymph node metastases were often associated with mediastinal lymphadenopathy and/or other distant metastatic disease. This study also showed that US was superior to CT in detecting non-palpable supra-clavicular lymph node metastases. Finally, the yield was again very low in otherwise apparently operable patients with NSCLC. In one study of patients with NSCLC and probable stage N2 disease, 46% of patients were found to have supra-clavicular lymph node metastases, and this obviated the need for other staging procedures in 42%.21 These results have two implications. First it means that US-guided FNAB of supra-clavicular lymph nodes will obviate the need for more invasive staging procedures in a significant number of patients, sparing them the risks of the procedure and making considerable cost savings for the health-care economy. Second, it will upstage a significant number of patients, and this can have considerable therapeutic consequences as in many cases this will mean a shift from so-called curative treatment modalities to a more palliative approach. However, the yield and benefit are greatest in patients who are already suspected of having at least stage IIIA disease, and the yield in patients with stage I and II disease is much more limited, making its routine application for this subset of patients much more debatable. This finding was confirmed in another study in which only 3/117 patients were upstaged by supra-clavicular US-guided biopsy of non-palpable lymph nodes.22 Chest radiography This is usually the starting point in further evaluation. Whilst it usually provides clues as to the diagnosis, it also gives valuable staging information as to tumor size and possible local invasion.23 It is as well to check the radiograph for rib erosion, elevation of the hemidiaphragm, the presence of other lung nodules, or evidence of an effusion (Figure 9.1). The presence of such features may allow one to cut short the process of

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the surgeon will wish to examine the airway with respiration suspended under general anesthesia, often using the rigid bronchoscope with its wider field of view and facility for larger biopsies. Bronchoscopy also allows the clinician to rule out other small endobronchial tumors and demonstrates anatomic variants of bronchial anatomy to the surgeon.

Figure 9.1 The chest radiograph of a patient with a mass in the right upper lobe (arrow). The film also shows gross widening of the superior mediastinum (arrow head), strongly suggestive of mediastinal nodal disease, but there is also a right pleural effusion. Aspiration cytology of the effusion gave the diagnosis of adenocarcinoma, allowed staging of the disease as T4 (stage IIIB), and also showed the patient to be inoperable.

assessment by establishing the diagnosis and staging the patient with a single investigation, such as pleural aspiration cytology. The posteroanterior and lateral films can also be useful for tumor localization in relation to the fissures. Hematologic parameters Parameters such as anemia, disturbance of liver enzymes, or elevation of serum alkaline phosphatase are reliable indicators, suggesting a greater probability of distant disease.24 Such tests are inexpensive and widely available, and should be a routine part of the staging process. Bronchoscopy For the patient who remains operable at this point a wide vista of additional tests may be appropriate. The diagnosis may be established by sputum cytology, an underutilized investigation, but for all patients except those with extensive disease, bronchoscopy will be undertaken. This provides an opportunity for more accurate determination of cell type by histologic examination and allows one to assess the proximal extent of the disease within the tracheobronchial tree. The fiberoptic bronchoscope is an excellent screening tool for the respiratory physician, but in borderline cases

Computerized tomography CT has greatly aided the staging of lung cancer and the proliferation of CT scanning facilities attests to the enormous value of this investigation. However, much depends upon technical aspects of the scanner, the protocol used for the study, and the experience of the radiologist.25 CT scans of the chest provide an enormous amount of three-dimensional information as to disease extent. One can analyze the individual components of the scan, assessing the accuracy with which CT can detect mediastinal gland involvement, mediastinal invasion, chest wall invasion, the presence of additional pulmonary nodules, or deposits in the abdominal organs or brain. However, in reality the value of the information provided by CT scanning is far greater than the sum of its component parts. The three-dimensional construct helps the surgeon anticipate the possible extent of resection, the technical problems that may be encountered, and the areas to inspect for possible tumor extension. The surgeon can use such information in evaluating the patient’s fitness for such extended surgery, to guide intraoperative assessment, and to plan the operative strategy to deal with likely areas of extension or concern. It does not matter to the surgeon that such areas of concern may prove to be fallacious, it is better to be prepared, but for the clinician the lack of specificity must be an ever-present concern in evaluating the true extent of disease. One would not want to deny the patient potentially curative surgery on the basis of a radiographic feature that lacks accuracy. Confirmatory tests are often necessary, particularly if the decision hinges upon a single, adverse CT feature. The significance of additional pulmonary nodules will depend upon geographic factors such as the local prevalence of benign granulomatous disease. In one study, two-thirds of such nodules were shown to be definitely benign, and only 11% were definitely malignant.26 Mediastinal lymph nodes can be seen more easily on CT than with conventional radiology.27 As the size of such nodes increases, so does the probability that they contain metastases. However, there is no size criterion below which deposits are excluded with certainty, nor above which deposits are certain to be present (Figure 9.2).

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Figure 9.2 A CT scan of the chest with contrast enhancement of the mediastinal vessels. An enlarged node is visible in the right paratracheal area (arrow). Although this node was larger than 1 cm, it was shown at mediastinoscopy to be benign, and this was confirmed at subsequent thoracotomy.

Figure 9.3 A CT scan of a patient with a left upper lobe tumor. The CT shows unequivocal evidence of irresectable involvement of the mediastinum with tumor encircling the main pulmonary artery to its origin. A left anterior mediastinotomy would be unnecessary unless tissue diagnosis was required.

As one increases the size limit permitted for normality, those nodes deemed ‘abnormal’ are more likely to contain metastases, and the evaluation gains greater specificity, but at the cost of declining sensitivity. If one applies a lower cut-off the reverse applies, sensitivity rises at the expense of falling specificity, and one is more likely to designate nodes as ‘abnormal’ when they do not contain metastases.28 This is the dilemma for the radiologist. The commonest compromise is to report nodes as abnormal if their short-axis diameter is greater than 1.0 cm.29 The accuracy of this assessment depends upon many factors: the speed of the scanner, the use of contrast to enhance the mediastinal vessels, and the rigor with which lymph node deposits are sought at thoracotomy. The reported sensitivity and specificity fall from 70–80% to 60% when the CT assessment is subjected to detailed intrathoracic staging.30–32 Abnormal nodes, larger than this, should be examined by mediastinal exploration to gain histologic confirmation of their involvement. Such enlarged nodes within the superior mediastinum are accessible to cervical mediastinoscopy and anterior mediastinotomy (see later). Enlarged nodes beyond the reach of these techniques can be accessible to video-assisted thoracoscopy (VATS),33 but such nodes have less impact on the results of surgical treatment and their accurate designation can usually be left until thoracotomy. If the CT scan of the chest shows the mediastinal nodes are within this size limit the surgeon may proceed to thoracotomy without mediastinal exploration.34 However, there are four classic risk factors for false negative mediastinal imaging studies (including position emission tomography (PET) scanning, which will be

discussed below). These are: large tumors, central tumors, PET-positive hilar nodes, and cell type of adenocarcinoma or large cell poorly differentiated carcinoma.35 This should be taken into account when deciding whether invasive mediastinal staging is indicated. Also, many surgeons will be more cautious (i.e. more extensive in their preoperative staging) when faced with a higher risk resection (right pneumonectomy, for example) or a high-risk patient, or both together. Mediastinal invasion may be suggested on CT, but this assessment is unreliable36 unless there is gross involvement (Figure 9.3). More frequently the CT scan of the chest will show that the tumor, and the associated atelectasis or consolidation, is contiguous with the mediastinal outline (Figure 9.4). If CT does not demonstrate a fat line separating these two opacities the radiologist will warn that invasion may be present.37 This judgement carries a sensitivity and specificity of around 60%,38 but is imperfect and dependent upon the experience of the radiologist. Such a worry can often be resolved by mediastinoscopy (Figure 9.5), with the addition of mediastinotomy in appropriate cases. A suggestion of mediastinal invasion beyond the reach of these techniques can be inspected using VATS, but is usually deferred until thoracotomy when a more determined assessment of resectability can be made without the danger of massive bleeding. The CT evaluation of chest wall invasion is similarly imperfect unless rib erosion or extension outside the chest wall can be demonstrated.39 Fortunately, such invasion does not preclude successful resection with good survival results.40,41 Most clinicians when requesting a CT scan will ask for the chest study to extend into the abdomen to the

106 Textbook of Lung Cancer Figure 9.4 A chest radiograph (a) and CT scan (b) of a patient with a tumor in the right middle lobe. This was initially deemed inoperable by another clinician based on his interpretation of the CT scan. The appearances are not unequivocal and at thoracotomy resection of a T2N0 tumor was possible by bilobectomy. The chest radiograph (c) was taken 3 years later and the patient is still well and diseasefree 12 years later.

Figure 9.5 The CT scan of a patient with a tumor in the right upper lobe encroaching upon the mediastinum and the right main bronchus. This was evaluated by mediastinoscopy and found to be resectable. The patient underwent right upper lobectomy and sleeve resection for a T2N1 tumor.

Figure 9.6 The CT of the abdomen suggested a liver metastasis. The appearances were not clarified by ultrasound and a needle biopsy showed a benign hemangioma.

lower pole of the kidneys in a search for distant metastases in the liver, abdominal nodes, adrenals, and kidneys. Whilst this is a useful addition to the CT protocol, an isolated abnormality should not be taken as proof unless there is confirmatory evidence that such an abnormality is metastatic (Figure 9.6).42 This may require CT-guided needle biopsy (Figure 9.7). We have

found this to be a useful role for PET, if this is available (see later). The addition of CT of the brain is debated. Undoubtedly the number of unsuspected metastases discovered is small, around 5%,12,43 but as this has a profound effect on the advisability of thoracotomy we routinely undertake CT of the brain, chest, and abdomen prior to surgery.44 If there is any suspicion of

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Figure 9.7 A CT-guided needle biopsy of an indeterminate mass in the right adrenal gland. It showed the presence of an adenoma.

brain metastases, and indeed for screening purposes, MRI should always be the preferred brain imaging modality unless local availability is an issue.45,46 Scintigraphic scans These are largely obsolete, with the possible exception of bone scintigraphy.47 This has retained a place in staging if and only if PET is not available. Most clinicians use bone scans selectively in ‘high-risk’ individuals in whom distant metastases have been suggested clinically by symptoms, or the presence of non-specific features such as weight loss or disturbed blood parameters.48,49 As false-positive bone scans can occur with trauma and degenerative conditions it is as well to follow up any abnormality with skeletal radiology, and in doubtful cases a local CT or MRI of the area.50 However, if a whole body PET scan is obtained then the bone scan is redundant. PET has both higher sensitivity and higher specificity than scintigraphic bone scans.51–53 However, despite this higher accuracy confirmatory studies should be performed if there is any doubt about the diagnosis of metastatic disease.12 Abdominal ultrasound This is widely available and, in experienced hands, is as good as CT at detecting metastases in the liver54 or adrenals.55 If CT is not available, US should be performed in high-risk cases. US is helpful to obtain additional information to characterize any abdominal abnormality on CT, and may obviate the need for needle biopsy. It is also a useful guiding technique for the biopsy, if required.

Mediastinal exploration This is a fundamental tool to select patients for surgery because of the strong negative prognostic implication of N2 and N3 disease. The ESTS has recently published guidelines on both the pre-operative and the intra-operative lymph node staging.17,35 If it is felt that the patient would be a candidate for induction (also called neo-adjuvant) therapy, then it may be desirable to avoid surgical staging of the mediastinum so that the most definitive procedure can be carried out in an unoperated and unscarred mediastinum at the end of the induction therapy (see section below on restaging of the mediastinum after induction therapy). It can also be desirable to avoid surgical staging in more frail patients. Unfortunately, the reliability (the combined sensitivity and specificity) of all techniques increases with invasiveness. The true gold standard of mediastinal staging is the systematic nodal dissection done at the time of thoracotomy. Mediastinoscopy has a false-negative rate of less than 10%,56 whereas all endoscopic techniques with FNAB have a false-negative rate of around 15% in the best of hands. So the decision as to how to proceed will depend on the clinical indices of suspicion for mediastinal lymph node involvement as well as the patient and the planned resection, as it is clearly desirable to avoid the discovery of false-negative staging at thoracotomy in a high-risk situation. So in most centers mediastinoscopy is now used selectively to evaluate the mediastinum when CT has suggested the presence of enlarged mediastinal nodes or mediastinal invasion,57 if there are PET-positive nodes in the mediastinum, or if there are other clinical indices leading to heightened suspicion of mediastinal lymph node involvement. Cervical mediastinoscopy58 is undertaken under general anesthesia through a short cervical incision. It allows inspection and biopsy of lymph nodes in the paratracheal region to both sides of the trachea, in the pretracheal area, and below the carina, excluding gross, often irresectable, nodal metastases. When the nodes are of a normal size and metastases are small and intranodal there is obviously a risk of sampling error, and this is the most common cause of false-negative mediastinoscopy. The one area where more overt mediastinal nodal deposits can be missed is classically the inferior part of station 7 (the subcarinal nodes) as well as its most posterior aspect. This risk can be minimized by dissecting station 7 off both left and right main bronchi, as well as off the pericardium posteriorly prior to taking biopsies. There are several reports of falsenegative rates of well over 10%. We feel that using a

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video mediastinoscope, with its greatly enhanced vision, this is unacceptable and, if this is the case, the surgeon should consider taking more care to identify all possible nodes, to dissect them out more so that larger biopsies can be taken safely, and to prepare the subcarinal fossa as described above so that it can be extensively biopsied. When the tumor is a left-sided tumor it is the practice of the authors to do this part of the mediastinoscopy quite aggressively because it then becomes part of the systematic nodal dissection. Likewise, as it is extremely difficult to reach L4 and L2 effectively through a left thoracotomy, it is the practice of the authors to resect as many nodes as possible at mediastinoscopy, again with the view that mediastinoscopy, if negative, will then become a seamless part of the operative management of the tumor, fulfilling the philosophy of intraoperative staging as described in the ESTS guidelines.17 Two more radical methods of mediastinal staging have been described. These are VAMLA (video-assisted mediastinoscopic lymphadenectomy) and TEMLA (transcervical extended mediastinal lymphadenectomy).59–61 As the names imply, both techniques aim to perform a radical mediastinal lymphadenectomy removing all the para-tracheal nodes as well as emptying out in a radical manner the subcarinal fossa (and therefore more than just station 7). TEMLA also aims to remove stations 5, 6, and 8. In experienced hands these techniques can be performed safely with entirely acceptable morbidity. However, at the moment experience is limited and they are only performed in a few centers. Furthermore their exact place in mediastinal staging remains to be established. First, do we truly want a perfect method to stage the mediastinum? Patients with true minimal N2 disease (single-station, intracapsular involvement) have a 25–40% five-year survival with surgery alone. It is uncertain whether it is in these patients’ best interest to be denied surgery because they are found to have N2 disease. Second, at the end of this chapter we shall explore the issue of restaging the mediastinum after induction chemotherapy. It is when the N2 disease has been eradicated that there is an indication for surgery. This would be impossible after VAMLA or TEMLA, making the decision whether to proceed with surgery more difficult because all that would be left would be to assess the decrease in the maximal standardized uptake value (SUV max) of the primary tumor as a measure of the response to induction chemotherapy. The major advantage for such techniques at present would appear to be in allowing the mediastinal component of systematic nodal dissection (see later) to be

performed prior to surgery when video-assisted resection is planned. Mediastinoscopy can also be very useful to assess direct mediastinal invasion by right upper lobe tumors, so in some cases it can also be useful to assess T stage and thus resectability. When wishing to inspect the area around the aortic arch and subaortic fossa, as in patients with tumors arising in the left upper lobe or reaching the left main bronchus, cervical mediastinoscopy should be supplemented by left anterior mediastinotomy.58 This allows digital examination and, if necessary, cautious biopsy of disease in this area (Figure 9.8). It is applied selectively depending upon the CT appearances in this area of the mediastinum.62 Some surgeons prefer to use VATS to biopsy stations 5 and 6. Such techniques do not exclude more subtle mediastinal disease but, with experience, ensure that complete resection is possible in 95% of negative cases.63,64 The surgeon will often be encouraged to proceed with thoracotomy and resection when other, less accurate techniques such as CT have raised doubts. When the lung cancer is in the left upper lobe and the CT shows only small-volume nodes, completely surrounded by fat, in the para- or subaortic area on CT, some surgeons do not routinely explore this area preoperatively because the five-year survival in patients with this pattern of nodal disease may be equivalent to that of patients with N1 (i.e. stage II) disease, and not that of patients with N2 (i.e. stage IIIA disease).65,66 Mediastinal needle biopsy This can be undertaken through the bronchoscope.67 Suitable target nodes should be identified in the main

Figure 9.8 This patient has a tumor in the left upper lobe and the surgeon is undertaking evaluation by cervical mediastinoscopy and left anterior mediastinotomy. After all biopsies have been taken, bi-digital palpation of the subaortic fossa will exclude invasion or gross mediastinal gland enlargement in this critical area.

Staging, classification, and prognosis 109

carina or the paratracheal area, usually on CT. This technique may obtain tissue diagnosis and confirm irresectability, but there is a small risk of false-positive samples.68,69 It cannot be considered to be a reliable alternative to staging the mediastinum by surgical exploration prior to thoracotomy, even with US-guided biopsies. Overall, bronchoscopic FNAB techniques have a false-negative rate of around 15%, so the main value of these techniques is when this minimally invasive technique proves mediastinal lymph node involvement. Transesophageal fine needle aspiration (with ultrasound guidence) EUS-FNA has been used to assess the presence of mediastinal node enlargement, but is limited by the same size criteria as CT.70 The transesophageal route is attractive as a conduit to examine the mediastinum below the carina, beyond the reach of the mediastinoscope, as well as the left para-tracheal area, checking areas where CT has suggested mediastinal lymph node involvement or tumor invasion. The results have proven unreliable,71 being of a similar order of magnitude as with trans-tracheal biopsies. The same caveats therefore apply to this technique, even with US guidance. However, it has been shown that EUS-FNA can be used to improve the yield of mediastinoscopy.69 In this study there were 36/100 patients who were ultimately proven to have N2/N3 disease. These were located within reach of EUS-FNA in 29 patients, and were positive at EUSFNA in 22. Mediastinoscopy detected N2 (17%) or N3 (2%) lymph node metastases in 19 of the 100 patients. These were located within reach of mediastinoscopy in 29 patients and were confirmed in 19 of these patients. Lymph node metastases were confirmed in 31 (86%) of 36 patients by either EUS-FNA or mediastinoscopy. The five lymph node metastases that were missed by both techniques were located at station 4L in one patient, 5 in one patient, 7 in two patients, and 8 in one patient. This study also showed that T4 status can be correctly assessed by this technique in a number of cases. Similar results with this combined technique have been reported by others.72 Positron emission tomography PET using the 18F-labeled glucose analog fluoro-2-deoxy-D-glucose (FDG-PET) has emerged as an exciting addition to the staging tests. It is expensive, and in many areas is still not widely available, and we are still assessing its cost-effectiveness. It provides an alternative, metabolic search for malignant disease that is independent of the anatomic features of the deposits and is

thus a useful tool to detect and characterize the primary tumor as well as loco-regional and distant metastases.73 It can characterize the lung lesion reliably in many cases,74 failing only to detect very small deposits and more indolent tumors such as broncho-alveolar carcinoma.75 False-positive cases can occur with chronic inflammatory conditions, most notably tuberculosis and histoplasmosis. PET may thus have a role in diagnosis and its place relative to bronchoscopy or needle aspiration is under discussion.76 PET is reliable for lesions that are over 8–10 mm in diameter, and should probably not be performed for smaller lesions.12 Interest, however, has focused on the possibility that PET could aid the non-invasive search for metastatic disease in the mediastinum and at distant sites.77 Initially it was said that PET is more accurate in the detection of mediastinal nodal disease than CT and even mediastinal exploration, with a reported sensitivity of 80–100% and specificity of 70–100%.78 However, the images produced by FDG-PET scanners are indistinct and lack anatomic precision (Figure 9.9). It is difficult to accurately define the margins of hilum and mediastinum. In many centers this problem has been addressed by concomitant PET and CT scanning in a dedicated PET-CT scanner. Two studies have shown the superiority of integrated PET-CT as compared to the combination of a PET study and a CT with correlation of the images by the examining physician.79,80 This superiority was found to be significant for the determination of T stage, N stage, and M stage. A final caveat regarding PET is that one study has shown it to be significantly less reliable in smokers (or recent quitters) than in non-smokers.81 The maximal SUV was also higher in never-smokers, both in the primary tumor and in mediastinal metastases. This could be due to the fact that the background FDG uptake is higher in smokers than in never-smokers. Most centers having access to PET continue to rely upon CT and confirm positive PET findings by mediastinal exploration, thus adding to the expense of staging.82 There is also the philosophical problem as to whether one wishes to detect all mediastinal nodal deposits. There are many reports of five-year survival of 20–30% after complete resection in the presence of truly minimal N2 disease.64,83–85 Mediastinal exploration will miss such subtle N2 disease, perhaps to the patient’s benefit, encouraging one to proceed with surgery with complete resection in 85% of cases.64 It is unknown to what extent detection of this minimal N2 burden and induction chemotherapy would alter the natural history of this entire very small subset of patients (because induction therapy does not eradicate

110 Textbook of Lung Cancer Figure 9.9 The chest radiograph (a) of a patient who presented with a tumor in the left lower lobe; there is an additional lesion at the right apex (arrow). The CT scan (b) did not suggest this additional lesion was a tumor. An FDG-PET study (c) showed high uptake in both lesions, and the rightsided lesion was confirmed histologically to be malignant.

N2 disease in the majority of patients with more bulky N2 disease). Furthermore, we do not know if the results of induction chemotherapy would be better, worse, or the same as adjuvant chemotherapy, which would now be offered to these patients unless contraindicated. PET will detect otherwise unsuspected distant metastases in 11–29% of patients otherwise thought suitable for thoracotomy.86–88 However, the specificity of this evaluation is not 100%. With regard to distant staging, the initial enthusiasm for PET needs to be tempered. A recent study with much larger numbers (350 patients) demonstrated solitary extrathoracic lesions in 72 patients (21%). A diagnosis was obtained in 69: 37 were true metastases, 32 were not. These 32 lesions proved to be unrelated malignancies in 6 and benign tumors or inflammatory lesions in 26.89 Similarly, in the study by Reed et al otherwise unsuspected metastatic disease was identified in 15/287 (5.2%), as well as three second primary tumors. However, PET also identified 19 potential areas of M1 disease that were proven not to be metastases (6.6%). Thus the sensitivity of PET for M1 disease was 83%, the specificity was 90%, the negative predictive value was 99%, and the positive predictive

value was 36%.90 This underscores the value of the recommendation in the current ACCP12 and NICE13 guidelines for histologic verification of apparent solitary metastases detected by PET. Similarly our experience with PET as a staging tool for the mediastinum has grown and some of the initial enthusiasm has been tempered by this experience. There have been many recent studies and all essentially show similar results to the three published reports.90–92 These studies included between 202 and 400 patients. The sensitivity of PET ranged from 64 to 71%, the specificity from 77 to 84%, the positive predictive value from 44 to 56%, and the negative predictive value from 87 to 91% (Table 9.5). An editorial by Kernstine explains why these values are the best one can expect with the current technology.93 What these results mean is that, if one relies exclusively on PET to rule out N2/ N3 disease, between 9 and 13% of patients will be found at thoracotomy to have unexpected N2 disease which might have precluded surgery. Putting together what we know from the CT era and this knowledge it seems reasonable to proceed with thoracotomy for small, peripheral tumors (unless known to be an adenocarcinoma or

Staging, classification, and prognosis 111

Table 9.5 Accuracy of PET-CT for mediastinal staging Reference

Number of patients

Sensitivity (%)

Specificity (%)

Positive predictive value (%)

Negative predictive value (%)

Reed et al90 Gonzalez-Stawinski et al91 Cerfolio et al92

303 202

61 64

84 77

56 45

87 88

400

71

67

44

91

poorly differentiated large cell carcinoma) on the basis of the PET scan alone, provided that the surgeon is prepared to resect unexpected minimal N2 disease if found, on the basis that surgery alone offers a 20–35% chance of cure in this situation.35 This might be improved with adjuvant chemotherapy if the patient is fit for this treatment modality. Otherwise, invasive staging of the mediastinum should be carried out. This does not make PET useless. First, in the apparent stage I (and possibly II) patients with peripheral lesions it can allow lung resection to be carried out without surgical staging of the mediastinum. Second, because it is precisely the patients with the highest risk of unsuspected mediastinal disease who are also at highest risk of distant metastatic disease that PET has the highest chance of detecting otherwise occult stage IV disease. Integrated PET-CT has been shown to be more accurate than PET alone with correlation to a previously performed CT;79,80 however not to a degree that fundamentally changes this discussion about the indications for surgical staging of the mediastinum. Despite all our improvements in non-invasive staging, invasive staging remains the closest we have to a prethoracotomy gold standard for the detection of N2 disease. The risk factors for unsuspected N2 disease that we knew from the CT era of staging are still pertinent in the PET age. They are tumor size, location, and histology and PET-positive hilar nodes.35 Large tumors, central tumors and adenocarcinoma/poorly differentiated large cell carcinomas present the greatest risk of false-negative non-invasive staging. The true gold standard for the precise diagnosis and assessment of N2 disease remains the intra-operative systematic nodal dissection.17 This is not only a staging tool but could also have a beneficial effect on outcome.94–97 Magnetic resonance imaging MRI is little or no more accurate than CT in routine staging. Some authorities consider that the ability to visualize in planes other than axial gives MRI an advantage

Figure 9.10 An MRI scan of a patient with a right-sided Pancoast tumor. The scan gives coronal reconstruction of this difficult area, but also suggested nodes at the main carina, which were confirmed to contain metastatic disease at mediastinoscopy.

in difficult areas such as the lung apex and lower mediastinum.98 Most would recommend MRI when evaluating Pancoast tumor (Figure 9.10).99 With modern, fast, multislice CT scanners and the software to do multiplanar reconstructions many of the advantages of MRI have been obviated. If appropriately thin cuts are obtained, modern CT scanners have higher spatial resolution than MRI. However, MRI remains of value as a problem-solving tool looking at the central nervous system. MRI is more accurate than CT at detecting and characterizing brain lesions.45,46,100 If there is a clinical suspicion of brain metastases then MRI should be obtained unless there are local availability issues. We would also recommend its use if CT of the brain shows an abnormality (to rule out multifocal disease) or when clinical suspicion remains after a negative CT. The routine use of MRI as a screening tool for asymptomatic brain metastases has not been shown to be of value. Similarly, if the CT raises doubts as to tumor extension around the spine and into the spinal canal, MRI will give clearer definition and valuable information. Whenever a neurosurgical opinion is to be sought, MRI should be obtained beforehand.

112 Textbook of Lung Cancer

The tests described above should allow one to determine cTNM and, in appropriate cases, recommend thoracotomy. For the surgeon, however, the staging process does not end there. We have come to appreciate that a detailed re-evaluation at thoracotomy is a valuable step prior to proceeding with resection. Intrathoracic staging will evaluate areas of concern remaining after CT and subsequent mediastinal evaluation, search for additional pulmonary nodules and pleural deposits not seen on CT,101 and permit a thorough evaluation of nodal extent by systematic nodal dissection.102 There is debate as to the value of pleural lavage cytology as a routine step immediately after opening the chest. Kondo and his colleagues found positive pleural cytology in 9% of cases and showed it to be a strong indicator of poor prognosis.103 Other workers have confirmed the incidence of positive cytology but did not find a statistically significant influence on prognosis after resection.104 We have reviewed our experience with pleural lavage cytology. We found malignant cells in the lavage in 4.5% of the 292 patients studied. Positive pleural lavage had a statistically highly significant and independent impact on survival: patients with positive pleural lavage had a median survival of only 13 months, as compared to 49 months for those with a negative lavage.105 Despite rigorous preoperative staging with CT and, where appropriate, mediastinal exploration, cTNM has been shown to be inaccurate in over half of the patients coming to thoracotomy.106 Whilst occasionally cTNM will overestimate the extent of disease, in most cases the disease will be shown to be more extensive. As yet we do not know precisely how the integration of newer (a)

STEP 1

(b)

tools such as PET-CT will improve this. It is clearly important that the surgeon obtains such valuable insight into the extent of disease before making a decision whether to proceed with resection, and when judging the extent of pulmonary resection necessary to achieve complete resection. Systematic nodal dissection (SND) begins with the excision of all mediastinal fat and the lymph nodes contained therein (Figure 9.11). It is recommended that the nodes be labeled in accordance with an internationally recognized chart such as that proposed by Naruke (Figure 9.12)107 or that of Mountain and Dressler (Figure 9.13).3 It is our routine to slice these nodes at the operating table and examine the internal architecture before deciding whether rapid histologic confirmation is necessary by frozen section analysis. If resection is deemed possible we proceed to examine the N1 nodes similarly, in a centrifugal fashion, until the extent of resection has been determined. The only nodes remaining in the resection specimen can be assumed to be N1. In such a way the surgeon will ensure complete resection with the minimum resection of lung parenchyma. We have shown that SND will disclose N2 disease in 18% of patients coming to thoracotomy without histologic evidence preoperatively, and only 60% of patients will be shown to be node negative.108 This study confirmed that SND could not be omitted on the basis of cell type, tumor size, tumor origin, lobe of origin, or by preoperative mediastinal exploration. As ‘skip’ lesions to the mediastinal nodes without hilar node involvement were found in 6% of cases, the assessment of the mediastinum is important irrespective of the findings in STEP 2

Figure 9.11 An operative specimen showing fat and lymph node stations removed during the first step in SND (a). These can be correlated with the Naruke chart to show that a complete circumnavigation of the right side of the mediastinum has been accomplished. Step 2 of the nodal dissection (b) removes the nodes from the fissure and the hila of the individual lobes.

Staging, classification, and prognosis 113

1 2

1

4

5 10

10

7

13 12 14

2 3 6

10

14

2

3

2 4

1

10

10 10

10

10

11

11

12 11

8

14 13

12

8

13 14 14

14 13 12 13

13 14

13 8 13

13

14 14 9

1 3p

8

9

2 3 4

3a

9

1 Superior mediastinal or highest mediastinal 2 Paratracheal 3 Pretracheal 1 3a anterior mediastinal 3p retrotracheal or 2 3a 3 posterior mediastinal 6 4 Tracheobronchial 5 4 5 Subaoratic or Botallo’s 6 Paraaortic (ascending aorta) 7 Subcarinal 8 8 Paraesophageal (below carina) 9 Pulmonary ligament 9 10 Hilar 11 Interlobar 12 Lobar … upper lobe middle lobe and lower lobe 13 Segmental 14 Subsegmental

Figure 9.12 The nodal chart devised by Naruke. The lymph node stations are numbered: 1–9 indicate mediastinal nodal stations. (Reproduced with permission of Dr T Naruke and Mosby Inc from J Thorac Cardiovasc Surg 1978; 76: 832–9.107)

the hilum. If mediastinal node deposits are discovered at thoracotomy and yet complete resection has been confirmed to be feasible, the surgeon must decide whether to proceed with resection, balancing the reduced prospects of survival after complete resection and the added morbidity and mortality of pulmonary resection. The surgeon will be aware that the patient has already necessarily incurred the morbidity and mortality of thoracotomy (annual returns, The Society of Cardiothoracic Surgeons of Great Britain and Ireland), and will base the decision to resect upon the patient’s fitness, the extent of resection necessary, the cell type, and the number and position of positive nodes. Complete resection will be deemed appropriate in 85% of cases, although the perioperative mortality is higher and the five-year survival reduced to around 20–30%.64,83–85

Subsequent histologic examination of lymph node stations removed at surgery will show metastases that the surgeon had not appreciated in up to 9% of cases.109 The pathologist will also study the specimen and attached lymph nodes, looking for the presence of pleural invasion and satellite lesions that may have eluded the surgeon. Some authors have suggested that the use of monoclonal antibody stains will detect nodal deposits not seen with conventional stains in up to 6% of lymph nodes in 22% of patients.110 Others have suggested that this is the result of taking additional slices of the nodes and that the majority of such micrometastases will be found with conventional stains by more thorough histologic examination.111 To establish the pTNM the clinician will thus have to scrutinize the operative findings and study the detailed pathology report. The accuracy of pTNM will depend heavily on the detailed nature of such reports.

RESTAGING AFTER INDUCTION CHEMOTHERAPY A full discussion of the place of induction chemotherapy in the management of NSCLC is outside the remit of this chapter. However, if multimodality therapy is considered, restaging of the patient prior to surgery is of paramount importance. Recently there have been studies that have challenged the role of surgery in all but true minimal N2 disease (i.e. intracapsular, single node N2 disease found at the time of thoracotomy), showing apparently similar results with radical radiotherapy after induction chemotherapy.112–114 However, in one of these studies114 there was a significantly improved progression-free survival with surgery and a trend towards increased overall survival, and the authors concluded that surgery can be considered in fit patients, especially if a pneumonectomy will not be required. In another,112 the number of complete responses (only 4% overall) was far less than usually found and the pneumonectomy rate (50%) was unusually high, so it does seem fair to consider the results of the experience to date as inconclusive. The authors of this European trial112 themselves point out that we do not know what the outcome would be in the patients who are now considered to be the appropriate candidates for surgery, i.e. those who have been downstaged from N2 to N1 or N0. It is interesting to note that in this same study the locoregional recurrence rate was much lower in the surgery arm (55% vs 32% in the radiotherapy arm). Finally, RTOG 89-01 was closed prematurely to give priority to another trial, which will

114 Textbook of Lung Cancer Figure 9.13 The nodal chart established by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC) in 1997.3 (See color plate section, page xv)

weaken the conclusions that can be drawn from this trial.113 With induction chemotherapy, typically 30–50% of patients will have the N2 nodes cleared of cancer by the induction therapy. It is interesting to note that, when there was sequential induction therapy comprising chemotherapy followed by chemoradiation therapy, and when PET was performed at the outset, after the chemotherapy and at the end of the induction process it was the postchemotherapy PET (and not the PET post-total induction therapy) that was the better predictor of survival.115 If the N2 nodes have been cleared of cancer, the fiveyear survival ranges from 29 to 44%,35,116,117 and if a pathologic complete response is observed the five-year survival is estimated to be 54% (median survival not reached).118 If, on the other hand, this is not the case then the five-year survival is 7–24%, usually below the 10–15% range in most studies. This is why it is considered essential to restage the mediastinum after induction therapy to avoid futile and potentially dangerous thoracotomies and resections if there is persistent N2 disease. Unfortunately there is no perfect tool to restage the mediastinum.35

Repeat mediastinoscopy has been used to restage the mediastinum. The best results have been published (and recently updated) by the Antwerp group.119 Over 10 years they had 32 patients who underwent repeat mediastinoscopy after induction therapy. They were able to perform the procedure in all patients and had only five false-negative repeat mediastinoscopies, yielding a sensitivity of 71%, a specificity of 100% and an accuracy of 84%. De Leyn et al reported the Leuven experience of 30 prospectively studied patients and, in their hands, there were only five positive repeat mediastinoscopies. In 18 cases the node which had been positive at the first mediastinoscopy could not be adequately assessed because of extensive scarring and fibrosis. All patients underwent thoracotomy and the systematic nodal dissection revealed persistent N2 disease in 17. Therefore the sensitivity of repeat mediastinoscopy was 29%, its specificity was 100%, and its accuracy only 60%.120 A Dutch group reported their experience with repeat mediastinoscopy in 15 patients. In 6 patients the procedure was considered to be inadequate; there were 9 adequate procedures – 2 were true positives and 2 were false negatives.121 The conclusion must be that in the real world repeat mediastinoscopy

Staging, classification, and prognosis 115

is a challenging operation with insufficiently robust results to recommend its routine use for restaging of the mediastinum after induction therapy. CT scanning is even more inaccurate for restaging than it is for primary staging.35 PET, when used for restaging the mediastinum after induction therapy, is less accurate than when used for primary staging, with a sensitivity of 50–60% and a specificity of 85–90%.35 Fused PET-CT is better that PET alone in this situation and in one study (with by far the best results) the sensitivity was 77%, the specificity was 92%, and the accuracy was 83%.120 However the results of fused PET-CT are not usually as good as this.35 Again, a variety of FNAB techniques have been described, with essentially the same sensitivity and specificity as when used in the chemo-naïve setting. Thus restaging of the mediastinum after induction therapy in N2 disease remains a fraught subject, often requiring a complex step-wise approach with CT, PET-CT, trans-tracheal or esophageal FNAB, and repeat mediastinoscopy, and still with a risk of false-negative assessment of the mediastinum.35 As we have seen, tissue diagnosis is the ideal restaging tool, but it is difficult and, even in the best hands, it will always have a finite false-negative rate; it also requires heavy use of time and resources, and can submit the patient to multiple procedures. PET has been shown to be an alternative, or surrogate way to restage the mediastinum after induction therapy. Cerfolio et al have published two papers on an overlapping patient population, looking at the change in the SUV max on PET before and after induction chemotherapy.122,123 In the first study122 they demonstrated that a drop in SUV max of 80% in the primary tumor predicted a pathologic complete response with a sensitivity of 90%, a specificity of 100%, and an accuracy of 96%. These results are roughly as accurate as the best combined invasive restaging strategies. In the second study123 they showed that a drop in SUV max of 75% predicted complete response. If the SUV max in the mediastinal nodes decreased by 55% there was a very high chance of being a partial responder. The median decrease in SUV max was 100% (range 75–100%) in complete responders, 58% (range 2–100%) in patients who had a complete response in the N2 nodes but residual viable tumor in the primary tumor, and 32% (range ⫺5–82%) in patients with residual N2 disease. In terms of N2 disease, PET-CT was less reliable. A decrease of SUV max of >55% had a likelihood ratio of 9.1 in predicting clearance of the N2 nodes, but in reality residual N2 disease was missed by PET-CT in 13/65 patients (20%). One group studied the SUV max before and after induction

chemotherapy.124 These patients underwent induction chemotherapy followed by chemo-radiation therapy then surgery. A PET-CT was performed at time 0, after the chemotherapy (t1), and at the end of the induction process (t2). Patients with either a complete response or less than 10% viable tumor cells in the tumor had a drop in SUV max of 67% at t1 and 73% at t2. Follow-up was short so the survival data are difficult to interpret. Another group used PET to study the metabolic rate of glucose.125 The multivariate analysis showed that the absence of N2/N3 disease at PET had a survival hazard ratio of 2.33 (95% CI 1.04–5.22; p <0.04). Reading from the graphs, this translates into a three-year survival of a little under 0.6 for N2/N3 negative patients vs around 0.25 for those with N2/N3 disease. The hazard ratio for each 10% drop in the metabolic rate of glucose was 0.99 (95% CI 0.98–0.99; p <0.01). A residual metabolic rate of glucose after induction of ≤0.13 had a hazard ratio of 1.95 (95% CI 1.28–2.97; p <0.002). Again, looking at the graphs this translates into a threeyear survival of around 0.6 vs 0 for a value >0.013. Restaging with PET may also reveal previously undetected metastases after induction chemotherapy. This was seen in 9/47 patients in one study,126 and in 10/56 in another.127 The only alternative would be to try to stage the mediastinum with any of the variety of FNAB techniques, and, if that fails but there is a high index of clinical suspicion of N2 disease, administer induction chemotherapy to the patient. This would allow mediastinoscopy to be performed in an unscarred mediastinum, hopefully with a much higher sensitivity. However this approach is unvalidated at present. There is one important pitfall with the whole concept of offering patients induction chemotherapy. The harsh reality is that only 30–50% of patients will be downstaged and offered surgery, the rest going on to radical radiotherapy. This means that their chemo-radiation therapy will be sequential instead of concurrent, and there is a consensus now that concurrent chemoradiotherapy is the standard of care in stage IIIA and IIIB disease. The patient needs to be aware of this when consent is sought for induction therapy.

OTHER PROGNOSTIC INDICATORS Table 9.6 summarizes known or supposed prognostic factors in surgically resected NSCLC. Cell type is not per se a prognostic indicator,128 but as we have discussed previously certain cell types (adenocarcinoma and large

116 Textbook of Lung Cancer Table 9.6 Prognostic factors in surgically resected NSCLC Prognostic factors

Tumor related

Host related

Environment related

Essential

T category N category Extracapsular nodal extension Superior sulcus location Intrapulmonary metastases Histologic type Grade Vessel invasion Tumor size Molecular/biologic markers

Weight loss Performance status

Resection margins Adequacy of mediastinal dissection

Gender Age

Radiotherapy dose Adjuvant radiotherapy

Additional

New and promising

Quality of life Marital status

Published with kind permission of the editors and the UICC.129

cell poorly differentiated carcinoma) represent a risk factor for presenting at a higher stage of disease. The failure of screening to improve survival in a screened population129 is in part due to so so-called overdiagnosis of indolent disease, proving that the term indolent adenocarcinoma is not an oxymoron. Only performance status equals stage in its impact on survival after all treatment modalities. Others factors such as weight loss and the presence of systemic symptoms are accepted as important. Cell type, degree of differentiation, and vascular invasion may be significant, but reports vary depending upon stage and whether surgery was possible.130 Sex is a prognostic indicator – females have better survival independently of TNM stage and histology.131–133 Age has an impact on treatment but is not an independent variable. Certainly information on these factors should be recorded and data presented in any report of results. There is great interest in biologic markers in lung cancer, and the hope that a panel of markers, including oncogenes and tumor suppresser genes, can provide an independent, biologic method of anticipating outcome. At present our knowledge of these markers is imperfect, and there are still no markers that have translated into the clinical setting because they do not discriminate in a sufficiently robust way to allow therapeutic decisions to be made.130 It is recommended that, where possible, cryopreserved tissue from well-staged, surgical specimens should be stored for future studies. On-going smoking is increasingly found to have an effect on prognosis. All textbooks cite that the risk of developing a second primary lung cancer following

successful management of NSCLC is 1% per patientyear, and this is doubled if the patient continues to smoke. It is now starting to emerge that smoking can interfere with the effectiveness of radiotherapy.134 Similarly, smoking can reduce the effectiveness of chemotherapy upregulation of the pathways targeted by chemotherapy, thus inhibiting chemotherapy-induced apoptosis.135 Smoking has a particularly strong inhibitory effect on tyrosine-kinase inhibitors (TKIs). The BR.21 study on erlotinib in NSCLC showed that plasma concentrations of the drug were around twice as high in non-smokers and ex-smokers compared to current smokers. This is attributed to a lack of induction of cytochrome P450 1 A isoforms by cigarette smoke as well as a higher incidence of K-ras mutations in smokers resulting in faster plasma clearance of erlotinib in smokers.136 Genomics are starting to show promise in identifying patients at high risk of recurrence.137 It remains to be proven whether these patients will benefit from more aggressive postoperative chemotherapy. Similarly, ERCC1 is an enzyme that can repair the DNA damage induced by cisplatin. When cisplatin-based adjuvant chemotherapy was given to patients, those with tumors that were ERCC1-negative had a significantly longer survival than those with ERCC1-positive tumors.138 The SUV max also seems to indicate prognosis.139 When the SUV max is higher than 10, tumors tend to be more likely to be poorly differentiated and to present at a higher stage. For each stage, if the SUV max is greater than the median value seen for that stage this also tends to indicate a poorer prognosis – for example

Staging, classification, and prognosis 117

in stage IB NSCLC the four-year survival was 80% for a SUV max lower than median, and only 66% when it was higher than the median (p = 0.048). These values were, respectively, 64% vs 32% (p = 0.028) for stage II and 64% vs 16% (p = 0.012) for stage IIIA.

PROGNOSIS The survival of patients with each stage of disease is discussed in detail in the chapters on treatment in this book, but a few comments are pertinent when considering staging. When reading the literature on the results of treatment of lung cancer, especially surgical series, the reader is reminded of two phenomena: what Shields has termed ‘the diminishing denominator’,140 and the impact of ‘stage migration’ or the Will Rogers effect.141 The diminishing denominator can give a false impression of the value of surgery in an advanced stage of lung cancer by reporting only the results on patients found to be within this stage at thoracotomy and surviving complete resection. Other patients are ‘censored’ from the analysis if found at thoracotomy not to fall into the study population, if resection is not possible, if incomplete resection has been performed, and even if dying after operation. The reported survival of patients in this stage who survive complete resection gives little guidance to the clinician armed only with cTNM, and results are further inflated by the use of actuarial survival statistics. Thus 300 patients with a presumptive advanced stage (IIIA for example) may proceed to thoracotomy. Eighty will be found to be in a lesser stage at thoracotomy, 60 will be technically irresectable (so-called open and close thoracotomy), 95 will undergo an incomplete resection (R1 or R2, as described in a previous section), and 15 will die after surgery. The analysis is thus restricted to the 50 patients who survived a complete resection for the designated advanced stage. Therefore the actuarial survival of the 10 who survive to five years after complete resection is computed to be 20%. Whilst this may impress the unwary, closer study reveals that more patients (15) will die of such unwarranted surgery than those in whom the prognosis is improved, at a cost of 220 major operations and much morbidity. Stage migration is an inevitable consequence of more detailed staging. As one refines the group under study, those eliminated usually cascade into the more advanced stages, swelling their numbers, although a few will prove to have less advanced stage disease. These new recruits to the higher stages have a better prognosis

than the original patients do in that group, defined by cruder staging techniques, and the prognosis of the group is thus improved. The shifting populations are evident in any study giving details of the results of surgery based upon cTNM and pTNM. In one study,142 the number of patients who fell into the T1N0 category fell from 349 to 264 when shifting from cTNM to pTNM and, conversely, the number of patients with T3N0 disease rose from 109 to 147. This demonstrates the improved staging achieved by thoracotomy. The fiveyear survival of patients based upon pTNM will always be superior to that based upon cTNM, and this effect is more pronounced in higher stage groups. In another study,2 the five-year survival of T1N0 patients rose from 61% to 67%, a 10% improvement, when moving from cTNM to pTNM, whilst survival of T3N0 patients rose from 22% to 38%, an improvement of 87% in the survival of this group. These statistical realities are legitimate, but one must resist the temptation to attribute the improved survival to the staging evaluation itself. The prognosis of NSCLC is very variable in different series. This is often a reflection of the rigor of both the pre- and intra-operative staging of the cancer. If pre-operative staging is not completely thorough there will be 10–20% undetected N2 disease at thoracotomy, provided that intra-operative staging has been done as it should. However, there are still many centers that do not routinely perform systematic nodal dissection (which in itself is a term which is often abused). A telltale sign is the five-year survival of stage I NSCLC. In properly staged patients this will be around 80%, down to around 65% when staging is less rigorous. Stage migration will then deploy its effects as stage progresses. When evaluating the benefits of any treatment for lung cancer it is important to study each paper carefully, to determine the true denominator, and to note all the tests used to define the population under study. Thus the reader may be better able to place into context the results reported in the following chapters.

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FURTHER READING Rami-Porta R, Ball D, Crowley J et al. on behalf of the International Staging Committee. The IASLC Lung Cancer Staging Project: proposals for the revision of the T Descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2007; 2: 593–602. Rusch VW, Crowley J, Giroux DJ et al. on behalf of the International Staging Committee on Cancer Research and Biostatistics. The IASLC Lung Cancer Staging Project: proposals for the revision of the N Descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2007; 2: 603–12. Postmus PE, Brambilla E, Chansky K et al. on behalf of the International Staging Committee. The IASLC Lung Cancer Staging Project: proposals for revision of the M Descriptors in the

forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2007; 2: 686–93. Groome PA, Bolejack V, Crowley JJ et al. on behalf of the International Staging Committee, Cancer Research and Biostatistics. The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M Descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumors. J Thorac Oncol 2007; 2: 694–705. Groome PA, Bolejack V, Crowley JJ et al. on behalf of the International Staging Committee, Cancer Research and Biostatistics. 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 tumors. J Thorac Oncol 2007; 2: 706–14.

10 Treatment of non-small cell lung cancer 10.1 Treatment of NSCLC: surgery Robert J Korst Contents Introduction • Historical summary • Stage I disease (T1–2N0) • Stage II disease (T1–2N1 and T3N0) • Stage III disease • Stage IV disease • Special considerations • Palliative surgery • Summary

INTRODUCTION Lung cancer is one of the leading causes of cancer death worldwide. Approximately 80% of cases of newly diagnosed lung cancer are of the non-small cell type (NSCLC). Unfortunately, a large percentage of these patients will have inoperable disease on the basis of distant metastases (stage IV) or locally advanced disease (stage IIIB). For the remaining patients with early stage disease (stage I and II), as well as selected patients with locally advanced disease (stage IIIA), complete surgical resection remains the best hope for cure, provided that the operative risk is tolerable. Over the past four decades, several points regarding the conduct of resection have become accepted as the surgical management of NSCLC has evolved. First, incomplete resections leaving either gross or microscopic disease behind will fail to cure the disease and are rarely indicated in a palliative setting. Intraoperative frozen section analysis should be employed frequently to ensure negative margins. Second, general oncologic principles should be followed, including the resection of the tumor and surrounding normal lung (lobectomy or pneumonectomy) with draining lymphatics and lymph nodes. Third, the mediastinal lymph nodes should be dissected to accurately stage the patient, and fourth, en bloc resection of the tumor and surrounding structures is desirable whenever technically possible. Survival following surgical resection for NSCLC is stage-dependent (Table 10.1.1). Despite the development of the principles mentioned above, less than 15% of all patients can presently be expected to be cured of their disease. This dismal figure underscores the need for prevention as well as continued investigation into better treatment options for patients with NSCLC. HISTORICAL SUMMARY Although non-anatomic pulmonary resection for lung cancer had been reported in 1895, the first anatomic

lobectomy was performed by Davies in 1912. It was not until the advent of an effective underwater drainage system, however, that pulmonary resection could safely be performed on more of a routine basis. Following a report by Graham of the first pneumonectomy in 1933, surgical resection became the treatment of choice for lung cancer. Over the next several decades, various types of anatomic lung resections continued to be described, including segmentectomy, sleeve lobectomy, and pneumonectomy, as well as resection for superior sulcus tumors. Through the 1970s and 1980s, it became recognized that despite radical resection with negative margins, many patients with resected NSCLC ultimately died of their disease, with the majority of recurrences being distant metastases. This fact was especially true for patients found to have disease metastatic to the lymph nodes (locally advanced disease) at the time of resection. As a result of this observation, strategies which combine treatment modalities (surgery, chemotherapy, and radiation) are becoming more popular and are the subject of active investigation for nearly all stages of NSCLC. In addition, recent breakthroughs in the use of adjuvant chemotherapy following complete resection of NSCLC are changing the postoperative management of patients with this deadly disease. STAGE I DISEASE (T1–2N0) Patients with this early stage of NSCLC typically present without symptoms and most are cured with primary surgical excision. These tumors are usually peripheral in location and are discovered on a routine chest radiograph. These peripheral ‘coin lesions’ are mainly adenocarcinomas, or bronchioloalveolar carcinomas. Uncommonly, a radiographically ‘occult’ tumor may be discovered. Unlike the peripheral lesions, occult tumors are mainly squamous in histology and patients may present with hemoptysis. Not infrequently, occult tumors are detected during screening bronchoscopy after a previous lung

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Table 10.1.1 Survival following resection for NSCLC by stage (see text for references) Stage

Stage I Overall T1N0M0 T2N0M0 Stage II T1–2N1M0 T3N0M0 Chest wall invasion Mediastinal invasion Proximal bronchus Stage III N2 Clinically negative mediastinum Clinically positive mediastinum

Five-year survival (%)

76 84 68 47 56 29 36

34 9

cancer resection,1 or in patients who have undergone bronchoscopy as part of the work-up for another process, such as head and neck or esophageal cancer. Complete surgical excision is the treatment of choice for stage I NSCLC, provided the operative risk is acceptable. Patients should undergo preoperative pulmonary function testing to assess lung reserve, as well as cardiac evaluation if indicated from the patient’s history. The operation of choice is anatomic lobectomy. Occasionally, a more extensive resection needs to be performed when the location of the tumor is such that removal of a single lobe is not adequate. When the tumor protrudes into the mainstem bronchus, sleeve lobectomy is the procedure of choice to obtain negative bronchial margins; however, a tumor involving the bronchus intermedius usually requires a bilobectomy, while a lesion more extensively involving the mainstem bronchus requires pneumonectomy. Pneumonectomy may also be indicated in the rare circumstance when the tumor is closely associated with the proximal, extrapericardial pulmonary artery. For upper lobe lesions that invade the pulmonary artery to the lower lobe a vascular sleeve resection can be performed, sparing the lower lobe. Multiple series now suggest that sleeve resection for central tumors produces results similar to that seen with pneumonectomy from an oncologic standpoint.2,3 Although limited resections (wedge resection or segmentectomy) remain an option for patients with poor

pulmonary reserve, this practice should be avoided whenever possible due to the higher rate of local recurrence and trend toward decreased long-term survival when these lesser resections are performed, a standard set by the results of The Lung Cancer Study Group (LCSG) trial 821.4 In this study, patients with T1N0 NSCLC were randomized to undergo either lobectomy or limited resection (wedge resection or segmentectomy). Patients who underwent limited resection had a significantly higher rate of local recurrence than those in the lobectomy group, with a survival difference approaching statistical significance. However, in the modern era of lung cancer screening using computed tomography (CT), many tumors are detected while still very small (<1–2 cm). This observation, combined with the emergence of retrospective studies reporting excellent survival rates following limited resection for small, T1 lung cancers,5,6 suggests that a trial similar to LCSG 821 should be initiated to reset the standard for these very small, screen-detected tumors. Most anatomic pulmonary resections for stage I NSCLC have traditionally been performed using a posterolateral thoracotomy, during which a rib-spreading retractor is utilized. However, many surgeons now undertake these resections using a complete, videothoracoscopic (VATS) approach. The most commonly performed type of VATS resection involves the creation of two thoracoscopy ports as well as a 6–8 cm ‘utility’ incision, the latter used for dissection of the hilum as well as specimen retrieval. Multiple published reports have suggested that anatomic pulmonary resections can be performed safely, and are oncologically sound when performed via VATS for early-stage lung cancer.7,8 Additional benefits include less postoperative discomfort as well as decreased length of hospital stay with the VATS approach compared to open thoracotomy. As a result, VATS lobectomy has replaced its open counterpart for the management of stage I lung cancer in many centers. Although it has been suggested that mediastinal lymph node dissection is unnecessary in patients with very small T1 tumors, the vast majority of patients undergoing resection for NSCLC should have this procedure routinely performed. Although this approach has never definitively been shown to improve survival, it is the only way to accurately stage a patient’s disease, and adds very little time and morbidity to the operation. In addition, approximately 16% of patients with peripheral T1N0 tumors where the primary tumor is less than 3 cm in size will have mediastinal node metastases.9 When resecting a right-sided tumor, the right paratracheal, pretracheal, subcarinal, and inferior pulmonary

Treatment of NSCLC: surgery 125

ligament nodes should be dissected. On the left, the preaortic, aortopulmonary window, subcarinal and inferior pulmonary ligament nodes are accessible. Given the uncertain survival benefit of complete mediastinal lymph node dissection for early-stage NSCLC, a randomized trial conducted by The American College of Surgeons Oncology Group is currently underway to investigate this question. Operative mortality following pulmonary lobectomy for all stages of disease should not surpass 2%, but should be considerably less for patients with stage I disease. Morbidity and mortality increase with higher stages of disease and extended resections. Operative mortality following pneumonectomy is near 6% in most series, with some being even lower.10 The five-year survival for patients with completely resected T1N0 lesions surpasses 80% in some reports, while this figure is reduced to approximately 65% for T2N0 tumors. The overall five-year survival for patients with completely resected stage I NSCLC is approximately 75%.11 Recurrences following complete resection for stage I NSCLC are mainly in the form of distant metastases, as displayed in Table 10.1.2. No form of adjuvant therapy has traditionally been recommended for patients undergoing resection of stage I NSCLC. Recent randomized trials, however, have suggested a small survival benefit for patients with completely resected stage IB-III NSCLC. One of these, the National Cancer Institute of Canada Clinical Trials Group (NCIC) trial JBR.10, randomized 482 patients with stage IB or II NSCLC to either surgery alone or platinum-based adjuvant chemotherapy.13 Patients in the adjuvant therapy arm enjoyed significantly longer overall survival (69% vs 54% at five years) compared to those who underwent surgery alone. Despite this, mature results of the Cancer and Leukemia Group B (CALGB) 9633 trial, performed exclusively in stage IB patients, did not support these findings. CALGB 9633 randomized

Table 10.1.2 Sites of first distant recurrence following resection in 159 patients with stage I NSCLC lung cancer12 Site

Brain Lung Liver Bone Other Disseminated

Number

51 20 14 11 8 5

344 patients with stage IB NSCLC to either surgery alone or surgery followed by four cycles of paclitaxel/ carboplatin chemotherapy.14 No statistically significant difference in survival was noted between groups. As a result, the role of adjuvant chemotherapy in the management of patients with completely resected stage IB NSCLC remains controversial. Many clinicians will recommend adjuvant chemotherapy to these patients if their tumors appear to possess characteristics associated with a poor prognosis (e.g. tumors greater than 5 centimeters, vascular/lymphatic invasion). Adjuvant radiotherapy is currently not recommended for patients with completely resected stage I NSCLC, in light of the results of a meta-analysis showing that postoperative radiotherapy may increase mortality in these patients.15 Most clinicians would agree that patients require follow-up after resection for NSCLC; however, the nature of the follow-up regimen remains controversial. Given the poor prognosis associated with recurrent metastatic disease in patients who have undergone resection of NSCLC, follow-up regimens should probably be geared toward the detection of second primary lung cancer (SPLC), which occurs with an annual cumulative incidence of 2% per patient/year of follow-up.16 Recent published data suggest that serial computed tomography (CT) of the chest has the ability to detect SPLC while still in its early stages;17 however, the cost-effectiveness of this approach has not yet been substantiated.

STAGE II DISEASE (T1–2N1 AND T3N0) N1 disease Patients with T1–2N1 NSCLC represent a small subset in the spectrum of this disease, usually comprising less than 10% of patients coming to surgery. As with stage I, the majority of patients can be effectively treated with lobectomy, although about a third will require pneumonectomy, mainly due to involved hilar lymph nodes adherent to the pulmonary artery or major bronchi. Similar to stage I disease, it is important to perform a thorough mediastinal lymph node dissection in this group of patients, especially since there is a higher incidence of occult N2 disease. Recurrence following complete resection for T1–2N1 NSCLC is common, with five-year survival rates approaching only 45%.18 As with stage I, the most common form of recurrence is distant metastatic disease, especially if the tumor is an adenocarcinoma. Patients enjoying a better prognosis tend to be those with small primary tumors, squamous histology, and only one involved lymph node.

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T3N0 disease Chest wall involvement T3 tumors invading the chest wall are readily amenable to surgical resection. As a general guideline, one rib above and one below the gross margin of the tumor should be taken to ensure negative margins. Although en bloc resection is desirable and should be achieved whenever possible, discontinuous resection can be done when absolutely necessary as long as meticulous attention is paid toward documenting margins. It currently remains controversial whether a complete chest wall resection, including ribs, is necessary for tumors invading only the parietal pleura. A parietal pleurectomy with negative deep margins may be sufficient, but should be used with extreme caution. Following resection, the issue of chest wall reconstruction needs to be addressed. The first question regarding this is whether the chest wall reconstruction is really necessary, and this usually depends on the assessment of chest wall stability. After resection of short segments of one or two ribs, or up to three posterior segments under the paraspinous muscles or scapula, reconstruction is not usually necessary. When reconstruction is undertaken, the marlex/methylmethacrylate sandwich technique readily restores stability and prevents the flail chest phenomenon during breathing (Figure 10.1.1). A Gore-Tex patch, stretched tightly, has also been used with acceptable results. Mortality following chest wall resection is low, but is related to the size and location of the defect in the chest wall, the amount of lung resected, and the technique of reconstruction. Factors which affect long-term survival following resection of these tumors are the extent of chest wall involvement, the ability to completely resect the tumor, and the presence or absence of lymph node involvement. The overall five-year survival of patients with T3N0M0 tumors invading the chest wall undergoing complete en bloc surgical resection is approximately 50–60%.19 Patients with a T3N0M0 tumor that involves only the parietal pleura have a better prognosis than those where the tumor invades into muscle and ribs. Tumors invading the mediastinum Tumors invading the mediastinal pleura, fat, nerves, and pericardium, but not the major mediastinal vessels or organs, represent another subset of the T3 classification. These patients have a notoriously poor five-year survival following surgical resection alone. In part, this poor survival is due to the high likelihood of mediastinal node metastases and the low rate of complete resection

Figure 10.1.1 Stage IIB NSCLC (T3N0M0) invading the chest wall. (a) Chest CT revealing a large lung mass invading the chest wall. Cervical mediastinoscopy was negative, while transthoracic needle aspiration revealed large cell carcinoma.(b) Chest radiograph following right upper lobectomy, mediastinal lymph node dissection, and resection of the involved chest wall. Stable reconstruction was achieved using a marlex mesh and methylmethacrylate prosthesis.

attained when the mediastinum is invaded. Additionally, even when these tumors are completely resected and the mediastinal nodes are negative, patients with T3 disease invading the mediastinum have a worse prognosis when compared to other types of T3 tumors.20 Due to the high frequency of N2 disease, patients with evidence of mediastinal invasion on CT scan should undergo cervical mediastinoscopy to rule out nodal involvement or T4 disease. If N2 disease is detected, induction (neo-adjuvant) therapy may offer these patients a better chance at long-term survival, if surgical resection is being considered. If there is no N2, N3, or T4 disease found at mediastinoscopy, these patients can undergo primary surgical resection with five-year survival rates of 30% if complete resection can be performed.20

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Tumors in proximity to the carina Tumors within 2 cm but not involving the main carina comprise another subset of T3 tumors. As with the other T3 tumors, patients with these proximal bronchial lesions are candidates for surgical resection. Technical considerations when resecting tumors involving the main bronchi pertain to the extent of resection, intraoperative airway management, and techniques of sleeve resection. Small, solitary squamous cell lesions confined to the left main bronchus with no invasion through the bronchial wall can very occasionally be handled with excision of the main bronchus alone, with total lung preservation and primary anastomosis. However, frequently these lesions are multiple and are best treated with endobronchial laser or radiation (brachytherapy). If resection is being considered for a solitary, proximal lesion on the right, however, usually a pneumonectomy or right upper lobe sleeve resection is required due to the close proximity of the right upper lobe orifice to the main bronchus. Sleeve lobectomy (vs pneumonectomy) is the preferred resection when possible for tumors extending into the orifice of the lobar or mainstem bronchus. When invasion into peribronchial tissues or N1 disease is present, sleeve lobectomy can be attempted if the disease is limited, but pneumonectomy is usually required for extranodal spread. If the tumor extends very close to the carina, resection of the main bronchus flush with the trachea may be required to encompass the tumor with negative margins. In this case, stapling of the bronchial stump may not be possible and a hand-sewn closure may be required. If not, tracheal sleeve pneumonectomy is the procedure of choice. Airway management and ventilation are of paramount importance when the proximal bronchi are resected. Standard double lumen endobronchial tubes or endobronchial blockers with single lung ventilation can be utilized for sleeve resections of the main bronchi. Tracheal sleeve pneumonectomy requires ventilation of the distal remaining lung. This problem can be handled in several ways, including passage of a thin, single lumen endotracheal tube past the anastomotic site, jet ventilation into the distal lung, or in-field ventilation through the open bronchus using sterile ventilator tubing. Factors which adversely affect long-term survival following resection include peribronchial extension of the tumor and the presence of N2 nodal metastases. Overall five-year survival following complete resection for tumors within 2 cm of the carina is currently reported to be 36%;21 however, patients with tumor confined to the main bronchi with no invasion of peribronchial tis-

sues or associated N2 disease have been reported to have a five-year survival of 80% in one series.22 Patients with T3 tumors approaching the carina associated with N2 nodal metastases separate from the primary tumor (‘true’ N2) have a negligible five-year survival. Patients with N2 disease which is present by virtue of direct spread from the primary tumor, however, remain surgical candidates. Therefore, it is mandatory to perform cervical mediastinoscopy prior to an attempted resection to identify those patients with ‘true’ mediastinal nodal disease who would receive no benefit from primary surgical resection. If N2 nodes are identified at cervical mediastinoscopy, induction therapy may be of value, but this awaits clinical trials. The role of adjuvant therapy for stage II NSCLC has evolved similar to that for stage I disease. The previously mentioned Canadian trial13 demonstrated a small, but significant survival benefit of adjuvant, platinumbased chemotherapy for patients with stage II NSCLC who have undergone complete surgical resection. Although no clear survival benefit has been noted, patients with incompletely resected tumors or those with mediastinal nodal metastases should receive postoperative radiation therapy to decrease the incidence of local recurrence.15 Intraoperative implantation of radioisotopes may potentially be of some benefit for those patients who undergo an incomplete resection. The role of induction chemoradiotherapy in poor prognostic T3 tumors (N2 disease, full thickness chest wall invasion) is now being investigated.

STAGE III DISEASE Stage IIIA (T3N1) disease T3 tumors with associated ipsilateral bronchopulmonary or hilar lymph node involvement comprise the first category of stage IIIA disease. The preferred treatment is, again, complete resection via lobectomy with mediastinal lymph node dissection. The previously mentioned issues concerning N1 disease apply in this setting as well. Stage IIIA (N2) disease The decision to perform primary surgical resection for patients with N2 disease requires careful preoperative selection, since the overall five-year survival for patients with N2 disease undergoing surgical resection alone is a mere 5–15%. Those with only single station, intracapsular nodal disease, T1 primary tumors, and ‘clinically’ negative mediastinums by mediastinoscopy or CT

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scanning are reported to enjoy a five-year survival of approximately 30% following complete surgical resection, compared to less than 10% for those with ‘bulky’ N2 disease identified preoperatively and those with associated T3 primary tumors.23 Patients with left upper lobe tumors and N2 disease confined to level 5 or 6 have the best prognosis of all, with five-year survival rates as high as 42% when completely resected.24 Unfortunately, patients with ‘minimal’ N2 involvement for whom primary surgery is beneficial represent a small fraction of all patients with N2 disease, and clearly further therapeutic advances need to be made for those patients with bulky, ‘clinical’ N2 disease. Although adjuvant radiotherapy provides no survival benefit compared to surgery alone, a reduction in local recurrence is seen.15 Unfortunately, 80% of patients undergoing surgical resection for NSCLC with N2 nodal disease recur at distant metastatic sites (especially brain), suggesting that further systemic therapy is needed to improve survival. Postoperative, adjuvant chemotherapy has been used in an attempt to improve survival for patients with resected stage IIIA (N2) NSCLC. Until recently, however, this strategy has not been shown to be of significant benefit in the adjuvant setting. In this regard, a meta-analysis of 52 previously conducted randomized trials of adjuvant chemotherapy for completely resected NSCLC suggested only a small advantage (5% at five years) of cisplatin-based chemotherapeutic regimens given in the adjuvant setting.25 As a result of the metaanalysis, the International Adjuvant Lung Cancer Trial (IALT) randomized 1867 patients with completely resected NSCLC to either observation or cisplatin-based chemotherapy.26 Of these, nearly 40% had stage III disease. The overall survival rate across all stages was significantly higher in the chemotherapy group (44.5% at five years) versus the surgery alone group (40.4%), representing a small, but significant advantage. Subgroup analysis, however, revealed that the patients which received the most benefit were those with stage III disease. Data from Japan has suggested a significant survival advantage for patients receiving oral tegafur plus uracil (UFT) following complete surgical resection of NSCLC compared with surgery alone. Although these results have not been reproduced in all studies using this strategy, and no data exist outside of Japan, a recent metaanalysis including data from 2003 patients demonstrated that adjuvant therapy with UFT does indeed provide a survival advantage.27 However, this agent is not available for use in the USA.

Multimodality therapy Induction chemotherapy emerged as an option for patients with N2 disease after it became clear that only a minority of these patients benefit from surgical resection alone and that preoperative radiation therapy has no effect on survival. To date, many phase II trials of induction chemotherapy or chemoradiation therapy both with and without postoperative adjuvant therapy have been reported. Preoperative chemotherapy, such as the MVP regimen utilized at The Memorial Sloan Kettering Cancer Center and The University of Toronto, has shown survival benefit in this group of patients when compared to historical controls.28,29 The majority of reports, however, deal with preoperative chemoradiation and essentially mirror the results of the previously mentioned induction chemotherapy trials. Although hundreds of patients have been enrolled in such phase II studies, no real effect of the treatment can be assessed for two reasons. First, the chemotherapy and radiotherapy protocols have varied widely from one trial to the next, as did the extent of preoperative staging, making the results difficult to interpret. Second, patients in these phase II trials are not randomized, and therefore no control groups exist other than historical data. Three small phase III trials do exist comparing induction chemotherapy and surgical resection to surgical resection alone in the treatment of patients with N2 disease (Table 10.1.3). Although different chemotherapy protocols were utilized and the numbers were small, the survival rates were significantly higher in two of these studies30,31 in the chemotherapy groups compared to the control arms, with the third showing a similar trend.32 Surprisingly, in all three studies, the rate of complete resection was no different in the treatment arms compared to the control arms. These three small phase III trials and the phase II trials that have been matched to historical controls seem to suggest an improvement in survival for these patients, at least with induction chemotherapy, but the results of current, larger phase III trials for N2 disease will be important, especially since a French trial suggested no benefit of induction chemotherapy for patients with N2 disease.33 Treatment-related mortality in the induction trials has resulted from the chemotherapy, radiation therapy, and surgery, or a combination of these modalities. Most trials report a treatment-related death rate in the range of 5–15%. Chemotherapy-related deaths are dependent on the specific agent and dose, as well as the immunosuppressive effects of these drugs. Morbidity following induction chemotherapy can be manifested in several organ systems. Pulmonary function studies should be

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Table 10.1.3 Three phase III trials of induction chemotherapy for NSCLC with ipsilateral mediastinal lymph node metastases Author

Number of patientsa

Chemotherapy agents

Percent resectablea

Median survivala,b

Pass32

13/14

85/86

29/16

Roth30

26/32

61/66

64/11

Rosell31

30/30

Cisplatin Etoposide Cisplatin Etoposide Cyclophosphamide Mitomycin Ifosfamide Cisplatin

85/90

26/8

a

Induction chemotherapy followed by surgery group/surgery alone group. Overall median survival in months.

b

repeated after induction chemotherapy to assess the pulmonary effects of such drugs as mitomycin and cyclophosphamide, which appear to be toxic to both the pulmonary endothelium and epithelium, resulting in impaired diffusion of gases. Cardiac toxicity of doxorubicin should be assessed with a myocardial imaging study following the administration of this drug, and creatinine clearance should be measured following treatment with cisplatin and the vinca alkaloids if the serum creatinine level has become elevated. These chemotherapyspecific toxicities demand that the induction chemotherapy patient be monitored more closely in the perioperative period to prevent failure of an already compromised organ system. Bronchial obstruction needs to be relieved prior to the administration of cytotoxic drugs to avoid postobstructive pneumonia and death during leukopenic events. This can be handled either with radiation therapy or endobronchial resection techniques/stents. Radiation therapy is also associated with toxicity that, when given in combination with chemotherapy and surgery, can result in the patient’s demise. Examples include the enhanced pulmonary toxicity when radiation therapy is used with mitomycin, the myocardial damage when used with doxorubicin, and the higher incidence of bronchopleural fistula in irradiated patients following pulmonary resection. Morbidity and mortality from the surgical procedure itself can be minimized by careful anesthetic management, close perioperative monitoring of cardiac, pulmonary, and fluid status, as well as some specific interventions to treat certain toxicities. For example, mitomycin pulmonary toxicity appears to be exacerbated by high inspired oxygen fractions. Therefore, the lowest possible oxygen concentration in the inspired gases should be used, while maintaining adequate oxygenation of the blood.

Perioperative corticosteroids can effectively treat both mitomycin and radiation-induced pulmonary toxicity as well. Tight control over fluid administration should be realized, thereby avoiding pulmonary edema as a result of impaired cardiac and renal function, but still maintaining enough volume for adequate end organ perfusion. Finally, the role of surgical resection itself for patients with N2 disease was addressed by the results of the North American Intergroup 0139 Trial.34 In this study, patients who received induction chemoradiotherapy were randomized to either surgical resection or continued radiotherapy without an attempt at resection. Although the initial survival analysis revealed no difference in overall survival, progression-free survival was significantly prolonged in the patients undergoing resection. This observation, combined with the higher treatmentrelated mortality in the surgical arm (mainly in pneumonectomy patients), suggests that if perioperative care can be optimized, especially for patients undergoing pneumonectomy, surgical resection may offer these patients the best chance for long-term survival. Stage IIIB (T4 or N3) disease Patients with this stage of locally advanced NSCLC are considered inoperable. Exceptions do exist, however, and generally apply to selected patients with T4 disease. Tracheal sleeve pneumonectomy can be considered for the occasional patient with endobronchial tumor involving the main carina; however, involvement of peribronchial tissue or lymph nodes should preclude this procedure. The five-year survival for patients with T4 (carina) N0 tumors undergoing tracheal sleeve pneumonectomy has been reported to approach 20%; however, the operative mortality from this procedure can be as high as 15–30%.35,36

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It is presently debated whether subclavian artery invasion represents T3 or T4 disease, but apical tumors invading this vessel should be resected if a complete resection can be performed. This vessel can be reconstructed either primarily or with a synthetic graft. Again, for patients to benefit from such an extended resection, node-negative status should be confirmed prior to resection using cervical mediastinoscopy. Sporadic reports exist concerning aortic resection for T4 tumors with an occasional long-term survivor,37 but no significant survival benefit has been demonstrated in these patients. Similarly, although technically possible, resection of tumors involving the vertebral body has not been shown to provide a survival advantage.38 These last two scenarios should be considered for clinical protocols involving induction chemo(radio)therapy, followed by reassessment. If a significant response is seen, resection can be considered in the protocol setting. If, at thoracotomy for presumed T3 disease, an incomplete resection is all that can be done due to involvement of mediastinal organs or vessels (T4), partial resection with implantation of radioisotopes combined with postoperative external beam radiation may provide some benefit with up to a 10% salvage rate, but has never been compared to primary (external) radiotherapy as an alternative approach. Although technically considered to be T4 disease, patients with multiple lesions in the same lobe (‘satellite’ lesions) constitute a unique subgroup of stage IIIB NSCLC. Following anatomic resection, patients with T4 disease due to the presence of satellite lesions enjoy appreciably longer survival than other subgroups of stage IIIB lung cancer.39 As a result, when satellite lesions are detected preoperatively, patients should undergo lobectomy and mediastinal lymph node dissection whenever possible.

STAGE IV DISEASE Surgery for stage IV disease is limited to young, healthy patients with a solitary site of metastatic disease, and an easily resectable primary tumor contained within the chest. An exhaustive search should be carried out prior to consideration of resection of stage IV disease, looking for other sites of metastatic disease not clearly evident by history and physical examination. Positron emission tomography (PET) may emerge as a useful test for this purpose, and all suspicious lesions should be biopsied to obtain a histologic diagnosis. Solitary bone, liver, and skin metastases are rare, but the following sites warrant mentioning due to their more frequent occurrence.

Brain metastases Approximately one-third of patients with NSCLC and brain metastases present initially with neurologic symptoms, with the lung cancer being found only after a search for the primary tumor has been carried out. In addition to the patients with stage IV disease at presentation, recurrences following resection of NSCLC are most commonly distant metastases, and of these, nearly 30% are located in the brain. It is now accepted that patients with solitary brain metastases from NSCLC are best treated by resection of the brain lesion followed by postoperative whole-brain radiation therapy. Using this strategy, five-year survival in these patients should approach 20%. Even if a cure is not obtained, survival is prolonged and quality of life improved when compared to a non-surgical approach.40 When patients present with NSCLC and a single, synchronous brain metastasis, and both lesions are resectable, the brain tumor should be resected prior to the primary tumor, provided that no urgent intrathoracic process is occurring (i.e. massive hemoptysis). This strategy is based on the observation that recovery from intracranial surgery is less intensive than that from thoracotomy. If the resectability of either lesion is in question prior to surgery, one should approach the questionable lesion first to ensure that both lesions can be completely resected prior to undertaking a potentially unnecessary operation. If a brain metastasis is found but a search for the primary tumor is negative, one should proceed with resection of the intracranial tumor. Adrenal metastases Solitary metastases to the adrenal glands are being diagnosed with greater frequency due to routine scanning of the upper abdomen with newer generation, spiral CT scanners. The utility of adrenalectomy for a solitary NSCLC metastasis has been reported in small case series and individual reports. In a relatively large series of patients with solitary adrenal metastases (23 patients), an overall survival of 23.3% was obtained after resection of the lung and adrenal lesions.41 Patients with metachronous lesions and a disease-free interval of more than six months received the greatest benefit from this aggressive approach.

SPECIAL CONSIDERATIONS Superior sulcus tumors Superior sulcus tumors are apical lung cancers that are at least T3 by definition, since they invade the chest wall. In addition to chest wall invasion, these tumors

Treatment of NSCLC: surgery 131

also invade neighboring vital structures including the brachial plexus, vertebral body, and subclavian vessels.42 Presenting symptoms almost always include pain in the shoulder radiating down the upper, inner aspect of the arm (T1 nerve root) as well as into the ulnar distribution in the hand (C8 nerve root). Patients may also have Horner’s syndrome, resulting from invasion of the stellate ganglion in the sympathetic chain, a condition which implies advanced local invasion. Treatment of these lesions is by surgical resection. Prior to resection, mediastinal node metastases must be ruled out using cervical medastinoscopy owing to the poor prognosis of these patients after resection when N2 disease is present. Several different operative approaches have been described, depending on whether the tumor invades the anterior or posterior aspect of the first rib. It is agreed that posterior lesions should be approached through a posterolateral thoracotomy extending up to the neck, as described by Shaw et al.42 This enables the scapula to be lifted off the chest wall and access to the apex of the hemithorax from outside the chest wall. Tumors that appear to invade more anteriorly can be approached through any number of anterior approaches, the most common being an L-shaped transcervical incision43 and the hemiclamshell approach.44 The advantage of the hemiclamshell incision is easy access to the pulmonary hilum for the performance of lobectomy with mediastinal lymph node dissection. In addition to lobectomy, the standard operation for superior sulcus tumors includes the resection of at least the first rib, the transverse processes of the vertebral bodies associated with each resected rib, and the T1 nerve root. Following complete resection, the five-year survival of patients with superior sulcus tumors approximates 30%. Unfortunately, many patients do not have a complete resection due to invasion of the previously mentioned vital structures. To address this issue, the Southwest Oncology Group Trial 9416 administered induction chemoradiotherapy in a phase II design to 111 patients with superior sulcus tumors.45 Of the 83 patients who underwent subsequent thoracotomy, 92% had a complete resection. The five-year survival was 44% for all patients and 54% for those who underwent a complete resection. Given these encouraging results, induction chemoradiotherapy followed by surgical resection has become the standard for patients with superior sulcus tumors in most centers. Multiple primary tumors It is not uncommon for patients to present with more than one lung malignancy. Either these tumors represent

synchronous primaries or one lesion is a metastasis from the other. When the tumors are of different histologies, the diagnosis of synchronous primary lung cancers is made. If the lesions are of the same histology, cervical mediastinoscopy should be routinely performed because if positive mediastinal nodes are discovered, the chance of one lesion being metastatic rises. Pathologic evidence of two separate primary tumors is the presence of carcinoma in situ in both lesions; however, this information is rarely present at the time of surgery.46 In many equivocal instances, the ‘benefit of the doubt’ is given to the patient and the tumors are labeled as synchronous primaries. Optimal oncologic treatment for patients with synchronous primary NSCLC is two staged lobectomies for contralateral tumors, and bilobectomy or pneumonectomy for ipsilateral tumors. In cases where the resectability of one lesion is questioned, the questionable tumor should be resected first. If the patient’s lung function permits only one lobectomy, a decision must be made as to which lesion will be resected via lobectomy and which will be approached with a limited resection. Generally, the limited resection should be reserved for the smaller, squamous cell cancers, since these are less likely to spread via lymphatics than adenocarcinomas. Limited resection should consist of segmentectomy instead of wedge resection whenever possible. A third option is to perform multiple segmentectomies in patients with limited pulmonary reserve. Bronchioloalveolar carcinoma Bronchioloalveolar carcinoma represents a unique subtype of NSCLC which appears to be increasing in incidence. This increase may be real, or may represent heightened recognition of this variant by pathologists. This disease seems to occur mainly in elderly women with a negligible smoking history. Three distinct clinical scenarios seem to be able to arise with BAC. First, and most common, patients may present with a solitary pulmonary nodule. These lesions are usually picked up by routine chest radiograph and are asymptomatic. Mediastinal lymph nodes are uncommonly involved. Treatment is lobectomy and long-term survival seems to be excellent. Second, some patients with BAC will present with small lesions that resemble infiltrates, termed groundglass opacities (GGOs). These lesions are not visible on standard chest radiography and are increasingly being detected on screening, low-dose, computed tomography (Figure 10.1.2). In addition, they tend to be multiple and also recur frequently following resection, especially

132 Textbook of Lung Cancer

be used to confirm negative margins, and when positive, further tissue should be resected. A positive bronchial resection margin can be treated by reresection of the bronchus and performance of a bronchoplastic procedure, or even pneumonectomy if necessary. Carcinoma in situ remaining at the bronchial stump may not adversely effect prognosis,49 but this has not conclusively been proven and even this early disease should currently be resected.

Figure 10.1.2 CT of the chest revealing a ground-glass opacity, a lesion not visible on chest radiography. Biopsy revealed bronchioloalveolar carcinoma.

in areas of lung distant from the primary tumor (multifocal BAC). This implies that this form of BAC may be spread throughout the airway by means of aerosol. Standard treatment is presently resection, but care must be given to the conservation of lung, since these tumors tend to recur with great frequency. Whether or not these patients benefit from repeated attempts at resection as opposed to observation is currently unknown. Third, a minority of patients will present with a lobar infiltrate representing lobar replacement with BAC. Radiologic studies give the appearance of dense consolidation that has arisen over a period of weeks to months. This presentation of BAC carries a poor prognosis, with many patients recurring with widespread infiltrative disease and respiratory failure following resection. For this reason, it is unknown whether these patients benefit at all from resection. Prognosis in patients with BAC seems to correlate most with the radiographic appearance of the lesion(s).47 Other factors that have been implicated as poor prognosticators in some studies, but not in others, are a mucinous histology and the presence of vascular invasion. The effect of chemotherapy remains unknown in patients with BAC. Isolated reports of successful double-lung transplantation for recurrent BAC with longterm survivors have been described, but this procedure remains investigational in the treatment of BAC.48 Positive resection margins Every attempt should be made intraoperatively to resect with negative margins. Frozen section analysis should

Completion pneumonectomy Patients with locally recurrent NSCLC or second primary tumors following resection should be evaluated in a similar fashion to those who present with their first cancer. If there is no evidence of distant disease and the remaining pulmonary function is adequate, these patients should be considered for completion pneumonectomy. Completion pneumonectomy is a technically challenging operation, requiring that the surgeon review the previous operative notes to learn about the anatomy and potential hazards of the reoperation. Mobilization of the lung should be performed intrapleurally whenever possible to avoid excessive bleeding and damage to neighboring structures. Intrapericardial ligation of the vessels also serves to reduce the chance of hemorrhage. Intraoperative use of topical hemostatic agents as well as efficient coagulating devices is helpful. Operative mortality following completion pneumonectomy is in the range of 10%, slightly higher than that seen with standard pneumonectomy.50 Postoperative morbidity is in the 20% range, with a significant proportion of complications related to bleeding. Longterm survival in patients with NSCLC who undergo this operation is approximately 30%, indicating that completion pneumonectomy is a worthwhile procedure in selected patients.50

PALLIATIVE SURGERY Pleural disease Patients with diffuse pleural disease (T4) typically present with dyspnea and a pleural effusion. The diagnosis should be confirmed and is most easily obtained by placement of a chest tube and examining the fluid for malignant cells. Once the diagnosis of a malignant pleural effusion is confirmed, pleurodesis with sterile talc or other pleural irritant is warranted to prevent recurrence. If a patient presents with obvious end-stage metastatic disease and a new pleural effusion, a simple thoracentesis may relieve some of the dyspnea and allow

Treatment of NSCLC: surgery 133

the patient to be discharged home to their family. This strategy should be reserved for patients who are anticipated to expire within the next few weeks. Thoracoscopic exploration is warranted in the following selected instances. First, if the fluid is negative for malignant cells and a malignant diagnosis will affect the treatment plan. Second, if the lung fails to re-expand after drainage of fluid, thoracoscopic intervention may be necessary just for the strategic placement of chest tubes to facilitate expansion, and third, after a poor result from a bedside pleurodesis as manifested by the rapid reaccumulation of fluid. The role of formal decortication is very limited in these patients due to their extremely short life expectancy. Endobronchial disease Unresectable endobronchial tumor is a not infrequent occurrence in patients with NSCLC. Typically, these patients may present with airway occlusion with distal pulmonary collapse and pneumonia, dyspnea, and hemoptysis. The endobronchial disease may be the manifestation of either the primary tumor extending proximally in the airway or of nodal disease eroding into the proximal tracheobronchial tree. Many times the patient has had a previous pulmonary resection and has a recurrence at the bronchial stump. Adequate palliation can be obtained using either laser or stenting techniques. For bleeding lesions, laser therapy with the Nd:YAG laser and electrocoagulation are the preferred approaches. Obstructing lesions can be treated using either approach. A combination of debridement through a rigid bronchoscope and laser treatment to obtain hemostasis is often an effective technique. Care must be taken not to blindly laser tumor in the proximal segmental bronchi as perforation can occur. Recently, photodynamic therapy (PDT) has been used in cases of endobronchial NSCLC. This technique needs further evaluation before it can be routinely used for this disease. Endobronchial stents are typically of the silicone rubber or self-expanding wire variety. The type of disease most amenable to stenting is that which is associated with a patent airway both proximal and distal to the obstructing lesion. Silicone stents are deployed using a rigid bronchoscope, while self-expanding wire stents are typically deployed over a guidewire using fluoroscopy as a guide. Silicone stents are removable, while wire stents are not; however, the indications for stent removal in patients with inoperable NSCLC are few. A recent development has been the introduction of an expandable, silicone stent which is removable. However, its application for lung cancer patients remains undefined.

SUMMARY Surgery for NSCLC has evolved considerably over the past 50 years. Resection is currently indicated for patients with early stage (I, II, selected IIIA) disease, while chemotherapy and radiation are used for more advanced disease. The mainstay of surgical therapy remains anatomic lobectomy with complete mediastinal lymph node dissection, provided the patient can physically tolerate this procedure. Care must be taken to ensure a complete resection since incomplete resections do not cure. Recent developments in the care of resectable lung cancer patients include the adoption of adjuvant chemotherapy for patients with completely resected stage II–III disease, the importance of surgical resection in the multimodal therapy regimen for stage IIIA NSCLC, as well as the use of induction chemoradiotherapy for superior sulcus tumors. With increasing use of lowdose, screening CT for individuals thought to be at high risk for the development of lung cancer, the discovery of much smaller tumors is increasing in frequency, and further studies are necessary to establish the standard of care for these lesions.

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Saito Y, Sato M, Sagawa M et al. Multicentricity in resected occult bronchogenic squamous cell carcinoma. Ann Thorac Surg 1994; 57: 1200–5. Ludwig C, Stoelben E, Olschewski M, Hasse J. Comparison of morbidity, 30-day mortality, and long-term survival after pneumonectomy and sleeve lobectomy for non-small cell lung carcinoma. Ann Thorac Surg 2005; 79: 968–73. Deslauriers J, Gregoire J, Jacques LF et al. Sleeve lobectomy versus pneumonectomy for lung cancer: a comparative analysis of survival and sites or recurrences. Ann Thorac Surg 2004; 77: 1152–6. Ginsberg RJ, Rubinstein L, for The Lung Cancer Study Group. Randomized trial of lobectomy versus limited resection for patients with T1 N0 non-small cell lung cancer. Ann Thorac Surg 1995; 60: 615–23. Port JL, Kent MS, Korst RJ, Libby D et al. Tumor size predicts survival within stage IA non-small cell lung cancer. Chest 2003; 124: 1828–33. Okada M, Nishio W, Sakamoto T et al. Effect of tumor size on prognosis in patients with non-small cell lung cancer: the role of segmentectomy as a type of lesser resection. J Thorac Cardiovasc Surg 2005; 129: 87–93. Daniels LJ, Balderson SS, Onaitis MW, D’Amico TA. Thoracoscopic lobectomy: a safe and effective strategy for patients with stage I lung cancer. Ann Thorac Surg 2002; 74: 860–4. McKenna RJ, Wolf RK, Brenner M, et al. Is lobectomy by video-assisted thoracic surgery an adequate cancer operation? Ann Thorac Surg 1998; 66: 1903–8.

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Asamura H, Nakayama H, Kondo H et al. Lymph node involvement, recurrence and prognosis in resected small peripheral, non-small cell lung carcinomas: are these carcinomas candidates for video-assisted lobectomy? J Thorac Cardiovasc Surg 1996; 111: 1125–34. Ginsberg RJ, Hill LD, Eagan RT et al. Modern 30-day operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg 1983; 86: 654–8. McCormack P, Martini N. Primary lung cancer. NY State J Med 1980; 80: 618. Martini N, Bains MS, Burt ME et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 1995; 109: 120–9. Winton TL, Livingston R, Johnson D et al. A prospective randomized trial of adjuvant vinorelbine and cisplatin in completely resected stage IB and II non small cell lung cancer. Intergroup JBR. Proc Am Soc Clin Oncol 2004; abstract 7018. Strauss G, Maddaus MA, Herndon JE II et al, for the CALGB Radiation Therapy Oncology Group. Adjuvant chemotherapy in stage IB non-small cell lung cancer: Update of CALGB protocol 9633. J Clin Oncol 2006; 24: 7007. PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and metaanalysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 1998; 352: 257–63. Rice D, Kim HW, Sabichi A et al. The risk of second primary tumors after resection of stage I nonsmall cell lung cancer. Ann Thorac Surg 2003; 76: 1001–8. Korst RJ, Gold HT, Kent MS et al. Surveillance computed tomography following complete resection for non-small cell lung cancer: results and costs. J Thorac Cardiovasc Surg 2005; 129: 652–60. Martini N, Burt ME, Bains MS et al. Survival after resection of stage II non-small cell lung cancer. Ann Thorac Surg 1992; 54: 460–6. Downey RJ, Martini N, Rusch VW et al. Extent of chest wall invasion and survival in patients with lung cancer. Ann Thorac Surg 1999; 68: 188–93. Martini N, Yellin A, Ginsberg RJ et al. Management of nonsmall cell lung cancer with direct mediastinal involvement. Ann Thorac Surg 1994; 58: 1447–51. Faber LP, Jensik RJ, Kittle CF. Results of sleeve lobectomy for bronchogenic carcinoma in 101 patients. Ann Thorac Surg 1984; 37: 279–85. Nakahashi H, Yasumoto K, Ishida T et al. Results of surgical treatment of patients with T3 non-small cell lung cancer. Ann Thorac Surg 1988; 46: 178–81. Martini N, Flehinger BJ. The role of surgery in N2 lung cancer. Surg Clin North Am 1987; 67: 1037–49. Patterson GA, Piazza D, Pearson FG et al. Significance of metastatic disease in subaortic lymph nodes. Ann Thorac Surg 1987; 43: 155–9. Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized, clinical trials. BMJ 1995; 311: 899–909. Arriagata R, Bergman B, Dunant A et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected nonsmall cell lung cancer. N Engl J Med 2004; 350: 351–60.

27. Hamada C, Ohta M, Wada H et al. Survival benefit of oral UFT for adjuvant chemotherapy after completely resected non-small cell lung cancer. Proc Am Soc Clin Oncol 2004; abstract 7002. 28. Martini N, Kris MM, Flehinger BJ et al. Preoperative chemotherapy of stage IIIa (N2) non-small cell lung cancer: the Memorial Sloan-Kettering experience with 136 patients. Ann Thorac Surg 1993; 55: 1365–74. 29. Burkes RL, Ginsberg RJ, Shepherd FA et al. Induction chemotherapy with mitomycin, vindesine and cisplatin for stage III unresectable non-small cell lung cancer: results of the Toronto phase II trial. J Clin Oncol 1992; 10: 580–6. 30. Roth JA, Fossella F, Komaki M et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small cell lung cancer. J Natl Cancer Inst 1994; 86: 673–80. 31. Rosell R, Gomez-Codina J, Camps C et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small cell lung cancer. N Engl J Med 1994; 330: 153–8. 32. Pass HI, Pogrebniak HW, Steinberg SM et al. Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg 1992; 53: 992–8. 33. Depierre A, Milleron B, Moro-Sibilot D et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II and IIIA non-small cell lung cancer. J Clin Oncol 2002; 20: 247–53. 34. Albain KS, Scott CB, Rusch VW et al. Phase III comparison of concurrent chemotherapy plus radiotherapy (CT/radiotherapy) and CT/radiotherapy followed by surgical resection for stage IIIA (pN2) non-small cell lung cancer (NSCLC): initial results from Intergroup trial 0139 (RTOG 93-09). Proc Am Soc Clin Oncol 2003; abstract 2497. 35. Dartevelle PG, Khalife J, Chapelier A et al. Tracheal sleeve pneumonectomy for bronchogenic carcinoma: a report of 55 cases. Ann Thorac Surg 1988; 46: 68–72. 36. Tsuchiya R, Goya T, Naruke T, Suemasu K. Resection of tracheal carina for lung cancer. Procedure, complications and mortality. J Thorac Cardiovasc Surg 1990; 99: 779–87. 37. Tsuchiya R, Asamura H, Kondo H et al. Extended resection of the left atrium, great vessels, or both for lung cancer. Ann Thorac Surg 1994; 57: 960–5. 38. Grunenwald D, Mazel C, Girard P et al. Total vertebrectomy for en bloc resection of lung cancer invading the spine. Ann Thorac Surg 1996; 61: 723–6. 39. Detterbeck FC, Jones DR, Kernstine KH, Naunheim KS. Lung cancer. Special treatment issues. Chest 2003; 123 (1 Suppl): 244–58S. 40. Burt M, Wronski M, Arbit E et al. Resection of brain metastases from non-small cell lung carcinoma. Results of therapy. J Thorac Cardiovasc Surg 1992; 103: 399–411. 41. Mercier O, Fadel E, de Perrot M et al. Surgical treatment of solitary adrenal metastasis from non-small cell lung cancer. J Thorac Cardiovasc Surg 2005; 130: 136–40. 42. Shaw RR, Paulson PL, Kee JL Jr. Treatment of the superior sulcus tumor by irradiation followed by resection. Ann Surg 1961; 154: 29–40. 43. Dartevelle P, Chapelier AR, Macchiarini P et al. Anterior transcervical-thoracic approach for radical resection of lung tumors invading the thoracic inlet. J Thorac Cardiovasc Surg 1993; 105: 1025–34.

Treatment of NSCLC: surgery 135 44. Korst RJ, Burt ME. Cervicothoracic tumors: results of resection by the ‘hemiclamshell’ approach. J Thorac Cardiovasc Surg 1998; 115: 286–95. 45. Rusch VW, Giroux DJ, Kraut MJ et al. Induction chemoradiation and surgical resection for superior sulcus non-small cell lung carcinomas long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007; 25: 313–8. 46. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg 1975; 70: 606–12. 47. Ebright MI, Zakowski MF, Martin J et al. Clinical pattern and pathologic stage but not histologic features predict outcome for

bronchioloalveolar carcinoma. Ann Thorac Surg 2002; 74: 1640–6. 48. Etienne B, Bertocchi M, Gamondes J-P et al. Successful doublelung transplantation for bronchioloalveolar carcinoma. Chest 1997; 112: 1423–4. 49. Snijder RJ, de la Riviere AB, Elbers HJJ, van den Bosch JMM. Survival in resected stage I lung cancer with residual tumor at the resection margin. Ann Thorac Surg 1998; 65: 212–16. 50. Gregoire J, Deslauriers J, Guojin L, Rouleau J. Indications, risks and results of completion pneumonectomy. J Thorac Cardiovasc Surg 1993; 105: 91.

10.2 Treatment of NSCLC: radiotherapy Merideth MM Wendland, William T Sause Contents Introduction • Early disease • Locally advanced disease • Superior sulcus tumors • Altered fractionation radiation therapy • Toxicity and patient selection • Prophylactic cranial irradiation • Palliative therapy • Conclusion

INTRODUCTION In the USA, lung cancer is the number one cause of cancer-related death for both men and women.1 In 2005, an estimated 175 000 new cases of lung cancer will be diagnosed and roughly 159 000 deaths from lung cancer will occur. Approximately 80% of patients with primary lung cancer are diagnosed with non-small cell lung cancer (NSCLC).2 Radiation therapy remains a valuable therapeutic modality in the treatment of NSCLC. In early stage disease, definitive radiation therapy may be employed for patients who refuse or are medically unfit to undergo surgical resection. Radiation therapy may also be used as adjuvant therapy for patients with incomplete resection or node-positive disease. At initial presentation, many patients who receive a diagnosis of NSCLC have locally advanced disease. Historically, these patients were treated with primary thoracic radiation therapy with poor longterm survival rates secondary to both progression of local disease and development of distant metastases. With the goal of improving clinical outcomes, multiple permutations of combined-modality therapy for locally advanced NSCLC have been investigated. The optimal treatment for locally advanced NSCLC continues to evolve, but combined-modality therapy has led to improved survival rates versus treatment with radiation alone, and is the standard of care.

EARLY DISEASE In general, patients with stage I and II disease who are medically fit undergo definitive surgical resection with good results. Newer data have demonstrated that adjuvant chemotherapy after complete surgical resection can improve overall survival.3–6 For patients who are medically unfit for or refuse surgery, definitive radiation therapy is an alternative treatment modality that

still offers curative potential. Although outcomes with radiation alone are inferior compared to those obtained with complete surgical resection, five-year cause-specific survival rates of approximately 30% in stage I and II disease have been obtained with the use of modern radiation therapy planning and delivery techniques.7–9 Doses considered to be ‘curative’ when using radiation therapy alone are considered to be approximately 65 to 70 Gray (Gy) with standard fractionation (1.8 to 2.0 Gy per fraction, five fractions per week), or a radiobiologically equivalent dose when altered fractionation is utilized. Dose escalation with conventionally fractionated radiation therapy has demonstrated a dose–response relationship with respect to both local control and survival.10,11 Such dose escalation has not been associated with an increase in acute toxicity when three-dimensional conformal radiation techniques are utilized.12,13 Stereotactic body radiation therapy using hypofractionation has been shown to produce excellent local control rates with acceptable toxicity.14,15 A current phase II Radiation Therapy Oncology Group (RTOG) protocol will evaluate the safety and efficacy of delivering 60 Gy in three fractions using stereotactic techniques in patients with early stage NSCLC. When considering combined-modality therapy, potential advantages of radiation therapy in the preoperative setting include possible improvement of the resectability of large tumors, prevention of dissemination of tumor at the time of surgical resection, and the use of lower doses of radiation. Disadvantages of this approach include the inability to determine the precise surgical stage and an increased risk of postoperative complications such as wound healing. Randomized data have failed to demonstrate a statistically significant survival benefit for the use of preoperative radiation therapy in the treatment of early stage NSCLC.16 Postoperative radiation therapy (PORT) has also been investigated in the context of randomized trials. The Lung Cancer Study Group (LCSG) evaluated the role of

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PORT consisting of 50 Gy in 25 fractions to the mediastinum following complete surgical resection in patients with stage II and III squamous cell lung carcinoma.17 The rate of local failure as the site of first failure was reduced from 20% to 1% (p <0.01) with the addition of PORT for patients with node-positive disease. This did not result in an overall survival benefit for stage II patients, as approximately two-thirds of first failures were distant. For patients with N2 disease, there was an improvement in overall survival, although this difference was not significant. In a randomized trial by the Medical Research Council (MRC), patients with stage II and III disease were randomized to receive 40 Gy of PORT or no further therapy.18 In subgroup analysis, patients with N1 disease did not have improved outcomes with the addition of PORT. For patients with N2 disease, the addition of PORT resulted in a one month improvement in median overall survival, delayed time to local recurrence, and a longer interval to the development of bone metastases. A meta-analysis performed by the PORT Meta-analysis Trialists Group confirmed that PORT does not confer a survival benefit for patients with early stage NSCLC and may actually decrease survival for patients with stage I and II disease, with a reduction in two-year survival rate from 55% to 48% with the addition of PORT.19 Other studies have supported the conclusion that PORT may result in increased toxicity without survival benefit in stage I and II disease, but it may be advantageous in stage III disease.20–24

LOCALLY ADVANCED DISEASE Definition It is estimated that 30% of patients with NSCLC have locally advanced disease without distant metastases at presentation, but few such patients present with disease amenable to primary surgical resection with curative intent.25 The term locally advanced as applied to NSCLC generally implies stage III disease.26 Stage III disease is subdivided into IIIA and IIIB. Generally speaking, patients with stage IIIA disease (e.g. ipsilateral mediastinal nodal involvement) have potentially resectable disease at presentation, while those with stage IIIB disease (e.g. mediastinal invasion, contralateral nodal involvement) do not. Further, the volume of ipsilateral mediastinal nodal disease has prognostic value.27 Thus, individuals with stage III NSCLC comprise a heterogeneous group of patients with a range of prognoses based upon disease extent at diagnosis. As such, these patients present a unique therapeutic challenge.

Single-modality therapy While treatment with radiation therapy alone for patients with locally advanced NSCLC is potentially curative, long-term survival rates are disappointing and generally are less than 15%.28,29 Analyses of the patterns of failure following treatment with radiation therapy alone demonstrate that the poor survival rates are related not only to the inability of local therapy to control the primary tumor, but also to the development of distant metastases.29,30 The RTOG established prognostic groups determined by recursive partitioning analysis (RPA) based on four RTOG trials of patients with inoperable NSCLC treated with definitive radiation therapy.31 Patterns of failure of 1547 patients with stage II, IIIA, or IIIB NSCLC treated with radiation therapy alone were then determined based on RPA prognostic group.32 The median survival and the rates of primary and distant failures varied significantly based on RPA class, suggesting that specific cohorts of patients may benefit from more aggressive treatment directed at specific sites of failure. Combined-modality therapy When local control is defined by complete clinical, radiographic, endoscopic, and histologic remission, the local failure rate is as high as 92% at 5 years.30 Distant failure rates after radiation therapy alone are approximately 80%.29 These findings have led to the exploration of combined-modality therapy utilizing chemotherapy in the treatment of such patients. Many possible combinations of induction therapy have been investigated in a multitude of trials evaluating the role of combined-modality therapy in the treatment of locally advanced NSCLC. Interpretation of the data and comparisons of results between even well designed trials are difficult for many reasons. There have been several changes in the staging systems over time and the terms ‘unresectable’, ‘marginally resectable’, and ‘locally advanced’ have been variably defined. Additionally, no standards exist regarding the extent of surgical staging or resection, the dose of radiation therapy delivered, or the chemotherapeutic agents used and in what combinations and doses. The optimal treatment of locally advanced NSCLC continues to be defined, but long-term survival rates have improved with combinedmodality therapy, which is now considered the standard of care.33–35 There are two basic treatment protocols for administering combined chemotherapy and radiation. Sequential treatment with chemotherapy followed by radiation therapy was the first widely utilized combination in locally

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advanced NSCLC. Concurrent chemoradiation has demonstrated promising results with respect to prolonging survival, and is considered the current standard of care. Sequential chemoradiation When radiation therapy follows induction chemotherapy, the effects of chemotherapy decrease the local tumor burden and may permit delivery of radiation to a reduced tumor volume. Induction chemotherapy may also eliminate or prevent the growth of subclinical systemic disease. Increased drug delivery with less overall toxicity is also more likely compared to concurrent administration. Potential drawbacks of sequential administration include a prolonged overall treatment time, excessive toxicity due to chemotherapy preventing or delaying the delivery of radiation, induction of accelerated repopulation, and chemotherapy-induced tumor cell resistance resulting in reduced radiation efficacy.36–38 Many phase II trials have been designed to evaluate whether or not survival is improved with the addition of induction chemotherapy to radiation therapy in patients with locally or regionally advanced NSCLC. Although these trials have had conflicting results, several phase III trials (Table 10.2.1) and three meta-analyses have demonstrated a survival benefit, and recent updates have provided relatively long-term data.

In North America, the Cancer and Leukemia Group B (CALGB) 8433 trial is the landmark study of sequential chemoradiation versus radiation therapy alone for the treatment of locally advanced NSCLC.39 A total of 155 eligible patients with clinical or surgical T3 or N2 NSCLC without evidence of distant metastases were randomized to induction chemotherapy with cisplatin and vinblastine followed by radiation therapy or radiation therapy alone. Radiation therapy to a total dose of 60 Gy in 30 fractions was the same in both arms and began on day 50 in the combined-modality arm. All patients had a good performance status and minimal weight loss prior to study entry. The addition of chemotherapy did not impair the ability to deliver radiation therapy, with 88% of patients in the combined-modality arm and 87% of patients on the radiation therapy alone arm completing radiation therapy per protocol. Longterm seven-year followup confirms that induction chemotherapy improves median survival compared to radiation therapy alone.40 Three other modern cisplatinbased trials have confirmed the CALGB experience. A US Intergroup trial randomized 458 eligible patients with good performance status, minimal weight loss, and unresectable, localized NSCLC to receive once daily radiation therapy to 60 Gy in 2 Gy fractions with or without induction cisplatin and vinblastine.41 Patients

Table 10.2.1 Randomized trials of chemotherapy and radiation therapy versus radiation therapy alone Trial

CT

RT dose (Gy)

Median survival (months)

p value

Three-year survival (%)

VP

60 60

13.7 9.6

VP

60 60 69.6 BID

13.8 11.4 12.3

VCPC

65 65

12.0 10.0

0.02

6b 3b

MIC

50c 50c

13.0 9.9

0.056

14 10

CALGB39,40 0.012

23 11

US Intergroup41,42 5b 8b 6b

a

0.03

French43,44

MRC45

CT: chemotherapy; RT: radiation therapy; CALGB: Cancer and Leukemia Group B; MRC: Medical Research Council; VP: vinblastine, cisplatin; VCPC: vindesine, cyclophosphamide, cisplatin, lomustine; MIC: mitomycin, ifosfamide, cisplatin; BID: twice daily. a Versus the sequential arm. b Five-year rates. c Median RT dose.

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randomized to a third arm received radiation therapy alone twice daily to a total dose of 69.6 Gy. Median survival was statistically superior for the combined-modality arm versus either the standard radiation therapy arm or the twice-daily radiation therapy arm. Final results of this study confirmed combined-modality therapy improves median survival, but five-year survival rates remained poor at less than 10%.42 In another phase III trial conducted in France, 353 patients with unresectable locally advanced squamous cell or large cell lung carcinoma were randomized to receive either radiation therapy alone (65 Gy in 2.5 Gy fractions) or three monthly cycles of cisplatin-based chemotherapy followed by the same radiation therapy regimen.43 There was a significant decrease in distant metastases for the combined-modality arm and the median and two-year survival rates (21% vs 14%, p = 0.02, overall).44 Re-analysis revealed that only 8% of patients had continued local control at five years.30 Five-year survival rates remained poor at 6% and 3%, likely secondary to the high rate of local failure on both arms. The MRC randomized 447 eligible patients with good performance status and localized, inoperable NSCLC to receive radiation therapy alone or cisplatin-based induction chemotherapy followed by radiation therapy.45 On both arms, the median radiation therapy dose was low at 50 Gy. Median survival was improved with the addition of chemotherapy, although this difference was of borderline significance. As demonstrated by the above randomized trials, the addition of platinum-based induction chemotherapy to radiation therapy results in improved survival as compared to radiation therapy alone. This is particularly true for short-term survival, but modest improvements in long-term survival have been observed as well. Several smaller randomized trials have failed to confirm a survival benefit for the addition of induction chemotherapy, but these trials may have lacked the power to detect small differences in survival.46–49 Three large meta-analyses have demonstrated a small but consistent survival benefit in the order of 5–10% at one year for the addition of induction chemotherapy to radiation therapy for locally advanced NSCLC.50–52 Sequential versus concurrent chemoradiation The benefit of combined-modality treatment with radiation therapy and chemotherapy was established by the CALGB 8433 trial and confirmed by other randomized phase III studies.40,42,44,45 These trials, however, did not address the optimal sequencing of the two modalities. Potential advantages of concurrent chemoradiation

include sensitization of tumor cells to radiation and reduced overall treatment time.53 Potential disadvantages of concurrent chemoradiation include increased morbidity requiring reductions in the dose intensity of chemotherapy and unplanned delays in the administration of radiation therapy.37,38,54 An important early European Organization for Research and Treatment of Cancer (EORTC) trial randomized 331 patients with unresectable stage I, II, or III NSCLC to treatment with radiation therapy alone, radiation therapy with weekly cisplatin (30 mg/m2), or radiation therapy with daily cisplatin (6 mg/m2).55 On all three arms, the same definitive split-course radiation therapy schedule consisting of 60 Gy in 20 fractions with a three-week rest after the first 30 Gy was utilized. The administration of daily cisplatin was shown to significantly improve overall survival (16% vs 2% at three years, p = 0.009 overall) and disease-free survival (31% vs 19% at two years, p = 0.003 overall) compared to radiation therapy alone. The weekly cisplatin arm also revealed a trend towards improved survival compared to the radiation alone arm. The survival benefit observed with the addition of low-dose daily cisplatin was likely due to radiation sensitization and improved local control. While the EORTC trial above addressed the feasibility of administering chemoradiation in a multicenter setting and confirmed a survival benefit for combined-modality therapy, it still did not address the optimal timing of the two modalities. Several additional randomized trials were designed to answer this question (Table 10.2.2). The West Japan Lung Cancer Group (WJLCG) conducted a large phase III trial to directly compare survival for sequential versus concurrent cisplatin-based chemoradiation.56 A total of 314 eligible patients with unresectable stage III NSCLC were entered on the trial. Both the response rate and the median survival were significantly improved for patients who received concurrent chemoradiation as compared to sequential treatment. The RTOG also compared sequential versus concurrent chemoradiation in a phase III randomized trial (RTOG 94-10).57,58 In this trial, patients with unresected stage II–III NSCLC and good performance status were randomized to receive sequential chemoradiation, or concurrent chemoradiation with radiation delivered either once or twice daily. With a median follow-up of 6.0 years, the concurrent arm receiving once-daily radiation therapy had an improved median survival compared to the sequential arm. The median survival of patients on the concurrent twice-daily radiation therapy arm was not statistically different from the sequential arm.

140 Textbook of Lung Cancer Table 10.2.2 Randomized studies evaluating sequential versus concurrent administration of chemotherapy and radiation therapy Trial

Arm

WJLCG56

Sequential Concurrent Sequential Concurrent, RT qd Concurrent, RT BID Sequential Concurrent Sequential Concurrent

RTOG 94-10

Czech59 French

60

57

Response rate (%)

66.6 84.0 NR NR NR 47 80 NR NR

p value

0.0002 NR NR 0.001 NR

Median survival (months)

13.3 16.5 14.6 17.0 15.2 12.9 16.6 13.8 15.0

p value

0.04 0.046a 0.296a 0.023 0.41

WJLCG: West Japan Lung Cancer Group; RTOG: Radiation Therapy Oncology Group; qd: once daily; BID: twice daily; NR: not reported. a Versus the sequential arm.

Two additional randomized phase III trials, one conducted in the Czech Republic and another conducted in France, both demonstrated a significant improvement with respect to median survival for concurrent chemoradiation versus sequential treatment.59,60 Based in part on the results of the above randomized trials, the administration of chemotherapy and radiation therapy concurrently, rather than sequentially, is considered the standard of care for patients with locally advanced NSCLC. Induction chemoradiation Once the efficacy and feasibility of concurrent chemoradiation for locally advanced NSCLC was established, this approach replaced chemotherapy alone as the induction regimen prior to surgery in many trials. An important example is SWOG 8805, a phase II trial designed to test the feasibility of concurrent chemoradiation followed by surgical resection in 126 patients with stage IIIA and IIIB disease.61 Induction therapy consisted of cisplatin and etoposide given concurrently with thoracic irradiation to 45 Gy. Patients with unresectable disease, incomplete resection, or positive mediastinal nodes received an additional two cycles of chemotherapy and radiation therapy to a total dose of 59.4 Gy. Morbidity and mortality associated with this trial were high. Mature results revealed no survival difference between patients with stage IIIA and IIIB disease, with a median survival of 13 months and 17 months, respectively.62 Absence of tumor in mediastinal nodes at surgery was the strongest predictor of long-term survival after thoracotomy, with a median survival of 30 months

versus 10 months, and three-year survival of 44% vs 18% (p = 0.0005). With the encouraging results of the above SWOG phase II trial and others, an Intergroup phase III trial conducted by the RTOG was initiated.63 In this trial, all patients received induction chemoradiation and were then randomized to surgical resection or further chemoradiation. Induction chemoradiation consisted of cisplatin and etoposide given concurrently with 45 Gy of radiation therapy. Patients with responsive or stable disease following induction therapy underwent surgical resection followed by two postoperative cycles of chemotherapy, or continued radiation therapy to a total dose of 61 Gy concurrent with two additional cycles of chemotherapy. A total of 429 patients were entered on the study, all with stage IIIA, N2 disease. These patients were highly selected in that they had to be potential candidates for pulmonary resection and eligibility criteria also required a Karnofsky Performance Status (KPS) of 70 or greater. Of the 396 analyzable patients, 202 were randomized to undergo surgical resection following induction chemoradiation and 194 received definitive chemoradiation. The most recent results were reported with a minimum of 2.5 years of follow-up per patient (Table 10.2.3). There were 16 (7.9%) deaths on the chemoradiation and surgery arm and 4 (2.1%) deaths on the chemoradiation only arm. A higher rate of death was observed following pneumonectomy versus lobectomy (26% versus 1%, respectively). Although progression-free survival was significantly improved with the addition of surgery, median survival and five-year survival rates were not significantly different between the two arms.

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Table 10.2.3 Results of Intergroup trial 0139 (RTOG 9309), comparing induction chemoradiation followed by surgical resection versus definitive chemoradiation63 Arm

Number of patients

ChemoRT ChemoRT + S p value

Progression-free survival (months)

194 202

10.5 12.8 0.017

Median survival (months)

Five-year survival (%)

22.2 23.6 0.24

20.3 27.2 0.10

ChemoRT: chemoradiation; S: surgery; NR: not reported.

Pathologic N0 disease at the time of surgical resection predicted for long-term survival. These results suggest that, while surgical resection after induction chemoradiation increases progression-free survival compared to definitive chemoradiation in patients with stage IIIA NSCLC, the addition of surgery may also increase the morbidity and mortality of treatment without improving overall survival. Surgical resection following induction chemoradiation may be considered in fit patients, particularly if a lobectomy is to be performed. The German Lung Cancer Cooperative Group (GLCCG) conducted a phase III randomized study to investigate the timing and fractionation of radiation therapy when surgery is planned in patients with locally advanced NSCLC.64 In this trial, 558 patients with stage IIIA and IIIB disease received induction chemotherapy consisting of three cycles of cisplatin and etoposide. Patients were then randomized to receive hyperfractionated radiation therapy with concurrent carboplatin and vindesine followed by surgery, or surgery followed by standard fractionated radiation therapy to 54 Gy without concurrent chemotherapy. There was no difference between the two arms with respect to response rate after induction, complete resection rate (45% in both arms), treatment-related mortality, and three-year progression-free survival and overall survival.

SUPERIOR SULCUS TUMORS Tumors of the superior sulcus, also known as Pancoast’s tumors, are a distinct subset of locally advanced NSCLC. Previously considered inoperable and fatal, the use of single-modality radiation therapy has led to five-year survival rates as high as 46%.65 The use of trimodality therapy is now considered standard of care for patients with tumors of the superior sulcus. This is based primarily on a phase II (Intergroup 0160, SWOG 9416) study in which 110 eligible patients with T3–4, N0–1 tumors of the superior sulcus received

induction therapy consisting of cisplatin and etoposide given concurrently with thoracic irradiation to 45 Gy.66,67 This induction regimen was identical to that given in SWOG 8805.61 A total of 95 (86.4%) patients had stable disease or response to induction chemoradiation and underwent surgical resection followed by an additional two cycles of chemotherapy. Complete resection was performed in 83 (94.3%) of the 88 patients who underwent thoracotomy. Pathologic complete response was seen in 32 (36.4%) of the thoracotomy specimens and an additional 26 (39.5%) revealed minimal microscopic disease. The five-year and median survivals were 53% and 71 months, respectively, for patients who had a complete resection, and 41% and 33 months, respectively, for all patients who were eligible for resection. This represented a significant improvement over historical data for NSCLC of the superior sulcus.

ALTERED FRACTIONATION RADIATION THERAPY Hyperfractionated and accelerated fractionation radiation therapy have been investigated as potential approaches to improve outcomes in patients with locally advanced NSCLC. Delivering multiple fractions per day works to counteract the effect of accelerated repopulation that occurs during normal treatment breaks. An adequate interval between fractions, generally six hours or longer, allows for repair of sublethal damage in normal tissues, thus minimizing any increase in acute side-effects. Late effects are also decreased due to the lower dose per fraction.53 A European multicenter trial randomized 563 patients with locally advanced NSCLC and good performance status to either conventional radiation therapy or continuous hyperfractionated accelerated radiotherapy (CHART).68 The CHART regimen consisted of 36 fractions of 1.5 Gy each given three times per day on 12 consecutive days. The use of CHART was associated with a 9% improvement in overall survival at

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two years (29% vs 20%, p = 0.004). CHART was also associated with an increase in severe dysphagia (19% vs 3%), but this occurred primarily after the completion of radiation therapy and thus did not interfere with radiation delivery. Subgroup analyses revealed the greatest benefit was for patients with squamous cell histology. Jeremic and colleagues randomly assigned 131 patients with stage III NSCLC to receive twice daily radiation therapy to a total dose of 69.6 Gy with or without lowdose daily carboplatin and etoposide.69 The combinedmodality arm demonstrated an improved median survival (22.0 vs 14.0 months) and an improved four-year survival (23% vs 9%, p = 0.021). This represents an approximately six-month improvement in median survival as compared to the concurrent chemoradiation arms utilizing once daily radiation (Table 10.2.2).56,57,59,60 A randomized study by the Eastern Cooperative Oncology Group (ECOG 2597) compared once-daily radiation therapy to hyperfractionated accelerated radiation therapy (HART) following two cycles of induction chemotherapy with carboplatin and paclitaxel.70 Once-daily radiation therapy was delivered with 2.0 Gy fractions to a total dose of 64 Gy. HART consisted of a total dose of 57.6 Gy using 1.5 Gy fractions delivered three times per day. The study was closed early due to poor accrual. Based on the 141 patients who were enrolled, median survival was 20.3 months on the HART arm and 14.9 months on the daily radiation therapy arm (p = 0.28). This also represents an approximately 6-month improvement in median survival as compared to the concurrent chemoradiation arms utilizing once-daily radiation (Table 10.2.2).56,57,59,60 While the initial results of altered fractionation radiation therapy in the treatment of locally advanced NSCLC are promising, at this time there is no confirmed additional survival benefit for altered fractionation radiation therapy alone over concurrent chemotherapy and radiation therapy. The hyperfractionated radiation therapy arms of the United States Intergroup trial and RTOG 94-10 trial were unable to confirm a significant survival benefit when compared to conventional radiation therapy, even with long-term follow-up.42,58 Combining chemotherapy with altered fractionation radiation therapy has shown promise, but this approach has yet to be optimally defined and continued investigation is warranted.

TOXICITY AND PATIENT SELECTION In locally advanced NSCLC, combined-modality therapy improves disease control at the cost of increased

toxicity. Without exception, patients enrolled on the combined-modality or ‘more aggressive’ treatment arms of clinical trials experience increased toxicity as compared to single-modality controls.39,41,55–57 Important factors that influence outcome in patients with locally advanced NSCLC include age, performance status, and degree of weight loss.71–73 Aggressive combinedmodality treatments require a ‘fit’ cohort of patients and proper patient selection is critical, as highlighted by the results of RTOG 90-15.74 This phase I/II trial utilized cisplatin and vinblastine concurrent with twice-daily radiation (1.2 Gy twice daily to 69.6 Gy) to treat patients with unresected stage II, IIIA, or IIIB NSCLC. All patients had a good performance status (KPS ≥70), but this trial was initiated while RTOG 88-08 was still in progress and, due to competition for enrollment, minimal weight loss was not included in the eligibility criteria. Of the 42 eligible patients, 76% had greater than 5% weight loss preceding study entry. Grade 4 or higher acute toxicity was observed in 45% of patients, with 7% of patients dying of sepsis related to chemotherapy-induced leukopenia. Median survival was 12.2 months in all patients and 17.5 months for the ten patients with less than 5% weight loss. Consideration must also be given to the timing of surgical resection and the type of surgery that is planned after induction therapy. In general, preoperative chemotherapy has not been shown to increase postoperative morbidity and mortality.75,76 Review of the Memorial Sloan Kettering experience, however, has revealed that right pneumonectomy following induction chemotherapy significantly increases the risk of surgical complications, with 24% of patients dying postoperatively.76 The mechanism behind the increased mortality after right pneumonectomy is not well understood and the role of radiation therapy, if any, in increasing the risk of death is not known.

PROPHYLACTIC CRANIAL IRRADIATION The risk of central nervous system (CNS) failure is low in patients with early stage disease who undergo surgical resection. For patients with locally advanced disease, 15–30% will experience CNS failure as the site of first relapse.62,77,78 The overall CNS failure rate increases with increasing survival and is on the order of 20–50%.62,77–79 Prophylactic cranial irradiation (PCI) has been shown in prospective randomized trials to delay and reduce the incidence of failure within the brain, but it has not been shown to improve survival.80,81 These studies have

Treatment of NSCLC: radiotherapy 143

been criticized for poor control of extracranial disease, which was the cause of death in the majority of patients and also likely contributed to reseeding of the brain after whole brain radiation therapy was completed. An ongoing North American Intergroup phase III trial conducted by the RTOG randomizes patients with stage III NSCLC who have been treated with definitive combined-modality therapy and have responsive or stable disease to receive 30 Gy in 15 fractions of whole brain radiation therapy or no PCI. A study by the West German Cancer Center will randomize patients with locally advanced NSCLC to one of two fractionation schemes of PCI (24 Gy in 12 fractions or 30 Gy in 15 fractions), or no PCI. These trials, which will collect data on both survival and neuropsychologic sequelae of treatment, will hopefully clarify the role of PCI in patients with locally advanced NSCLC.

PALLIATIVE THERAPY Palliative endobronchial therapy can provide symptomatic improvement for bronchial symptoms such as hemoptysis and obstructive pneumonia. Radiation can be delivered with low-dose rate sources or, more commonly, with a high-dose-rate source using a remote afterloading device. Common treatment regimens include 21 Gy in three fractions delivered at 1.0 cm depth with a high-dose-rate source and 30 Gy delivered at 1 Gy per hour for low-dose-rate sources. No significant differences between the two techniques with respect to bronchoscopic response rate or complications have been identified.82,83 Symptomatic improvement is usually rapid and is generally seen in 50% of patients.84,85 Radiation therapy remains a useful palliative tool in the treatment of patients with distant metastatic NSCLC. Common sites of metastatic disease include brain and bone. For patients with brain metastases, radiation therapy is generally employed, either as a sole modality or in combination with surgical resection. The role of stereotactic radiosurgery, particularly in patients with controlled extracranial disease, continues to be defined.86 Between 20 and 40% of patients with NSCLC will develop osseous metastases.87 Focal external beam radiation therapy is the most common method used to treat symptomatic bone metastases. Several fractionation schemes are commonly employed, but recent data in patients with metastatic breast or prostate cancer suggest that 8 Gy in a single fraction provides equivalent pain control to the more protracted schedule of 30 Gy in 10 fractions, although the retreatment rate is significantly higher.88

Superior vena cava (SVC) syndrome results from compression of the SVC with compromised return of venous blood flow to the heart. SVC syndrome occurs in approximately 5% of all patients with lung cancer and it is characterized by presentation with dyspnea, facial and neck swelling, and distention of the veins of the upper chest wall. Initial management may consist of medical therapy such as diuretics and/or corticosteroids. Effective palliation is often quickly achieved by the use of radiation therapy. Commonly, several large fractions of 4 Gy are given for the first several days of treatment.89,90 Palliation of the symptoms associated with SVC syndrome is seen in approximately 90% of patients within three weeks of initiation of therapy.91,92 CONCLUSION Lung cancer is a very common disease and even relatively small advances in treatment have the potential to impact the survival of thousands of patients. In the past two decades, many trials of combined-modality therapy have been conducted in an attempt to improve the survival of patients with NSCLC. The role of radiation therapy is limited in patients with early stage disease and is best suited to treat patients who are medically unfit or refuse to undergo surgery. Radiation therapy may also be used in this setting for patients who do not undergo a complete surgical resection. The best overall therapeutic regimen remains unclear in patients with locally advanced disease, but the use of combined-modality therapy in the treatment of such patients has resulted in a modest but reproducible survival benefit compared to single-modality therapy. Concurrent administration of chemotherapy and radiation therapy for patients with locally advanced NSCLC has been shown to significantly improve survival as compared to sequential therapy in randomized trials and is the standard of care. The role of surgery in this setting continues to be defined. Based on patterns of failure, attention has focused on improving local control and preventing progression of distant disease. It is hoped that with continued advances in all therapeutic modalities, the survival of patients with NSCLC will continue to improve. REFERENCES 1. 2.

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for locally unresectable non-small cell lung cancer. A randomized, phase III trial. Ann Intern Med 1991; 115: 681–6. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995; 311: 899–909. Marino P, Preatoni A, Cantoni A. Randomized trials of radiotherapy alone versus combined chemotherapy and radiotherapy in stages IIIa and IIIb nonsmall cell lung cancer. A meta-analysis. Cancer 1995; 76: 593–601. Pritchard RS, Anthony SP. Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non-small-cell lung cancer. A metaanalysis. Ann Intern Med 1996; 125: 723–9. Hall EJ. Radiobiology for the Radiologist, 5th edn. Philadelphia, PA: Lippincott Williams & Wilkins, 2000. Belani CP. Multimodality management of regionally advanced non-small-cell lung cancer. Semin Oncol 1993; 20: 302–14. Schaake-Koning C, van den Bogaert W, Dalesio O et al. Effects of concomitant cisplatin and radiotherapy on inoperable nonsmall-cell lung cancer. N Engl J Med 1992; 326: 524–30. Furuse K, Fukuoka M, Kawahara M et al. 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 1999; 17: 2692–9. Curran WJ, Scott C, Langer C et al. Phase III comparison of sequential vs. concurrent chemoradiation for patients (pts) with unresected stage III non-small cell lung cancer (NSCLC): initial report of Radiation Therapy Oncology Group (RTOG) 9410. Proc Am Soc Clin Oncol 2000; 19: 484a (abstract 1891). Curran WJ, Scott CB, Langer CJ et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemoradiation for patients with unresected stage III NSCLC: RTOG 9410. Proc Am Soc Clin Oncol 2003; 22: 621 (abstract 2499). Zatloukal P, Petruzelka L, Zemanova M et al. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 2004; 46: 87–98. Pierre F, Maurice P, Gilles R et al. A randomized phase III trial of sequential chemo-radiotherapy versus concurrent chemoradiotherapy in locally advanced non small cell lung cancer (NSCLC) (GLOT-GFPC NPC 95-01 study). Proc Am Soc Clin Oncol 2001; 20: abstract 1246. Rusch VW, Albain KS, Crowley JJ et al. Surgical resection of stage IIIA and stage IIIB non-small-cell lung cancer after concurrent induction chemoradiotherapy. A Southwest Oncology Group trial. J Thorac Cardiovasc Surg 1993; 105: 97–104; discussion 104–6. Albain KS, Rusch VW, Crowley JJ et al. Concurrent cisplatin/ etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995; 13: 1880–92. Albain KS, Swann RS, Rusch VR et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): outcomes update of North American Intergroup 0139 (RTOG 9309). Proc Am Soc Clin Oncol 2005: abstract 7014.

146 Textbook of Lung Cancer 64. Ruebe C, Riesenbeck D, Semik M et al. Neoadjuvant chemotherapy followed by preoperative radiochemotherapy (hfRTCT) plus surgery or surgery plus postoperative radiotherapy in stage III non-small cell lung cancer: results of a randomized phase III trial of the German lung cancer cooperative group. Int J Radiat Oncol Biol Phys 2004; 60: S130. 65. Rusch VW, Parekh KR, Leon L et al. Factors determining outcome after surgical resection of T3 and T4 lung cancers of the superior sulcus. J Thorac Cardiovasc Surg 2000; 119: 1147–53. 66. Rusch VW, Giroux DJ, Kraut MJ et al. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg 2001; 121: 472–83. 67. Rusch VW, Giroux D, Kraut MJ et al. Induction chemoradiotherapy and surgical resection for non-small cell lung carcinomas of the superior sulcus (Pancoast tumors): mature results of Southwest Oncology Group trial 9416 (Intergroup trial 0160). Proc Am Soc Clin Oncol 2003; 22: 634 (abstract 2548). 68. Saunders M, Dische S, Barrett A et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee. Lancet 1997; 350: 161–5. 69. Jeremic B, Shibamoto Y, Acimovic L et al. 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 1996; 14: 1065–70. 70. Belani CP, Wang W, Johnson DH et al. 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 2005; 23: 3760–7. 71. Stanley KE. Prognostic factors for survival in patients with inoperable lung cancer. J Natl Cancer Inst 1980; 65: 25–32. 72. Paesmans M, Sculier JP, Lecomte J et al. Prognostic factors for patients with small cell lung carcinoma: analysis of a series of 763 patients included in 4 consecutive prospective trials with a minimum follow-up of 5 years. Cancer 2000; 89: 523–33. 73. Werner-Wasik M, Scott C, Cox JD et al. Recursive partitioning analysis of 1999 Radiation Therapy Oncology Group (RTOG) patients with locally-advanced non-small-cell lung cancer (LANSCLC): identification of five groups with different survival. Int J Radiat Oncol Biol Phys 2000; 48: 1475–82. 74. Byhardt RW, Scott CB, Ettinger DS et al. Concurrent hyperfractionated irradiation and chemotherapy for unresectable nonsmall cell lung cancer. Results of Radiation Therapy Oncology Group 90-15. Cancer 1995; 75: 2337–44. 75. Siegenthaler MP, Pisters KM, Merriman KW et al. Preoperative chemotherapy for lung cancer does not increase surgical morbidity. Ann Thorac Surg 2001; 71: 1105–11. 76. Martin J, Ginsberg RJ, Abolhoda A et al. Morbidity and mortality after neoadjuvant therapy for lung cancer: the risks of right pneumonectomy. Ann Thorac Surg 2001; 72: 1149–54.

77. Stuschke M, Eberhardt W, Pottgen C et al. 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 1999; 17: 2700–9. 78. Andre F, Grunenwald D, Pujol JL et al. Patterns of relapse of N2 nonsmall-cell lung carcinoma patients treated with preoperative chemotherapy: should prophylactic cranial irradiation be reconsidered? Cancer 2001; 91: 2394–400. 79. Mamon HJ, Yeap BY, Janne PA et al. High risk of brain metastases in surgically staged IIIA non-small-cell lung cancer patients treated with surgery, chemotherapy, and radiation. J Clin Oncol 2005; 23: 1530–7. 80. Cox JD, Stanley K, Petrovich Z et al. Cranial irradiation in cancer of the lung of all cell types. JAMA 1981; 245: 469–72. 81. Russell AH, Pajak TE, Selim HM et al. Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1991; 21: 637–43. 82. Roach M 3rd, Leidholdt EM Jr, Tatera BS et al. Endobronchial radiation therapy (EBRT) in the management of lung cancer. Int J Radiat Oncol Biol Phys 1990; 18: 1449–54. 83. Lo TC, Beamis JF Jr, Villanueva AG et al. Intraluminal brachytherapy for malignant endobronchial tumors: an update on low-dose rate versus high-dose rate radiation therapy. Clin Lung Cancer 2001; 3: 65–8. 84. Chang LF, Horvath J, Peyton W et al. High dose rate afterloading intraluminal brachytherapy in malignant airway obstruction of lung cancer. Int J Radiat Oncol Biol Phys 1994; 28: 589–96. 85. Gustafson G, Vicini F, Freedman L et al. High dose rate endobronchial brachytherapy in the management of primary and recurrent bronchogenic malignancies. Cancer 1995; 75: 2345–50. 86. Chougule PB, Burton-Williams M, Saris S et al. Randomized treatment of brain metastasis with gamma knife radiosurgery, whole brain radiotherapy or both. Int J Radiat Oncol Biol Phys 2000; 48: 114 (abstract 117). 87. Napoli LD, Hansen HH, Muggia FM et al. The incidence of osseous involvement in lung cancer, with special reference to the development of osteoblastic changes. Radiology 1973; 108: 17–21. 88. Hartsell WF, Scott CB, Bruner DW et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 2005; 97: 798–804. 89. Rubin P, Green J, Holzwasser G et al. Superior vena caval syndrome. Slow low-dose versus rapid high-dose schedules. Radiology 1963; 81: 388–401. 90. Scarantino C, Salazar OM, Rubin P et al. The optimum radiation schedule in treatment of superior vena caval obstruction: importance of 99mTc scintiangiograms. Int J Radiat Oncol Biol Phys 1979; 5: 1987–95. 91. Davenport D, Ferree C, Blake D et al. Response of superior vena cava syndrome to radiation therapy. Cancer 1976; 38: 1577–80. 92. Slawson RG, Scott RM. Radiation therapy in bronchogenic carcinoma. Radiology 1979; 132: 175–6.

10.3 Treatment of NSCLC: chemotherapy Athanasios G Pallis, Sophia Agelaki, Vassilis Georgoulias Contents Introduction • Adjuvant chemotherapy after surgical resection • Preoperative (neoadjuvant) chemotherapy • Chemotherapy for locally advanced unresectable (IIIA and IIIB) NSCLC • Chemotherapy for patients with advanced NSCLC • Patients populations with special considerations • Second-line therapy • Targeted therapies in advanced NSCLC

INTRODUCTION The clinical development of chemotherapeutic agents in non-small cell lung cancer (NSCLC) was initially focused in the setting of stage IV disease. During the 1980s and early 1990s, six drugs, namely cisplatin, ifosfamide, mitomycin C, etoposide, vindesine, and vinblastine, were considered active against NSCLC, with response rates reported in excess of 15%.1,2 Combination chemotherapy, most commonly cisplatin-based, was also investigated. Generally, higher objective responses were achieved but still the benefit for the patients was unclear by that time. Subsequent randomized trials and meta-analyses established the value of chemotherapy in the treatment of patients with advanced NSCLC.3,4 The next steps were aimed at the development of chemotherapy from a palliative measure to a curative one, through its incorporation into aggressive combined modality treatments for locoregionally advanced disease, and/or its administration as adjuvant to radical surgery. More recently, during the 1990s, a new generation of compounds such as the taxanes (paclitaxel and docetaxel), the topoisomerase inhibitors (irinotecan, topotecan), active analogs (gemcitabine), antimetabolites (pemetrexate), and vinka alkaloids (vinorelbine) were integrated in the treatment of NSCLC.5 These drugs administered in patients with metastatic disease obtained singleagent activity in the range of 20–30%. When used in combination with other active agents such as the platinums, significant response rates, often in excess of 40%, were reported in pilot phase II studies. The newer agents have been also successfully used in chemotherapy regimens for the treatment of patients with earlier stages of disease as well as in combined-modality treatment programs.

ADJUVANT CHEMOTHERAPY AFTER SURGICAL RESECTION Surgery remains the only curative treatment modality for patients with NSCLC. However, even after complete resection the overall survival remains disappointing, with the five-year survival rates ranging from 67% for patients with T1N0 disease to 23% for patients with N2 disease.6 Efforts to improve the survival of patients with operable NSCLC have examined the addition of chemotherapy (CMT) and/or radiotherapy (RT) in the postoperative setting. The rationale for the use of systemic therapy in completely resected NSCLC lies in the detection of early micrometastatic disease at the time of surgery and in the clinical observation that distant recurrence is the predominant cause of relapse and death after surgery. From the first randomized trials to the 1995 meta-analysis Early trials of postoperative chemotherapy started in the 1960s failed to demonstrate any benefit on survival by the incorporation of alkylating and immunotherapeutic agents.7 The vast majority of subsequent trials employing cisplatin-based regimens8–11 did not show any significant effect of chemotherapy on survival. Common drawbacks in these studies were the overestimation of the potential benefit of adjuvant chemotherapy in the calculation of the sample size, the imbalance in patient and treatment characteristics, the unfeasibility of reaching the planned accrual, and, finally, the low compliance with most chemotherapy regimens used. In 1995 a meta-analysis on the role of chemotherapy in the treatment of NSCLC separately reviewed eight trials, assigning a combined total of 1394 patients to cisplatin-based adjuvant chemotherapy.12 A 13% reduction

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in the risk of death [hazard ratio (HR) 0.87 (95% CI: 0.74–1.02)] corresponding to an absolute survival benefit of 3% at two years (95% CI: 0.5% detriment to 7% benefit) and 5% (95% CI: 1% detriment to 10% benefit) at five years, in favor of chemotherapy, was reported.12 Despite the marginal statistical significance (p = 0.08), these findings encouraged the initiation of several randomized trials investigating the role of platinum-based regimens in patients with completely resected stage I, II, and IIIA NSCLC (Table 10.3.1). These trials used different types of chemotherapy and included different proportions of stages I to IIIA NSCLC. The North American Intergroup Trial INT0115 was the only trial that compared the combination of chemotherapy plus thoracic radiotherapy versus radiotherapy alone in patients with completely resected stage II or IIIA NSCLC.13 INT0115 was negative, but yet, the trial was underpowered to detect the small survival benefit suggested by the meta-analysis and used thoracic radiotherapy as the comparator that is not considered as the standard reference arm. The Big Lung Trial was also clearly underpowered to look at differences in survival in the range of 5%. With a median follow-up of only 2.9 years no significant benefit was shown by the addition of cisplatin-based chemotherapy pre- (4%) or postoperatively (96%).14 In the next sections the most important recent trials of adjuvant chemotherapy are presented. Adjuvant Lung Project Italy (ALPI trial) The ALPI trial randomized 1209 patients with surgically staged I–IIIA NSCLC to receive MVP (mitomycin 8 mg/m2, day 1; vindesine 3 mg/m2, days 1 and 8; CDDP 100 mg/m2, day 1, every three weeks) for three cycles (n = 606), or no treatment (n = 603).15 Stratification factors included center, tumor size, lymph node involvement, and the intention to perform radiotherapy. After a median follow-up of 64.5 months the study failed to demonstrate any significant difference in terms of overall survival [HR 0.96 (95% CI: 0.81–1.13); p = 0.589] and progression-free survival [HR 0.89 (95% CI: 0.76–1.03); p = 0.128]. Median overall survival was 55 months in the chemotherapy arm and 48 months in the surgery alone arm, while progression-free survival was 37 and 29 months for the treatment and control arms, respectively. No significant effect between treatment and stage of the disease emerged. Treatment compliance data indicate that 69% of the patients received the per protocol planned three cycles of chemotherapy, although half of them required some dose adjustment or omission. Chemotherapy was never

started in an additional 9%, mainly due to consent withdrawal. Radiotherapy was completed in 65% of the patients initially planned in the MVP arm and in 83% of the control group. International Adjuvant Lung Cancer trial (IALT trial) The IALT trial randomly allocated patients with surgically resected stage I, II, or III NSCLC to receive cisplatin-based chemotherapy or observation.16 The primary endpoint was overall survival and secondary endpoints were disease-free survival (DFS), second-primary cancers, and adverse events. A total of 3300 patients was required for the trial to have 83% power with a twosided test to detect an absolute improvement of 5%, and 90% power to detect a 5.6% difference in overall survival at five years. However, the trial was terminated prematurely after the enrollment of 1867 patients out of the 3300 initially planned because of a slow down in patient recruitment rate. Each participating center had to determine the pathologic stage of the disease to include, the dose of cisplatin (80, 100, 120 mg/m2 per cycle for 3–4 cycles), the drug to be combined with cisplatin (etoposide, vinorelbine, vindesine, or vinblastine) and the administration of sequential chest radiotherapy. Finally, 932 patients were enrolled in the chemotherapy arm and 935 in the control group. Approximately 37% had disease stage I, 24% stage II, and 39% stage III. Twenty-seven percent of patients received postoperative radiotherapy, while cisplatin plus etoposide was the most frequently utilized regimen. After a median follow-up period of 56 months, the DFS rate at five years was 39.4% for the chemotherapy arm vs 34.3% for the observation arm [HR 0.83 (95% CI: 0.74–0.94; p <0.003)]. Furthermore, overall survival favored the chemotherapy arm [44.5 vs 40.4% at five years; HR 0.86; (95% CI: 0.76–0.98); p <0.03]. Compliance with chemotherapy was relatively poor, with 74% of the patients in the chemotherapy arm receiving at least three treatment courses. Moreover, 70% of the patients treated with chemotherapy and assigned to chest radiotherapy completed their course, compared with 84% of these who did not receive chemotherapy. Seven (0.8%) patients died of chemotherapy-related toxicity. The results observed in the IALT trial are in the same range as those reported in the 1995 meta-analysis.7 The large number of patients in the IALT analysis may explain the significance of the results compared with the smaller number of analyzed patients in the ALPI trial. Moreover, the use of a three-drug regimen and the higher

No of

488

1209

1867

381

119

ALPI trial15

IALT trial16

Big Lung Trial14

JCOG 9304 trial28

patients

INT011513

Trial

IIIA (N2)

I–IIIA

I–IIIA

I–IIIA

II–IIIA

Disease stages included

VP-16 (120 mg/m2, d 1–3); CDDP (60 mg/m2, d 1)/ radiotherapy only (both arms received a total of 50.4 Gy radiotherapy) Mit 8 mg/m2, d 1; VND 3 mg/m2, d 1 & 8; CDDP 100 mg/m2, d 1, q3w, for three cycles/observation CDDP + vinka alkaloids or VP-16/observation CDDP/VND, CDDP/mit/If, CDDP/mit/ vinblastine or CDDP/VNB/ observation CDDP 80 mg/m2, d 1; VND 3 mg/m2, d 1 & 8: ×3 cycles/ observation

CT regimen/ control arm

Table 10.3.1 Reported phase III trials of adjuvant chemotherapy in NSCLC

58

64

74

69

69

Compliance to CT (%)

Median

NR

34.6

56

64.5

44

follow-up (months)

Hazard

0.86

1.02

—

−2b

−7.9c

0.96

0.93

ratio of death

4.1

1

−6a

Five-year absolute survival benefit (%)

(Contiuned)

0.89

0.90

<0.03

0.589

0.56

p

149

840

ANITA trial24 IB–IIIA

IB

65

CDDP (50 mg/m2, d 1 & 8 q 4w); VNB (25 mg/m2)/ observation PCL 200 mg/m2/ carboplatin AUC 6/observation CDDP 100 mg/m2/ VNB 30 mg/m2/ observation 56d

85

74 (at 12 mo) 61 (at 24 mo) 80

Compliance to CT (%)

UFT (250 mg/m2/day) for 2 years/ observation UFT/observation

CT regimen/ control arm

>70

48

6.44 (years) 60

72

Median follow-up (months)

8.6

3

15

4.6

3

Five-year absolute survival benefit (%)

0.79

0.80

0.69

0.77

—

Hazard ratio of death

0.013

0.32

0.011

0.011

0.047

p

b

Estimated 5-year survival rates were 39% for the RT only group and 33% for the CT-RT group. Estimated 2-year survival rates were 60% for the observation group and 58% for the CT group. c 5-year survival rates were 28.2% in the chemotherapy arm and 36.1% in the control group. d Dose density of vinorelbine. CT: chemotherapy; RT: radiotherapy; q3W: every three weeks; VP-16: etoposide; UFT: oral uracil-tegafur; CDDP: cisplatin; Mit: mitomycin; VND: vindesine; If: Ifosfamide; VNB: vinorelbine; PCL: paclitaxel; carboplatin AUC 6: carboplatin Area Under Curve 6.

a

344

IB–II

482

CALGB 9633 trial22,23

I–III

2003

UFT metaanalysis18 NCIC-JBR10 trial19

I

Disease stages included

999

No of patients

UFT trial17

Trial

Table 10.3.1 Continued

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frequency of postoperative radiotherapy in the ALPI trial might also have led to the negativity of this trial. UFT adjuvant trials Uracil-tegafur (UFT) is a combination of uracil, an inhibitor of dihydropyrimidine dehydrogenase (DPD), and tegafur, a prodrug of 5-fluorouracil, that has been extensively studied in Japanese patients with NSCLC. UFT has been studied either as single-agent therapy following surgery or following one or more cycles of cisplatin-based chemotherapy. In all those trials, UFT was administered as a single daily oral dose over a prolonged period of time. The largest trial on postoperative UFT therapy randomly assigned 999 patients with completely resected pathologic stage I adenocarcinoma to receive either oral uracil-tegafur (250 mg/m2/day) for two years (498 patients) or no treatment (501 patients).17 Stratification factors were tumor stage (T1 vs T2), sex, and age. The median follow-up period was 72 months in the UFT group and 73 months in the control group. The fiveyear overall survival rate was 88% (95% CI: 85–91) for the UFT group and 85% (95% CI: 82–89) for the control group. Survival benefit was significant in patients with T2 tumors (85% vs 74% for the UFT and observation groups, respectively; HR 0.48; 95% CI: 0.29–0.81; p = 0.005), while for patients with T1 disease no significant difference was observed. Although toxicity was minimal, compliance was only 74% at 12 months and 61% at 24 months. Recently, a meta-analysis examining the effectiveness of UFT as postoperative treatment of NSCLC was published.18 This meta-analysis included 2003 eligible patients; most (98.8%) had squamous cell carcinoma or adenocarcinoma, and stage I disease; the tumor classification was T1 in 1308 (65.3%), T2 in 674 (33.6%), and the nodal status was N0 in 1923 (96.0%). The median duration of follow-up was 6.44 years. The survival rates at 5 and 7 years were significantly higher in the surgery plus UFT group (81.5% and 76.5%, respectively) than in the surgery alone group (77.2% and 69.5%, respectively; p = 0.011 and 0.001, respectively). The overall pooled hazard ratio was 0.74 (95% CI: 0.61–0.88; p = 0.001). National Cancer Institute of Canada (NCIC) JBR10 trial This trial randomly assigned 482 patients with completely resected, pathologic stage IB and II (patients with T3N0 disease were excluded) to receive either postoperative adjuvant chemotherapy with cisplatin (50 mg/m2, days 1 and 8 every 4 weeks for four cycles) and vinore-

lbine (25 mg/m2, reduced from 30 mg/m2 for unacceptable toxicity, weekly for 16 weeks) or no chemotherapy.19 The study endpoints were overall survival, recurrencefree survival, quality of life, and toxicity. At five years of follow-up, the five-year survival rates were 69% for the chemotherapy arm and 54% for the control arm [HR 0.69 (95% CI: 0.52–0.92); p = 0.011], with an absolute survival benefit of 15% for patients receiving chemotherapy. Subgroup analyses according to stratification factors did not demonstrate significant improvement in survival for patients with disease stage IB receiving chemotherapy compared to the observation group (p = 0.79). In the planned stratified Cox regression analysis, significant factors associated with improved survival included chemotherapy as compared with observation (HR for the difference in survival, 0.67; 95% CI: 0.51–0.89; p = 0.006) and squamous histology as compared with adenocarcinomas (p = 0.005). Despite the positive results, compliance with chemotherapy was relatively low, with only 65% of the patients receiving three or four cycles. Moreover, 77% had at least one dose reduction or omission and 55% required one or more dose delays. Nineteen percent of the patients who received at least one dose required hospitalization for medical problems related to toxicity. There were two chemotherapy-related deaths. Furthermore, treatment was associated with a significant negative impact on quality of life.20 A retrospective analysis evaluated the influence of age on survival, chemotherapy delivery, and toxicity in the BR.10 trial.21 Overall survival for patients older than 65 years was better with chemotherapy versus observation [HR 0.61 (CI: 0.38–0.98); p = 0.04) despite the fact that older patients received significantly fewer doses of cisplatin and vinorelbine. Fewer elderly patients completed treatment and more refused treatment compared to the young (p = 0.03). The authors concluded that patients older than 75 years require further study. Cancer and Leukemia Group B (CALGB) 9633 trial This trial randomly assigned 344 patients with completely resected stage IB (T2N0) NSCLC to four cycles of paclitaxel/carboplatin chemotherapy (paclitaxel 200 mg/m2/carboplatin AUC 6) versus surgery alone. Like the NCIC CTG study, there was no planned thoracic radiotherapy. In this trial compliance with chemotherapy was high, with 85% of the patients receiving three or four treatment cycles. In the first report of the trial,22 after a median follow-up time of 34 months, 71% of patients who had received chemotherapy were alive compared with 59% of those who had surgery alone

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[HR 0.62 (95% CI: 0.41–0.95); p = 0.028]. Overall survival at four years and failure-free survival also favored the chemotherapy group. However, an updated analysis after 54 months of median follow-up showed a nonsignificant trend towards improvement of overall survival by the addition of chemotherapy [HR 0.80 (90% CI: 0.60–1.07); p = 0.1]. A significant prolongation in DFS favoring adjuvant chemotherapy was still present [HR 0.74 (90% two-sided CI: 0.57–0.96); p = 0.027].23 It should be noted though that the trial does not have adequate power to detect small differences in overall survival that may be clinically significant. Adjuvant Navelbine International Trialists Association (ANITA) trial Patients participating in the ANITA trial were required to have completely resected, stage IB–IIIA NSCLC. This trial randomized 840 patients to postoperative chemotherapy (four cycles of cisplatin 100 mg/m2 every 4 weeks and 16 cycles of vinorelbine at 30 mg/m2 weekly) or observation only.24 The five-year survival rates favored the chemotherapy arm; 51.2% vs 42.6% of the patients were alive in the chemotherapy and the control group, respectively [HR 0.79 (95% CI: 0.66–0.95); p = 0.013]. In a subset analysis, chemotherapy significantly improved survival in stages II and IIIA, but not in stage IB. ANITA confirmed the results of the NCIC and CALGB trials in a less selected population (disease stage IB–IIIA) observed for a longer follow-up period (>70 months). However, in this trial significant chemotherapy-related toxicity was also reported, with 84.6% and 12.5% of the patients experiencing grade 3–4 neutropenia and febrile neutropenia, respectively. The median percentage of chemotherapy dose delivered was only 56% and 76% for vinorelbine and cisplatin, respectively. Recent meta-analyses Eleven randomized controlled trials including a total of 5716 patients reported after the 1995 meta-analysis were reviewed in an abstracted-data-based meta-analysis.25 In this analysis, hazard ratio estimates suggested that adjuvant chemotherapy yielded a significant survival advantage over surgery alone [HR 0.872 (95% CI: 0.805– 0.944); p = 0.001]. In a subgroup analysis, cisplatinbased chemotherapy regimens (3786 patients) showed consistent results, with the HR estimates in most trials favoring adjuvant chemotherapy (HR 0.891 (95% CI: 0.815–0.975); p = 0.012). In addition, single-agent UFT therapy (1751 patients) resulted in a significant survival benefit, with an HR of 0.799 (95% CI: 0.668–0.957; p = 0.015).

A second meta-analysis based on abstracted data from 19 randomized adjuvant trials that enrolled 7200 patients was reported by Sedrakyan et al.26 This meta-analysis added summary data from seven trials and approximately 5000 patients to information provided by the 1995 meta-analysis.12 An 11% reduction in the mortality was reported for cisplatin-based regimens and 17% for UFT treatment, as compared to surgery alone. It should be noted that neither meta-analysis included the newer trials that reported substantial benefits associated with adjuvant chemotherapy.19,22,24 A third meta-analysis pooled individual patient data from the five largest trials (ALPI, ANITA, BLT, IALT, and JBR10) of cisplatin-based chemotherapy in completely resected patients conducted after the 1995 meta-analysis.27 With a median follow-up of 5.1 years the overall HR of death was 0.89 (95% CI: 0.82–0.96; p <0.005), corresponding to a five-year absolute benefit of 4.2% by the addition of chemotherapy. The benefit varied with stage, with the HR for stage IA 1.41 (95% CI: 0.96–2.09), stage IB 0.93 (95% CI: 0.78–1.10), stage II 0.83 (95% CI: 0.73–0.95), and stage III 0.83 (95% CI: 0.73–0.95). The recent data from randomized adjuvant trials have changed the standard of care for patients with completely resected NSCLC. Consistent reductions in the risk of death have been observed with cisplatinbased adjuvant chemotherapy. Subset analysis of the large randomized trials,16,19,24 as well as the recent metaanalysis,27 suggests that the benefit is greatest in patients with stages II and III. The role of chemotherapy in earlier disease stages and the optimal drug to combine with cisplatin remain to be determined. Advantages in disease-free survival and three-year survival might support the consideration of adjuvant paclitaxel/carboplatin in stage IB NSCLC. Up to now there are no confirmatory data on the efficacy of UFT in the adjuvant treatment of NSCLC outside of Japan. Considering the significant chemotherapy-associated toxicity, one might suggest that this treatment should be restricted to those patients with good performance status, rapid recovery from surgery, and no significant comorbidity. No prospective data are available on the postsurgical management of elderly patients with resected disease.

PREOPERATIVE (NEOADJUVANT) CHEMOTHERAPY Induction chemotherapy before surgery Preoperative chemotherapy presents several theoretic advantages, including reduction of tumor volume that

Treatment of NSCLC: chemotherapy 153

could enhance local control, evaluation of response to chemotherapy, early eradication of micrometastatic disease, and higher patient compliance compared to postoperative chemotherapy. Phase II studies evaluating the role of preoperative chemotherapy in patients with stage IIIA disease demonstrated an average response rate of 60%, with 55% of patients undergoing thoracotomy and 49% having complete resections; median survival time was approximately 16 months, and five-year survival rate was 30% in chemoresponsive patients, with 50% of patients achieving a pathologic complete response.5 Phase III trails of neoadjuvant therapy in NSCLC, are presented in Table 10.3.2. In a randomized trial by Rosell et al, patients with stage IIIA NSCLC were randomly assigned to undergo either immediate surgery, or surgery preceded by three cycles of chemotherapy with mitomycin (6 mg/m2), ifosfamide (3 g/m2), and cisplatin (50 mg/m2).29 In another trial, patients with stage IIIA NSCLC were randomly allocated to three cycles of preoperative chemotherapy with cyclophosphamide (500 mg/m2, day 1), etoposide (100 mg/m2, days 1 to 3), and cisplatin (100 mg/m2, day 1) or to upfront surgery alone.30 In both studies, radiotherapy was administered in over half of the patients. An interim analysis revealed a statistically significant difference in favor of the induction chemotherapy arm in both studies, resulting in a termination of the accrual after only 60 patients (out of the 120 initially planned) had been enrolled. The observed survival differences also remained highly significant in

subsequent analyses after almost seven years of followup.31,32 It should be noted that the small number of patients included in these studies weakens the power of their observations. Furthermore, the trial by Rosell et al29 has been criticised because of the poor survival outcomes of the control arm. One study randomly assigned patients with stage IIIA (T0–3) or T3 (N0–1), or locally treatable stage IIIB (T4, N3), NSCLC to receive neoadjuvant docetaxel (100 mg/m2 every three weeks) (n = 134) or no chemotherapy (n = 140) before surgery or curative-intention radiotherapy.33 Median survival was 14.8 months in the docetaxel group and 12.6 months in the control group (p = non-significant). Median times to disease progression were 9.0 months (docetaxel arm) and 7.6 months (control arm). Preoperative chemotherapy might also have a role in earlier disease stages. In a multicenter phase III study conducted by the French Thoracic Cooperative Group, 355 patients with clinical IB–IIIA disease were randomly assigned to receive two cycles of induction mitomycin (6 mg/m2, day 1), ifosfamide (1.5 g/m2, days 1 to 3), and cisplatin (30 mg/m2, days 1 to 3) followed by surgery and two postoperative cycles or surgery alone.34 Patients with pT3 or pN2 received postoperative radiation. The overall response to induction chemotherapy was 64%. Although median survival favored the chemotherapy arm, the difference failed to reach statistical significance (37 months for the chemotherapy arm vs 26 months for the surgery alone arm, p = 0.15). Subgroup analysis

Table 10.3.2 Phase III trials of neoadjuvant chemotherapy in NSCLC Trial

No of patients

Disease stages included

CT regimen/ control arm

Median survival (months)

p

CEP ×3→surgery→ CEP ×3 vs surgery PIM→surgery→RT vs surgery→RT PE ×2→surgery→ PE ×4 vs surgery MIP ×2 → surgery → MIP ×2 vs surgery

64 vs 11

0.008

26 vs 8

<0.001

28.7 vs 15.6

NS

37 vs 26

NS

14.8 vs 12.6

NS

42 vs 37

NS

MD Anderson30

60

IIIA (N2), some IIIB

Spain29

60

IIIA (N2)

NCI36

27

IIIA (N2) biopsy

French Thoracic Cooperative Group34 Mattson et al33

355

IB–IIIA

274

III

Pisters et al35

354

IIA–IIIA

T×3→surgery vs surgery Ta/Carbo ×3→ surgery vs surgery

C: cyclophosphamide; E: etoposide; P: cisplatin; I: ifosphamide; M: mitomycin; T: docetaxel; Ta: paclitaxel; Carbo: carboplatin, NS: non-significant.

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revealed a significant benefit in patients with N0–1 disease [relative risk (RR) 0.68 (95% CI: 0.49–0.96); p = 0.027], but not for the group with N2 disease [RR 1.04 (95% CI: 0.68–1.60); p = 0.85]. Finally, a recently reported phase III study evaluated neoadjuvant chemotherapy in patients with clinical stage T2N0, T1–2N1, and T3N0–1 (excluding superior sulcus tumors). Patients were stratified by clinical stage (IB/IIA vs IIB/IIIA) and were randomized to receive either paclitaxel and carboplatin (every three weeks for three cycles) plus surgery or surgery alone.35 The primary endpoint was a 33% increase in overall survival over the expected 2.7 years median for surgery alone. After a median follow-up of 28 months during which 354 patients had been enrolled, the trial was prematurely terminated due to the positive data coming from the adjuvant chemotherapy trials. Median progressionfree survival was 29 months for the neoadjuvant group and 20 months for the surgery only group [HR 0.85 (CI: 0.63–1.14); p = 0.26]. Median overall survival was 42 months and 37 months, for the preoperative and surgery only arms, respectively [HR 0.88 (CI: 0.63–1.23); p = 0.47]. In general, preoperative chemotherapy induces a high rate of objective responses. Further investigation is required to select the ideal regimen in terms of efficacy and safety and to identify subgroups of patients and/ or predictive factors associated with greater benefit. Randomized trials evaluating the comparative efficacy of adjuvant and neoadjuvant chemotherapy are also warranted. Induction chemoradiotherapy before surgery The concurrent administration of chemotherapy with radiotherapy has been used before surgery in patients with stage III disease in an effort to improve survival outcomes. Although surgery might be associated with higher morbidity and mortality after preoperative treatment, the feasibility of this approach has been demonstrated in several phase II studies. In the North American Intergroup trial 0139 (INT 0139), 429 patients with T1–3 pN2 disease deemed resectable at presentation were randomized either to induction concurrent chemoradiotherapy with 45 Gy and cisplatin (50 mg/m2 on days 1, 8, 29, and 35) and etoposide (50 mg/m2 days 1 to 5 and 29 to 33) followed by surgery (for non-progressors) or to definitive chemoradiation (with cispaltin and etoposide) to 61 Gy.37 Both groups received consolidation chemotherapy with two cycles of cisplatin and etoposide. Although progressionfree survival was significantly prolonged in the surgery

arm (14.0 vs 11.7 months; p = 0.02), overall survival was not different (22 months) between arms. There were more early non-cancer deaths on the surgical arm, but overall survival curves crossed so that, by year 3, the overall survival favored the surgery arm (38% vs 33%). Long-term follow-up of the INT 0139 confirmed the superior progression-free survival and showed a trend for superior five-year overall survival for the trimodality therapy.38 In a subgroup analysis, patients who achieved pathologic N0 disease had a favorable long-term survival. Moreover, patients who underwent lobectomy had superior survival over patients receiving definitive chemoradiotherapy (p = 0.002). The German Lung Cancer Cooperative Group randomly assigned 558 patients with selected pathologic stages IIIA and IIIB NSCLC subsets to chemotherapy with cisplatin/etoposide for three cycles followed by hyperfractionated radiotherapy to 45 Gy concurrently with carboplatin/vindesine and then surgery or chemotherapy with cisplatin/etoposide for three cycles followed by surgery and then radiotherapy to 54 Gy.39 Both groups received additional radiotherapy if a complete resection was not achieved. Of note, both arms received radiotherapy but the timing and fractionation, as well as the chemotherapy drugs, differed. No significant differences were observed regarding the three-year progression-free survival (18% vs 20%, p = non-significant) and the three-year survival (26% vs 25%, p = non-significant). This study has been criticized because of the low resection rates, and the inclusion of radiotherapy in both arms. The role of aggressive induction therapies in the management of resectable stage III disease remains to be determined. It seems that in N2 disease, patients who achieve significant downstaging experience prolonged survival. However, the optimal management of these patients with surgery versus definitive chemoradiation needs further clarification. The role of chemoradiation before surgery in earlier disease stages needs to be identified.

CHEMOTHERAPY FOR LOCALLY ADVANCED UNRESECTABLE (IIIA AND IIIB) NSCLC Up to one-third of patients with NSCLC present with disease that remains localized to the thorax, but is considered too extensive for surgical treatment (stages IIIA and IIIB). Historically, radiotherapy (RT) represented the standard of care for these patients.40 However, results were disappointing with five-year survival

Treatment of NSCLC: chemotherapy 155

rates of less than 5%, due to the high incidence of both locoregional relapses and distant metastases. This observation led to efforts for the development of more active, multimodality therapies that incorporate chemotherapy. Chemotherapy followed by radiotherapy Several randomized phase III studies compared RT with the bimodality therapy of induction chemotherapy, followed by RT. Generally, studies with larger sample size incorporating more intensive chemotherapeutic regimens demonstrated a significant survival benefit in favor of the combined modality treatment (Table 10.3.3). It was also suggested that the main impact of systemic chemotherapy was a reduction in the rate of distant relapses.41 The positive results of these randomized trials have been confirmed by two meta-analyses.12,42

Concurrent chemoradiotherapy The simultaneous administration of chemotherapy and RT provides the advantages of early administration of systemic treatment as well as the additional theoretic benefit of increasing locoregional control. Furthermore, concurrent chemoradiotherapy offers a reduction in the treatment time compared to the sequential approach. In the clinical setting, concomitant chemoradiotherapy is associated with significant toxicities including esophagitis, risk of radiation pneumonitis, and increased myelosuppression. The results of several phase II studies provided preliminary evidence supporting the feasibility of the addition of chemotherapy to RT.45 Subsequent randomized trials, employing either the concurrent or the sequential mode, compared the combined therapy with RT alone (Table 10.3.4). Several trials demonstrated a significant

Table 10.3.3 Selected phase III trials comparing sequential chemo-RT vs RT only, in patients with advanced NSCLC Trial

n

Stage

Regimen

Survival (median)

CALGB 843343

155

III

PV→RT (60 Gy) vs RT (60 Gy)

RTOG, ECOG, and SWOG44

452

III

PV→RT (60 Gy) vs RT (60 Gy) vs HFx-RT (69.6 Gy)

CMT + RT 13.8 months; RT 9.7 months (p = 0.0066) 3-year survival: CMT + RT 23%; RT 10% (p = 0.012) 7-year survival: CMT + RT 13%; RT 6% (p = 0.012) Median survival: CMT + RT 13.2 months (p = 0.04 vs RT); RT 11.4 months; HFx-RT 12 months (NS) 3-year survival; CMT+RT 17%; RT 11%; HFx-RT 14% 5-year survival: CMT+RT 8% (p = 0.04 vs RT); RT 5%; HFx-RT 6% (NS)

P: cisplatin; V: vindesine; HFx-RT: hyperfractionated RT; CMT: chemotherapy.

Table 10.3.4 Randomized phase III trials comparing combined chemoradiotherapy versus radiotherapy alone Trial

n

Regimen

Survival (median)

Le Chevalier46 Schaake-Koning47

354 331

Soresi48 Morton49 Blanke50

95 121 215

PLVC + RT (65 Gy) vs RT (65 Gy) P (weekly) + RT vs P (daily) + RT vs RT P + RT (50 Gy) vs RT (50 Gy) MACCu + RT vs RT P + RT ×3 cycles vs RT

2-year survival: 21% vs 14% (p = 0.02) 2-year survival: 19% vs 26% vs 13% (p = 0.009; daily P + RT vs RT) 16 months vs 11 months; p = NS 2-year survival: 21% vs 16%; p = NS 43 weeks vs 46 weeks; p = 0.394

P: cisplatin; V: vindesine; L: lomustine; C: cyclophosphamide; M: methotrexate; A: doxorubicin; Cu: CCNU; NS: non-significant.

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survival benefit in favor of the combined modality treatment,46,47 whereas others did not.48–50 Two large meta-analyses suggested a small, but statistically significant improvement in survival with the combinedmodality regimens. In the meta-analysis by Pritchard and Anthony, a significant decrease in the relative risk of death with combined therapy was shown at both one and three years in patients with unresectable stage III disease.51 Similarly, Marino et al reported a 24% reduction in the risk of death at one year and a 30% reduction at two years for combined cisplatin-based chemotherapy and radiotherapy.42 Definitive testing of concurrent chemoradiotherapy versus the sequential approach in the phase III setting has been also performed (Table 10.3.5). The concurrent administration of platinum-based chemotherapy with radiotherapy demonstrated a modest although statistically significant survival benefit compared with the

sequential administration. Median survival was 15–17 months in the concurrent arm versus 12.9–14.6 months in the sequential arms.52–55 It is interesting that the two largest randomized trials have demonstrated remarkably similar results.52,54 The West Japan Lung Cancer Group randomly assigned 320 patients to a combination of cisplatin (80 mg/m2, days 1 and 29), vindesine (3 mg/m2, days 1, 8, 29, and 36), and mitomycin (8 mg/m2, days 1 and 29) given concurrently with 56 Gy of radiotherapy, split into two 28 Gy courses separated by 10 days, versus the same chemotherapy given as induction followed by 56 Gy of continuous radiotherapy.52 The concurrent approach was significantly superior (p = 0.03998), with a median survival of 16.6 versus 13.3 months and five-year survival rates of 15.8% versus 8.9%, respectively. RTOG 9410 evaluated the use of cisplatin (100 mg/m2, days 1 and 29) and vinblastine (5 mg/m2 weekly for five

Table 10.3.5 Phase III trials comparing sequential versus concurrent chemoradiotherapy Trial

n

Regimen

Survival (median)

p

West Japan52

320

P/Vin/M + RT (56 Gy; split course) vs P/Vin/M → RT (56 Gy; continuous)

Concurrent 16.6 months; sequential 13.3 months

0.03998

Two-year survival: concurrent 34.6%; sequential 27.4% Five-year survival: concurrent 15.8%; sequential 8.9% Concurrent 15 months; sequential 13.8 months Two-year survival: concurrent 35%; sequential 23% Sequential 17 months; concurrent (daily RT) 14.6 months; concurrent (HFx-RT) 15.6 months Four-year survival: sequential 12%; concurrent (daily RT) 21%; concurrent (HFx-RT) 17% Concurrent 16.6 months; sequential 12.9 months Three-year survival: concurrent 18.6%; sequential 9.5%

NR

GLOT-GFPC57

RTOG 94–1054

Czech Republic55

212

610

102

PE + RT (66 Gy) → PV vs PV → RT (66 Gy) PVi → RT (60 Gy) vs PVi + RT (60 Gy) vs PE + HFx-RT (69.6 Gy)

PV + RT (60 Gy) vs PV → RT (60 Gy)

P: cisplatin; Vin: vindesine; M: mitomycin; E: etoposide; V: vinorelbine; Vi: vinblastine; HFx-RT: hyperfractionated RT; NS: non-significant; NR: not reported.

NR NS NS 0.046

0.046

0.023 NR

Treatment of NSCLC: chemotherapy 157

doses) followed by once-daily radiotherapy (60 Gy) versus cisplatin and vinblastine at the same doses given concurrently with the same radiotherapy, or cisplatin (50 mg/m2, days 1, 8, 29, and 36) and oral etoposide (50 mg twice daily for 10 doses on weeks 1, 2, 5, and 6) given concurrently with hyperfractionated radiotherapy (69.6 Gy given in 1.2 Gy fractions twice daily). In this trial 610 patients with unresectable NSCLC were randomly assigned to one of three arms. Both the median survival and the four-year survival were significantly better in the concurrent daily radiotherapy arm when compared with the sequential arm (17 vs 14.6 months; p = 0.038) and (21% vs 12%), respectively. The hyperfractionated radiotherapy arm showed a median survival of 15.6 months, that did not reach statistical significance compared with the sequential treatment.54 Movsas et al reported on the quality adjusted time without symptoms of toxicity analysis of RTOG 9410.56 Although reversible non-hematologic toxicity was higher in the sequential arm, the overall mean toxicity was highest in the sequential arm, further supporting the use of concurrent chemoradiation in locally advanced unresectable disease. Multiple efforts in the phase I/II setting focused on the incorporation of the newer chemotherapeutic agents such as paclitaxel, gemcitabine, vinorelbine, and topoisomerase I inhibitors into chemoradiotherapy treatment. In general, acceptable toxicity and high response rates have been demonstrated. In a randomized phase III trial by Fournel et al, a trend towards better survival was observed in favor of the concurrent approach.57 However, chemotherapy was different between the two arms. In the sequential arm, cisplatin (120 mg/m2 days 1, 29, and 57) and vinorelbine (30 mg/m2 weekly for 12 doses) was followed by thoracic irradiation (66 Gy in 33 fractions). In the concurrent arm, cisplatin and etoposide for two cycles were given with the same radiation dose. Patients received consolidation chemotherapy with cisplatin (80 mg/m2 on days 78 and 106), plus vinorelbine (30 mg/m2 weekly for eight cycles). The median survival was 13.8 months for the sequential and 15 months for the concurrent arm (p = non-significant). The two-year survival showed a trend in favor of concurrent chemoradiotherapy (35% vs 23% for sequential), with updated results awaited. Induction chemotherapy followed by concurrent chemoradiotherapy The potential advantage of using both induction and concurrent modality treatments lies in the enhancement of both the exposure to systemically active doses of chemotherapy and locoregional control of the disease.

Two hundred and eighty-three patients with inoperable stage III NSCLC were entered into a randomized trial by the Cancer and Leukemia Group B (CALGB) and the Eastern Cooperative Oncology Group.58 All received induction chemotherapy with vinblastine and cisplatin for five weeks followed by radiation therapy or radiotherapy concomitantly with weekly carboplatin. There was no difference with respect to overall survival (13% with carboplatin and 10% with radiotherapy alone) at four years. CALGB also conducted a trial which randomly assigned 303 patients with stage IIIA/B disease to receive induction paclitaxel (200 mg/m2) and carboplatin (AUC 6) for two cycles, followed by either radiotherapy alone (60 Gy) or the same radiotherapy concurrently with weekly paclitaxel (60 mg/m2). Median survival was 19.2 months versus 14.6 months in favor of the concurrent chemoradiotherapy arm, but the difference did not reach statistical significance.59 Another CALGB trial randomly assigned 366 patients to either induction paclitaxel (200 mg/m2) and carboplatin (AUC 6) followed by chemoradiotherapy [66 Gy concurrently with weekly carboplatin (AUC 2) and paclitaxel (50 mg/m2)] versus immediate chemoradiotherapy alone. Both median and one-year survival were similar between the two arms (14.0 months, 48% versus 11.4 months, 58%; p = 0.154).60 The role of consolidation therapy after concurrent chemoradiation has also been investigated. Southwest Oncology Group (SWOG) reported on a phase II study of concurrent chemoradiation with full doses of cisplatin (50 mg/m2, days 1, 8, 29, and 36) and etoposide (50 mg/m2, days 1 through 5, and days 29 through 33) followed by three cycles of docetaxel single agent (75 to 100 mg/m2). In this group of patients with pathologically documented stage IIIB disease, a promising median survival of 27 months was achieved.61 However, only 59% of the 83 relevant patients received all three cycles of docetaxel, illustrating the difficulties of consolidation chemotherapy after definitive chemoradiation. In a randomized phase II non-comparative study by Belani et al, patients with unresected stage IIIA and IIIB disease received two cycles of induction paclitaxel and carboplatin followed by sequential RT (n = 91), or two cycles of induction paclitaxel and carboplatin followed by weekly paclitaxel and carboplatin with concurrent RT (n = 74), or weekly paclitaxel and carboplatin plus concurrent RT followed by two cycles of paclitaxel and carboplatin (n = 92).62 The three arms were to be compared with a historical control using the sequential chemoradiotherapy arm of the RTOG 8808 trial, for which the

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available reported median survival time was 13.7 months.63 Median survival times for the sequential and concurrent arms were 13 and 12.7 months, respectively. The concurrent/consolidation arm was associated with the best outcome (median overall survival 16.3 months, p = 0.34) and greater toxicity rates. Currently, concomitant chemoradiotherapy is considered the standard therapy of unresectable stage III NSCLC. However, it applies only to patients with good performance status. For the present, there is no value of adding induction chemotherapy with currently established agents. The role of consolidation chemotherapy remains to be confirmed in randomized trials. CHEMOTHERAPY FOR PATIENTS WITH ADVANCED NSCLC Patients with advanced NSCLC (stage IIIB with pleural or pericardial effusion or stage IV), treated with best supportive care (BSC) alone, have a median survival of 4–5 months and a one-year survival of approximately 10%.64 Throughout the 1970s and 1980s, combination chemotherapy (usually cisplatin-based) resulted in objective responses rates in 20 to 30% of lung cancer patients, but median survival was only six to eight months, and few patients survived longer than one year. The most frequently used regimens were the combinations of cisplatin with etoposide, vindesine, or vinblastine. Several randomized trials, addressing the question of whether the benefit of chemotherapy outweighed the cost of toxicity over best supportive care alone, demonstrated a small, but statistically significant survival benefit for patients receiving chemotherapy.5 Due to limitations in most of these studies, meta-analyses were performed to address the same question.42,65,66 In the largest of these meta-analyses, alkylating agents were associated with a detrimental effect on survival, while cisplatin-based chemotherapy conferred a 27% reduction in the risk of death, and a 10% absolute increase in one-year survival rates.12 Thus systemic cisplatin-based chemotherapy has since been considered as standard care in most patients with advanced NSCLC.67 First-line therapy Platinum-based chemotherapy Between 1981 and 1991, several randomized trials, with more than 1900 patients enrolled, evaluated a wide range of first-generation cisplatin-based chemotherapy regimens.68–71 No significant differences emerged between regimens, or between studies.

Le Chevalier et al were the first to compare the combination of a second-generation over a first-generation cisplatin-based doublet.72 In this trial, patients treated with cisplatin/vinorelbine had significantly longer median survival compared to those treated with cisplatin/ vindesine (40 weeks vs 32 weeks; p = 0.04). Moreover, this study demonstrated that cisplatin was necessary since a cisplatin/vinorelbine combination was superior to vinorelbine alone (40 weeks vs 31 weeks; p = 0.01) (see Table 10.3.6.). Further randomized trials addressing the same question demonstrated that second-generation regimens are generally associated with improved efficacy, toxicity, quality of life, or a combination of these endpoints, although statistically significant survival gain was not uniformly found. More recently, second-generation cisplatin-based regimens have been more widely used. Direct comparison of these regimens in randomized phase III trials failed to demonstrate a particular combination to be clearly superior for NSCLC. The results of appropriately sized trials comparing second-generation platinumbased doublets are presented in Table 10.3.7. ECOG 1594, one of the largest randomized trials, assigned a total of 1207 patients with advanced NSCLC to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. Patients were stratified according to ECOG performance status (0 or 1 vs 2), weight loss in the previous six months (<5% vs ≥5%), the stage of disease (IIIB vs IV or recurrent disease), and the presence or absence of brain metastases. In this study no difference was observed in terms of response rate or overall survival between the different chemotherapy regimens; response rates ranged from 17 to 22% and median survival from 7.4 to 8.1 months. The cisplatin/gemcitabine arm showed significantly longer time to tumor progression when compared with the reference arm (4.2 vs 3.4 months, p = 0.001). Differences in the toxicity profiles of each regimen were identified, with cisplatin/gemcitabine causing more thrombocytopenia, cisplatin/docetaxel causing more neutropenia, and the carboplatin/paclitaxel arm causing the lowest rate of potentially life-threatening adverse events.81 TAX 326 was another large trial that randomized 1218 patients to one of three treatment groups: docetaxel/ cisplatin (DC regimen), docetaxel/carboplatin (DCb regimen), or the control arm of vinorelbine/cisplatin (VC regimen). Patients treated with DC had a median survival of 11.3 versus 10.1 months for VC-treated patients (p = 0.044). The two-year survival rate was 21% and

Treatment of NSCLC: chemotherapy 159

Table 10.3.6 Randomized trials of cisplatin plus a new agent versus cisplatin plus an old agent Trial

Therapy

Le Chevalier72 V/P Vi/P Bonomi73 Ta (low)/Pa Ta (high)/P E/P Giaccone74 Ta/P Ten/P Cardenal75 G/P E/P Niho76 CPT/P Vi/P Negoro77 CPT/P Vi/P Kubota78 T/P Vi/P

No of patients

206 200 198 201 200 166 166 68 67 100 103 129 122 151 151

Odds ratio (%)

Median survival (weeks)

30 19 25.3 27.7 12.4 28 41 41 22 29 22 44 32 37 21

40 32 41.2 43.3 32.9 42.9 42.0 37.7 30.3 45 50 50 46 49.3 41.9

One-year survival (%)

40 32 37.4 40.3 32 41 43 26 32 43 48 46 38 48 43

p

0.04

0.048b NS NS NS NSc NS

a Paclitaxel (low): 135 mg/m2 intravenously over 24 hours; paclitaxel (high): 175 mg/m2 intravenously over 24 hours plus granulocyte colony-stimulating factor. b Comparing the two paclitaxel groups combined with the etoposide/cisplatin group; other comparisons were not significant. c Survival differences were significant in the stage IV subset. P: cisplatin; Vin: vindesine; E: etoposide; V: vinorelbine; Carbo: carboplatin; Ta: paclitaxel; Ten: Teniposide; G: gemcitabine; T: docetaxel; Vi: vindesine; CPT: irinotecan; NS: non-significant; NR: not reported.

Table 10.3.7 Selected phase III trials comparing second-generation platinum-based doublets Trial

n

Regimen

Median survival (months)

p

SWOG 950979 ILCSG80 ECOG 159481 TAX 32682

408 607 1207 1218

P/V vs Carbo/Ta Carbo/Ta vs P/V vs P/G P/Ta vs P/G vs P/T vs Carbo/Ta P/V vs P/T vs Carbo/T

8.0 vs 8.0 9.9 vs 9.5 vs 9.8 7.8 vs 8.1 vs 7.4 vs 8.1 10.1 vs 11.3 vs 9.4

NS NS NS 0.04a NSb

a

P/V vs P/T, p = 0.04 in favor of P/T. P/V vs Carbo/T, p = NS. P: cisplatin; V: vinorelbine; Carbo: carboplatin; Ta: paclitaxel; G: gemcitabine; T: docetaxel; Vi: vindesine; CPT: irinotecan; NS: non-significant; NR: not reported. b

14% for DC and VC, respectively. Overall response rate was 31.6% for DC and 24.5% for VC (p = 0.029). Median survival (9.4 vs 9.9 months, p = 0.657) and objective response rate (23.9% vs 24.5%) were similar for patients treated with DCb and VC, respectively. The incidence of neutropenia, thrombocytopenia, infection, and febrile neutropenia was similar with all three regimens. Patients treated with either docetaxel regimen had a consistently improved quality of life compared to those treated with VC.82

Non-cisplatin-containing chemotherapy Cisplatin-based chemotherapy is associated with considerable cisplatin-related toxicity.83 Thus, nausea and emesis are often severe and delayed, whereas neurotoxicity, renal toxicity, and ototoxicity are dose-related and difficult to handle. Cisplatin administration requires additional hydration that is intolerable to a significant proportion of NSCLC patients due to old age and/or concomitant cardiac or cardiopulmonary diseases. Additionally, a prolonged hospital stay is mandatory,

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critical from the convenience as well as the economic aspects.84,85 Cisplatin versus carboplatin The substitution of cisplatin for carboplatin has been employed as a means to overcome cisplatin-related incovenience. Several randomized trials have compared cisplatin with carboplatin doublets.82,86,87 In a trial by Rosell et al, 618 patients were randomized to receive paclitaxel in combination with either cisplatin or carboplatin. The study was designed to demonstrate a non-inferior response rate with carboplatin.This was the only trial to demonstrate a statistically significant improvement in overall survival in favor of the cisplatin arm (9.8 vs 9.2 months, p = 0.019).86 TAX 326, although not designed to directly compare the 814 patients randomized to docetaxel/cisplatin and docetaxel/carboplatin arms, demonstrated a statistically significant improvement in survival for docetaxel/cisplatin compared to the control arm of cisplatin/vinorelbine. Cisplatin/vinorelbine itself resulted in numerically superior survival outcomes compared to the carboplatin/docetaxel combination.82 Finally, a meta-analysis using abstracted data identified eight trials including 2948 patients that evaluated

the substitution of cisplatin for carboplatin. Cisplatinbased chemotherapy resulted in higher response rates without any difference in overall survival [HR 1.050 (95% CI: 0.907–1.216); p = 0.515). Based on the above data it is reasonable to conclude that cisplatin might be slightly superior to carboplatin. Although this difference is slim, it might have an impact for earlier disease stages. The choice of the compound to be used should be made on a case to case basis and should be tailored to the patient’s needs.88 Platinum versus non-platinum doublets The development of the newer agents led to novel, effective non-platinum-containing chemotherapy regimens and to the initiation of several randomized trials designed to determine whether these regimens are comparable to platinum-based combinations in terms of efficacy.89–95 In general, these trials did not demonstrate a statistically significant survival benefit in favor of patients treated with platinum-based doublets (see Table 10.3.8). In three trials, a trend towards better overall survival was observed in patients treated with platinum-based combinations.91,92,95 On the other hand, another study demonstrated that the combination of vinorelbine and gemcitabine was superior to vinorelbine plus carboplatin

Table 10.3.8 Platinum- versus non-platinum-based doublets Author

Regimen

Georgoulias89

T/P T/G Ta/C Ta/G G/V G/P P/V G/P Ta/P Ta/G G/P G/P/V G/V → V/If GVP GV V/P T/G

Kosmidis90 Gridelli91

Smit92

Alberola93

Laack94 Georgoulias95

No of patients

441 248 254 501

490

557

287 117 134

Response rate (%)

Median TTP (months)

32 31 28 35 25 }30

9.5 8 6.3 6.1 17 weeks 22 weeks 22 weeks 5.6 4.4 3.9 6.3

10 9.5 10.4 9.8 32 weeks 38 weeks 38 weeks 8.9 8.1 6.7 9.3

5.7 19.3 22.3 8.5 8

8.1 32.4 weeks 35.9 weeks 9.7 9

37 32 28 42 41 27 28.3 13 39.2 30

Median OS (months)

p

One-year survival (%)

NR NS 0.32 0.08

NS

41.7 41.4 NR

32.6 35.5 26.5 38

NS NS 0.96 5

P: cisplatin; V: vinorelbine; G: gemcitabine; T: docetaxel; If: Ifosfamide; Ta: paclitaxel; C: carboplatin; Epi: epirubicin; NR: not reported; NS: non-significant; TTP: time to tumor progression; OS: overall survival.

34 27.5 33.6 34.3 40.8

Treatment of NSCLC: chemotherapy 161

in terms of response rate, progression-free survival, overall survival, and clinical benefit.96 In most trials, non-platinum doublets were associated with a more favorable toxicity profile.89,91,93–95 However, in two of them no significant differences in terms of toxicity were reported.90,92 Two trials evaluating the issue of cost-effectiveness reported contradictory results, with one study demonstrating superiority of platinumbased doublets,92 whereas in the other no difference between the two arms was reported.90 It should be noted here that none of the above mentioned trials was adequately sized to test equivalence, precluding safe conclusions regarding the comparative activity of platinum versus non-platinum doublets. A recently published meta-analysis reviewed 37 randomized phase II and III studies comparing a platinumbased regimen with the same regimen either without cisplatin or with cisplatin replaced by a non-platinum compound, in patients with advanced NSCLC.97 This meta-analysis included a total of 7633 patients and reported on the response rates, activity, and survival of platinum- versus non-platinum-based chemotherapy. A 62% increase in the odds ratio (OR) for response was attributable to platinum-based therapy (p <0.0001). When the analysis was restricted in trials that had combinations of the newer agents as the comparator, the benefit was 17% in favor of platinum (14 trials including 3204 patients; p = 0.042). Overall, the one-year survival rate was 34% and 29% for the platinum- and non-platinum-containing regimens, respectively (p = 0.0003). However, when platinumbased therapies were compared to combinations of the newer agents, no statistically significant increase in oneyear survival was found (36% vs 35%, p = 0.17). When the toxicity of platinum-based regimens was compared with newer, non-platinum combinations, significantly higher hematologic toxicity, nausea and vomiting, and toxic death rate were observed, but no significant increase in febrile neutropenia rate, neurotoxicity, or nephrotoxicity was reported.97 Accordingly, the current American Society of Clinical Oncology (ASCO) guidelines make no distinction between platinum-based and non-platinum doublets as the preferred first-line treatment in patients with advanced NSCLC.98 Two drugs versus one drug A third way to deal with the chemotherapy toxicity in patients with advanced NSCLC is to use a single-agent chemotherapy rather than combination treatments. Several trials have compared a doublet versus a singleagent therapy (Table 10.3.9).

Most studies evaluated a platinum-based doublet versus the corresponding non-platinum monotherapy,102–104,106,107 some tested a new drug versus a platinum older drug combination,99,101 and others compared cisplatin monotherapy versus a platinum new drug combination.84,85,105,108 In general, new single agents were shown to be equally effective and less toxic than the old cisplatinbased doublets.99,101 However, most of the studies evaluating the newer agents over a platinum new drug combination have clearly demonstrated a superiority for the combination therapy.85,102,104,105 Similarly, most of the studies comparing platinum agents to newer platinum-based doublets demonstrated a superiority for the combination therapy.105,108 Based on the above data, ASCO guidelines98 suggest that two-drug combination chemotherapy remains the standard first-line treatment of patients with advanced NSCLC. Triplets for the treatment of advanced NSCLC Several randomized trials evaluated the potential role of three-drug combinations as a means of improving survival outcomes in NSCLC. The most recent studies are presented in Table 10.3.10. Although three drug combinations led to significantly higher response rates, they failed to demonstrate any benefit in terms of time to tumor progression and overall survival, while they were associated with significantly higher toxicity. Duration and timing of first-line therapy The optimal duration of treatment in patients with advanced NSCLC has also been evaluated in randomized trials. In a trial by Smith et al, 308 patients were randomized to receive three or six cycles of mitomycinvinblastine and cisplatin.112 No survival difference was observed between the two arms, while patients receiving six treatment cycles experienced significantly higher toxicity. In a randomized trial by Socinski et al, 230 patients received the paclitaxel/cisplatin doublet for either four cycles, or until disease progression.113 Upon progression, all patients were treated with weekly paclitaxel. The median survival did not differ significantly between the two arms (8.5 months for the ‘until progression’ group vs 6.7 for the ‘four cycles’ group, p = 0.63). It is interesting to note that in the treat ‘until progression’ arm the median number of cycles administered was four. Toxicity was higher in this arm due to the cumulative neuropathy. Accordingly, ASCO guidelines support the administration of no more than six cycles of first-line chemotherapy. In non-responding patients treatment should be stopped at four cycles.98

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Table 10.3.9 Randomized studies comparing single-agent versus combination therapy Author

Regimen

Manegold99

G P/E P/Vin P/CPT-11 CPT-11 G P/Vin P/Vin P/V V G/C G Ta/P Ta P/G P P/Tir P T/P T

Negoro100

Vansteenkiste101 Le Chevalier102

Sederholm103 Lilenbaum104 Sandler105 von Pawel85 Georgoulias106

No of patients

156

ORR (%)

17.2 7 31.7 43.7 20.5 20.2 20 19 30 14 30 12 30 16 30.4 11.1 27.5 13.7 36.5 21.7

398

169 612

229 586 522 446 319

Median TTP (months)

4.2 3.7 NR

Median OS (months)

p

NR

45.6 weeks 46 weeks 50 weeks 9.2 6.7 13.7 5.5 NR 8.0 9.2 7.2 6 11 4 9 8.5 NR 6.5 5.6 9.1 3.7 7.6 12.9 weeks 34.6 weeks 11.6 weeks 27.7 weeks 4.0 10.5 2.5 8

One-year survival (%)

NR

NR

NS

38.3 41.8

0.13 0.01a

NS 0.023 0.004 0.0078 NS

22 19.3 NR

NR 36 31 39 28 33.9 22.5 44 43

a

P/V vs V. G: gemcitabine; P: cisplatin; E: etoposide; Vin: vindesine; V: vinorelbine; C: carboplatin; T: docetaxel; Ta: paclitaxel; Tir: tirapazamine; NR: not reported; NS: non-significant; ORR: overall response rate; TTP: time to tumor progression; OS: overall survival.

Table 10.3.10 Randomized trials comparing triplets versus doublets for the treatment of advanced NSCLC Author

Regimen

Alberola93

P/G P/G/V G/V G/V/P P/G M/I/P Ca/G M/I/P M/Vin/P P/V P/G P/G/V

Laack94 Crino109 Danson110

Comella111

No of patients

370 287 307 372

180

ORR (%)

Median survival (months)

42 41 13 28 38 26 30 33

9.3 8.2 8.3 7.5 8.6 9.6 8.5 8.7

25 30 47

8.1 9.7 11.8

p

NS NS NS NS

NS

P: cisplatin; G: gemcitabine; V: vinorelbine; M: mitomycin; I: ifosfamide; Ca: carboplatin; Vin: vinblastine.

The optimal time for the patients to be started on chemotherapy has not been studied in randomized trials. However, since chemotherapy clearly prolongs survival and patients with impaired performance status

(PS) demonstrate poor tolerance to chemotherapy, the current recommendations suggest the initiation of treatment as soon as possible, prior to any deterioration of patients’ PS.98

Treatment of NSCLC: chemotherapy 163

PATIENT POPULATIONS WITH SPECIAL CONSIDERATIONS Elderly populations About 40% of patients diagnosed with NSCLC are aged 70 years or older. It is estimated that only 25% of elderly patients finally receive chemotherapy.114 Elderly patients were frequently excluded from large co-operative group trials due to considerations for increased toxicity. However, in an analysis of the Statistics, Epidemiology, and End Results (SEER) database, the efficacy of chemotherapy in the elderly is equivalent to that in younger patients.115 Moreover, age has not been established as an independent prognostic factor for survival. The Elderly Lung Vinorelbine Italian Study (ELVIS) was one of the first large prospective randomized trials to evaluate the role of chemotherapy in elderly patients.116 A total of 161 patients 70 years of age or older were randomized to receive vinorelbine (30mg/m2, days 1 and 8, every three weeks) or BSC. Overall survival was significantly better in the vinorelbine arm (28 weeks versus 21 weeks, p = 0.03) and quality of life was significantly improved with chemotherapy. The same group of investigators subsequently conducted the Multicenter Italian Lung Cancer in the Elderly Study (MILES), designed to test whether the combination of vinorelbine and gemcitabine was superior to either single agent alone.117 This trial, which enrolled 698 patients, failed to demonstrate any difference in terms of response rate or overall survival between arms. However, a smaller trial (n = 120) that compared vinorelbine monotherapy to the vinorelbine-gemcitabine combination reported a survival benefit in favor of the combination arm (median overall survival 6.7 months vs 4.2 months, p <0.01).118 Currently, ASCO guidelines recommend single-agent therapy for the treatment of elderly patients with NSCLC.98 Patients with poor performance status PS has been consistently identified as one of the most important prognostic factors in patients with advanced NSCLC.5 It has also been established that patients with ECOG PS of 0–1 derive significant benefit from systemic chemotherapy, while patients with ECOG PS 3–4 should be offered palliative care.5 However, it is less clear which is the optimal treatment of patients with PS 2. Generally, these patients have short survival and are anticipated to experience high toxicity rates when combination chemotherapy is considered.81,119,120 For the present, most of the data regarding the management of this particular patient population are mainly derived

from subgroup analysis of larger trials. It should be noted though that PS 2 patients constitute only a small proportion of patients enrolled in first-line treatment trials, despite the fact that they account for 30–40% of the total NSCLC population. In an interim analyis of ECOG 1594 trial, PS 2 patients experienced high rates of severe toxicity in all three cisplatin-based doublets.81 However, patients treated in the carboplatin/paclitaxel arm had acceptable toxicity rates, suggesting that this regimen could be suitable for further evaluation in this patient population.81 Subgroup analysis of PS 2 patients from a CALGB trial that randomized patients to receive paclitaxel monotherapy or a combination of carboplatin and paclitaxel demonstrated significantly superior survival and tolerable toxicity for patients treated with the combination.104 Until definitive data derived from trials focusing on this particular group of patients emerge, single-agent chemotherapy with the newer agents should be the preferred option for PS 2 patients.121 Carboplatin- or lowdose cisplatin-based chemotherapy might also be used.121 In any case, patient preferences, the existing co-morbidities, and the anticipated chemotherapy-related toxicity should be considered prior to the final decision.

SECOND-LINE THERAPY The availability of new active regimens in the first-line setting has prompted several investigators to consider second-line therapy for patients with advanced NSCLC, since a substantial percentage of patients maintain a good PS upon recurrence. Initial studies employing the newer agents either alone122,123 or in combination124,125 showed significant activity in pretreated patients with advanced NSCLC. However, most of these studies were small, and many did not report details on prior treatment or patient characteristics; in addition, although all the studies reported response rates, very few provided median survival times or one-year survival rates, thus precluding safe conclusions for the value of second-line chemotherapy. Docetaxel was the first agent to be tested as secondline therapy in randomized phase III trials. In a study by Fossella et al, 373 patients pretreated with platinumcontaining regimens were randomized either to two dose levels of docetaxel (75 mg/m2, or 100 mg/m2) or to a single agent (ifosfamide or vinorelbine) control arm.126 Although no statistically significant difference was observed in terms of overall survival between the three arms, docetaxel 75 mg/m2 resulted in a longer time to

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progression and higher one-year survival rates compared to the control arm (32% vs 19%, p = 0.025). Furthermore, about 30% of patients in the control group eventually received docetaxel, a fact that may have diminished observable differences between the two arms. In a trial by Shepherd et al, 204 patients with platinum refractory disease were randomized to receive docetaxel 100 mg/m2 or best supportive care alone.127 An interim analysis that identified significant toxicity in the docetaxel arm led to the reduction of docetaxel dose to 75 mg/m2. The final analysis showed that, although the response rate was only 7%, patients treated with docetaxel achieved a higher time to tumor progression (2.5 vs 1.6 months, p <0.001) and overall survival (7 vs 5 months, p = 0.047) compared to the control group. The study by Shepherd et al established docetaxel as the standard comparator arm for subsequent randomized trials. Based on the results of these studies, the FDA approved docetaxel as second-line therapy in NSCLC. A non-inferiority phase III study compared docetaxel with pemetrexed, a multitargeted antifolate, as secondline therapy in NSCLC.128 Five hundred and seventy-one patients were randomized to receive docetaxel (75 mg/m2) or pemetrexed (500 mg/m2) plus vitamin supplementation. No significant difference was observed in overall (pemetrexed 8.3 months vs docetaxel 7.9 months) or one-year survival (29.7% for both drugs). Furthermore, neutropenia and febrile neutropenia were significantly lower with pemetrexed. This trial led to the approval of pemetrexed in the second-line treatment of NSCLC. A weekly schedule of docetaxel was compared with the classic every three weeks schedule in two randomized phase III trials.129,130 In the trial by Gridelli et al,129 comparable overall survival rates were reported (6.7 vs 5.8 months for the weekly arm) but the weekly schedule was associated with better safety and quality of life profiles. In contrast, in the trial by Schuette et al,130 a trend towards better survival was observed for patients in the weekly arm (>8 months versus 5.8 months, p = 0.08). Additional investigations in the field of second-line therapy focused on the introduction of two-drug combinations in the second-line setting that generally resulted in high toxicity rates without any survival benefit over monotherapy.131

TARGETED THERAPIES IN ADVANCED NSCLC Although chemotherapy has resulted in some progress in the overall management of patients with lung cancer in recent years, with increasing use of neoadjuvant and

adjuvant strategies and second-line chemotherapy, treatment outcomes for NSCLC continue to be disappointing. Fortunately, the picture is changing with the introduction of targeting therapies. Inhibition of the epidermal growth factor receptor (EGFR) family is at the forefront, led by the tyrosine kinase inhibitors gefitinib (Iressa®) and erlotinib (OSI-774 Tarceva®), but angiogenesis inhibition with bevacizumab (Avastine®) has also produced interesting data from recent trials. The basis for the development of this mode of therapy is described elsewhere in this book. Erlotinib has been approved by health authorities in many countries for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. The study by the Canadian Clinical Trials Group delivered the backbone of the data for this decision. The study included a total of 731 patients randomized using a 2:1 randomization scheme: 488 in the erlotinib arm and 243 in the placebo arm. EGFR status was determined for 238 of the 731 study patients for whom tissue samples were available prior to the study. A positive EGFR expression status was defined as having at least 10% of cells staining for EGFR. Survival of erlotinib-treated patients was superior to that of placebo-treated patients and median survival duration of erlotinib-treated patients was 6.7 months, compared with 4.7 months for placebo-treated patients. Exploratory univariate analysis showed a larger survival prolongation in two subsets of patients: those who never smoked and those with EGFR-positive tumors. Erlotinib was also superior to placebo in terms of progression-free survival, and had a response rate of 8.9 versus 0.9%. Severe rash occurred in 8% and severe diarrhea occurred in 6% of erlotinib-treated patients.132 Similar results have been obtained in phase II trials with erlotinib. The clinical and biologic features associated with EGFR have been analyzed in studies performed in the US, Europe, South Korea, Taiwan, China, and Japan, and considerable efforts have been made to identify predictive factors for response to elucidate the molecular mechanisms involved. The most important advance has been the identifiation of somatic mutations in the 90% or so of patients with objective responses to gefitinib or erlotonib. In addition to non-smoker females and adenocarcinoma, Asian descent has turned up as an important predictive prognostic factor associated with the response and survival benefit of both gefitinib and erlotinib. In addition to the phase III trials with the two tyrosine kinase inhibitors, several articles have been published based on experience with a compassionate-use program

Treatment of NSCLC: chemotherapy 165

in patients with advanced NSCLC who have failed prior chemotherapy or were unfit for chemotherapy. Some of the studies have specifically analyzed the efficacy and tolerability of gefitinib in patients with poor performance status or in elderly patients. All studies have shown that gefitinib has clinical antitumor activity and also good tolerability, with higher response rates in the Asian studies than in European or European-heritage Americans.133 With respect to bevacizumab, a monoclonal antibody directed against the vascular endothelial growth factor (VEGF), the results of a randomized trial in 444 patients with metastatic NSCLC were presented at the ASCO meeting in 2005. Bevacizumab was added to paclitaxel and carboplatin (PCB) and compared with chemotherapy alone (PC). The response rate (27% versus 10%, p <0.0001), progression-free survival (6.4 months versus 4.5 months, p <0.0001), and median survival (10.2 months versus 12.5 months, p = 0.0075) were higher in the bevacizumab arm. Both regimens were well tolerated, but hemorrhage was more frequent in the PCB arm (4.1% versus 1.0%). There were 11 treatmentrelated deaths (9 in the PCB arm and 2 in the PC arm), of which 5 were due to hemoptysis, all in the PCB arm. It is noteworthy that the trial excluded patients with squamous cell carcinoma, and thus mainly included patients with adecarcinoma.134,135 REFERENCES 1. Bakowski MT, Crouch JC. Chemotherapy of non-small cell lung cancer: a reappraisal and a look to the future. Cancer Treat Rev 1983; 10: 159–72. 2. Joss RA, Cavalli F, Goldhirsch A et al. New agents in nonsmall cell lung cancer. Cancer Treat Rev 1984; 11: 205–36. 3. Johnson DH. Treatment strategies for metastatic non smallcell lung cancer. Clin Lung Cancer 1999; 1: 34–41. 4. Vokes EE, Bitran JD. Non-small-cell lung cancer. Toward the next plateau. Chest 1994; 106: 659–61. 5. Schrump DS, Altorki NK, Henschke CL et al. Non-small cell lung cancer. In: DeVita VT, Hellman S, Rosenberg SA, eds. Principles and Practice in Oncology, 7th edn. Philadelphia: Lippincott-Williams & Wilkins, 2005: 753–809. 6. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111: 1710–17. 7. Pisters KM, Le CT. Adjuvant chemotherapy in completely resected non-small-cell lung cancer. J Clin Oncol 2005; 23: 3270–8. 8. Holmes EC, Gail M. Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large-cell undifferentiated carcinoma. J Clin Oncol 1986; 4: 710–15. 9. Niiranen A, Niitamo-Korhonen S, Kouri M et al. Adjuvant chemotherapy after radical surgery for non-small-cell lung cancer: a randomized study. J Clin Oncol 1992; 10: 1927–32.

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Treatment of NSCLC: chemotherapy 167 53. Pierre F, Perol M, Gilles R. A randomized phase III trial of sequential chemoradiotherapy versus concurrent chemoradiotherapy in locally advanced NSCLC (GLOT-GFPC NPC 95-01 study). Proc Am Soc Clin Oncol 2001; 20 (312a): abstract 1246. 54. Curran WJ, Scott CB, Langer CJ. Long-term benefit is observed in a phase III comparison of sequential versus concurrent chemo-radiation for patients with unresected stage III NSCLC: RTOG 9410. Proc Am Soc Clin Oncol 2003; 22: abstract 2499. 55. Zatloukal P, Petruzelka L, Zemanova M et al. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 2004; 46: 87–98. 56. Movsas B, Scott C, Curran WJ et al. A Quality-Adjusted Time Without Symptoms or Toxicity (QTWiST) analysis of Radiation Therapy Oncology Group (RTOG) 94-10. Proc Am Soc Clin Oncol 2001; 19: abstract 1247. 57. Fournel P, Robinet G, Thomas P et al. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d’Oncologie Thoracique-Groupe Francais de Pneumo-Cancerologie NPC 95-01 Study. J Clin Oncol 2005; 23: 5910–17. 58. Clamon G, Herndon J, Cooper R et al. Radiosensitization with carboplatin for patients with unresectable stage III non-smallcell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol 1999; 17: 4–11. 59. Huber RM, Scmidt M, Flentje M. Induction chemotherapy and following simultaneous radio/chemotherapy versus induction chmemotherapy and radiotherapy alone in inoperable NSCLC (stage IIIA/IIIB). Proc Am Soc Clin Oncol 2003; 22: abstract 2501. 60. Vokes EE, Hemdon JE, Kelley MJ et al. Induction chemotherapy followed by concomitant chemoradiotherapy versus chemoradiotherapy alone for regionally advanced unresectable nonsmall-cell lung cancer: initial analysis of a randomised phase III trial. Proc Am Soc Clin Oncol 2004; 23: abstract 7005. 61. Gaspar L, Gandara D, Chansky K. Consolidation docetaxel following concurrent chemoradiotherapy in pathologic stage IIIb nonsmall cell lung cancer (NSCLC) (SWOG 9504): patterns of failure and updated survival. Proc Am Soc Clin Oncol 2003; 20 (315a): abstract 1255. 62. Belani CP, Choy H, Bonomi P et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multimodality protocol. J Clin Oncol 2005; 23: 5883–91. 63. Sause WT, Scott C, Taylor S et al. 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 1995; 87: 198–205. 64. Laskin JJ, Sandler AB. State of the art in therapy for non-small cell lung cancer. Cancer Invest 2005; 23: 427–42. 65. Souquet PJ, Chauvin F, Boissel JP, Bernard JP. Meta-analysis of randomised trials of systemic chemotherapy versus supportive treatment in non-resectable non-small cell lung cancer. Lung Cancer 1995; 12 (Suppl 1): S147–54.

66. Grilli R, Oxman AD, Julian JA. Chemotherapy for advanced non-small-cell lung cancer: how much benefit is enough? J Clin Oncol 1993; 11: 1866–72. 67. Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. Adopted on May 16, 1997 by the American Society of Clinical Oncology. J Clin Oncol 1997; 15: 2996–3018. 68. Ruckdeschel JC, Finkelstein DM, Ettinger DS et al. A randomized trial of the four most active regimens for metastatic nonsmall-cell lung cancer. J Clin Oncol 1986; 4: 14–22. 69. Bonomi PD, Finkelstein DM, Ruckdeschel JC et al. Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: a study of the Eastern Cooperative Oncology Group. J Clin Oncol 1989; 7: 1602–13. 70. Weick JK, Crowley J, Natale RB et al. A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol 1991; 9: 1157–62. 71. Kris MG, Gralla RJ, Kalman LA et al. Randomized trial comparing vindesine plus cisplatin with vinblastine plus cisplatin in patients with non-small cell lung cancer, with an analysis of methods of response assessment. Cancer Treat Rep 1985; 69: 387–95. 72. Le Chevalier T, Brisgand D, Douillard JY et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol 1994; 12: 360–7. 73. Bonomi P, Kim K, Fairclough D et al. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 2000; 18: 623–31. 74. Giaccone G, Splinter TA, Debruyne C et al. Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced non-small-cell lung cancer. The European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 1998; 16: 2133–41. 75. Cardenal F, Lopez-Cabrerizo MP, Anton A et al. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic nonsmall-cell lung cancer. J Clin Oncol 1999; 17: 12–18. 76. Niho S, Nagao K, Nishiwaki Y. Randomized multicenter phase III trial of irinotecan (CPT-11) and cisplatin (CDDP) versus CDDP and vindesine (VDS) in patients with advanced nonsmall cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1999; 18 (492a): abstract 1897. 77. Negoro S, Masuda N, Takada Y et al. Randomised phase III trial of irinotecan combined with cisplatin for advanced nonsmall-cell lung cancer. Br J Cancer 2003; 88: 335–41. 78. Kubota K, Watanabe K, Kunitoh H et al. Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. J Clin Oncol 2004; 22: 254–61. 79. Kelly K, Crowley J, Bunn PA Jr et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell

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80.

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83. 84.

85.

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lung cancer: a Southwest Oncology Group trial. J Clin Oncol 2001; 19: 3210–18. Scagliotti GV, De MF , Rinaldi M et al. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 2002; 20: 4285–91. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92–8. Fossella F, Pereira JR, von PJ et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003; 21: 3016–24. Schiller JH. Current standards of care in small-cell and nonsmall-cell lung cancer. Oncology 2001; 61 (Suppl 1): 3–13. Gatzemeier U, von Pawel J, Gottfried M et al. Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-smallcell lung cancer. J Clin Oncol 2000; 18: 3390–9. von Pawel J, von Roemeling R, Gatzemeier U et al. Tirapazamine plus cisplatin versus cisplatin in advanced nonsmall-cell lung cancer: a report of the international CATAPULT I study group. Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non-Small-Cell Lung Tumors. J Clin Oncol 2000; 18: 1351–9. Rosell R, Gatzemeier U, Betticher DC et al. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol 2002; 13: 1539–49. Klastersky J, Sculier JP, Lacroix H et al. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organization for Research and Treatment of Cancer Protocol 07861. J Clin Oncol 1990; 8: 1556–62. Hotta K, Matsuo K, Ueoka H et al. Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 2004; 22: 3852–9. Georgoulias V, Papadakis E, Alexopoulos A et al. Platinumbased and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet 2001; 357: 1478–84. Kosmidis P, Mylonakis N, Nicolaides C et al. Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol 2002; 20: 3578–85. Gridelli C, Gallo C, Shepherd FA et al. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003; 21: 3025–34. Smit EF, van Meerbeeck JP, Lianes P et al. Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group – EORTC 08975. J Clin Oncol 2003; 21: 3909–17.

93. Alberola V, Camps C, Provencio M et al. Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol 2003; 21: 3207–13. 94. Laack E, Dickgreber N, Muller T et al. Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced nonsmall-cell lung cancer: from the German and Swiss Lung Cancer Study Group. J Clin Oncol 2004; 22: 2348–56. 95. Georgoulias V, Ardavanis A, Tsiafaki X et al. Vinorelbine plus cisplatin versus docetaxel plus gemcitabine in advanced nonsmall-cell lung cancer: a phase III randomized trial. J Clin Oncol 2005; 23: 2937–45. 96. Tan EH, Szczesna A, Krzakowski M et al. Randomized study of vinorelbine-gemcitabine versus vinorelbine-carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer 2005; 49: 233–40. 97. D’Addario G, Pintilie M, Leighl NB et al. Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol 2005; 23: 2926–36. 98. Pfister DG, Johnson DH, Azzoli CG et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 2004; 22: 330–53. 99. Manegold C, Drings P, von Pawel J et al. A randomized study of gemcitabine monotherapy versus etoposide/cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer. Semin Oncol 1997; 24 (3 Suppl 8): S8. 100. Negoro S, Masuda N, Takada Y et al. Randomised phase III trial of irinotecan combined with cisplatin for advanced nonsmall-cell lung cancer. Br J Cancer 2003; 88: 335–41. 101. Vansteenkiste JF, Vandebroek JE, Nackaerts KL et al. Clinicalbenefit response in advanced non-small-cell lung cancer: a multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine. Ann Oncol 2001; 12: 1221–30. 102. Le Chevalier T, Brisgand D, Soria JC et al. Long term analysis of survival in the European randomized trial comparing vinorelbine/cisplatin to vindesine/cisplatin and vinorelbine alone in advanced non-small cell lung cancer. Oncologist 2001; 6 (Suppl 1): 8–11. 103. Sederholm C. Gemcitabine versus gemcitabine/carboplatin in advanced non-small cell lung cancer: preliminary findings in a phase III trial of the Swedish Lung Cancer Study Group. Semin Oncol 2002; 29 (3 Suppl 9): 50–4. 104. Lilenbaum RC, Herndon J, List M et al. Single-agent (SA) versus combination chemotherapy (CC) in advanced non-small cell lung cancer (NSCLC): a CALGB randomized trial of efficacy, quality of life (QOL), and cost-effectiveness. Proc Am Soc Clin Oncol 2002: abstract 2. 105. Sandler AB, Nemunaitis J, Denham C et al. 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 2000; 18: 122–30. 106. Georgoulias V, Ardavanis A, Agelidou A et al. Docetaxel versus docetaxel plus cisplatin as front-line treatment of patients with advanced non-small-cell lung cancer: a randomized, multicenter phase III trial. J Clin Oncol 2004; 22: 2602–9.

Treatment of NSCLC: chemotherapy 169 107. Negoro S, Masuda N, Takada Y et al. Randomised phase III trial of irinotecan combined with cisplatin for advanced nonsmall-cell lung cancer. Br J Cancer 2003; 88: 335–41. 108. Wozniak AJ, Crowley JJ, Balcerzak SP et al. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol 1998; 16: 2459–65. 109. Crino L, Scagliotti GV, Ricci S et al. Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced nonsmall-cell lung cancer: a randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol 1999; 17: 3522–30. 110. Danson S, Middleton MR, O’Byrne KJ et al. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer 2003; 98: 542–53. 111. Comella P, Frasci G, Panza N et al. Randomized trial comparing cisplatin, gemcitabine, and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non-small-cell lung cancer: interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group. J Clin Oncol 2000; 18: 1451–7. 112. Smith IE, O’Brien ME, Talbot DC et al. Duration of chemotherapy in advanced non-small-cell lung cancer: a randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol 2001; 19: 1336–43. 113. Socinski MA, Schell MJ, Peterman A et al. 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 2002; 20: 1335–43. 114. Earle CC, Venditti LN, Neumann PJ et al. Who gets chemotherapy for metastatic lung cancer? Chest 2000; 117: 1239–46. 115. Earle CC, Tsai JS, Gelber RD et al. Effectiveness of chemotherapy for advanced lung cancer in the elderly: instrumental variable and propensity analysis. J Clin Oncol 2001; 19: 1064–70. 116. The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 1999; 91: 66–72. 117. Gridelli C, Perrone F, Gallo C et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003; 95: 362–72. 118. Frasci G, Lorusso V, Panza N et al. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol 2000; 18: 2529–36. 119. Sweeney CJ, Zhu J, Sandler AB et al. Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic nonsmall cell lung carcinoma. Cancer 2001; 92: 2639–47. 120. Soria JC, Brisgand D, Le CT. Do all patients with advanced non-small-cell lung cancer benefit from cisplatin-based combination therapy? Ann Oncol 2001; 12: 1667–70. 121. Gridelli C, Ardizzoni A, Le CT et al. Treatment of advanced non-small-cell lung cancer patients with ECOG performance

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11

Treatment of small cell lung cancer

11.1 Treatment of SCLC: surgery Hisao Asamura, Riken Kawachi Contents Introduction • Primary surgery • Induction chemotherapy plus adjuvant surgery • Salvage surgery

INTRODUCTION The role of surgery in the management of small cell lung cancer (SCLC) remains a controversial and as yet undecided issue despite re-examination of this role over the past 30 years. The British Medical Research Council performed two large, randomized, prospective trials of surgery versus radiotherapy in the 1960s and 1970s, which reported the failure of surgery alone to control this disease when compared to radiotherapy.1,2 Although the results of this trial set the standards for non-surgical treatment for SCLC thereafter, this study must be criticized from the present view point for the following issues: •

•

• •

SCLC located in the peripheral lung was excluded from the study since only tumors diagnosed by rigid bronchoscopy prior to the treatment were enrolled. Complete resection of the tumor could be achieved in only 48% of the patients assigned to the ‘surgery’ arm. No intraoperative staging was done. Modern clinical staging techniques (CT scan and mediastinoscopy) were not used. As a result, these studies included very few patients with very early stage disease (T1–2N0M0) who are thought to benefit from surgery most.

In the late 1960s and mid-1970s, surgery for early stage SCLC was championed by other reports, where survival was significant for tumors located in the periphery of the lung confined to the lung, with N0 status, and treated by lobectomy.3,4 Reports in the late 1970s and early 1980s further demonstrated that surgical therapy alone could provide curative treatment in up to 25% of such patients.5,6 A report by the Veterans Administration Surgical Oncology Group showed a 23% five-year survival rate for 132 patients resected, and concluded that resection was definitely indicated in patients with T1N0 lesions, and probably indicated in those with T1N1 or T2N0 lesions.6

Since these earlier studies, the arrival of new diagnostic tools, such as the higher resolution CT scan and positron emission tomography, has enabled identification of very limited disease with a higher potential for cure. In addition, platinum-based combination chemotherapeutic regimens have become available since the early 1980s, with an objective response rate as high as 80%. With the addition of postoperative chemotherapy, even better long-term survival in this very early stage of disease has been reported. In stage I disease, up to 70% of patients will be cured. In more advanced disease (stages II and IIIA), when the tumor is totally excised at surgery and treated with postoperative chemotherapy, five-year survivals in the range of 20–30% can be expected.7,8 However, as for non-small cell lung cancer (NSCLC), the prognosis of patients with N2 disease is quite poor, and the chance of surgical intervention is least.9,10 The role of surgery in multimodality therapy to improve control of the primary site has been investigated by utilizing induction chemotherapy prior to surgical resection.11–13 These programs have also included consolidation chemotherapy as well as mediastinal radiotherapy with or without prophylactic cranial irradiation. The final role that has been suggested for surgery in the treatment of SCLC is that of ‘salvage’ treatment when primary chemo-irradiation fails to control the local disease or when recurrence occurs and only the primary site is affected.14 In these instances, surgical treatment after reinduction chemotherapy has been utilized as a ‘salvage’ procedure. In summary, the present-day role of surgery in the management of SCLC can be categorized into four groups: • • • •

primary surgery (surgery alone); primary surgery followed by systemic adjuvant chemotherapy; induction (neoadjuvant) chemotherapy/chemoradiotherapy followed by surgery; and salvage surgery after definitive chemoradiotherapy.

Treatment of SCLC: surgery

Upfront surgery without any following additional treatment is becoming less common since the higher activity in extensive disease (ED) SCLC has been established and become well known. Another reason for upfront surgery is preoperatively undiagnosed tumors, especially clinical T1 and T2N0 diseases in peripheral locations, which continue to be resected by surgeons and are found to be SCLC postoperatively. PRIMARY SURGERY (SURGERY ALONE AND SURGERY WITH POSTOPERATIVE CHEMOTHERAPY) Complete resection of SCLC, often without prior knowledge of the cell type, will result in significant five-year survival. Several reports have suggested that early stage SCLC can be cured by surgical resection alone (Table 11.1.1).10,12,15–29 For instance, Shah et al15 retrospectively analyzed the prognosis of 28 patients who received surgery alone for SCLC; and reported a fiveyear survival of 43.3%. They have stated that the prospects of cure by operation are similar to those with NSCLC. However, the most recent series reporting their data suggest that postoperative chemotherapy is a necessary part of treatment (Table 11.1.1).23 In most centers, following surgical resection, a minimum of four to six courses of adequate two- or three-drug regimen chemotherapy is advised. In a co-operative international lung cancer multimodality treatment trial, 112 patients with SCLC underwent initial surgical resection and were then randomized to receive one of two intensive postoperative chemotherapy regimens.30 The projected 36-month survival rate for 43 patients with N0 disease was 65%; for 43 with N1 disease, 52%; and for 26 with N2 disease, 29%. If hilar and mediastinal lymph node disease is found at the time of surgery, postoperative mediastinal irradiation is also advised, although its role is not certain. The role of prophylactic cranial irradiation has yet to be decided as well. More recently, Brock and co-workers emphasized that highly selected patients with SCLC might benefit from surgery and adjuvant chemotherapy, particularly if the chemotherapy was platinum-based.23 In the retrospective study, the five-year survival for patients with stage I disease who received adjuvant chemotherapy was 63%, and among them, the five-year survival for patients receiving platinum chemotherapy was 86%. In the Japan Clinical Oncology Lung Cancer Study Group trial (JCOG9101), the study also reported better survival for early stage SCLC patients.22 Sixty-one patients with completely resected SCLC received chemotherapy. Ninety percent of the patients received two to four

171

courses of chemotherapy consisting of cisplatin and etoposide. Three-year survival was 61%, 68% in clinical stage I disease. Badzio and co-workers, in their retrospective analysis, demonstrated a beneficial effect for surgical resection.21 They used matched case–control methodology to minimize selection bias. A group of 134 patients were selected for comparative analysis; 67 were treated with surgical resection followed by chemotherapy and 67 were managed with chemoradiotherapy. They demonstrated a significant difference in survival between operated and non-operated patients. Five-year survival in patients treated with and without surgery was 27% and 4%, respectively. The relative hazard ratio of death in patients treated with surgery was 0.42 (95% confidence interval 0.28–0.61). In their study, survival advantage was observed in patients with N0/N1 except for N2 disease, and they suggested that surgery added to chemotherapy might benefit in limited SCLC. However, it is still difficult to compare this multimodality surgical approach to chemoradiation alone, since medical oncologists on the whole do not classify these ‘very limited’ tumors as a separate entity.31 Despite this, some retrospective analyses have been performed. Osterlind and co-workers, in their retrospective analysis, failed to demonstrate any beneficial effect for surgical resection.32 While they demonstrated a significantly better prognosis for 79 patients who met criteria for surgical resectability prior to treatment than for 696 patients who did not, there was no significant difference in survival between 33 operated and 46 non-operated patients. Again in this study, however, only 33% of the operated patients underwent complete resection, which suggested that the criteria for resectability were not predictive enough, and the authors’ unfavorable statement regarding the benefit of surgery was not conclusive. On the other hand, Shepherd and co-workers have suggested a twofold improvement in survival utilizing surgery as part of the treatment, by improving control of the primary site.12 It must be emphasized that the description of stage of patients in such a study, by not only limited disease (LD)–ED but also the tumor, node, metastasis (TNM) system is crucial to make the comparison possible between primary surgery and chemoradiation alone.

INDUCTION CHEMOTHERAPY PLUS ADJUVANT SURGERY The role of surgery in more proximal tumors with clinical N1 or minimal N2 disease (but still resectable by

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Table 11.1.1 The clinical outcome of patients who underwent primary surgery with or without postoperative adjuvant chemotherapy for SCLC Author

No of patients

Median survival (months)

(a) Surgery + chemotherapy ISC-LCSG16 183 Coolen17

15

Davis18

37

Muller19

45

18

Toronto Group12 Salzer10 Cataldo20

79 25 60

21

Badzio21

67

JCOG22

61

Brock23

45

(b) Surgery ± chemotherapy Lucchi24 127

Miyazawa25 Merkle26 Maassen27

12 25 170 124

(c) Surgery alone Coolen17

15

Shah15

28

Sorensen28 Shore29

76 40

a

30-month survival. 3-year survival.

b

18

Five-year survival rate (%)

63a (TN0M0) 37b (TN2M0) 27 60 (stage I) 50 (stage I) 35 (stage II) 21 (T3N2) 36 57 (stage I) 28 (stage II) 34 (stage IIIA) 40 25 (N2 disease) 40 (stage I) 36 (stage II) 15 (stage III) 27 59 (stage I) 31 (stage II) 4 (stage III) 57 76 (stage I) 38 (stage II) 39 (stage III) 63 (stage I) 25 (stage II/III) 22.6 47.2 (stage I) 14.8 (stage II) 14.4 (stage III) 50 (latter period) 8 (former period) 18 20 13 12 (stage I) 43.3 57.1 (stage I) 55.5 (stage II) 12 27

Treatment of SCLC: surgery

173

Table 11.1.2 The clinical outcome of patients who underwent induction (neoadjuvant) chemotherapy followed by surgery for SCLC Author

No of patients

Median survival (months)

17

Salzer37 Holoye38 Johnson39 Lad40 Wada41

11 37 25 38 11 13 14 14 26 24 70 17

Fujimori43

21

61.9

Eberhardt42 Veronesi44

46 23

36 24

Prager33 Baker34 Williams35 Shepherd36

33 21 Not reached (stage I) 16 (stage II) 12 (stage III)

Five-year survival rate (%)

65a 48 36

47 25 19 15.4 30.70 80 (c-stage I/II) 50.3 (p-stage I/II) 66.7a 73.3a (c-stage I/II) 46 25a 91a (stage I) 14a (stage II/III)

a

3-year survival.

NSCLC criteria) is less apparent. The results of ever published studies are summarized in Table 11.1.2.33–44 Among these, the experience of the Toronto Group12 and the Innsbruck Group10 suggested that with this combined modality treatment, utilizing surgery as an adjuvant, five-year survival rates in the range of 40% can be obtained (Table 11.1.3). Those tumors with good responses to chemotherapy, having been downstaged by the time of surgery to an N0 level, have a five-year survival rate as high as 60–70%. Persisting nodal disease yields a less satisfactory 20–30% five-year survival rate. An interesting side-light of such therapy is the fact that many of the resected tumors contain no remaining SCLC, but do contain persisting elements of NSCLC. The North American Lung Cancer Study Group reported the results of a randomized trial comparing the non-surgical to the adjuvant surgical approach in limited disease (Figure 11.1.1).40 Although most of the 146 patients randomized following induction chemo-

Table 11.1.3 Induction chemotherapy followed by surgery for SCLC (the Toronto Group results) Stage

Overall N0 N1 N2

No of patients

Median survival (years)

Estimated five-year survival rate (%)

38 11 13 14

1.8 Not reached 1.3 1

38 45 30 40

therapy were initially staged as ‘limited’ (versus ‘very limited’), the results of this randomized trial showed no difference in survival of either arm. In 70 patients in the surgery group, complete resection was possible in 77%, and the pathologic complete response rate after induction chemotherapy was 19% compared with the clinical complete response rate of 40%. This study also

174 Textbook of Lung Cancer Registration

Induction chemotherapy (CAV) × 5

Objective response

therapy followed by surgery, the comparative, randomized study between standard chemoradiotherapy and multimodality treatment including surgery is not realistic. The future directions of the study should be, therefore, the well-prepared phase II trial with novel regimens as an induction treatment after the most updated preoperative staging, including PET scanning.

Randomize

Thoracotomy

No surgery

Thoracic and brain radiation

Figure 11.1.1 Diagram of study design of Lung Cancer Study Group Study 832.

failed a subset analysis that attempted to isolate the ‘very limited’ group, although very few patients were included in this subset. Eberhardt and co-workers reported an excellent local control and remarkable long-term survival in LD-SCLC patients undergoing aggressive trimodality treatment.42 Of 46 patients with LD-SCLC undergoing induction therapy (chemotherapy for stage I/II, chemoradiotherapy including hyperfractionated accelerated radiotherapy for stage IIIA/IIIB), 32 patients underwent surgical resection with a complete resection rate of 72%. The authors reported that the median survival and five-year survival rate of all 46 patients were 36 months and 46%, respectively. Especially for 32 completely resected patients, 68 months and 63% were reported, as well as a 100% local control rate. This kind of aggressive multimodality approach using intensive local therapy such as surgery and hyperfractionated accelerated radiotherapy might be promising in the treatment of LD-SCLC, and may be one of the future directions for trials in these patients. Looking at the results of the ever published studies, the five-year survival rates of patients who underwent induction (neoadjuvant) chemotherapy and subsequent surgery ranged from 25 to 65%, and many were at around 40%. These data clearly indicated that such a multimodality approach to LD-SCLC is feasible, and promising in terms of prognosis. However, the role of surgery in the multimodality treatment has not been clearly defined by the small to medium sized one-arm study. On the other hand, considering the limited number of patients who might be candidates for induction

SALVAGE SURGERY The Toronto Group has promulgated the concept of ‘salvage’ surgery for SCLC, in which two situations are clearly defined.14 Tumor recurrence might happen at exactly the same place as the primary site, even after a complete response (CR) has been achieved by definitive chemoradiotherapy (Figure 11.1.2a). Alternatively the persistent primary tumor might grow after definitive chemoradiotherapy is over (Figure 11.1.2b). Salvage surgery is generally indicated in these two special cases with a curative intent. Patients with mixed SCLC/ NSCLC at diagnosis and persistent NSCLC after induction chemotherapy are also prime candidates for this type of surgery, since the non-small cell component of the primary tumor might remain because of the difference in the response to the systemic chemotherapy. For this category of surgery for SCLC, it is important to differentiate the concept of salvage surgery from that of planned induction chemoradiotherapy followed by surgery. In the latter setting, the surgery is planned upfront as a part of treatment plan, usually for resectable, histologically proven SCLC, where the schedule and dose are determined on the premises of the following surgery. In salvage surgery, the chemoradiotherapy is planned definitively for itself, and the indication for surgery arises only when the clinical situation after definitive chemoradiotherapy fits the criterion for it. For this purpose, mediastinoscopy is utilized to eliminate patients with unresectable disease. In the Toronto study, 28 patients with limited SCLC who did not have a complete remission with standard treatment, or who had only local recurrence after treatment and appeared to be completely resectable, underwent surgery. Pathologic examination showed only SCLC in 18 patients, mixed SCLC and NSCLC in 4, and only NSCLC in 6. A median survival of 74 weeks and a five-year survival rate of 23% were reported. This study suggests the existence of occasional SCLC patients who will benefit from salvage surgery after relapse or failure to respond to chemotherapy and radiotherapy.

Treatment of SCLC: surgery

175

Salvage surgery

(a) PR

Cx-Rx

Salvage surgery

(b) CR

Cx-Rx

Recurrence

Figure 11.1.2 Indication of ‘salvage’ operations in the treatment of SCLC. Surgical resection is considered when the recurrent tumor shows up at exactly the same site as the primary tumor after a complete response (CR) has been achieved by definitive chemoradiotherapy (a), or when the persisting primary tumor grows after the definitive chemoradiotherapy is over (b).

REFERENCES 1.

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3. 4.

5. 6.

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8.

Miller AB, Fox W, Tall R. Five-year follow-up of the Medical Research Council’s comparative trial of surgery and radiotherapy for the primary treatment of small-celled or oat-celled carcinoma of the bronchus. Lancet 1969; 12: 501–5. Fox W, Scadding JG. Medical Research Council’s comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of the bronchus: ten year follow-up. Lancet 1973; 2: 63–5. Lennox SC, Flavell G, Pollock DJ. Results of resection for oatcell carcinoma of the lung. Lancet 1968; 2: 925–7. Higgins GA, Shields TW, Keehn RJ. The solitary pulmonary nodule. Ten year follow-up of Veterans Administration Armed Forces Cooperative Study. Arch Surg 1975; 110: 570–5. Mountain CF. Clinical biology of small cell lung cancer: relationship to surgical therapy. Semin Oncol 1978; 5: 272–9. Shields TW, Higgins GA, Matthews NJ, Kiihn RJ. Surgical resection in the management of small-cell carcinoma of the lung. J Thorac Cardiovasc Surg 1982; 84: 481–8. Karrer K, Shields TW, Denck H et al. The importance of surgical and multimodality treatment for small cell bronchial carcinoma. J Thorac Cardiovasc Surg 1989; 97: 168–76. Shepherd FA, Ginsberg RJ, Evans WK et al. Reduction in local recurrence and improved survival in surgically treated patients

9.

10. 11.

12.

13.

14.

15.

with small cell lung cancer. J Thorac Cardiovasc Surg 1983; 89: 498–506. Meyer JA, Gullo JJ, Ikins PM et al. Adverse prognostic effect of N2 disease in treatment of small cell carcinoma of the lung. J Thorac Cardiovasc Surg 1984; 88: 495–501. Salzer GM, Muller LC, Huber H et al. Operation for N2 small cell lung carcinoma. Ann Thorac Surg 1990; 49: 759–62. Shepherd FA, Ginsberg RJ, Patterson GA et al. A prospective study of adjuvant surgical resection after chemotherapy for limited small cell lung cancer: a University of Toronto Lung Oncology Group study. J Thorac Cardiovasc Surg 1989; 97: 177–86. Shepherd FA, Ginsberg RJ, Feld R et al. Surgical treatment for limited small-cell lung cancer. The University of Toronto Lung Oncology Group experience. J Thorac Cardiovasc Surg 1991; 101: 385–93. Prager RL, Foster JM, Hainworth JD et al. The feasibility of adjuvant surgery in limited-stage small cell carcinoma: a prospective evaluation. Ann Thorac Surg 1984; 38: 622–6. Shepherd FA, Ginsberg R, Patterson GA et al. Is there ever a role for salvage operations in limited small-cell lung cancer? J Thorac Cardiovasc Surg 1991; 101: 196–200. Shah SS, Thompson J, Goldstraw P. Results of operation without adjuvant therapy in the treatment of small cell lung cancer. Ann Thorac Surg 1992; 54: 498–501.

176 Textbook of Lung Cancer 16. Karrer K, Ulsperger E. Surgery for cure followed by chemotherapy in small cell carcinoma of the lung. Acta Oncologica 1995; 34: 899–906. 17. Coolen L, van den Eeckhout A, Deneffe G et al. Surgical treatment of small cell lung cancer. Eur J Cardiothorac Surg 1995; 9: 59–64. 18. Davis S, Crino L, Tonato M et al. A prospective analysis of chemotherapy following surgical resection of clinical stage I–II small-cell lung cancer. Am J Clin Oncol 1993; 16: 93–5. 19. Muller LC, Salzer G, Huber H et al. Multimodal therapy of small cell lung cancer in TNM stages I through IIIa. Ann Thorac Surg 1992; 54: 493–7. 20. Cataldo I, Bidoli P, Brega MP et al. Long term survival for resectable small cell lung cancer. Lung Cancer 2000; 29 (Suppl 1): abstract 428. 21. Badzio A, Kurowski K, Karnicka-Mlodkowska H et al. A retrospective comparative study of surgery followed by chemotherapy vs. non-surgical management in limited-disease small cell lung cancer. Eur J Cardiothorac Surg 2004; 26: 183–8. 22. Tsuchiya R, Suzuki K, Ichinose Y et al. Phase II trial of postoperative adjuvant cisplatin and etoposide in patients with completely resected stage I–IIIa small cell lung cancer: the Japan Clinical Oncology Lung Cancer Study Group Trial (JCOG9101). J Thorac Cardiovasc Surg 2005; 129: 977–83. 23. Brock MV, Hooker CM, Syphard JE et al. Surgical resection of limited disease small cell lung cancer in the new era of platinum chemotherapy: its time has come. J Thorac Cardiovasc Surg 2005; 129: 64–72. 24. Lucchi M, Mussi A, Chella A et al. Surgery in the management of small cell lung cancer. Eur J Cardiothorac Surg 1997; 12: 689–93. 25. Miyazawa N, Tsuchiya R, Naruke T et al. A clinicopathological study of surgical treatment of small cell carcinoma of the lung. Jpn J Clin Oncol 1986; 16: 297–307. 26. Merkle NM, Mickisch GH, Kayser K et al. Surgical resection and adjuvant chemotherapy for small cell carcinoma. Thorac Cardiovasc Surg 1986; 34: 39–42. 27. Maassen W, Greschuchna D. Small cell carcinoma of the lung – to operate or not? Surgical experience and results. Thorac Cardiovasc Surg 1986; 34: 71–6. 28. Sorensen HR, Lund C, Alstrup P. Survival in small cell lung carcinoma after surgery. Thorax 1986; 41: 478–82. 29. Shore DF, Paneth M. Survival after resection of small cell carcinoma of the bronchus. Thorax 1980; 35: 819–22. 30. Karrer K, Shields TW, Denck H. The importance of surgical and multimodality treatment for small cell bronchial carcinoma. J Thorac Cardiovasc Surg 1989; 97: 168–76. 31. Shepherd FA, Ginsberg R, Evans WK et al. ‘ Very limited’ small cell lung cancer (SCLC): results of non-surgical treatment. Proc Am Soc Clin Oncol 1984; 2: 223 (abstract C-870).

32. Osterlind K, Hansen M, Hansen HH et al. Treatment policy of surgery in small cell carcinoma of the lung: retrospective analysis of a series of 874 consecutive patients. Thorax 1985; 40: 272–7. 33. Prager RL, Foster JM, Hainsworth JD et al. The feasibility of adjuvant surgery in limited-stage small cell carcinoma: a prospective evaluation. Ann Thorac Surg 1984; 38: 622–6. 34. Baker RR, Ettinger DS, Ruckdeschel JD et al. The role of surgery in the management of selected patients with small-cell carcinoma of the lung. J Clin Oncol 1987; 5: 697–702. 35. Williams CJ, McMillan I, Lea R et al. Surgery after initial chemotherapy for localized small-cell carcinoma of the lung. J Clin Oncol 1987; 5: 1579–88. 36. Shepherd FA, Ginsberg RJ, Patterson GA et al. A prospective study of adjuvant surgical resection after chemotherapy for limited small cell lung cancer. A University of Toronto Lung Oncology Group study. J Thorac Cardiovasc Surg 1989; 97: 177–86. 37. Salzer GM, Muller LC, Huber H et al. Operation for N2 small cell lung carcinoma. Ann Thorac Surg 1990; 49: 759–62. 38. Holoye PY, Shirinian M. Adjuvant surgery in the multimodality treatment of small-cell lung cancer. Am J Clin Oncol 1991; 14: 251–3. 39. Johnson DH, Einhorn LH, Mandelbaum I et al. Postchemotherapy resection of residual tumor in limited stage small cell lung cancer. Chest 1987; 92: 241–6. 40. Lad T, Piantadosi S, Thomas P et al. A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy. Chest 1994; 106 (Suppl): 320S–3S. 41. Wada H, Yokomise H, Tanaka F et al. Surgical treatment of small cell carcinoma of the lung: advantage of preoperative chemotherapy. Lung Cancer 1995; 13: 45–56. 42. Eberhardt W, Stamatis G, Stuschke H et al. Aggressive trimodality treatment including chemoradiation induction and surgery (S) in LD-small-cell lung cancer (LD-SCLC) (Stages I–IIIB). Long-term results. Prognostically oriented multimodality treatment including surgery for selected patients of small-cell lung cancer patients stages IB to IIIB: long-term results of a phase II trial. Br J Cancer 1999; 81: 1206–12. 43. Fujimori K, Yokoyama A, Kurita Y et al. A pilot phase 2 study of surgical treatment after induction chemotherapy for resectable stage I to IIIA small cell lung cancer. Chest 1997; 111: 1089–93. 44. Veronesi G, Scanagatta P, Leo F et al. Adjuvant surgery after carboplatin and VP16 in resectable small cell lung cancer. J Thorac Oncol 2007; 2: 131–4.

11.2 Treatment of SCLC: radiotherapy Christopher M Lee, William T Sause Contents Introduction • Where are we now? • Current recommendations • Radiotherapy for palliation • Future directions

INTRODUCTION Small cell carcinoma of the lung (SCLC) comprises approximately 20% of newly diagnosed bronchogenic malignancies.1 Multiple studies have revealed SCLC to be a highly aggressive carcinoma that is clinically and biologically very different from non-small cell carcinoma of the lung (NSCLC). Due to significant chemosensitivity and the known high propensity of spread beyond the chest, chemotherapy was utilized as the primary treatment of this disease several decades ago.2–4 Despite the extreme chemosensitivity and remarkable initial response rates in patients with limited stage disease, the use of chemotherapy alone led to intrathoracic failures in up to 80% of patients and mean survivals of only 10–14 months.2 After it was revealed that radiotherapy could decrease locoregional failures, it became increasingly utilized in the 1970s and 1980s. It was only after two separate meta-analyses reported improved survival outcomes with the use of radiation therapy in combined modality treatment that thoracic irradiation (TI) was accepted as a necessary part of the standard of care. Both meta-analyses reported a 5–7% improvement in two- and three-year survival and an approximate 25% improvement in local control rates with the addition of radiotherapy treatment.5,6 Concurrent thoracic irradiation with platinum-based chemotherapy is now considered the standard treatment in limited stage SCLC. The use of a concurrent cisplatin/etoposide regimen has significantly decreased the toxicity observed from prior regimens containing cyclophosphamide, doxorubicin, and vincristine, leading to significant improvement in patient tolerability to combined modality therapy.2–4,7–9 A survival benefit with the use of prophylactic cranial irradiation (PCI) in patients with limited stage disease who have experienced a complete response to initial concurrent therapy with TI and systemic chemotherapy was also confirmed in a meta-analysis.10 Despite recent advances in treatment, the optimal treatment strategies for individual patients with newly

diagnosed SCLC remain elusive. A number of questions require further study in this disease, such as optimization of both chemotherapy (schedule, choice of agents, timing, dosing) and radiation therapy (dose, fractionation, timing, volume treated) regimens. In addition, statistical analysis cannot replace clinical judgment when considering the individual patient, tumor characteristics, and the potential risks and benefits of specific therapies. Hopefully with further information gained from ongoing and future research endeavors, appropriate therapy will be utilized to decrease the death rate from this thoracic malignancy. Future work is also needed to continue to delineate clinical and biologic factors which can guide treatment and account for disparities in outcome between varied subsets of patients. As will be further addressed in this chapter, the optimal timing, dose, and fractionation schedules for PCI continue to be under study.

WHERE ARE WE NOW? Thoracic irradiation Many practical issues, such as radiation dose, volume, fractionation, and optimal integration with chemotherapy, remain unresolved. Trying to ‘fine-tune’ combinedmodality treatment for SCLC is a formidable challenge. It must be accepted that the individual benefits attributable to the different parts of this puzzle are likely to be numerically small, and manipulation of one aspect may produce a cascade of events with conflicting effects on overall outcome. These methodologic problems have resulted in substantial difficulty in designing appropriate randomized trials to address these questions. No large randomized trials have been performed looking at radiation dose as the only variable. Previous retrospective analyses of thoracic radiation used after cyclophosphamide- and doxorubicin-containing chemotherapy regimens have suggested that radiation doses as high as 50–60 Gy are necessary for durable local control (standard fractionation). Even in the current era of

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concurrent thoracic radiation therapy and chemotherapy, a major site of recurrence continues to be within the previously irradiated field (30% in-field alone recurrence and 20% in-field recurrence combined with systemic recurrence).11,12 Choi et al reported improved local control for doses of 40–50 Gy compared with doses of <40 Gy.11 An additional study by Papac et al reported local control of 97% after use of 60 Gy.13 Choi and coworkers from the Cancer and Leukemia Group B (CALGB) identified 70 Gy to be the maximum tolerated dose of radiation using standard fractionation for treatment in combination with chemotherapy.12 In addition, the CALGB reported results from a phase II trial of 70 Gy thoracic irradiation in combination with three cycles of concurrent carboplatin and etoposide, following an induction with two cycles of paclitaxel and topotecan. Their reported median failure-free survival was 12.9 months and median overall survival was 19.8 months, with a one-year survival of 70%.14 Miller et al have also reported supporting evidence that higher radiation doses are tolerable.15 They retrospectively evaluated outcomes of 65 patients treated with 58–66 Gy (standard fractionation), with either concurrent or sequential chemotherapy, and found that the treatment was extremely tolerable. Komaki et al reported on the Radiation Therapy Oncology Group (RTOG) 9712 study, which was a phase I dose-escalation study, of thoracic radiation therapy with concurrent cisplatin/etoposide in limited stage SCLC. Thoracic radiation was given in 1.8 Gy daily fractions to a total dose of 36 Gy, followed by smaller boost fields encompassing only the gross disease delivered with escalations of 1.8 Gy bid during the final days to establish the maximum tolerated dose (MTD). The MTD was found to be 61.2 Gy in 34 fractions of 1.8 Gy when given with two cycles of cisplatin/ etoposide (concurrently) and followed by two additional cycles of cisplatin/etoposide.16 A further practical question concerns the optimal target volume for thoracic irradiation. This issue is increasingly debated now that the standard of care has changed from sequential to concurrent thoracic radiation with chemotherapy. The tradition of irradiating large volumes covering all ‘prechemotherapy tumor involvement’ with generous margins or prophylactic irradiation of distant lymphatic drainage sites may no longer be necessary, and more modest radiation treatment volumes will lead to lower rates of serious pulmonary toxicity. There remains no consensus at this point as to whether prechemotherapy or postchemotherapy visible volumes should be treated.17–20 The optimal safety margin around the visible tumor and necessary elective nodal radiation

also remain sources of study and debate. A common treatment policy constructs treatment fields to encompass the original tumor with 1.5–2.0 cm margins. One prospective trial by Kies et al revealed no difference between large-field thoracic radiation therapy and limited-field therapy, although conflicting results are apparent in the literature.15–18,20,21 A balance must be made with each individual patient which evaluates potential toxicity of enlarging radiation fields versus the risk of local recurrence of disease. New imaging modalities such as positron emission tomography (PET) are also expected to help answer key questions regarding optimal treatment volumes. With recent increased interest in altered fractionation schedules for radiation therapy, accelerated hyperfractionation appears to be a logical choice for SCLC due to the high sensitivity of cancer cells, the normal-tissuesparing effect of twice-daily fractionation (with a greater than six-hour interval between fractions), and the ability to defeat rapid proliferation of tumor cells. Several phase II studies of radiation given in multiple daily fractions, either concurrently with cisplatin and etoposide or in an interdigitated sequence, have been followed by a large intergroup randomized trial.22,23 In this study, 417 patients were treated with concurrent TI starting with the first cycle of etoposide and cisplatin (PE) chemotherapy and randomized between a standard schedule (1.8 Gy in 25 daily fractions over five weeks to a total dose of 45 Gy) or a hyperfractionated schedule (45 Gy in 1.5 Gy fractions twice daily over three weeks). With mature follow-up, the five-year survival rate was significantly improved in the twice-daily arm (26 vs 19%). However, the hyperfractionated arm had higher rates of acute toxicity, as would be expected.23 An additional trial studying this issue was a North Central Cancer Treatment Group (NCCTG) study, which compared concurrent cisplatin/etoposide (two cycles) and either twice-daily, split-course TI to 48 Gy in 5.5 weeks or once-daily TI to 50.4 Gy in daily fractions of 1.8 Gy, both given after three cycles of cisplatin/ etoposide. They found no difference in three-year overall survival and locoregional control between the splitcourse/twice-daily fractionation and daily fractionation treatment schemas.24 Schild et al reported the median and five-year survival rates to be 20.4 months and 22% for twice-daily versus 20.5 months and 21% for oncedaily thoracic radiation, respectively (p = 0.7).25 In analyzing these studies side-by-side, it appears that one possible explanation is that the split-course regimen is an inferior regimen due to an extension of overall treatment time allowing for tumor cell regeneration.

Treatment of SCLC: radiotherapy 179

The issue of radiotherapy timing is also not resolved. An early three-arm randomized CALGB trial suggested that the best survival/toxicity ratio can be obtained by delaying radiation until the fourth cycle of chemotherapy.26 This may be in part due to a marked reduction in the chemotherapy dose when thoracic radiation was applied early and also due to high rates of treatmentrelated fatalities in schedules using concurrent radiation with cyclophosphamide, methotrexate, lomustine, and doxorubicin. More recent trials which utilize cisplatin/ etoposide or cisplatin/etoposide alternating with cyclophosphamide/doxorubicin/vincristine show clear superiority for early (cycle one or two of chemotherapy) utilization of TI.27–29 These randomized trials testing the timing of thoracic irradiation are illustrated in Table 11.2.1.20,26–29 Fried et al performed a meta-analysis which evaluated the timing of TI in combined modality therapy for limited-stage SCLC.30 This analysis of 1524 patients revealed a significantly higher twoyear survival in the early group, and there was a suggestion of a similar trend at three and five years. This advantage was also thought to be due to the significantly improved outcomes found in trials employing platinum-based chemotherapy and hyperfractionated radiation therapy regimens. Once-daily regimens and doxorubicin-based chemotherapy were found not to provide any statistically significant improvements in overall survival.

Brain metastases and prophylactic cranial irradiation Brain metastases are common sites of failure in SCLC and multiple reports have confirmed that prophylactic cranial irradation (PCI) has a role in the therapeutic strategy among patients with limited stage disease who are complete responders to systemic chemotherapy and thoracic irradiation.5,10 At diagnosis, 20% of patients have evidence of spread into the brain, which rises to 50% at two years and to more than 80% postmortem.31–34 The concept of PCI, taken from settings such as acute lymphoblastic leukemia, demonstrated 20 years ago that moderate radiation doses can significantly reduce the rate of brain metastases. In multiple small historical trials, no evidence of survival benefit was seen and the short overall survival underestimated the degree of the observed risk. In addition, initial reports of CNS morbidity subsequent to cranial irradiation tempered the enthusiasm for PCI in the past.35–39 Nevertheless, the problem of CNS disease and its control have continued to evolve in clinical practice. The modest effectiveness of radiotherapy or chemotherapy for patients with established brain metastases as well as the subsequent functional consequences and negative impact that brain metastases have on quality of life has lead to re-evaluation of PCI in a series of second-generation trials. These were designed to address issues of effectiveness as well as morbidity of treatment.

Table 11.2.1 Trials evaluating the timing of thoracic irradiation Author

RT timing

RT dose

Five-year survival rate (%)

p

Cycle 1 Cycle 4

50 Gy/24 fx

7 13

0.08

Week 3 Week 15

40 Gy/15 fx

20 11

0.008

Week 1 Week 18

40–45 Gy/22 fx

11 12

0.4

Week 1 Week 6

54 Gy/36 fx

30 15

0.052

Cycle 1 Cycle 4

45 Gy/30 fx

24 18

0.097

Perry26

Murray28

Work20

Jeremic27

Takada29

RT timing: radiation therapy timing with respect to chemotherapy; RT dose: radiation therapy prescribed dose; fx: number of fractions.

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Oncologists have found through multiple recent studies that the use of PCI alone with lower dose-fractionation schedules (<3 Gy), and without concomitant chemotherapy, does not lead to significant long-term neurotoxicity.33,40 It should be emphasized that these recent trials have included patients who have experienced complete remission following systemic chemotherapy and thoracic irradiation for limited stage disease. This has been confirmed by multiple recent prospective trials which have included neurologic assessments (before and after therapy) in their study requirements. These have revealed that, on initial pretreatment neuropsychologic assessments (prior to PCI administration), 40–60% of patients had documented abnormalities, and initial results have not shown any significant differences in neurocognitive function when comparing those patients who received PCI with those who did not.10,33,40–42 The only prospective trial which documented a significant decrease in cognitive function in a PCI group was a CALGB trial which utilized concurrent chemotherapy with brain irradiation. All patients in this trial had PCI administered with chemotherapy and there was a noted significant change in neurocognitive function during the course of treatment, which suggests that the combination of chemotherapy and PCI has a negative impact on cognitive functioning.43 These studies concluded that PCI should be administered without concomitant chemotherapy and lower fractionation schedules (<3 Gy) should be considered for all patients who experience a complete response after initial treatment with systemic chemotherapy and thoracic irradiation.

CURRENT RECOMMENDATIONS Radiotherapy plays an important role in the treatment of SCLC patients. Its optimal utilization requires close collaboration between all the specialists involved in the care of these patients, and thoracic radiation oncologists should be an intrinsic part of the multidisciplinary team. Only in this way can safe and efficient progress be made in this regard. Limited stage patients with SCLC should be managed by specialists using a formal multimodality protocol of treatment, and preferably in the context of a clinical trial. The accepted standard practice in many centers is to use concurrent chemotherapy with radiation delivered early in the course of chemotherapy treatment to a dose equivalent of 50 Gy with standard fractionation (approximately 10 Gy/ week). Concurrent chemoradiotherapy with drugs other than cisplatin and etoposide may necessitate dose

modifications and reductions on the grounds of toxicity. Having selected the patients who are likely to go on to TI and possibly PCI, it is important to obtain a prechemotherapy radiologic series that will inform subsequent radiotherapy planning. This preferably would include a computed tomography (CT) scan of the thorax and upper abdomen. These must be available, together with a contemporary and comparable series of radiologic investigation, to the radiation oncologist at the time of treatment planning (Figure 11.2.1). The decision on what radiotherapy treatment volume to use will depend on the extent of original tumor involvement, the degree of response to and the choice of chemotherapy, the patient’s lung function and performance status, and the dose, fractionation, and timing of the radiotherapy course. In practice, most radiation oncologists would irradiate areas of prechemotherapy involvement with a margin consistent with safety. This is a minimum of 1 cm on the transverse and 2 cm in the sagittal plane of involvement. Prophylactic irradiation of nodal sites remote from the initial sites of involvement, such as routine irradiation of the supraclavicular fossa in patients with upper lobe tumors, is probably not necessary and adds considerably to toxicity. Because SCLC often presents in the vast majority of cases with a bulky central tumor and extensive mediastinal involvement, these treatment volumes are large. In addition, irradiation of large intrathoracic tumor volumes to a high and homogeneous dose represents a technical challenge. The main trade-offs are between the radiation dose delivered to surrounding normal lung, esophagus, and heart, and the radiation tolerance of the spinal cord. A safe approach requires composite and sophisticated planning techniques (Figures 11.2.2 and 11.2.3), similar

Figure 11.2.1 Prechemotherapy axial CT image illustrating a newly diagnosed small cell carcinoma of the left lower lung lobe.

Treatment of SCLC: radiotherapy 181

to those used in the treatment of NSCLC, often using phased or ‘shrinking’ field techniques. The choice of volume for PCI is simple. The entire cranial cavity and contents need to be irradiated, usually using opposing lateral portals (Figure 11.2.4). The areas needing particular attention are the meningeal reflections of the cribriform fossa and middle cranial fossa. TI and PCI administered using conventional doses and fractionation after chemotherapy lead in most cases only to trivial acute side-effects. Tiredness, esophagitis, and lymphopenia are the most common. They are self-limiting, and in the vast majority of cases do not require further treatment beyond simple symptomatic measures. Administration of concurrent chemotherapy and hyperfractionated accelerated TI regimens is much more toxic, with esophagitis and hematologic

toxicity often being dose-limiting. These may be slow to recover from, and may compromise further treatment tolerance. The most significant side-effects are late pulmonary toxicity, late CNS toxicity of PCI: spinal cord damage, and cardiac failure due to irradiation of large areas of the heart and to anthracyclines.

RADIOTHERAPY FOR PALLIATION The exquisite radioresponsiveness of SCLC makes radiotherapy a useful agent for palliative treatment of metastatic, symptomatic, or recurrent disease in patients resistant to or unsuitable for systemic chemotherapy. The approach will best be individualized and similar to that used in NSCLC. In general, short and undemanding courses of irradiation including single-fraction treatments can be used, aimed at symptom control through tumor shrinkage and associated with little or no additional toxicity. Commonly used regimens include 37.5 Gy in 15 fractions, 30 Gy in 10 fractions, 20 Gy in five fractions, or single treatments of 8–10 Gy.

FUTURE DIRECTIONS

Figure 11.2.2 Anterior-posterior digitally reconstructed radiograph (DRR) illustrating a typical radiation portal which includes the primary tumor mass and adjacent hilar/mediastinal lymph nodes. (See color plate section, page xv)

Future clinical trials are necessary to evaluate optimal treatment schedules for patients newly diagnosed with SCLC. The current vogue for accelerated hyperfractionated regimens, with their associated increased survival rates and increased levels of acute toxicity, also needs continual future critical evaluation. The optimization of scheduling of thoracic irradiation and chemotherapy is another area where further work is needed. The current Figure 11.2.3 Conformal radiotherapy planning techniques allow escalated radiation doses to be delivered safely with simultaneous sparing of surrounding critical structures. In this example, a combination of anterior-posterior and oblique fields (four fields in total) are utilized to decrease radiation dose to the nearby spinal cord. (See color plate section, page xvi)

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REFERENCES 1. 2.

3.

4.

5.

6. Figure 11.2.4 Right lateral digitally reconstructed radiograph (DRR) illustrating a typical portal used for prophylactic cranial irradiation. (See color plate section, page xvi)

7.

8.

evidence suggests that earlier use of thoracic irradiation proximate to the initiation of chemotherapy is better, but future work is also needed to continue to delineate clinical and biologic factors which can guide treatment and account for disparities in outcome between varied subsets of patients. Prospective randomized trials of large versus small radiation treatment volumes would help physicians in treatment planning decisions as well as potentially facilitate the introduction and standardization of newer radiation techniques such as conformal radiotherapy treatment or intensity-modulated radiation therapy (IMRT). The use of radiosensitizing agents and biomarker-specific targeted therapies is also a large area of ongoing research endeavors, and successes in these pursuits would be welcomed in helping to improve the therapeutic ratio. Now that prophylactic cranial irradiation has been accepted as standard of care for select subsets of patients, many questions remain with respect to specific dose and optimal radiation schedule. Future clinical trials will only be truly successful if continual toxicity surveillance of long-term survivors is performed to monitor the late effects of treatment and patient outcomes. Formal evaluation of the palliative role of radiotherapy in relapsing patients would also help to define the role of second- and thirdline chemotherapy regimens. Hopefully with further information gained from ongoing and future research endeavors, appropriate therapy will be utilized to continue to decrease the morbidity and mortality rate from this thoracic malignancy.

9.

10.

11.

12.

13.

14.

15.

16.

Greenlee RT, Hill-Harmon MB, Murray T et al. Cancer statistics, 2001. CA Cancer J Clin 2001; 51: 15–36. Cohen MH, Creaven PJ, Fossieck BE Jr et al. Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 1977; 61: 349–54. Cohen MH, Ihde DC, Bunn PA Jr et al. Cyclic alternating combination chemotherapy for small cell bronchogenic carcinoma. Cancer Treat Rep 1979; 63: 163–70. Hansen HH. Should initial treatment of small cell carcinoma include systemic chemotherapy and brain irradiation? Cancer Chemother Rep 3 1973; 4: 239–41. Pignon JP, Arriagada R, Ihde DC et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992; 327: 1618–24. Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 1992; 10: 890–5. Arriagada R, Le Chevalier T, Baldeyrou P et al. Alternating radiotherapy and chemotherapy schedules in small cell lung cancer, limited disease. Int J Radiat Oncol Biol Phys 1985; 11: 1461–7. Murray N, Coy P, Pater JL et al. 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 1993; 11: 336–44. Van Oosterhout AG, Ganzevles PG, Wilmink JT et al. Sequelae in long-term survivors of small cell lung cancer. Int J Radiat Oncol Biol Phys 1996; 34: 1037–44. Auperin A, Arriagada R, Pignon JP et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999; 341: 476–84. Choi NC, Carey RW. Importance of radiation dose in achieving improved loco-regional tumor control in limited stage smallcell lung carcinoma: an update. Int J Radiat Oncol Biol Phys 1989; 17: 307–10. Choi NC, Herndon JE 2nd, Rosenman J et al. Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer. J Clin Oncol 1998; 16: 3528–36. Papac RJ, Son Y, Bien R et al. Improved local control of thoracic disease in small cell lung cancer with higher dose thoracic irradiation and cyclic chemotherapy. Int J Radiat Oncol Biol Phys 1987; 13: 993–8. Bogart JA, Herndon JE 2nd, Lyss AP et al. 70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limitedstage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808. Int J Radiat Oncol Biol Phys 2004; 59: 460–8. Miller KL, Marks LB, Sibley GS et al. Routine use of approximately 60 Gy once-daily thoracic irradiation for patients with limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2003; 56: 355–9. Komaki R, Swann RS, Ettinger DS et al. Phase I study of thoracic radiation dose escalation with concurrent chemotherapy for

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patients with limited small-cell lung cancer: Report of Radiation Therapy Oncology Group (RTOG) protocol 97-12. Int J Radiat Oncol Biol Phys 2005; 62: 342–50. Kies MS, Mira JG, Crowley JJ et al. Multimodal therapy for limited small-cell lung cancer: a randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders; and with wide-field versus reducedfield radiation in partial responders: a Southwest Oncology Group Study. J Clin Oncol 1987; 5: 592–600. Perez CA, Krauss S, Bartolucci AA et al. Thoracic and elective brain irradiation with concomitant or delayed multiagent chemotherapy in the treatment of localized small cell carcinoma of the lung: a randomized prospective study by the Southeastern Cancer Study Group. Cancer 1981; 47: 2407–13. Roof KS, Fidias P, Lynch TJ et al. Radiation dose intensification in limited-stage small-cell lung cancer. Clin Lung Cancer 2003; 4: 339–46. Work E, Nielsen OS, Bentzen SM et al. Randomized study of initial versus late chest irradiation combined with chemotherapy in limited-stage small-cell lung cancer. Aarhus Lung Cancer Group. J Clin Oncol 1997; 15: 3030–7. Liengswangwong V, Bonner JA, Shaw EG et al. Limited-stage small-cell lung cancer: patterns of intrathoracic recurrence and the implications for thoracic radiotherapy. J Clin Oncol 1994; 12: 496–502. Johnson BE, Bridges JD, Sobczeck M et al. Patients with limited-stage small-cell lung cancer treated with concurrent twicedaily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine. J Clin Oncol 1996; 14: 806–13. Turrisi AT 3rd, Kim K, Blum R et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999; 340: 265–71. Bonner JA, Sloan JA, Shanahan TG et al. Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma. J Clin Oncol 1999; 17: 2681–91. Schild SE, Bonner JA, Shanahan TG et al. Long-term results of a phase III trial comparing once-daily radiotherapy with twicedaily radiotherapy in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004; 59: 943–51. Perry MC, Eaton WL, Propert KJ et al. Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 1987; 316: 912–18. Jeremic B, Shibamoto Y, Acimovic L et al. Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: a randomized study. J Clin Oncol 1997; 15: 893–900. Murray N, Coy P, Pater JL et al. 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 1993; 11: 336–44.

29. Takada M, Fukuoka M, Kawahara M et al. 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 2002; 20: 3054–60. 30. Fried DB, Morris DE, Poole C et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 2004; 22: 4837–45. 31. Komaki R, Cox JD, Whitson W. Risk of brain metastasis from small cell carcinoma of the lung related to length of survival and prophylactic irradiation. Cancer Treat Rep 1981; 65: 811–14. 32. Nugent JL, Bunn PA Jr, Matthews MJ et al. CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer 1979; 44: 1885–93. 33. Arriagada R, Le Chevalier T, Borie F et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 1995; 87: 183–90. 34. Ball DL, Matthews JP. Prophylactic cranial irradiation: more questions than answers. Semin Radiat Oncol 1995; 5: 61–8. 35. Aroney RS, Aisner J, Wesley MN et al. Value of prophylactic cranial irradiation given at complete remission in small cell lung carcinoma. Cancer Treat Rep 1983; 67: 675–82. 36. Baglan RJ, Marks JE. Comparison of symptomatic and prophylactic irradiation of brain metastases from oat cell carcinoma of the lung. Cancer 1981; 47: 41–5. 37. Beiler DD, Kane RC, Bernath AM et al. Low dose elective brain irradiation in small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 1979; 5: 941–5. 38. Cox JD, Komaki R, Byhardt RW et al. Results of whole-brain irradiation for metastases from small cell carcinoma of the lung. Cancer Treat Rep 1980; 64: 957–61. 39. Cox JD, Petrovich Z, Paig C et al. Prophylactic cranial irradiation in patients with inoperable carcinoma of the lung: preliminary report of a cooperative trial. Cancer 1978; 42: 1135–40. 40. Gregor A, Drings P, Burghouts J et al. Randomized trial of alternating versus sequential radiotherapy/chemotherapy in limited-disease patients with small-cell lung cancer: a European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study. J Clin Oncol 1997; 15: 2840–9. 41. Bunn PA Jr, Kelly K. Prophylactic cranial irradiation for patients with small-cell lung cancer. J Natl Cancer Inst 1995; 87: 161–2. 42. Wolfson AH, Bains Y, Lu J et al. 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 2001; 24: 290–5. 43. Ahles TA, Silberfarb PM, Herndon J 2nd et al. Psychologic and neuropsychologic functioning of patients with limited smallcell lung cancer treated with chemotherapy and radiation therapy with or without warfarin: a study by the Cancer and Leukemia Group B. J Clin Oncol 1998; 16: 1954–60.

11.3 Treatment of SCLC: chemotherapy Heine H Hansen, Morten Sørensen Contents Introduction • Second-line chemotherapy • Treatment of elderly and poor-prognosis patients • Targeted therapies

INTRODUCTION In the last decade much attention has been directed towards the treatment of non-small cell lung cancer (NSCLC), resulting in considerable progress in its management, which is in contrast to small cell lung cancer (SCLC). The treatment of SCLC has, unfortunately, been at a standstill in recent years, with relatively few large clinical randomized trials, which may reflect the lack of innovative treatment options but also a declining proportion of lung cancer patients presenting with SCLC, which now in many countries constitutes less than 20% of all newly diagnosed lung cancers. Thus, in the US the proportion of SCLC among all lung cancer histologic types decreased from 17.26% in 1986 to 12.95% in 2002. Noteworthy, in the same study, the proportion of women with SCLC increased from 28% in 1973 to 50% in 2002.1 Still, the treatment of SCLC continues to represent a major challenge. Despite a high rate of initial response, most patients will eventually relapse and long-term survival remains a disappointing 10–15%. The disseminated nature of SCLC, displaying a high frequency of metastases at the time of diagnosis combined with a high sensitivity to cytostatic agents, has led to the use of chemotherapy as the primary treatment of choice in all its stages. In the overview provided in this chapter, the current standard chemotherapy in the management of SCLC will be discussed. The most effective agents are listed in Table 11.3.1. The most commonly used combinations include a platinum compound together with the podophyllotoxins, usually etoposide. Combinations including vincristine, cyclophosphamides/ifosfamides, doxorubicin, or taxanes are also highly active. Examples of frequently used treatment schedules are listed in Table 11.3.2.2,3 In a trial by Sundstrøm et al,4 including 436 eligible patients with limited (n = 214) and extensive disease (n = 222), a combination of etoposide and cisplatin was shown to be superior to a three-drug combination of cyclophosphamide, epirubicin, and vincristine. For all patients

the two- and five-year survival rates in the EP (etoposide and platinum) arm (14% and 5%) were significantly higher compared with the three-drug arm (6% and 2%, p = 0.0004). Patients with limited disease received thoracic radiotherapy concurrently with chemotherapy cycle three, and those achieving complete remission during the treatment period also received cranial irradiation. Among the new agents, much attention has been given to the incorporation of the new topoisomerase inhibitors in combination with either cisplatin or carboplatin (Table 11.3.3). In a Japanese study5 that included only patients with extensive disease, survival rates with a combination of irinotecan plus cisplatin were superior to those with etoposide and cisplatin, with one-year survival being 58.4% versus 37.9%, and median survival 12.8 months versus 9.4 months; also response rates of 84% versus 68% were in favor of irinotecan and cisplatin. Grade 3 and 4 diarrhea occurred in 16% in the irinotecan combination compared with none in the etoposide arm. The study was prematurely stopped after the enrollment of 152 patients out of the planned 230 patients, as recommended by a preplanned interim analysis. A confirmatory randomized study was initiated in the US by Hanna et al,6 with randomization of 331 patients to either irinotecan or etoposide, both in combination with cisplatin. An unequally balanced randomization was performed, allocating one-third of patients to etoposide and two-thirds to the irinotecan arm. In both arms, four cycles were delivered every three weeks. After the enrollment of 30 patients, inclusion was restricted to patients in performance status 0 and 1 due to an excessive toxic death rate among patients with performance status 2. As in the Japanese study, myelotoxicity and febrile neutropenia were more frequent in the etoposide arm, whereas gastrointestinal toxicity was more common in the irinotecan arm, including 21% of patients suffering from grade 3–4 diarrhea. Unfortunately, this study could not confirm the encouraging

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Table 11.3.1 Agents used in SCLC: most frequently chosen agents for inclusion in combination regimens

Alkylating agents Cisplatin Carboplatin Ifosfamide Cyclophosphamide Antimitotic agents Vincristine Paclitaxel Topoisomerase inhibitors Etoposide Irinotecan Topotecan Doxorubicin Table 11.3.2 Commonly used regimens in SCLC Regimen

PE Cisplatin Etoposide CE Carboplatin Etoposide ICE Ifosfamide Carboplatin Etoposide

– with or without midcycle vincristine

Dosage and schedule

25 mg/m2 iv on days 1–3 or 60–80 100 mg/m2 iv on days 1–3 or 115 mg/m2 iv days 3–5 q 3 wks AUC 6 day 1 iv 100–120 mg/m2 iv days 1–3 q 3 wks 5000 mg/m2 iv day 1 + 300–400 mg/m2 iv day 1 100–200 mg/m2 iv days 1–3 + mesna 500 mg/m2 day 1 and 3000 mg day 2 1.0 mg/m2 day 14

Japanese data and no significant differences were seen in the overall survival, time to progression, or response rate. Median survival times were 9.3 versus 10.2 months in the irinotecan/cisplatin and etoposide/cisplatin arms, respectively. The differences observed between the American and the Japanese studies might be related to differences in the scheduling of both cisplatin and irinotecan. Also other factors, such as pharmacogenetic variations in the two study populations might contribute to the different

results. Polymorphisms exist between Asians and Caucasians with regard to the gene responsible for the glucuronidation of SN-38, the active metabolite of irinotecan. Preliminary data from a German study on 59 evaluable patients have also been published and the study will proceed as a phase III trial comparing, again, irinotecan versus etoposide, but in this study combined with carboplatin rather than cisplatin.7 It is conceivable that the data from the latter trial combined with existing data may determine whether etoposide or irinotecan is the superior drug in combination with platinum compounds in SCLC. In one of the largest randomized trials ever conducted in patients with extensive SCLC, topotecan given orally together with cisplatin was compared with iv etoposide plus cisplatin in 784 patients with extensive SCLC. Overall survival was equal, 9.1 vs 9.3 months.8 With respect to some of the other newer agents, paclitaxel has been tested in several trials combined with standard etoposide and platinum-based chemotherapy. Used as single agent, paclitaxel has shown response rates of 29–41% in both previously treated and untreated SCLC patients. Based on survival data, none of three randomized trials published increased median survival in patients with extensive disease, but add to the risk of toxic death in frail patients with extensive disease.9 Results from other trials trying to incorporate epirubicin or gemcitabine have also been rather disappointing, with no differences in response rates or progression-free or overall survival compared to standard regimens.9 With respect to scheduling of drugs, it has been demonstrated that etoposide is more effective when given as a five-day course than when the same dose is given over 24 hours. Prolonged periods of three to four weeks of continuous treatment of etoposide are being explored at present. In that regard, it is noteworthy that oral etoposide has been shown to be inferior to combination chemotherapy administered iv.10 For both limited and stage I–III and extensive stage IV disease, the overall response rates achieved are >70%, whereas complete response with no clinical or histopathologic evidence of malignancies is initially obtained in 30–40% of patients with limited disease and 15–20% of patients with extensive disease. The median survival for patients with limited disease is about 14–18 months, and usually 8–10 months for extensive disease, whereas long-term survival (beyond five years) is 10–15% and 3–5%, respectively, for the two stages. One should be aware that survival results vary according to selection criteria and more representative results from national studies may be less encouraging. With respect to the duration

186 Textbook of Lung Cancer Table 11.3.3 Major randomized trials evaluating topoisomerase I inhibitors in combination with platinum in extensive SCLC No of patients

Etoposide + CDDP Irinotecan + CDDP Etoposide + CDDP Irinotecan + CDDP Etoposide + carboplatin Irinotecan + carboplatin Etoposide + CDDP Topotecan (oral) + CDDP

Response rate (%)

154 331 59 784

68 84 44 48 50 71 69 63

Median survival (months)

9.4 12.8 10.2 9.3 12 10 9.3 9.1

Author

Sundstrøm4 Noda5 Hanna6 Schmittel7

CDDP: cisplatin.

of treatment needed to produce optimal results, a period of 4–6 months, usually corresponding to 4–6 cycles of chemotherapy, is currently an acceptable standard. A meta-analysis of published, randomized controlled trials suggests, however, that maintenance or consolidation therapy improves survival. New randomized clinical trials are therefore needed to further refine the place of this approach in the treatment of SCLC.11 In recent years, new approaches to chemotherapy have been undertaken to improve the treatment results, including dose-dense chemotherapy, which has the theoretic potential to augment tumor cell kill. The role of dose-dense therapy remains controversial in SCLC due to conflicting results in various randomized studies conducted over the years.12 Intensity of chemotherapy can be increased, particularly as a consolidation treatment by the use of autologous bone-marrow infusion, and more recently by peripheral blood stem cells. One of the most recent trials to evaluate this treatment concept has been performed by British investigators, who randomly assigned 318 ‘better-prognosis patients’ to standard combination chemotherapy with ifosfamide, carboplatin, and etoposide (ICE) delivered at four-week intervals or to dose-dense ICE in similar doses, but given at two-week intervals supported by granulocyte colony-stimulating factor (GCSF) (filgrastim) and autologous blood transfusions.13 Chest radiotherapy was performed according to local guidelines, which for all patients consisted of sequential radiotherapy. Approximately 10% of all patients had extensive disease. The median relative dose intensities were 99% and 182% in the standard and dose-dense arms, respectively. Response rates, median survival times, and two-year survival rates were 80% versus 88%, 13.9 versus 14.4 months, and 22% versus 19% in the standard and dose-dense arms, respectively. The authors concluded that the dose-dense strategy has reached a

plateau and further attempts to pursue this strategy in SCLC do not seem justified.13 In a French study, more intensive treatment with four instead of two drugs resulted in an improved one-year survival (40% versus 27%), but with more severe hematologic toxicity.14 Other treatment approaches include scheduling of drugs based on cell-kinetic observations15 or the use of anticoagulants such as warfarin, but the results are inconclusive. Noteworthy in that regard are the data by Altinbas et al,16 who randomized 84 limited and extensive disease patients to combination chemotherapy with or without the addition of low molecular weight heparin (LMWH) (dalteparin, 5000 U daily). Treatment was safe, with no treatment-related deaths and only a few manageable bleeding episodes. Overall survival increased significantly in the LMWH arm to 13 months, compared with 8 months in the chemotherapy-alone arm. The study represents a very small sample size and the hypothesis needs to be evaluated in a properly sized randomized phase III study. Another attempt to improve chemotherapy is alternating combination chemotherapy using different noncross-resistant combinations, because resistant clones of SCLC cells, which are present either at the time of diagnosis or develop during chemotherapy, are thought to be the reason for treatment failure in most patients. Again, the impact on survival is modest. The use of biologic response modifiers, such as interferon as maintenance therapy or adjuvant vaccination with Bec2/bacille Calmette-Guerin, has also been tested, but again with disappointing results.17,18 GCSF and granulocyte macrophages CSF, given to counter the hematologic effects of combination chemotherapy, lessen the severity of neutropenic episodes, but they do not appear to influence survival significantly, in spite of the increased doses of chemotherapy.19 Nor did the addition of GCSF to

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primary antibiotic prophylaxis result in cost savings in the study by Timmer-Bonte et al.20

SECOND-LINE CHEMOTHERAPY Because of its high relapse rate, the management of relapsed SCLC is a very common clinical problem. Good-quality studies to guide the decision-making process are very scarce, even though new evidence has emerged from recent studies. Using non-cross-resistant regimens at multifocal relapse, a response rate of 20–25% is obtained, with a median duration of survival of 3–4 months. If there is a longer chemotherapy-free interval before relapse, the same drug combination that initially produced a response may be repeated, with response rates up to 50%, but again the effect is rather shortlasting. Until recently it was not known whether second-line therapy influences survival as no randomized trials had compared chemotherapy against best supportive care (BSC). To answer this important question, 141 relapsed patients were randomly allocated to oral topotecan 2.3 mg/m2 on days 1–5 every three weeks or to best supportive care.21 Prognostic and predictive factors for response were equally balanced. Approximately twothirds of the patients had performance status 0 or 1. Topotecan resulted in a modest response rate of 7% and 44% of patients achieved stable disease. Median survival time with BSC was 13.9 weeks (95% confidence interval (CI) 11–18.6 weeks), and with topotecan 25.9 weeks (95% CI 18.3–31.6 weeks), and the overall six-month survival rate was 49% compared with 26% on the best supportive care arm (p = 0.01). The largest numerical survival benefit was seen in patients with the longest treatment-free interval. Dyspnea and pain were reduced in the topotecan arm compared with best supportive care (3% versus 9% and 3% versus 6%, respectively), indicating better symptom control in the topotecan arm.21 It is still an open question which type of second-line therapy is superior. Randomized trials have found that intravenous topotecan resulted in equal response rates and survival compared with a combination of cyclophosphamide, doxorubicin, and vincristine (CAV).22 Furthermore, iv and oral topotecan showed similar responses in a randomized trial.23 It is also noteworthy that amribucin, a totally synthetic 9-aminoanthracycline, has shown significant activity with an overall response rate of 50% (CL25–75%) in a phase II study including 60 Japanese patients with refractory or relapsed SCLC.24 If the patient has a local relapse and has not received irradiation previously, palliative radiotherapy is often the treatment of choice as second-line treatment.

TREATMENT OF ELDERLY AND POOR-PROGNOSIS PATIENTS Knowledge of the optimal treatment of the elderly is limited, as most large randomized trials tend to exclude elderly patients. This occurs despite the fact that more than one-third of patients with SCLC are >70 years old and the proportion of elderly in the population is continuously increasing, as the average expected lifetime increases in the general population.25 In patients >70 years old, Ardizzoni et al26 evaluated two regimens of cisplatin and etoposide – full dose (FD) and reduced dose (RD) – in a two-stage, randomized, non-comparative phase II design. The primary endpoint was the rate of treatment success defined as the proportion of patients receiving at least three courses of the planned dose of full dose chemotherapy on time and achieving an objective response without grade 3 and 4 toxicity or any chemotherapy-related complications. The median number of adminstered cycles was four in both arms and approximately the same percentage of patients completed the treatment per protocol in both arms (75 vs 22%). Median survival times and one-year survival rates were 31 versus 41 weeks and 18% versus 39% on the RD and FD arms, respectively. RD chemotherapy thus offers no advantage over FD chemotherapy, which is in accordance with previously randomized trials, indicating that presumably less toxic treatment regimens can compromise the goal of palliation, symptom control, and survival. In another study with an elderly population in which more than 90% of the 220 patients were >70 years old and 25% of patients had performance status 2 or 3, split-dose cisplatin was compared with carboplatin in combination with etoposide. Response rates, palliation score, and progression-free and overall survival were equal, indicating that carboplatin can substitute for cisplatin in a palliative setting without compromising clinical outcome.27

TARGETED THERAPIES The use of therapies based on mechanisms that target critical molecular pathways of tumors has also been tested in SCLC, but to a lesser degree than in NSCLC. Phase II trials have explored the use of maintenance therapy with the antiangiogenic drug thalidomide, and the drug has also been evaluated in a phase III trial with 119 patients, which was stopped prematurely because of low accrual rate.28,29 The data from the study of 92 randomized patients are inconclusive, but noteworthy is the longer median survival on the thalidomide arm

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compared with the placebo-treated arm (11.7 months versus 8.7 months). Other interesting phase II trials have used temsirolimus, which targets the mTOR kinase,30 and also bortezomib, which is a proteasome inhibitor,31 while other agents tested include G3139, an antisense oligonucleotide directed at the BCL2 gene.32 In addition the EGFR tyrosine kinase inhibitors gefitinib and imatinib, a KIT receptor tyrosine kinase, and the farnesyltransferase inhibitor R115777 have been evaluated in patients with relapsed SCLC,33–35 but the studies are too small to justify firm conclusions. REFERENCES 1. Govindan R, Page N, Morgensztern D et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic and end results database. J Clin Oncol 2006; 24: 4539–44. 2. Laurie SA, Logan D, Markman BR et al. Practice guideline for the role of combination chemotherapy in the initial management of limited-stage small-cell lung cancer. Lung Cancer 2004; 43: 223–40. 3. Thatcher N, Qian W, Clark PI et al. Ifosfamide, carboplatin, and etoposide with midcycle vincristine versus standard chemotherapy in patients with small-cell lung cancer and good performance status: clinical and quality-of-life results of the British Medical Research Council Multicenter Randomized LU21 Trial. J Clin Oncol 2005; 23: 8371–9. 4. Sundstrøm S, Bremnes RM, Kaasa S. Cisplatin and etoposide (EP-regimen) is superior to cyclophosphamide, epirubicin, and vincristine (CEV-regimen) in small cell lung cancer: results from a randomized phase III trials with 5-year follow-up. J Clin Oncol 2002; 20: 4665–72. 5. Noda K, Nistriwaki Y, Kawahara M et al. Irinotecan plus cisplatin compared with eposide plus cisplatin for extensive small cell lung cancer. N Engl J Med 2002; 346: 85–91. 6. Hanna NH, Bunn PA, Langer C et al. Randomized, phase III trial comparing irinotecan/cisplatin (IP) with etoposide/cisplatin (EP) in patients with previously untreated, extensive-stage small cell lung cancer (SCLC). J Clin Oncol 2006; 24: 2038–43. 7. Schmittel A, Fischer von Weikersthal L, Sebastian H et al. Irinotecan plus carboplatin versus etoposide plus carboplatin in extensive disease small cell lung cancer: a randomized phase II trial. Proc Am Soc Clin Oncol 2005; 24: 632 (abstract 7046). 8. Eckardt JR, von Pawel J, Papai Z et al. Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naïve patients with extensive-disease small-cell lung cancer. J Clin Oncol 2006; 24: 2044–51. 9. Sørensen M. Treatment of small cell lung cancer. In: Hansen HH, ed. Lung Cancer Therapy Annual 5. London: Taylor & Francis, 2006. 10. Souhami RL, Spiro SG, Rudd RM et al. Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 1997; 89: 577–80.

11. Bozcut H, Artac M, Ozdogan M, Savas B. Does maintenance/ consolidation chemotherapy have a role in the management of small cell lung cancer (SCLC)? Cancer 2005; 104: 2650–7. 12. Wolf M. Dose intensive chemotherapy in small cell lung cancer. Lung Cancer 2001; 33 (Suppl 1): S125–35. 13. Lorigan P, Woll PJ, O’Brien ME et al. Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl Cancer Inst 2005; 97: 666–74. 14. Pujol JL, Daurés JP, Riviére A et al. Etoposide plus cisplatin with or without the combination of 4´-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 2001; 93: 300–8. 15. Hirsch FR, Hansen HH, Hansen M et al. The superiority of combination chemotherapy including etoposide based on in vivo cell cycle analysis in the treatment of extensive small-cell lung cancer: a randomized trial of 288 consecutive patients. J Clin Oncol 1987; 5: 585–91. 16. Altinbas M, Coskun HS, Er O et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2004; 2: 1266–71. 17. Ruotsalainen TM, Halme M, Tamminen K et al. Concomitant chemotherapy and IFN-α for small cell lung cancer: a randomized multicenter phase III study. J Interferon Cytokine Res 1999; 19: 253–9. 18. Giaccone G, Debruyne C, Felip E et al. Phase III study of adjuvant vaccination with Bec2/Bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer (European Organisation for Research and Treatment of Cancer 0897108971B; Silva study). J Clin Oncol 2005; 23: 6854–64. 19. Timmer-Bonte JN, de Boo TM, Smit HJ et al. 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 2005; 23: 7974–84. 20. Timmer-Bonte JNH, Adang EMM, Smit HJM et al. Cost-effectiveness of adding granulocyte colony-stimulating factor to primary prophylaxis with antibiotics in small-cell lung cancer. J Clin Oncol 2006; 24: 2991–7. 21. O’Brien MER, Ciuleanu T-E, Tsekov H et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol 2006; 24: 5441–7. 22. von Pawel J, Schiller JH, Shepherd FA et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999; 17: 658–67. 23. von Pawel J, Gatzemeier U, Pujol JL et al. Phase II comparator study of oral versus intravenous topotecan in patients with chemosensitive small-cell lung cancer. J Clin Oncol 2001; 19: 1743–9. 24. Onda S, Masuda N, Seto T et al. Phase II trial of amrubicin for treatment of refractory or relapsed small-cell lung cancer: Thoracic Oncology Research Group Study 0301. J Clin Oncol 1996; 24: 5448–53. 25. Rossi A, Maione P, Colantuoni G et al. Treatment of small cell lung cancer in the elderly. Oncologist 2005; 10: 399–411.

Treatment of SCLC: chemotherapy 189 26. Ardizzoni A, Favaretto A, Boni L et al. Platinum-etoposide chemotherapy in elderly patients with small-cell lung cancer: results of a randomized multicenter phase II study assessing attenuated-dose or full-dose with lenograstim prophylaxis – a Forza Operativa Nazionale Italiana Carcinoma Polmonare and Gruppo Studio Tumori Polmonary Veneto (FONI-CAP-GSTPV) study. J Clin Oncol 2005; 23: 569–75. 27. Kunitoh H, Okamoto H, Watanabe K et al. Randomized phase III trial of carboplatin (Cb) or cisplatin (P) in combination with etoposide (E) in elderly or poor-risk patients with extensive disease small cell lung cancer (ED-SCLC): report of a Japan Clinical Oncology Group Trial (JCOG9702). Lung Cancer 2005; 49: 553 (abstract O-155). 28. Cooney MM, Subbiah R, Chapman A et al. Phase II trial of maintenance daily oral thalidomide in patients with extensive-stage small cell lung cancer (ES-SCLC) in remission. Proc Am Soc Clin Oncol 2005; 24: 661 (abstract 7166). 29. Pujol J, Breton J, Gervais R et al. A prospective randomized phase III, double-blind, placebo-controlled study of thalidomide in extended-disease (ED) SCLC patients after response to chemotherapy (CT). Lung Cancer 2005; 49: S54 (abstract O-159). 30. Pandya K, Levy D, Hidalgo M et al. A randomized phase II ECOG trial of two dose levels of temsirolimus (CCI-779) in patients with

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extensive stage small cell lung cancer in remission after induction therapy. Lung Cancer 2005; 49: S54 (abstract O-158). Lara PN, Chansky K, Davies AM et al. Bortezomib (PS-341) in relapsed or retractory extensive stage small cell lung cancer: a Southwest Oncology Group phase II trial (SO327). J Thorac Oncol 2006; 1: 996–1001. Rudin CM, Slgia R, Wang MR et al. CALGB 30103: a randomized phase II study of carboplatin and etoposide (CE) with or without G3139 in patients with extensive stage small cell lung cancer (ES-SCLC). Proc Am Soc Clin Oncol 2005; 24: 662 (abstract 7168). Moore Am, Estes D, Govindan R et al. A phase II trial of gefitinib in patients with chemosensitive and chemorefractory relapsed neuroendocrine cancer. A Hoosier Onology Group Trial. Proc Am Soc Clin Oncol 2005; 24: 600 (abstract 7160). Krug LM, Crapanzano JP, Azzoli CG et al. Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: a phase II clinical trial. Cancer 2005; 103: 2128–31. Haymach JV, Johnson DH, Khuri FR et al. Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer. Ann Oncol 2004; 15: 1187–93.

12 Malignant mesothelioma Bruce Robinson, Anna Nowak, Cleo Robinson, Jenette Creaney Contents Introduction • Epidemiology • Pathogenesis • Pathobiology • Global transcriptional profiling in MM • Immunobiology • Animal models • Clinical presentation and course • Diagnosis • Management • Future directions

INTRODUCTION Malignant mesothelioma (MM) is an aggressive malignant tumor of serosal surfaces. It most commonly affects the pleura, but also involves peritoneal and occasionally other serosal surfaces. It was considered a rare disease before about 1960, but has increased dramatically in incidence since that time, almost certainly owing to the widespread use of asbestos fibers in the postwar industrial boom. Our aim in this chapter is to summarize the main features of the disease and provide an update of recent developments. The latter should be of substantial interest to the reader, since there have been a number of recent publications in mesothelioma research that not only have begun to unravel the mysteries of the disease, but have also provided a new palliative standard of care, and the prospect of further new approaches to therapy for this otherwise treatment-resistant problem. Advances have been in the area of pathogenesis and mechanisms, particularly the identification of the growth factors involved in the disease, the potential role of nonasbestos agents such as the SV40 virus, and the identification of tumor suppressor gene lesions in this disease. Advances have also been made in the immunobiology and immunotherapy of the disease, in the development of new chemotherapy trials, and in the areas of epidemiology and medicolegality. In this chapter, we shall begin by reviewing the epidemiology and biology of MM, particularly with regard to its pathogenesis and immunobiology. We shall then summarize the clinical aspects of the disease, and finish the chapter with a discussion of possible future directions based upon these recent advances. EPIDEMIOLOGY In 1960 Wagner et al1 reported an association between asbestos and both pleural and peritoneal MM in a case

series of the North Western Cape Province of South Africa, where blue asbestos (crocidolite) was mined. Since then, many reports supporting the relationship between occupational or environmental exposure to asbestos and the subsequent development of MM have been published from all parts of the world.2,3 The relationship is clearly one of cause and effect. This has been shown in case series and cohort studies. Wagner’s initial study identified the difference in risk from direct occupational exposure and brief or indirect exposure to asbestos. The risk of development of MM is directly related to the duration and intensity of exposure to asbestos. Therefore, if asbestos exposure occurred at a young age then the lifetime risk of development of MM is higher than in someone whose exposure occurred at a later age. Asbestos workers had direct occupational exposure to asbestos, and their families received brief or indirect exposure via clothes and hair brought home from the work-place.4 Other employees working in the same area as asbestos workers were also subject to greater risk. Epidemiologic studies have shown that 50–80% of individuals with MM have an identifiable exposure to asbestos.5 Therefore in 20–50% of cases there is no obvious exposure to asbestos, and examination of the lung mineral fiber content shows that in many of these subjects there is a lower lung fiber burden than seen in subjects with asbestosis.6 This supports the evidence that MM may occur after brief and indirect exposure to asbestos. As a group, however, patients with MM have markedly increased lung fiber burdens when compared with a reference population. Asbestos fiber dimensions and type play an important role in the development of MM, with longer and thinner asbestos fibers causing more damage than shorter and wider fibers because they can deposit within and penetrate the lungs (see below). The critical fiber dimensions appear to be less than 0.25 mm in diameter and greater than 5 mm in length to produce MM, and,

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while the risk of developing MM from exposure to chrysotile fibers is lower than that from amphibole fibers, large amounts of chrysotile can cause MM, possibly because of contaminating tremolite fibers.7 A potential role for SV40 is also described. PATHOGENESIS Mesothelial tissues Mesothelial tissues include all those that line the cavities that were derived from the embryonic mesodermal celomic cavity. The tissue develops as a continuous epithelial layer, which covers the pleura, the pericardium, and the peritoneal cavity. In the pleura, it exists as a single layer of mesothelial cells, resting on a basement membrane. The cells are variable in shape, from flat to cuboidal to columnar. Their rate of division is generally slow, but it is increased in response to inflammatory damage. Mesothelial cells are actively phagocytic in culture, and they can take up asbestos fibers.8 This may be important in their susceptibility to transformation, since they are not normally exposed to chronic insults. Etiologic agents Asbestos Asbestos is a collective name for a group of fibrous minerals composed of hydrated magnesium silicate. They divide into serpentines, which are short and curved, such as chrysotile, and amphiboles, which are long and needle-like, such as crocidolite. Not all of the different forms have had widespread commercial use – in fact, 90% of industrial asbestos is chrysotile. The mining and use of asbestos were maximal in 1973, and are now in decline because it has become clear that exposure to asbestos can cause a number of pulmonary conditions. These include pleural plaques, diffuse pleural thickening, rounded atelectasis, and asbestos-related pleural effusions. As mentioned above, there is an association between asbestos and MM, and it now seems reasonably clear that the duration and dose of exposure to asbestos correlate with the risk of developing MM.9 The physical characteristics of the asbestos fibers are important in the development of MM. It is generally thought that the amphiboles, particularly crocidolite, are more carcinogenic for mesothelial tissues.5 Some cases of MM occur following exposure to chrysotile, although this apparent association may be due to contamination of this form with amphiboles. However, in experimental situations, the two groups of asbestos fibers are equally mutagenic to mesothelial cells. In

these studies, the chrysotile was introduced intrapleurally, and it may be that the shape of these fibers makes it less likely that they would penetrate the intact lung after inhalation. Consistent with this hypothesis, the most carcinogenic fibers in animal studies have been shown to have a diameter of less than 1.5 µm and a length of greater than 8 µm, i.e. a high length-to-width ratio.10 The disease progresses through the formation of granulomatous lesions that have a surface layer of mesothelium, with subsequent neoplastic transformation. Mesothelial cells have been shown to be 10 times more sensitive than bronchial epithelial cells to the direct cytotoxic effects of asbestos fibers,11 but, after intraperitoneal injection of asbestos, the initial response is from macrophages, with resultant inflammation and cytokine production.12 The fibers cause iron-catalyzed generation of reactive oxygen metabolites, which have a direct toxic effect, causing DNA point mutations and strand and chromosomal breaks.13 These events usually lead to cellular apoptosis, but particular mutations, combined with the direct mitotic damage of cells by asbestos fibers14 and the increased proliferation induced by inflammation, may increase the risk that these cells survive despite their genetic changes. The end result is malignant transformation. SV40 The double-stranded DNA virus SV40 has been suggested as a possible etiologic agent in the development of MM. In 1994, Carbone and co-workers found SV40like sequences in 60% of frozen MM specimens by polymerase chain reaction (PCR). The majority of these patients also had a history of asbestos exposure, raising the possibility of SV40 acting as a co-carcinogen. SV40 is a papovavirus whose normal host is the monkey. As a small virus, it is dependent on its host for the enzymes of replication except for the large T antigen (TAG). When the virus infects a cell, the TAG is transcribed from the viral genome. TAG binds to the specific SV40 origin of replication, pulling apart the DNA strand, allowing viral DNA synthesis. In this way, the virus is able to bypass the normal cellular controls on replication, and will even do so in quiescent cells. This process is facilitated by TAG binding to both p53 and the retinoblastoma protein (pRb), with inactivation of these cell cycle checkpoints. It is presumed, but not proven, that SV40 was introduced into humans as a result of the Salk polio vaccines used in the 1950s. It has been estimated that up to 30% of vaccines used were contaminated by SV40 as a result of culturing the poliovirus in rhesus monkey kidney

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cells. SV40 had long been known to be tumorigenic in rodents, but in 1992 Bergsagel et al15 found evidence of TAG sequences in childhood tumors. This discovery was followed by evidence obtained by Carbone’s group,16 suggesting an oncogenic role of SV40 in causing MM in hamsters. They found that 100% of hamsters that were injected with intrapleural SV40 developed MM, and this led to the sequencing of SV40 in human MM by this group.17 Since then, a number of other studies have confirmed Carbone’s findings, with the proportion of cases ranging from 44 to 86% of MMs tested. One dissenting group has been that of Strickler,18 who examined MM tissue from 50 patients with two separate primer sets and did not detect any SV40 sequences. This group also undertook a retrospective cohort study comparing those people who were likely to have received contaminated polio virus against those who did not, and found no increase in the incidence of a number of cancers, including mesothelioma.19 As Strickler’s group concedes, the cohort studied has not yet reached the age of peak incidence for MM. In two separate studies, Carbone’s group have gone on to study possible mechanisms by which SV40 may contribute to the pathogenesis of MM. They have found that the SV40 sequences present in MM tissue samples retain the ability to inactivate both p5320 and pRb.21 The potential to overcome these checkpoints in cellular proliferation could be crucial in enabling a tumor to survive and progress. While such speculation is inviting, reservations remain about the place of SV40 in cancer. Clearly SV40 is not essential for the development of MM, since many cases do not express TAG sequences. Are such tumors different in their behavior – and what of those that do not express TAG? There may be as yet undiscovered co-factors that are more important for tumorigenesis. If we are to accept the polio vaccine contamination hypothesis then why is TAG expressed in tumors of children who were too young to be immunized in this setting? Artefactual presence would call into question all of the above research, but there must otherwise be previously undescribed vertical transmission of the virus or some other means of human infection. Further investigations and more accurate molecular and proteomic reagents are required to determine more clearly how SV40 fits into the pathogenesis of MM. Other agents One-quarter of people who develop MM have had no known exposure to asbestos. While some of these cases

may arise from occult exposure, a number of other possible agents have been proposed to cause the disease. These include thoracic radiotherapy, intrapleural thorium dioxide, and other silicates, including erionite and zeolite. The numbers of cases attributed to radiation exposure are very small. A genetic predisposition has also been suggested by occasional reports of clusters of disease within a family, but again numbers are small and co-exposure is difficult to exclude. Although asbestos exposure and smoking have been shown to be synergistic in terms of the likelihood of development of bronchogenic carcinoma, there is no known association between smoking and MM.22 Pathogenesis The molecular evolution of most tumors is currently believed to follow that of the classic model described for the development of colon cancer by Volgelstein et al.23 In this model, a single cell develops a genetic mutation that enables it to proliferate despite absent or even negative growth-stimulatory signals from normal tissue. Such mutations can occur in response to a carcinogen such as asbestos in MM, as discussed above. The multistep accumulation of further mutations to cells in this clone leads to the development of the hallmarks of a frank malignancy, namely autocrine growth, invasion, and the ability to metastasize. This whole process may occur over a period of many years. Alterations enabling this malignant pattern of growth to occur may include oncogene activation or mutation, loss of tumor suppressor genes, and autocrine or paracrine secretion of growth factors. Determining which changes a cell undergoes to develop this malignant phenotype has the potential to provide insights into new methods of treatment for a tumor. In MM, considerable progress has been made over the last ten years in elucidating candidate factors, but no clear single pathogenic pathway has yet been found. Chromosomal abnormalities Asbestos is known to induce chromosomal mutations directly. This may occur by the production of reactive metabolites as mentioned above, by interference with the mitotic spindle at division, or by direct chromosomal adherence resulting in fragmentation. The majority of cases of MM subjected to cytogenetic study have shown karyotypic changes,24 and a wide range of complex and heterogeneous chromosomal abnormalities have been described. Chromosomal gains have been found to be as frequent as losses, and some of these are relatively common, such as loss of 4, 22, 9p, and 3p,

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and gain of 7, 5, and 20.25 Significant correlation between certain losses (1 and 4) and a high content of asbestos fibers in lung tissue has been shown. The mean chromosomal number has also been shown to correlate with survival in patients with MM. Those patients with a normal chromosome number and no clonal abnormalities had the longest average survival.26 Of the many abnormalities described, there are some alterations that are of particular interest in terms of pathogenesis. Monosomy 22 is the most common numerical cytogenetic change, and has been correlated with mutations in the neurofibromatosis type 2 (NF2) gene.27 The loss of at least one locus in 1p (nearly all in 1p22) was found in 74% of examined specimens,28 and 42–62.5% of cases of MM have been found to have loss of heterozygosity of one or more loci on chromosome 3p.29 These changes are of interest in that there is a gene for cellular senescence on chromosome 1 and a tumor suppressor gene located on chromosome 3.13 Polysomy of chromosome 7 is common, and the number of copies of the short arm of this chromosome has been found to be an adverse prognostic feature.24 The loci for the epidermal growth factor receptor (EGFR) and the plateletderived growth factor A chain (PDGF-A) are both present on this chromosome (see below). In one study, 83% of cell lines had deletions of 9p,30 which is the location of the gene for p16INK4 (see below). Sixty-one percent of MM specimens were also found to have allelic losses in 6q in four discrete locations, most of which had losses in more than one of these regions.31 As was postulated by Bell et al,31 the consistent losses seen in certain areas may imply that these regions are the sites of tumor suppressor genes, the loss of which is central to the development of the tumor. Oncogenes Specific oncogenes have been found to be central to the progression of many malignancies, but as yet this has not been particularly well studied in MM. Of interest, however, are the findings that the v-src gene has been shown to cause MM in chickens32 and that the EJ-ras gene causes tumorigenic transformation of mesothelial cells when transfected.33 There is no evidence that these oncogenes play a role in human MM. The most promising candidates have been c-fos and c-jun, which have been implicated in animal models. The levels of both c-fos and c-jun mRNA have been shown to be upregulated when rat pleural mesothelial cells are exposed to asbestos.34 This pathway has been further investigated by showing that these changes are prevented by the use of N-acetylcysteine35 and by calphostin C, a protein

kinase C inhibitor.36 Such findings could implicate these proto-oncogenes in the pathogenesis of MM, but the levels of c-Fos protein were found to be similar in MM and non-neoplastic mesothelial tissue.37 Wild-type K-Ras was found in all 20 MM cell lines examined by Metcalf et al.38 c-Myc immunocytochemical expression is common,39 but c-myc was not found to be amplified in murine MM cell lines.40 Tumor suppressor genes In order for a tumor to continue to proliferate in the face of genomic damage, it is necessary that it avoid the normal cellular processes for the detection of such damage. Tumor suppressor genes enable the cell either to arrest the cell cycle with the possibility of repair or to undertake programmed cell death (apoptosis). Mutation or loss of a tumor suppressor gene enables an altered cell to continue through the cell cycle unchecked, and allows further proliferation. The most well-described of the tumor suppressors is TP53, which is known to be mutated in a majority of human cancers.41 Alterations in TP53 have been found in 75% of murine MM cell lines,42 but wild-type p53 was normally expressed in most human MM cell lines38 and demonstrated by immunohistochemistry in primary tumors.43 The retinoblastoma protein pRb prevents progression of a damaged cell into S phase when it is hypophosphorylated. Its level of expression in human MM cell lines has been shown to be normal.44 Mouse double-minute 2 (MDM2), a protein that can inhibit the function of both p53 and pRb, is not overexpressed in human MM,45 although a proportion has been shown to have positive staining for MDM2.46 The possibility of expressed pRb being abnormal in this tumor has been raised by the finding that a monoclonal antibody specific for the epitopes between exons 21 and 27 showed no immunoreactivity by immunohistochemistry, whereas a polyclonal antiserum showed staining in all MMs examined.47 In keeping with the frequent loss of chromosome 9, the product of the CDKN2 gene, p16INK4, was found to be abnormally expressed in 12 of 12 primary MMs and 15 of 15 MM cell lines.48 p16INK4 normally inhibits phosphorylation of pRb, and thus its loss would allow uncontrolled progress through this stage of the cell cycle. Deletions of the portion of chromosome 9 containing CDKN2A, but not CDKN2B, were also found in MM cell lines,49 whereas p16 has previously been found to be deleted in 85% of MM cell lines but only 22% of primary tumors.50 Seventy-two percent of primary MMs have also been found to have co-deletions of p15 and

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p16.51 p16/CDKNA2 was homozygously deleted in 59 out of 80 human tumors52 and patients with intact p16 had a significant survival advantage.53 The third tumor suppressor of particular interest in MM is the NF2 gene. This was found to be mutated in 41% of MM cell lines examined by Sekido et al54 and 53% of cell lines examined by Bianchi et al.55 This latter group also found that three-quarters of these mutations were confirmed to be present in the primary tumor. This finding for MM in humans does not correlate with the disease in rats, where mutations were not found.56 The Wilms’ tumor gene (WT1) is expressed in normal mesothelium during embryogenesis. It is potentially interesting in view of the fact that one of the actions of the WT1 protein is to control the transcription of genes such as those for PDGF-A,57 insulin-like growth factor (IGF)-II,58 transforming growth factor (TGF-β),59 and the IGF-I receptor (IGF-IR).60 All of these have been described as potential autocrine growth factors in MM, and the deletion of WT1 could allow excessive production. Expression of WT1 mRNA has been found in most human MM cell lines examined and in most primary tumors.61,62 The level of expression has been found to be variable, but there was no inverse correlation found between expression of WT1 and IGF-II or PDGF-A.63 A further study using mutational screening found no significant changes to WT1, and also found no correlation between WT1 immunostaining and EGFR or IGF-IR levels.64 PATHOBIOLOGY The diagnosis of MM is usually made on the basis of histologic analysis, from which the tumor can be classified as follows: 1.

2.

3.

4.

Epithelial: the tumor mass consists of papillary, tubular, acinar-like, or solid tissue in which cuboidal tumor cells form a pavement-like appearance. The amount of stroma within the tumor is variable. Sarcomatous: the tumor mass consists of spindleshaped cells forming organized bundles, though whirls, ‘herring bone’, or irregular patterns of tumor cells also occur. Desmoplastic: the tumor mass consists of a sizable connective tissue component with variable cellularity and pleomorphism. Epithelium-like structures are not present in this form. Biphasic: the tumor mass consists of a mix of the epithelial and sarcomatous forms. This is the most common type.

Differential diagnosis of MM from reactive mesothelium or adenocarcinoma is an important aspect of analysis of biopsy samples. Cytologic diagnosis is based first on the malignant nature of the samples by generally applicable criteria (nuclear polymorphism, irregularity of nuclear membrane, chromatin distribution), followed by confirmation of the mesothelial characteristics. These characteristics include a characteristic cytoplasmic appearance, a brushlike border and multinucleation. Further confirmation can be obtained by ultrastructural analysis, showing long microvilli and numerous intermediate filaments.65 The differential diagnosis of MM from metastatic adenocarcinoma has been facilitated by the availability of extensive immunohistochemical panels, including mesothelial markers such as calretinin, mesothelin, podoplanin, and thrombomodulin, and glandular markers such as CEA, LeuM1, and B72.3. In addition more specific markers of lung adenocarcinoma such as TTF-1 are now available.66 However, distinguishing MM from benign mesothelial cells remains a challenging area in cytologic diagnosis. Strong membrane staining for EMA on the majority of mesothelial cells is considered indicative of malignancy.67

GLOBAL TRANSCRIPTIONAL PROFILING IN MM Using various global transcription profiling ‘microarray’ strategies, several studies have been performed in MM with various aims: to understand the genetics and biology of MM, to identify genes that may be useful for early diagnosis, for determining prognosis, and to identify potential targets for the development of new therapies. Experimental models examining asbestos-induced transformation of mesothelial cells68 as well as studies using human MM patient samples have shown activation of pathways common to the development of many cancer types. Such functions relate to growth and proliferation, cell-cycle progression, apoptosis, invasion, and metastasis. Pathways including the insulin-like growth factor-1, p38 MAPK, Wnt/β-catenin, and integrin signaling have been found to be important for MM development.69,70 Diagnostic strategies for distinguishing MM from lung adenocarcinoma have been suggested based upon gene expression profiling.71,72 As well, specific markers such as osteopontin were shown in gene expression studies to be upregulated in MM, and may be of possible value as a serum marker for MM.73 Some studies have concentrated on finding gene ‘signatures’ that can be used as to predict prognostic

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indicators for MM.74–77 However, it appears that clinical prognostication based on gene expression profiling is not significantly superior to that achieved using classic clinical parameters such as age, sex, epithelial histology, lymph node status, and tumor stage.77 Global microarray profiling, however, has revealed potential new clinical targets such as the aurora kinases.77

IMMUNOBIOLOGY The human disease In contrast to many other tumors, there is little evidence in MM that specific immune responses are initiated against the tumor during the course of the disease. Some descriptions of leukocytic infiltrations have been reported in the literature, but these examples are rather non-systematic and use very broad characterizations. What is evident is that the extent of infiltration depends on the individual tumor.78,79 One unusual form of MM is termed lymphohistiocytoid MM – so called because there is evidence of lymphocytes infiltrating the tumor mass.80 Although suggestive of specific immune recognition of the tumor, there is no direct evidence that supports this hypothesis, and these cells may simply reflect a non-specific inflammatory response. In fact, early attempts to isolate MM-reactive killer cells from patients proved unsuccessful.81 Overall, the lack of tumor-infiltrating lymphocytes (TILs), as with many other tumors, has been attributed either to a lack of tumor antigen expression or to other factors, such as the secretion of immunosuppressive cytokines, that diminish the overall immunogenicity of the tumor. However, more recent work has suggested that an immune response is generated in a significant proportion (28%) of MM patients.82 In these studies, patient sera reacted with a panel of human MM cell lines as determined by Western blot analysis. When sequential sera were analyzed, it was found that the titer increased with the progression of the disease. Importantly, the MM-reactive antibodies within the sera were of the IgG class, indicative of immunoglobulin class switching, and hence the involvement of the cellular arm of the immune response, which is obligatory for this process. These are important data, which will lead to identification of a number of potential tumor-associated antigens (TAAs), the characterization of which will be invaluable in the context of potential vaccination strategies or immunotherapeutic treatments. In addition, clinical studies have suggested that, even if an immune response is not a normal event in the

disease process, this malignancy may be susceptible to immunotherapy. In a small trial using intralesional therapy with granulocyte–macrophage colony-stimulating factor (GM-CSF), while there was no direct evidence of a tumor-specific immune response, the one patient who showed a partial response also had an intense lymphocytic infiltration in biopsy samples.83 Apart from using this direct administration of a cytokine, efforts have been made to utilize gene therapy techniques in treatment. In particular, the use of genes encoding cytokines has been the most prevalent, in the hope that they will boost or enhance any ongoing antitumor response. Although gene therapy has provided some encouraging results in animal models, the difficulty with this technique in solid tumors, such as MM, is the inability to transduce all tumor cells with the gene of interest. Therefore some emphasis has been placed on trials in which cytokine genes are transferred via viral vectors such as vaccinia. The growth of tumors is often considered to be immunosuppressive, and MMs have been shown to secrete a number of cytokines or factors that are known to modulate immune responses, including PDGF, TGF-β, and interleukin-6 (IL-6). As is quite often the case with such products, they are responsible for coordinating or mediating a number of processes, and PDGF and TGF-β have also been shown to be growth factors for MMs. The role of these molecules in influencing the immune response to MM has not been investigated deeply, and what we know has been elucidated in animal models (see below). Another potential mechanism whereby MMs might evade immune recognition is by the downregulation of HLA class I molecules, such as has been reported for melanoma. However, a survey of a panel of human and murine lines has shown that these tumors all express class I molecules, and therefore they can still be targets for the immune response.

ANIMAL MODELS A number of different models of MM have been established in animals to understand the pathogenesis of the disease and to test potential therapeutic agents. Spontaneous mesotheliomas have not been described in mice or hamsters and occur very rarely in rats. However, natural and synthetic fibers, chemicals, and metals have been shown to induce pleural and peritoneal mesotheliomas in rodents.84 Additionally, intrapleural inoculation of hamsters with SV40 virus causes pleural

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mesotheliomas in 100% of cases.85 The injection of asbestos fibers into pleural and peritoneal cavities produces malignant mesotheliomas in 20–30% of mice.86,87 These mouse mesotheliomas are comparable to the human disease with respect to latency, superficial growth of tumor on the serosal surface, and the accumulation of ascites.88 Although this is not a viable working model for the testing of therapies due to the long latency period and low incidence of disease development, it has led to the generation of many asbestosinduced mesothelioma cell lines.86 Subcutaneous inoculation of these mesothelioma cell lines into syngeneic mice induces solid tumors which grow rapidly and are easily accessible for monitoring efficacy of drug treatments. As these tumors exhibit the diagnostic characteristics of the human tumor, despite their anatomic dislocation, they have been used extensively to study the immunobiology of MM89 and to evaluate efficacy of chemotherapies, immunotherapies, and combination therapies.90–92 More recently, genetically modified transgenic mouse mesothelioma models, with features of asbestos-induced mesothelioma, have been devised and it is hoped that these new models will enable further testing of drug therapies and study of the disease. Although loss or mutation of p53 is not considered a trait of mesothelioma, the first transgenic model used was a p53 knockout mouse, originally created to study a range of cancers. Although a proportion of homozygous p53−/− knockout mice developed disease soon after asbestos inoculation, these mice have a short lifespan of only 22 weeks and the rest died of other causes, rendering them unsuitable for modeling this disease.93 More promisingly, the heterozygous p53+/− knockout mice have a longer lifespan and 76% of these mice had developed asbestos-induced mesothelioma compared to 32% wild-type mice, at 44 weeks after initial asbestos exposure. These p53+/− heterozygous mice have been used in further studies investigating loss of heterozygocity in asbestos-induced tumors.94 Human malignant mesotheliomas frequently accumulate genetic alterations affecting the Nf2 and CDK2A/Arf tumor suppressor gene loci. When Nf2+/− knockout mice are exposed to asbestos, they develop mesothelioma more rapidly and at a higher incidence than wild-type littermates.95,96 Analysis of the tumors showed that they recapitulated the most common molecular features of human malignant mesothelioma. They had frequent deletions in the Arf/CDK2A locus, inactivation of p53, and activation of the AKT signaling pathway.97

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10 20 30 40 50 60 70 80 90 100 Weeks after asbestos exposure

Figure 12.1 Mice expressing SV40 are more susceptible to asbestos-induced MM. Mice bearing the SV40 Large T gene driven by the mesothelin promoter showed increased sensitivity to asbestos-induced MM. Shown is the survival of these mice (‘MexTAg transgenic mice’) after two injections of 3 mg asbestos were given in the peritoneum, 4 weeks apart. Mouse lines 299h, 304i, 266s, and wt (wild-type) contain 100, 30, 1, and 0 copies of TAg, respectively. The number of animals in each group is noted. Median survival times were line 299h, 24 weeks; line 304i, 36 weeks; line 266s, 55 weeks, and wt, 56 weeks. Log rank tests showed survival was significantly different between all mouse lines, with the exception of 266s and wt. p Values were 0.005 or less.98

The injection of asbestos fibers into the peritoneum of mice induces mesotheliomas in less than a third of mice, between 7 months and 2 years after the first asbestos exposure. Although this method has provided the mouse mesothelioma cell lines that are useful tools in the subcutaneous model, the model itself is impractical for further studies of the disease, such as assessment of drug efficacy. We have constructed a novel transgenic mouse model, MexTAg, which directs SV40 TAg expression to the mesothelial compartment using the mesothelin promoter. When MexTAg mice, containing 100 copies of the TAg transgene (299h mice), are injected with asbestos, not only do all of the animals develop MM but disease occurs much more rapidly than in wild-type mice (Figure 12.1).98 At 38 weeks all 299h mice had developed MM, whereas 87% of wildtype mice remained healthy. Furthermore, at the end of the experiment, only 25% of wild-type mice had developed MM. Thus, this model is suitable to examine the efficacy of preventative and therapeutic drugs and also to investigate the molecular events occurring at the early stages of MM development. While MexTAg mice unexposed to asbestos did not develop MM, in another transgenic mouse model, which expresses SV40 TAg under the control of the cytokeratin 19 gene, MM and other tumor types developed; however it was unfortunate that these mice were unable to breed.99

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Applications to therapy As mentioned above, immunomodulatory molecules such as TGF-β are produced by MM cells as obligate growth factors. One could therefore hypothesize that interventions that target such factors may be very effective from two aspects: first, by interfering with the growth cycle of the tumor cells, and, second, by allowing an immune response to be generated. In experiments in which TGF-β production was reduced by inhibiting translation of these proteins using antisense DNA technology, tumor growth could be inhibited but not eradicated.100 Inhibition of tumor growth was concomitant with treatment – the effects were lost on cessation of treatment. No evidence of an improved antitumor response was noted in these experiments. This result may have several explanations, including that the amount of TGF-β required for tumor cell growth is significantly greater than that required for immunosuppression. Such approaches are worthy of further investigation – possibly in combination with other treatments. See the section below on ‘Future directions’.

CLINICAL PRESENTATION AND COURSE MM usually develops in males with a history of occupational exposure to asbestos. The latency period between asbestos exposure and the development of MM is at least 20 years.1,101 Therefore patients are usually over 50 years of age.102 However, non-occupational exposure does occur, and in some of these cases the exposure occurred in childhood. Patients with pleural MM usually present with symptoms of chest pain or discomfort, dyspnea, and cough. In fact, the presence of chest wall pain in any at-risk patient is a strong clue to the possible presence of MM. Early in the course of the disease, dyspnea is the commonest symptom, and is due to the presence of an effusion. The majority of patients with pleural MM will have a malignant pleural effusion, which is usually bloodstained, often loculated, and of large volume. As the tumor progresses, chest discomfort or tightness may occur. The dyspnea may improve because of fusion of the pleural surfaces and resolution of the effusion, or therapeutic talc pleuradesis. Unremitting chest pain may occur as the tumor locally invades the intercostal nerves. Eventually, the lung becomes encased by tumor, leading to worsening of dyspnea and chest tightness. The tumor commonly spreads by direct extension to involve the chest wall, the mediastinum, other pleura or the diaphragmatic surface, the pericardium, and the liver. Invasion of the pericardium leads

to a pericardial effusion, which worsens the dyspnea. Spread to local lymph nodes occurs in 40% of cases, but hematogenous spread is less common and rarely clinically significant. Weight loss occurs in the late stages of the disease. Examination findings in the early stages of the disease usually reflect the presence of a pleural effusion, with dullness to percussion and reduced breath sounds. As the tumor progresses and encases the entire hemithorax, the hemithorax may contract, chest expansion becomes noticeably restricted, and dullness to percussion and reduced breath sounds are found over the affected area. Breathing sounds can be ‘harsh’ rather than reduced, and sometimes are frankly ‘bronchial’ in nature. Protrusion of tumor through the intercostal spaces tends to occur at sites of previous thoracocentesis, chest tube insertion, or thoracotomy incision. Supraclavicular lymphadenopathy and ascites may be present if the tumor has spread to these areas. Paraneoplastic syndromes are rare, but can include hypercalcemia, autoimmune hemolytic anemia, and inappropriate secretion of antidiuretic hormone (SIADH).103 Thrombocytosis with a platelet count of greater than 400 000/µl occurs in approximately 30% of cases,102 but does not commonly lead to increased thrombotic events. Those with peritoneal disease experience abdominal pain and distension, weight loss, anorexia, and bloating. Peritoneal MM rarely invades superiorly through the diaphragm.

DIAGNOSIS Radiology The most common chest X-ray abnormality in early stage disease is the presence of a pleural effusion. Pleural thickening or small focal pleural masses may be seen on computed tomography (CT) of the chest, and CT is useful in differentiating pleural fluid from pleural thickening,104 although ultrasound is often required. CT scanning also provides information on the state of the pulmonary parenchyma, the mediastinum, and invasion of the chest wall.105,106 As the disease progresses there is diffuse involvement of the pleura and larger, pleurally-based masses may become obvious. The pleural effusion often becomes loculated. Eventually, the lung becomes encased in a thick pleural rind of tumor that compresses the underlying lung. Magnetic resonance imaging (MRI) is useful for delineation of chest wall invasion. MM is also FDG-PET avid; however the role of PET scanning in staging, prognosis, and treatment planning is still under investigation.107,108

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Cytology Most patients with MM present with a pleural effusion, and therefore thoracocentesis is often the first diagnostic procedure. Large amounts of pleural fluid should be obtained and sent for cytologic examination; this will be diagnostic in 30–50% of cases.103 The fluid should be examined using light microscopy and immunochemical stains for cytokeratins and vimentin and immunohistochemical stains (especially CEA and EMA) to differentiate adenocarcinoma from MM (see above). The accuracy of EMA in cytologic studies depends upon the clone of antibody used in the analysis. The combination of cytologic assessment of pleural fluid and histopathology on closed pleural biopsy specimens can increase diagnostic accuracy for pleural malignancy, including MM.112 Biomarkers Measurement of tumor markers in effusions may provide a complementary tool to aid in effusion diagnosis. Differential levels of CEA, cancer antigen (CA)15.3, CA72.4, CA19.9, CA549, neuron-specific enolase, or cytokine fragment 19 (CYFRA 21-1) differentiate malignant from benign effusions.113,114 However, there are fewer data available for the differential diagnosis of MM from other cancers. Low levels of CEA in effusions of MM patients provide a strong negative predictive value for this disease.115–117 However, there are few studies reporting markers with a positive predictive value for MM. Elevated CA15-3 levels have been reported in MM,114–116 and in one study as being able to differentiate

MANAGEMENT MM is an almost uniformly fatal disease that is not usually curable with surgery, chemotherapy, or radiotherapy.

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lack of useful pleural tissue; difficulty in interpretation of small biopsy samples;111 the need to distinguish MM from reactive mesothelial inflammation and metastatic pleural tumors; difficulty in differentiating histologic subtype on a small specimen.

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between MM and bronchial cancer.116 Higher levels of hyaluronic acid have been reported in effusions from MM patients compared to those with other malignant diseases; however the difference was too small for diagnostic purposes,117 whereas there is discrepancy in the literature on the ability of CYFRA 21-1 levels to differentiate between MM and other pleural malignancies.116,117 Recently, we showed that mesothelin levels in effusions above 20 nM are highly suggestive of malignancy, particularly of MM; at this cut-off value the assay had a sensitivity of 77% for non-sarcomatoid MM, and a specificity of 98% relative to non-malignant effusions and 86% relative to non-MM malignancies (Figure 12.2).118 Mesothelin levels have also been shown to be useful in monitoring disease progress/regression.118 Elevated mesothelin levels were observed in some effusions before a definitive cytologic and/or histologic diagnosis could be made. One patient, an 87-year-old male, who presented with recurrent blood-stained exudative effusions which were negative for malignancy by cytologic examination, had elevated mesothelin levels in his effusion. In this case a definitive diagnosis of MM was made 10 months after the initial mesothelin-positive effusion sample.

SMRP(OD 420 nm)

Histopathology Accurate diagnosis of MM can be time-consuming, and may require more than one diagnostic procedure because of the difficulty in obtaining malignant tissue for histopathologic assessment. Pleural biopsies, obtained via closed or open (thoracoscopy/thoracotomy) procedures, improve the diagnostic yield. Pleural biopsy samples should be assessed by immunohistochemistry and electron microscopy, since these are the important studies to assist in making a definitive diagnosis.109,110 The major problems associated with closed pleural biopsies are:

Figure 12.2 Serum mesothelin in MM patients versus asbestos-exposed controls. Individual patient data are plotted as the mean absorbance measurement at 420 nm of duplicate serum samples diluted 1 in 100. Dashed line represents the normal range. (Adapted from Robinson et al,119 with permission.)

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The potential treatment options are the same as for other malignancies, namely surgery, radiotherapy, chemotherapy, immunotherapy, gene therapy, supportive care, or combination therapy utilizing some or all of the above treatments. However, there are major differences from other cancers, because in MM it is often difficult to objectively quantify the location and extent of disease, and the patients are older and often have underlying illness that makes them unfit for aggressive, rigorous treatment plans. The relative rarity of the condition means that few large prospective clinical trials have been published, and clinicians must rely on retrospective clinical trials with small numbers of patients. Here, we concentrate on the palliative management of patients with advanced disease, the most common presentation. However, surgery with the aim of cure will also be discussed. Chemotherapy Until 2003, there were no randomized clinical trials demonstrating an improvement in survival, quality of life, or lung function for any palliative chemotherapy regimen in MM. In 2003, a landmark clinical trial was published by Vogelzang et al, comparing overall survival, response rates, toxicity, and quality of life in 226 patients with advanced MM randomized to cisplatin plus pemetrexed, and 222 to single-agent cisplatin.120 Patients receiving cisplatin and pemetrexed had a significantly longer median survival than those on cisplatin alone (12.1 months versus 9.3 months, p = 0.02). Forty-one percent of patients on the combination arm had objective tumor responses, compared with 17% in the single-agent arm (p <0.0001). The combination arm experienced greater toxicity; however this was rarely clinically significant and was in part ameliorated by supplementation with folate and vitamin B12. This trial also demonstrated small but statistically significant benefits for combination chemotherapy in global quality of life and symptom distress measures, and larger benefits for pain, dyspnea, and cough after 18 weeks of treatment.121 Similar results have been obtained for another combination chemotherapy using cisplatin and raltitrexed, significantly improving overall survival as compared with cisplatin alone.122 Single-arm studies also suggest good response rates for cisplatin and gemcitabine,123,124 but this combination has not been tested in phase III clinical trials. Overall, these studies have shown that combination chemotherapy, in appropriate patients, can give palliative benefits by decreasing tumor bulk, increasing survival, improving lung function, and improving quality of life. The timing of chemotherapy (on diagnosis versus when symptomatic)

and duration of chemotherapy (four versus six versus more cycles of treatment) are questions for further study. There are currently no predictive markers of response to chemotherapy, although patients with ECOG performance status of 2 or worse may be less likely to benefit.121,124 Radiotherapy Hemithoracic radiotherapy has a limited role in the palliative management of MM due to the difficulty in delivering adequate doses to a large treatment field. However, low-dose palliative radiotherapy to limited fields can very effectively relieve pain from enlarging chest wall masses.125 Radiotherapy also has an important prophylactic role in preventing chest wall infiltration and development of masses at the sites of previous invasive instrumentation such as chest drains or pleural biopsies.126 All patients at risk of local chest wall infiltration should be considered for this simple procedure. Immunotherapy and gene therapy These are relatively new treatment options, and their role alone or in combination with surgery or radio- or chemotherapy has not yet been adequately evaluated. It is known that systemic interferon-α (IFN-α),127,128 IL-2,129 and GM-CSF83 have some activity in selected cases of MMs, but none has achieved a response rate sufficient to warrant their recommendation in all patients. Combining IFN-α with chemotherapy has also produced no added benefit.130 Surgery Four types of operation have been performed as treatment for mesothelioma: extra pleural pneumonectomy (EPP), pleurectomy/decortication, limited pleurectomy, and thoracoscopy with talc pleurodesis. EPP involves an en bloc resection of the pleura, lung, ipsilateral hemidiaphragm, and pericardium. Butchart et al131 reported that this procedure carried an operative mortality rate of 30%, but since then there have been a few studies reporting a reduction in operative mortality rate to 6–9%.132–135 This was most likely due to improved patient selection, experience, and better postoperative care. Median survival in these studies ranged from 8 to 16 months. Pleurectomy/decortication involves attempting to remove all obvious pleural disease without removing the underlying lung. The operative mortality rate is 1.8%;136 however, long-term survival is not significantly increased in most patients. Limited pleurectomy is a palliative procedure designed to resect part of the parietal pleura to control a pleural effusion. Thoracoscopy

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with talc pleurodesis is an effective palliative procedure for control of effusion. Overall, in most cases, surgical procedures alone will not lead to any significant improvement in survival. However, Sugarbaker et al137 showed that trimodality therapy (resection of tumor, chemotherapy, and radiotherapy) in highly selected patients can lead to a small proportion of patients with long-term survival. In this study, operative morbidity rate was measured at 17%, mortality rate was 6%, and overall survival was 16 months. There are no completed randomized clinical trials to support this practice; however the MARS trial, run out of the United Kingdom, is currently randomizing patients to surgery as part of trimodality therapy, or palliative management (including chemotherapy) alone. Patient selection for ‘curative’ surgery is not standardized; however an aggressive approach to staging and preoperative investigation that may include PET scanning, mediastinoscopy, contralateral thoracoscopy with blind biopsies, and laparoscopy has been advocated.138 Optimal surgical technique is also debated.139,140 Referral to a thoracic surgeon with experience in EPP should be considered in fit patients with early stage, potentially resectable disease. Chemotherapy and radiotherapy Chemotherapy and radiotherapy are components of socalled ‘trimodality’ therapy; however the optimum timing (pre- or postoperative), regimen, and duration of chemotherapy are unclear. Clinical trial results are not yet available to inform these decisions. In clinical practice, a common approach is to use cisplatin and pemetrexed due to the demonstrated activity of this combination in advanced disease.120 However, it is still unclear whether chemotherapy is best used preoperatively or postoperatively. Neoadjuvant chemotherapy may avoid a morbid operation in patients with rapidly advancing and treatment-resistant disease, and patients are fitter preoperatively. However, some surgeons consider EPP to be more technically challenging postchemotherapy, and would prefer an adjuvant approach. A disadvantage of adjuvant chemotherapy is that not all patients will be fit enough for treatment after surgery. There are several approaches to integrating postoperative radiotherapy into the trimodality program. The lowest locoregional recurrence rates post-EPP are in those series using high-dose postoperative hemithorax irradiation.141 Recent guidelines for three-dimensional conformal radiotherapy suggest a dose of 54 Gy in 30 fractions five days per week to the ipsilateral thoracic cavity, chest wall incisions, and drains, with attention

to normal tissue tolerance for the contralateral lung, spinal cord, heart, esophagus, and other vital structures.142 Intensity-modulated radiotherapy (IMRT) is a promising newer technology that may deliver better local control results;143 however it is not widely available, and there have been reports of subsequent fatal pneumonitis which suggest caution in implementing this technology.144 Nevertheless, only patient series using an aggressive multimodality approach achieve clinically meaningful five-year survival rates.145

FUTURE DIRECTIONS In this section, we shall highlight directions in which MM research is heading, focusing on aspects that could prove to be clinically useful. Diagnosis There has recently been an upsurgance of interest in the use of tumor biomarkers for the clinical management of MM. Soluble mesothelin-related proteins in particular are being intensively investigated. Mesothelin is a differentiation marker of mesothelial cells. Through various post-transcriptionally and post-transcriptionally processed soluble forms of mesothelin can be detected in the serum and in the pleural fluid of patients with MM. Approximately 50% of MM patients have elevated levels at the time of diagnosis, and up to 84% with advanced disease.118,146 There is considerable interest in screening asbestosexposed individuals for the early detection of MM. Given that mesothelin levels have been observed to be elevated in some individuals up to five years before clinical presentation, mesothelin represents a strong candidate for a screening program.146 However, the sensitivity of the screening program will be limited, given that at diagnosis not all individuals have detectable mesothelin proteins in their sera. Currently, methods of combining different biomarkers and a program that measures changes in biomarker values, rather than absolute values, are being evaluated. The principle reason for developing a screening strategy for MM would be to commence treatment on early stage tumors which would hopefully prove more effective than treatment in more advanced disease. However, prospective studies and randomized trials would be required to test such an hypothesis. Therapy Future therapies in MM will have two aims. The first is to alleviate symptoms. Patients with MM often experience

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profound weight loss, fevers, hypoalbuminemia, and pain. Recent studies have identified cytokines that are likely to contribute to this, particularly IL-6. In animal studies, blockade of IL-6 has had a profound effect on animals’ clinical status, although the actual antitumor effect was modest, and possibly related to the improvement in the host’s well-being. If a simple method of inhibiting IL-6 activity in vivo can be established, it is likely that this could be given to patients with MM to alleviate their systemic symptoms. Such therapy might involve receptor blockade or IL-6-signaling blockade (e.g. via the SOCS molecules).147 The second area in which new developments in therapy might occur is in the generation of antitumor effects. Development of new agents Anti-angiogenic agents VEGF is an autocrine growth factor in MM,148 and VEGF expression in MM is correlated with microvessel density,149 a poor prognostic feature in this disease.150 Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody which acts by blocking VEGF binding to the VEGF receptor. A clinical trial of bevacizumab in combination with chemotherapy is completed but as yet unreported. Other anti-angiogenic agents including thalidomide are currently in clinical trials in mesothelioma. Immunotherapy Trials have begun of immunotherapy in its various forms in MM, and it is likely that in the future the limited but clear success of this approach will be augmented, probably in combination with other therapies. While established agents such as recombinant IFN-α have had limited but surprising effects,127 combining this approach with chemotherapy has not proved more efficacious.130 This may be partly because of the toxicity of chemotherapeutic approaches. It is therefore likely that future immunotherapeutic approaches to MM will involve other strategies, particularly the local administration of immunomodulatory agents The continuous infusion of GM-CSF into MM produced some tumor shrinkage and mononuclear cell infiltrates, but proved technically demanding.83 Less technically demanding means to improve delivery of these agents to the tumor are likely to be developed. There are three possibilities: improved continuous-infusion technology, depot release preparations, and gene therapy. The last is the most advanced. Initial studies using immunologic gene therapy in MM have involved the administration of virus–

cytokine constructs. In one pilot study, this approach was shown to be feasible to produce a T-cell infiltrate in the tumor and to be free of side-effects in the patient and in contacts.151 These are very early days for the immunologic gene therapy of MM, and there is no doubt that in the future we shall see further developments in this area. Other gene therapy strategies that have been utilized have included herpes simplex TK ‘suicide gene’ therapy, which has produced some responses, and which may be working by a combination of tumor shrinkage and necrosis generating antitumor immune effects. Other gene therapy approaches that have been utilized preclinically include the use of antisense oligonucleotides to block MM growth factors such as PDGF and TGF-β. This approach has proved most efficacious in vivo, and has caused a profound reduction in tumor growth in animal models.100 It is likely that future treatment of MM will involve such gene therapy approaches, provided that the concentration of antisense oligonucleotides can be increased within tumors to a level sufficient to cause the required biologic effects. Recently, the autolgous MM tumor has been used in vaccine studies, with local GM-CSF used as the adjuvant. This approach clearly induced anti-MM immune responses, although substantial tumor regressions were not seen.152 Combination therapies It seems likely that the most effective treatment of MM will require combination therapy. Combinations include some of those described above, for example molecular approaches to increase the sensitivity of tumor cells to chemotherapeutic agents combined with systemic administration of such agents, or a combination of suicide gene therapy with immunotherapy. In addition, it is possible that chemotherapy can be strategically combined with immunotherapy in a way that augments the efficacy of each; for example, it is possible that cycles of drug therapy may alter the antigenic profile of tumor cells so that they provide new targets for immunotherapy. The future development of effective therapies in MM is likely to rely on two fundamental principles. First, it will be essential to understand the basic biology and immunology of the disease before optimal therapies can be developed. MM is a disease that has remained mysterious for many years, yet over the past five years or so the underlying pathogenic mechanisms and immunobiology have begun to be elucidated. Second, it is likely that combined therapy will be necessary, and that each component will need to have independently proven efficacy,

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i.e. it will be important to build on treatments that already have a track record of clear success at reducing tumor bulk. Tumor biology and epidemiology In terms of epidemiology, it would be interesting to see whether, in the future, other agents besides asbestos are either sole etiologic agents in MM or act as co-factors with asbestos. The recent identification of the SV40 virus as a potential factor in the development of MM is of interest,20 and it will also be interesting to see if other infectious agents that have known oncogenic effects are identified. A number of viruses are at least partially trophic to the pleural mesothelium (e.g. causing the clinical syndrome of viralpleurisy), and a potential role for such viruses in the generation of MM may be identified in the future. Similarly, there are a large number of cases of MM in whom the level of asbestos exposure is no higher than that of the background population. It has been assumed that these cases represent the unfortunate small proportion of patients who develop a tumor with low levels of carcinogen (similar to the small proportion of sun-exposed individuals who develop UVinduced skin cancers). Nevertheless, it remains possible that other agents may be identified as etiological agents in MM. For example, many patients with MM are farmers, and, while it has always been assumed that this is because they have been exposed to asbestos in their farming activities, it would be interesting to determine whether or not inhalation of potentially carcinogenic pesticides may contribute to the development of the disease. Finally, the future may see the development of preventive measures in MM. There are some populations that are at extremely high risk of developing MM, for example, those exposed to crocidolite as children. A number of studies have been undertaken in an attempt to reduce their risk, such as the use of prophylactic vitamin A. This has shown some efficacy, but many of these individuals still develop MM.153 The abovementioned identification of MM antigens raises the possibility that a tumor vaccine may be developed for MM. Such at-risk groups would welcome such a vaccine. However, there are two major hurdles to overcome. First, these vaccines are difficult to test because they need to be given to large numbers of patients and followed for a long period of time before any valid efficacy can be determined: for example something like 5000–10 000 patients, followed over a period of five years or so. Second, as most tumor antigens are selfantigens, the risk of autoimmune disease in vaccinated patients would be substantial. This may cause pleurisy,

peritonitis, or pericarditis. It is thus possible that the development of an MM vaccine may be limited by the almost inevitable occurrence of such side-effects in a significant proportion of those vaccinated. If these sideeffects are minimal then the benefit may outweigh the risk, but the logistics of determining this are substantial. Most tumor vaccines are used in an adjuvant setting, i.e. they are used in patients once the disease is already diagnosed. In many ways, the future directions in MM research and treatment will parallel those for other tumors, and yet, in other ways, in view of the rather unusual clinical and biologic behavior of MM, they will be unique to that disease. Certainly MM is a very aggressive disease that has been largely resistant to all therapeutic attempts tried. In view of the increasing incidence of this disease and the poor success rate with current therapies, it is hoped that in the future the application of modern molecular and biologic techniques to the problem, in association with the commitment of managing clinicians to utilize novel therapeutic approaches, combined with the courage of the afflicted population, will lead to the development of improved methods of diagnosis, therapy, and prevention of MM.

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136. Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural pneumonectomy in malignant pleural malignant mesothelioma. J Thorac Cardiovasc Surg 1991; 102: 1–9. 137. Sugarbaker DJ, Strauss GM, Lynch TJ et al. Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol 1993; 11: 1172–8. 138. Alvarez JM, Ha T, Musk W et al. Importance of mediastinoscopy, bilateral thoracoscopy, and laparoscopy in correct staging of malignant mesothelioma before extrapleural pneumonectomy. J Thorac Cardiovasc Surg 2005; 130: 905–6. 139. British Thoracic Society Standards of Care, Statement on malignant mesothelioma in the United Kingdom. Thorax 2001; 56: 250–65. 140. Butchart EG. Contemporary management of malignant pleural mesothelioma. Oncologist 1999; 4: 488–500. 141. Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A Lung Cancer Study Group trial [see comment]. J Thorac Cardiovasc Surg 1991; 102: 1–9. 142. Senan S, van de Pol M. Considerations for post-operative radiotherapy to the hemithorax following extrapleural pneumonectomy in malignant pleural mesothelioma. Lung Cancer 2004; 45: S93–6. 143. Ahamad A, Stevens CW, Smythe WR et al. Promising early local control of malignant pleural mesothelioma following postoperative intensity modulated radiotherapy (IMRT) to the chest. Cancer J 2003; 9: 476–84. 144. Allen AM, Czerminska M, Janne PA et al. Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. Int J Radiat Oncol Biol Phys 2006; 65: 640–5. 145. Sugarbaker DJ, Flores RM, Jaklitsch MT et al. Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg 1999; 117: 54–63; discussion 63–5. 146. Robinson BW, Creaney J, Lake R et al. Mesothelin-family proteins and diagnosis of mesothelioma. Lancet 2003; 362: 1612–6. 147. Nicholson SE, Hilton DJ. The SOCS proteins: a new family of negative regulators of signal transduction. J Leukoc Biol 1998; 63: 665–8. 148. Strzzi L, Catalano A, Vianale G et al. Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J Pathol 2001; 193: 468–75. 149. Ohta Y, Shridhar V, Bright RK et al. VEGF, VEGF type C, and their receptors play an important role in angiogenesis and lymphangiogensis in human malignant mesothelioma tumors. Br J Cancer 1999; 81: 54–61. 150. Kumar-Singh S, Vermeulen PB, Weyler J et al. Evaluation of tumor angiogenesis as a prognostic marker in malignant mesothelioma. J Pathol 1997; 182: 211–16. 151. Robinson BW, Mukherjee SA, Davidson A et al. Cytokine gene therapy or infusion as treatment for solid human cancer. J Immunother 1998; 21: 211–17. 152. Powell A, Creaney J, Broomfield S et al. Recombinant GMCSF plus autologous tumor cells as a vaccine for patients with mesothelioma. Lung Cancer 2006; 52: 189–97. 153. de Klerk NH, Musk AW, Ambrosini GL et al. Vitamin A and cancer prevention II: comparison of the effects of retinol and beta-carotene. Int J Cancer 1998; 75: 362–7.

13 Summary of treatment Heine H Hansen Contents Introduction • Small cell lung cancer • Non-small cell lung cancer • Mesothelioma

INTRODUCTION A short summary of the management of small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and mesothelioma is given in this chapter based on the evidence from randomized trials, even though it should be realized that patients included in clinical trials are not representative of the patient population as a whole. Additional information on the management of lung cancer can be found in recent review articles.1–8 SMALL CELL LUNG CANCER Limited disease Surgical resection, followed by postoperative chemotherapy, is the treatment of choice for the rare patient who presents with stage I or II disease. The results for SCLC are equivalent to the treatment of stage I and II NSCLC. For the more typical SCLC patient who presents with bulky limited disease, combination chemotherapy is the mainstay of treatment, in conjunction with radiotherapy. For chemotherapy, the combination of etoposide and cisplatin (EP) has become the most commonly recommended regimen. The combination of carboplatin and etoposide produces similar results to cisplatin and etoposide, and has a more favorable toxicity profile. Maintenance chemotherapy does not result in any substantial improvement in survival. Based on meta-analyses, chest irradiation has shown superior survival results in patients receiving combination chemotherapy and radiotherapy compared with those receiving chemotherapy alone. The optimal timing and dosing of chest irradiation are still uncertain, but there is a tendency to initiate radiotherapy early during the first two courses, at total doses of at least 50 Gy. Hyperfractionated radiotherapy given twice a day has yielded superior survival data in one randomized trial compared with conventional radiotherapy when combined with cisplatin and etoposide. Prophylactic cranial irradiation (PCI) has also been demonstrated to have a statistically significant impact

on survival in patients with limited disease who achieve a complete remission, and it also reduces the lifetime risk of cerebral metastases. The optimal dose and timing of radiotherapy are again uncertain; most frequently, the total dose should not exceed 30 Gy given in fractions of 2.5 Gy daily. Extensive disease A combination of etoposide and cisplatin is the preferred standard treatment. The replacement of etoposide with irinotecan given together with cisplatin has resulted in significantly better median and one-year survival in one randomized trial, whereas no difference was observed in a subsequent trial. Again, carboplatin can be substituted for cisplatin because of similar activity and fewer side-effects, even though myelosuppression is greater. Recent results have indicated that a four-drug combination of etoposide, cisplatin, epirubicin, and cyclophosphamide may be superior to etoposide and cisplatin alone. With regard to maintenance therapy, the hypothesis has been tested of adding either oral etoposide or topotecan to the treatment regimen in patients demonstrating a response to initial therapy. The results showed a slight improvement with etoposide in terms of median progression-free survival, whereas topotecan did not show any significant difference. The impact of dose intensification remains uncertain. None of the phase III trials incorporating new agents have shown superior results compared with classic combinations such as cisplatin/carboplatin and etoposide. With respect to PCI, very recent data has also demonstrated benefit as measured by improvement in median survival in patients presenting with extensive SCLC. In patients presenting with poor prognostic factors, such as performance status 3–4, involvement of the liver and bone marrow, or severe co-morbid diseases, the initial dose of chemotherapy should be reduced, and careful monitoring is recommended over the first weeks. Elderly patients with poor performance status and widespread disease have a substantially higher risk of

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incurring treatment-related complications, and generally have a poor outcome. Supportive measures alone are often the best option for some of these patients. Recurrent disease The treatment options depend on the anatomic site of relapse, symptomatology, and previous treatment. Local relapse in patients without prior chest irradition is best treated with palliative radiotherapy. Late relapse in patients who initially responded to a platinum-containing regimen should be treated with the same regimen again. Otherwise, single-agent chemotherapy with topotecan or combination chemotherapy with cyclophosphamide, doxorubicin, and vincristine is the treatment of choice. Newer agents are being tested in this group of patients, either as single agents or in combinations, but usually yield response rates of < 20%. NON-SMALL CELL LUNG CANCER Stages I, II, and resectable IIIA Stage IA The standard therapy for stage I NSCLC continues to be complete surgical resection when possible. This should include lobectomy plus sampling of all mediastinal nodal stations or complete lymph node dissection. However, the surgical technique to perform a lobectomy or pneumonectomy and mediastinal exploration may change as experience with minimally invasive surgery grows. Recent data have revealed encouraging results with video-assisted thoracic surgery (VATS) lobectomy and mediastinal sampling or dissection. With minimally invasive surgery becoming more popular, the efficacy of minimal resections such as segmentectomy and wedge resection is also being readdressed as smaller tumors (<1–2 cm) are being identified with spiral computed tomography (CT) scans. Another critical question is the relationship of tumor size to nodal metastasis. Data have been presented suggesting that histology and size may be beneficial in determining nodal risk. For patients who are medically inoperable, advances in radiotherapy such as three-dimensional (3D) conformal and stereotactic radiosurgery are producing more durable results with decreased toxicity, and five-year survival rates up to 40%. Stage IB–IIIA The results of several large randomized trials of postoperative chemotherapy have been published, but these results differ and are therefore difficult to interpret.

It appears that the weight of evidence indicates that postoperative cisplatin-based chemotherapy improves survival after surgery in patients with stage IB to IIIA NSCLC, resulting in an absolute survival advantage at five years. Similar results have been obtained by Japanese investigators using an oral drug combination of uracil and tegafur (UFT), both in individual trials and when meta-analyses of the results were performed. The results were most impressive in patients with adenocarcinomas. Alternatively, neoadjuvant therapies are increasingly being used. Although large randomized trials investigating this important topic continue to enroll patients, recent experience has indicated that neoadjuvant chemotherapy does not significantly increase surgical morbidity or mortality. For patients with operable stage III (N2) disease, the number of lymph nodes involved and the ability to eradicate tumor from the lymph nodes with neoadjuvant therapy have been found to be important prognostic factors. The pivotal question about the role of surgery in the treatment of stage IIIA (N2) disease is still open and awaits the results from several ongoing trials. As multimodality therapy leads to improved survival for patients with operable NSCLC, an increased frequency of isolated brain metastases has been observed, and the potential value of PCI is being tested in selected subgroups. Inoperable stage III Concurrent chemotherapy/radiotherapy is the standard of care for patients with inoperable stage III NSCLC. However, numerous questions remain regarding the optimal means to combine these two modalities and whether there is a benefit of additional therapy before or after chemotherapy/radiotherapy. Randomized phase II trials with newer cytotoxic agents given with concurrent radiation or trials incorporating an induction or consolidation chemotherapy approach have failed to show median survivals beyond the standard 16–18 months in most instances. Trials evaluating altered radiotherapy fractions have also not improved survival. Important areas of future research include the roles of 3D conformal radiotherapy, intensity-modulated radiotherapy (IMRT), hyperfractionated radiotherapy, and the addition of targeted agents, with several of the latter demonstrating radiosensitization capabilities. Stage IV (and IIIB with pleural effusion) Doublet chemotherapy for stage IIIB with pleural effusion and stage IV NSCLC patients with adequate performance status has been shown in multiple randomized

Summary of treatment 209

studies to improve survival and quality of life, and remains the standard of care. Numerous randomized trials have been performed during the last decade in order to identify the best platinum-based regimen; no major differences have been observed with respect to efficacy – only with regard to toxicity and cost. Current trials have continued to support this finding. Furthermore, randomized trials that included a non-platinum regimen have shown such regimens to be equivalent in efficacy to platinum regimens, but with a more favorable toxicity profile. Controversy continues over the number of cycles of chemotherapy to be administered in the first-line setting. Several guidelines suggest a maximum of six cycles, but there is an accumulation of data indicating that three or four cycles are sufficient. Although numerous phase II cytotoxic regimens have been evaluated, none has produced amazing results. The major focus has therefore switched to targeted therapies. A variety of targeted agents are currently being evaluated. At the forefront of the promising agents are the epidermal growth factor receptor (EGFR) inhibitors, gefitinib (Iressa), erlotinib (Tarceva), and a monoclonal antibody against the vascular endothelial growth factor receptor (VEGFR), bevacizumab (Avastin). Among these, gefitinib and erlotinib have been approved by health authorities in various countries as second- or third-line treatment for NSCLC patients resistant to conventional combination chemotherapy. A host of targeted agents are in earlier stages of clinical evaluation, such as cyclooxygenase-2 (COX-2) inhibitors, the preapototic inhibitor exisulind, proteasome inhibitors, bexarotene (Targretin), and vaccines. Improving upon the efficacy of second-line docetaxel, investigators have focused on the addition of a second cytotoxic agent or on giving taxanes in a weekly schedule. Among the targeted agents, erlotinib has resulted in improved survival and quality of life in a large randomized trial comparing erlotinib with placebo. When added to platinum containing chemotherapy, bevacizumab has also yielded higher response rates, progression-free survival, and median survival in advanced NSCLC, with the majority of patients having adenocarcinoma, and it has recently been approved in the US and in Europe for this group of patients. Several small studies showed a favorable survival improvement for doublet therapy, but further investigation is needed. Pemetrexed (Alimta), a novel multitargeted antifolate, has in a randomized trial resulted in similar reponse rates, median survival, and overall

survival to docetaxel, but toxicity favored the pemetrexed arm, with significantly less neutropenia. For the elderly population or patient with poor performance status, two-drug cytotoxic combinations, single-agent chemotherapy with vinorelbine or gemcitabine, and targeted therapy with gefitinib or erlotinib have proved to be of therapeutic value.

MESOTHELIOMA Surgery should be considered when mesothelioma remains localized, usually as extrapleural pneumonectomy, with excision of the diaphragm and the pericardium en bloc. Palliative local procedures include partial pleurectomy, decortication, or pleurodesis. Chemotherapy and/or radiotherapy have not yet proved to be effective in preventing local recurrence, nor has the use of photodynamic therapy or intracavitary chemotherapy. With respect to chemotherapy, quantitative and qualitative overviews of the literature have suggested that cisplatin may play an important role in combination therapy. It is also emerging that response rates of 30–40% can be obtained when combining cisplatin with other agents, e.g. raltitrexel and pemetrexed. A combination of cisplatin and pemetrexed has in one randomized trial been superior to cisplatin alone, resulting in superior response rate, duration of response, and quality of life.

REFERENCES 1. 2. 3. 4. 5.

6.

7.

8.

Laskin JJ, Sandler AB. State of the art in therapy for non-small cell lung cancer. Cancer Invest 2005; 23: 427–42. Grunenwald DH. The role of surgery in non-small-cell lung cancer. Ann Oncol 2005; 16 (Suppl 2): ii220–2. Buter J, Giaccone G. Medical treatment of non-small-cell lung cancer. Ann Oncol 2005; 16 (Suppl 2): ii229–32. Giaccone G. Twenty-five years of treating advanced NSCLC: what have we achieved? Ann Oncol 2004; 15 (Suppl 4): iv81–3. Movsas B. Will future progress in non-small-cell lung cancer be step by step … or by leaps and bounds? J Clin Oncol 2005; 23: 5859–61. Ceresoli GL, Gridelli C, Santoro A. Multidisciplinary treatment of malignant pleural mesothelioma. The Oncologist 2007; 12: 850–63. Stahel R (ed). Acheving survival improvement in thoracic tumors: from therapeutic strategy management to pharmacogenomics. Lung Cancer 2007; 57: Suppl 2. Lally BE, Urbanic JJ, Blackstock AW et al. Small-cell lung cancer: have we made any progress over the last 25 years? The Oncologist 2007; 12: 1096–1104.

14 Therapeutic bronchoscopy for palliation of lung tumors Peter WA Kunst, Pieter E Postmus, Thomas G Sutedja Contents Introduction • Indications • Techniques to remove endobronchial tumors • Bronchoscopic treatment of extraluminal tumors • General remarks, economic aspects, and recommendations

INTRODUCTION Lung cancer, although rare at the beginning of the 20th century, is currently known to be the most lethal cancer in Western society, and its incidence is rising very fast in the developing countries. All societies with an increase in tobacco consumption will face increasing morbidity and mortality due to their smoking habits, including a steep increase in lung cancer incidence and mortality. The overall progress in therapeutic outcome during the last three to four decades has been small. The large majority of lung cancer patients are still doomed to die of their disease. For the patients with metastatic disease with or without locoregional tumor progression, optimal palliation to improve quality of life (QoL) is the main aim of treatment. This includes relief of symptoms such as shortness of breath, hemoptysis, pain, weight loss, and depression. Several approaches are available to establish temporary relief of symptoms including optimal pain medication, radiotherapy, chemotherapy, bronchodilation, and, in rare cases, even surgical resection. INDICATIONS The clinical tumor classification (TNM) and the patient’s general condition are important factors in the treatment strategy. Improving symptoms in central airway tumors is only meaningful if: • •

•

the larger airways obstructed by tumor are accessible to bronchoscopic instruments; airway collapse due to loss of integrity of the tracheobronchial wall can be prevented, for instance by stenting the airway; additional information on extraluminal disease and/or vascular involvement can be obtained by computed tomography (CT) or endobronchial ultrasonography (EBUS) to get additional information;

•

•

information about the regions with low gas exchange (i.e. after radiation or due to significant peribronchial disease) is taken into account, as these regions will improve little after treatment; a potential interference of immediate action, i.e. stenting and debulking, with additional treatment can be prevented. Such anticipation requires a conscious decision to apply a tailored strategy.1–7

For the majority of patients, relief of dyspnea, hemoptysis, severe cough, or obstructive pneumonia is the major goal. Improvement in gas exchange is the aim of airway reopening. Any bronchoscopic treatment may only enhance the dead-space ventilation if local perfusion is hampered by tumor growth. A disproportionate loss of regional perfusion together with CT findings of extensive peribronchial disease are good indicators for gross extraluminal involvement.8–14

TECHNIQUES TO REMOVE ENDOBRONCHIAL TUMORS Mechanical obstruction removal After the introduction of the most simple example of the rigid bronchoscope by Killian late in the 19th century, new therapies became available. The rigid bronchoscope could be used to core out tumor mechanically to obtain airway patency and immediately improve quality of life. Even after the introduction of the fiberoptic bronchoscopes and videobronchoscopes, the advantages of the rigid bronchoscope for the purpose of obstruction removal are clear. The larger working channel of the rigid scope provides better access, facilitating safer manipulation and the passage of larger instruments such as forceps and large-bore suction tubes to aspirate secretions and blood.9,10 This is a considerably more attractive option to using the fiberoptic scope, in which bleeding is expected and large amounts of tissue or secretions

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need to be evacuated.9,15 The rigid method safeguards better ventilation during the procedure of recanalization and allows additional stenting in the case of extraluminal obstruction to be carried out more easily. The disadvantage of the rigid technique – requirements for expertise, adequate sedation, or general anesthesia – may pose some hurdles. It is therefore important to consider whether interventional pulmonologists should limit their expertise to proficiency with the fiberoptic procedures alone when dealing with imminent suffocation in the worst possible scenario, while the majority of patients are at highest risk from locally advanced cancers that have failed previous conventional treatment modalities. Laser resection Laser is an acronym for light amplification by stimulated emission of radiation. Lasers produce a beam of monochromatic, coherent light that can induce vaporization, coagulation, hemostasis, and necrosis. Several types of lasers [argon, KTP, carbon dioxide (CO2), neodymium:yttrium–aluminium–garnet (Nd: YAG) can be used, depending on the considerations of physics and laser–tissue interaction. The most commonly used lasers are the CO2 laser, which is mainly used for superficial treatment in water-containing tissue, and the Nd: YAG laser, which has a much deeper scattering effect for treating bulky tumor in many oncologic disciplines. The latter has been the main choice to obtain a much greater penetration due to the deep scattering of 1064 nm wavelength light by tissue containing hemoglobin, hence its superior coagulative properties. The enormous heat-sink effect leads to obtaining late necrosis at a depth which cannot be determined, hence the use of a red pilot light and forward firing. In 1976 the first report on endobronchial use of a laser to vaporize the obstructing tumor was published by Laforet et al.16 Afterwards the use of lasers became popular, especially in the USA, because of an excellent promotion campaign by equipment manufacturers.17 Cavaliere and co-workers showed the benefits of the procedure in more than 2000 patients with over 90% immediate recanalization after treating obstruction in the main bronchi or trachea. The overall mortality is lower than 0.5%.18,19 Serious complications, which occur in less than 3% of all patients, are hemorrhage, pneumothorax, and cardiorespiratory failure over time. These are due to the profound heat transfer into tissue from the laser beam, which causes necrosis deep beyond

the surface of impact. Awareness of the anatomic relationship within the mediastinal organs is therefore necessary. The uncontrolled application of high power can lead to disastrous effects, such as perforation of the bronchial wall and too-extensive necrosis, because the depth effect of the Nd: Yag laser is not always immediately apparent. Therefore it is necessary to know the extent of the endobronchial mass to define the treatment area. Bronchography has been used prior to treatment to assess the length of the bronchial obstruction.20,21 Nowadays, CT scanning or EBUS might be useful for defining the extent of the endobronchial and peribronchial mass.22,23 A large observational study of the value of EBUS in therapeutic bronchoscopy showed that EBUS guided or changed therapy significantly in 43% of cases. Changes included adjustment of stent dimensions, termination of tumor debridement when nearing vessels, and referral for surgical interventions rather than endoscopic treatment.23 Electrocautery and argon plasma coagulation Electrocautery (EC) and argon plasma coagulation (APC) are the use of local heat application with probes that conduct electrons toward the target tissue (tissue welding). An alternating electrical current conduit is used to prevent neural and muscular responses. Many cheap, reusable applicators are available. Electrocautery and APC are other ‘hot’ alternatives to Nd:YAG.24 Although the costs of the EC and APC technique are far lower than for Nd:YAG, it has not become very popular in the USA, apparently without any obvious reason since the results are more or less comparable to the Nd:YAG laser and APC is superior in obtaining hemostasis of large mucosal hemorrhagic surfaces.25 The technique is simply based on the use of electrons to produce heat in the target tissue while the equipment is a standard facility in every operating theatre. An applicator or probe is needed which can be passed through the working channels of the rigid or flexible bronchoscope. This technique has a lower risk of airway perforation due to the superficial effects of electrons as they dissipate easily in tissue. APC uses ionized argon gas for the non-contact mode of tissue spraying conduit, which can superficially coagulate large hemorrhagic surfaces in a matter of seconds. Electrons always seek the pathway of least resistance; coagulation can be limited to a depth of only a few millimeters by choosing an appropriate energy setting. This self-limiting effect is especially exploited in APC, as the ionized argon gas deviates electrons towards the area of least resistance,

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i.e. hemorrhagic wet surfaces, and away from crusted, already treated, tissue. APC has been used in surgery for more than 20 years, particularly for the hemostasis of superficial bleeding. Although APC has become well established in gastrointestinal endoscopy since its introduction in 1991, very few reports of its use in bronchoscopy exist. Reichle et al showed that recanalization of malignant airway stenoses had good results in 67% of patients. Despite less penetration compared with the Nd:YAG laser, extensive bronchial tumors were treatable, and coagulated tumor fractions were removed either with forceps or the rigid bronchoscope tip.25 The second indication was bleeding in the central airways; good hemostasis was achieved in over 98% of patients.25 No head to head comparison of Nd:YAG laser and EC or APC has been done; from several phase II type studies the results seem to be more or less comparable. The estimated incidence of clinically significant bleeding in patients treated with EC is 2.5%.26 The most important advantage is the fact that, with EC and APC, the immediate coagulative effect is clearly visible and matches the histologic depth of necrosis – the principle of ‘you immediately see what you get’. Too much heat, however, can lead to extensive scarring. Cryotherapy Cryotherapy is repetitive rapid cooling (Jules Thompson effect) and spontaneous thawing of the target tissue, using liquid gas and specially designed flexible applicators to crystallize the cellular contents of the target tissue, causing late necrosis.27–31 The ultimate effect is caused by delayed disintegration of water-containing tissue. Thawing restores circulation, hence this technique is not suitable for quick palliation of a hemorrhagic mass, despite sparing cryoresistant cartilage and fibrous tissue. The simple equipment, reusable applicator, and easy principles are clear advantages. In a report by Forest et al,28 necrosis was found near the cryoprobe impact site and was maximal two hours after treatment; a second peak was observed after four days. Around this central necrotic area, apoptotic cells were found. Apoptosis was maximal after eight hours. Thus a second bronchoscopy is necessary to remove slough. No large series on local treatment with cryotherapy for early stage lung cancer are available in the literature; only a few reports have shown good results (complete response) when used for palliation.29,30 In a study in which patients with an obstructive tumor were treated with cryotherapy followed by irradiation, no sign of residual tumor was found in 17 of 26 patients.30

Endobronchial brachytherapy Brachytherapy comprises intraluminal irradiation of a tumor area within the tracheobronchial tree by means of a catheter. The catheter is connected to an afterloading device that transports the tiny radioactive source, iridium-192, to preprogrammed positions during the session, in a step wise fashion, according to precalculated volume dosimetry. Accurate sausagelike dosimetry with rapid fall-off towards the periphery is theoretically attractive. However, a tumor is not perfectly oval in shape, with the irregular extensions to smaller bronchi, while delivery of an accurate dose to the target volume is hampered by the patient’s breathing and cough, which may lead to movement of the catheter, despite the short (10–15 minutes) duration. Irradiation damages all tissue. Data from good randomized trials are available.32–35 Fractionated external radiotherapy is preferred over brachytherapy as an initial treatment in better performing patients because it provides better overall and more sustained palliation, with fewer retreatments and a modest gain in survival time.32 However, when both techniques are combined it increases local control,33 especially in the cohort of squamous cell cancer, in alleviating symptoms caused by local tumor recurrence,34 and provides higher rates of re-expansion of collapsed lung, resulting in (transient) lower levels of dyspnea. However, this beneficial effect was only observed among patients with obstructing tumors in the central airways.35 Elusive accuracy in dosimetry, expensive equipment, need for repeated doses and non-selective damage causing radiation stenosis, fibrosis, and late fatal hemorrhages or bronchial fistula are disadvantages.36,37 Photodynamic therapy Photodynamic therapy (PDT) is bronchoscopic illumination of tissue containing photosensitizers to initiate a photochemical cascade reaction due to the formation of oxygen radicals.12,38 Although photosensitizer molecules are selectively retained in the target tissue after injection, in vivo and histologic studies do not show selective tumor damage which may lead to deep eschar formation and extensive fibrosis. The degree of intra- and extraluminal tumor mass and tumor location may limit the efficacy of PDT, since optimal or homogeneous illumination is difficult to achieve.39,40 Cautious interpretation of apparent complete response by bronchoscopy is advocated since residual tumor might be present by microscopic evaluation. A cure cannot be expected in patients with tumor infiltration of the cartilage and bronchial

Mechanical crushing Iatrogenic foreign body Efer–Dumon set + various stents

Hemostasis

Equipment

Disadvantages

Lifesaving!

Outward displacement High expertise Outward displacement

Teams’ expertise for emergency Extraluminal only alternative!

Result

Performance Tissue damage

Mechanism

Indication

Logistics

Stent

Electrocautery and argon plasma coagulation

Cryotherapy

Photodynamic therapy

Brachytherapy

Special laser Standard facility and Liquid coolant Special laser and Special radiation requirements applicators with applicators requirements facility Intraluminal only, with different depth necrosis depending on each mechanism and technical application with or without dosimetric calculations; deep dosimetry in non-selective technique causes damage to the normal tissue surroundings of the central airways including the tracheobronchial wall! Extreme heat Shallow heat Rapid cooling Formation of Ionizing radiation transfer transfer slow thawing oxygen radicals High expertise Easy Easy Complex process Complex process Profound Superficial Crystallization Thrombosis and Structural damage carbonization coagulation of watery tissue secondary hypoxic necrosis Immediate, Immediately Hours–days + Hours–days + Days to weeks; invisible depth visible depth secondary secondary necrosis non-selective necrosis Profound Superficial Vascular Primary vascular Systemic vascular coagulation coagulation disruption! thrombosis disruption Burn, explosion, Superficial Delayed effect Prolonged skin Fibrosis, stenosis, and perforation scarring photosensitivity and hemorrhage Expensive Standard Liquid Special laser + special Expensive laser + laser facility + cheap coolant + applicators fibers + sensitizers! radiation facility fiber probes

Laser (Nd:YAG)

Table 14.1 Advantages and disadvantages of each technique for palliative treatment of tumor blockage in the central airways

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Table 14.2 Results of large series regarding palliative bronchoscopic treatment Technique

Results

Complications

Remarks

Stent (Dumon4)

1574 prostheses (1058 patients)

Tracheal 54%; LMB 21%; RMB 18%

Migration 9.5%; granuloma 7.9%; obstruction 3.6%

Nd:YAG (Cavaliere19)

2610 resections (1838 patients)

93% good results

60 cases (0.3%); mortality 0.4%

Elecrocautery (Sutedja24)

56

39/56 (70%) complete

1 bleeding 3.7%

Argon plasma (Reichle25) Cryotherapy (Maiwand30) PDT (review Moghissi38) HDR Brachytherapy (Speiser60)

364 (482 sessions)

67% good result

153

Dyspnea 64%; hemostasis 93% CR >70%

11 patients (7.2%)

Average time stent will be in place minimum 4 months maximum 4.7 years Mortality due to cardiovascular and respiratory problems Non-responders; extraluminal disease Excellent hemostasis No mortality

295

80% recanalization

Fatal bleeding 7%; stenosis 11%

ERT 60 Gy vs + HDR 2 × 4.8 Gy (Huber33)

Randomized 42 vs 56

Med. survival similar 28 vs 27 weeks!

Fatal bleeding 14.2%!

636

muscular layer.41–43 Secondary necrosis, due to tumor hypoxia, and fibrin plug formation make it necessary to perform a ‘clean-up’ bronchoscopy to prevent respiratory failure. Due to skin photosensitivity, which may occur in 20–40% of patients, although not leading to irreversible skin damage,44 new photosensitizers are sought.45 Fatal bleeding after PDT has been reported.44,46 As the PDT effect is known to be mainly vascular, caution is necessary in treating tumors close to large vessels. Cell culture studies and animal studies indicate a possible synergistic effect of combining PDT with ionizing radiation. One randomized study in a limited number of patients reported the benefit of PDT additional to external radiotherapy, with regard to quality of life and physiologic scores. PDT plus external radiotherapy provided a better and more durable local control compared to external radiotherapy alone.47

Various: non-fatal

Up to 28% skin photosensitivity No different effect of dose fractions, ND:YAG precanalizing procedures Squamous cell cohort 7 weeks longer median survival

Another study assessed the safety and effectiveness of combined brachytherapy and PDT in patients with bulky endobronchial lung cancer. Thirty-two patients were treated; tumors were extensive, with lengths ranging from 10 to 60 mm along the bronchus and estimated volumes ranging from 40 to 3500 mm3. At a mean follow-up of 24 months, 26 patients were free of residual tumor and local recurrence.48

BRONCHOSCOPIC TREATMENT OF EXTRALUMINAL TUMORS Stenting Stenting is the insertion of tailored endoprostheses to recanalize large airways and restore airway patency. It is the only possible solution for obstruction caused by extraluminal tumor compression. Since 1965,

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with the introduction of the Montgomery tube, many different kinds of stents have been developed.49 However, despite many improvements the optimal stent is still being sought. Nowadays there are rigid and flexible stents, made of different materials. The main point of consideration is the anatomic size of the airways and the cause of the limited airway patency. In benign disease a silicone stent is definitely preferred over a metallic one, whereas in malignant disease no stent is in favor.50–54 Depending on the position of the compression, either a Y-shaped stent or a normal one can be inserted. The second goal of stenting could be considered to be the sealing of fistulas between the respiratory tract and the digestive tract.55,56 The best way to introduce a stent is still by the rigid bronchoscope, although some stents can be inserted by the flexible scope. The literature has shown that stenting improves QoL and has a good acceptance and tolerance.57,58 Stent insertion can be simple; however dealing with the complications such as migration, perforation, granuloma, and infection can be a great challenge, and requires a certain level of expertise of the team.

GENERAL REMARKS, ECONOMIC ASPECTS, AND RECOMMENDATIONS Current bronchoscopic techniques provide the bronchoscopist with alternatives for local palliation. Each technique has its own merits and limitations. Treatment choice is based upon the following: clinical presentation, the experience and skill of the bronchoscopist, the availability of additional techniques, anesthetic care, intensive care for the post-treatment period, and technical support in the hospital. Economic aspects may further influence the choice. When the indications have been properly assessed, any of the treatments can be equally successful in dealing with an emergency situation, when a technique is chosen to immediately relieve the symptoms (Tables 14.1 and 14.2). as long as the bronchoscopist is aware of the limitations and dangers of each approach and is confident about the benefit of treatment. The frequent occurrence of emergency situations in patients with a poor prognosis makes it impossible, and maybe even unethical, to perform a randomized study to look for the best palliative technique. The population at risk is not homogeneous and the follow-up period might be expected to be relatively short. Many patients will die due to disease progression outside the treatment area. So the question about the best palliative

technique is and remains academic. However, what technique to use depends first on the availability in the center, second on the expertise with the technique, and third, on the oncology principle (curative vs palliative). Although some techniques might appear simple, it might be wise to concentrate a particular procedure in a limited number of centers, in order to minimize the complications, improve treatment of the complications, and to have a better local control or cancer-specific survival. The latter has never been proven for endobronchial therapy, but from other studies we know that the outcomes that measure tumour control relate to the surgeon’s expertise.59

REFERENCES 1. Bolliger CT, Mathur PN, Beamis JF et al. European Respiratory Society/American Thoracic Society. ERS/ATS statement on interventional pulmonology. European Respiratory Society/American Thoracic Society. Eur Resp J 2002; 19: 356–73. 2. Mathur PN, Edell E, Sutedja G et al. Treatment of early stage non-small cell lung cancer. American College of Chest Physicians. Chest 2003; 123 (1 Suppl): 176–80S. 3. Bolliger CT, Mathur PN, eds. Interventional Bronchoscopy. Progress in Respiratory Research, Vol 30. Basel, Switzerland: Karger Publishers, 2000. 4. Dumon MC, Dumon JF, Perrin C et al. Silicone tracheobronchial endoprosthesis. Rev Mal Resp 1999; 16: 641–51. 5. Freitag L. Tracheobronchial stents. In: Bolliger CT, Mathar PN, eds. Interventional Bronchoscopy. Progress in Respiratory Research, 1999: Vol. 30. 171–86. 6. Cortese DA, Edell ES, Kinsey JH. Photodynamic therapy of early stage squamous cell carcinoma of the lung. Mayo Clin Proc 1997; 72: 595–602. 7. Ikeda S. Atlas of Early Cancer of Major Bronchi. Tokyo: Igakushoin publisher, 1976. 8. Lam S, Muller NL, Miller RR et al. Laser treatment of obstructive endobronchial tumours: factors which determine response. Lasers Surg Med 1987; 7: 29–35. 9. Miller JI Jr. Rigid bronchoscopy. Chest Surg Clin North Am 1996; 6: 161–7. 10. Mathisen DJ, Grillo HC. Endoscopic relief of malignant airway obstruction. Ann Thorac Surg 1989; 48: 469–73. 11. Mehta AC, Livingstone DR. Biopsy excision through a fiberoptic bronchoscope in the palliative management of airway obstruction. Chest 1987; 91: 774–5. 12. Petrou M, Kaplan D, Goldstraw P. Bronchoscopic diathermy resection and stent insertion: a cost effective treatment for tracheobronchial obstruction. Thorax 1993; 48: 1156–9. 13. Dumon JF, Shapsay S, Bourceraou J et al. Principles for safety in application of neodymium YAG laser in bronchology. Chest 1984; 86: 163–8. 14. Dumon JF. A dedicated tracheobronchial stent. Chest 1990; 97: 328–32. 15. Mathisen DJ, Grillo HC. Endoscopic relief of malignant airway obstruction. Ann Thorac Surg 1989; 48: 469–73.

216 Textbook of Lung Cancer 16. Laforet EG, Berger RL, Vaughan CW. Carcinoma obstructing the trachea. Treatment by laser resection. N Engl J Med 1976; 294: 941. 17. Hooper RG. Electrocautery in endobronchial therapy. Chest 2000; 117: 1820. 18. Personne C, Colchen A, Leroy M et al. Indication and technique for YAG laser resection in bronchology: a critical analysis based on 2,285 resections. J Thorac Cardiovasc Surg 1986; 91: 710–15. 19. Cavaliere S, Venuta F, Foccoli P et al. Endoscopic treatment of malignant airway obstruction in 2,008 patients. Chest 1996; 110: 1536–42. 20. George PJ, Pearson MC, Edwards D et al. Bronchography in the assessment of patients with lung collapse for endoscopic laser therapy. Thorax 1990; 45: 503–8. 21. Joyner LR, Maran AG, Sarama R, Yakaboski A. NeodyniumYAG laser treatment of intraluminal lesions. A new mapping technique via the flexible fiberoptic bronchoscope. Chest 1985; 87: 419–27. 22. Herth F, Ernst A, Schulz M, Becker H. Endobronchial ultrasound reliably differentiates between airway infiltration and compression by tumor. Chest 2003; 123: 458–62. 23. Herth F, Becker HD, LoCicero J 3rd et al. Endobronchial ultrasound in therapeutic bronchoscopy. Eur Resp J 2002; 20: 118–21. 24. Sutedja T, van Boxem TJ, Schramel FM et al. Endobronchial electrocautery is an excellent alternative for Nd-YAG laser to treat airway tumors. J Bronchol 1997; 4: 101–5. 25. Reichle G, Freitag L, Kulleman HJ et al. Argon plasma coagulation in bronchology: a new method – alternative or complementary? Pneumologie 2000; 54: 508–16. 26. Homasson JP. Endobronchial electrocautery. Semin Resp Crit Care Med 1997; 18: 535–43. 27. Deygas N, Froudarakis M, Ozenne G et al. Cryotherapy in early superficial bronchogenic carcinoma. Chest 2001; 120: 26–31. 28. Forest V, Peoc´h M, Campos L et al. Effects of cryotherapy or chemotherapy on apoptosis in a non small cell lung cancer xenografted into SCID mice. Cryobiology 2005; 50: 29–37. 29. Vergnon JM, Schmitt T, Alamarine E et al. Initial combined cryotherapy and irradiation for unresectable non-small cell lung cancer. Preliminary results. Chest 1992; 102: 1436–40. 30. Maiwand MO. The role of cryosurgery in palliation of tracheobronchial carcinoma. Eur J Cardiothorac Surg 1999; 15: 764–8. 31. Maiwand MO, Evans JM, Beeson HE. The application of cryosurgery in the treatment of lung cancer. Cryobiology 2004; 48: 55–61. 32. Stout R, Barber P, Burt P, Hopwood P et al. 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 2000; 56: 323–7. 33. Huber RM, Fischer R, Hautmann H et al. Does additional brachytherapy improve the effect of external radiation? A prospective, randomized study in central lung tumors. Int J Radiat Oncol Biol Phys 1997; 38: 533–40. 34. Taulelle M, Chauvet B, Vincent P et al. High dose rate endobronchial brachytherapy: results and complications in 189 patients. Eur Resp J 1998; 11: 162–8.

35. Langendijk H, de Jong J, Tjwa M et al. External irradiation versus external irradiation plus endobronchial brachytherapy in operable non-small cell lung cancer: a prospective randomized study. Radiother Oncol 2001; 58: 257–68. 36. Sutedja G, Baris G, Schaake-Koning C, van Zandwijk N. High dose rate brachytherapy in patients with local recurrences after radiotherapy of non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1992; 24: 551–3. 37. Khanavkar B, Stern P, Alberti W, Nakhosteen JA. Complications associated with brachytherapy alone or with laser in lung cancer. Chest 1991; 99: 1062–5. 38. Moghissi K, Dixon K. Is bronchoscopic photodynamic therapy a therapeutic option in lung cancer. Eur Resp J 2003; 22: 535–41. 39. Sutedja G, Lam S, LeRiche JC et al. Response and pattern of failure after photodynamic therapy for intraluminal stage I lung cancer. J Bronchol 1994; 1: 295–8. 40. Okunaka T, Kato H, Konaka C et al. Photodynamic therapy for multiple primary bronchogenic carcinoma. Cancer 1991; 68: 253–8. 41. Hayata Y, Kato H, Konaka C et al. Hematoporphyrin derivative and laser photoradiation in the treatment of lung cancer. Chest 1982; 82: 269–77. 42. Hayata Y, Kato H, Konaka C et al. Photoradiation therapy with hematoporphyrin derivative in early and stage I lung cancer. Chest 1984; 86: 169–77. 43. Balchum OJ, Doiron DR, Huth GC et al. Photoradiation therapy of endobronchial lung cancer. Large obstructing tumours, non-obstructing tumours and early stage bronchial cancer lesions. Clin Chest Med 1985; 6: 255–75. 44. Dougherty TJ, Cooper MT, Mang TS. Cutaneous phototoxic occurrences in patients receiving Photofrin. Lasers Surg Med 1990; 10: 485–8. 45. Canete M, Ortega C, Gavalda A et al. Necrotic cell death induced by photodynamic treatment of human lung adenocarcinoma A-549 cells with palladium (II)-tetraphenylporphycene. Int J Oncol 2004; 24: 1221–8. 46. Sutedja G, Baas P, Stewart F et al. A pilot study of photodynamic therapy in patients with inoperable non-small cell lung cancer. Eur J Cancer 1992; 28a: 1370–3. 47. Lam S, Kostashuk EC, Coy P. A randomized comparative study of the safety and efficacy of photodynamic therapy using Photofrin II combined with palliative radiotherapy versus palliative radiotherapy alone in patients with inoperable obstructive bronchogenic carcinoma. Photochem Photobiol 1987; 46: 893–7. 48. Freitag L, Ernst A, Tomas M et al. Sequential photodynamic therapy (PDT) and high dose brachytherapy for endobronchial tumour control in patients with limited bronchogenic carcinoma. Thorax 2004; 59: 790–3. 49. Montgomery WW. T-tube tracheal stent. Arch Otolaryngol 1965; 82: 320–1. 50. Bolliger CT. Airway stents. Semin Resp Crit Care Med 1997; 18: 563–770. 51. Dumon JF. A dedicated tracheobronchial stent. Chest 1990; 97: 328–32. 52. Freitag L, Eicker R, Linz B et al. Theoretical and experimental basis for the development of a dynamic airway stent. Eur Resp J 1994; 4: 2038–45. 53. Bolliger CT, Probst R, Tschopp K et al. Silicone stent in the management of inoperable tracheobronchial stenoses. Indications and limitations. Chest 1993; 104: 1653–9.

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54. Colt HG, Dumon JF. Airway stents: present and future. Clin Chest Med 1995; 16: 465–78. 55. Kishi K, Nakao T, Goto H et al. A fast placement technique for covered tracheobronchial stents in patients with complicated esophagorespiratory fistulas. Cardiovasc Intervent Radiol 2005; 12: 485–9. 56. Colt HG, Meric B, Dumon JF. Double stents for carcinoma of the esophagus invading the tracheobronchial tree. Gastrointest Endosc 1992; 38: 485–9. 57. Vonk-Noordegraaf A, Postmus PE, Sutedja TG. Tracheobronchial stenting in the terminal care of cancer patients

with central airways obstruction. Chest 2001; 120: 1811–14. 58. Vergnon JM, Costes F, Bayon MC et al. Efficacy of tracheal and bronchial stent placement on respiratory functional tests. Chest 1995; 107: 741–6. 59. Hoghson DC, Fuchs S, Ayanian JZ. Impact of patient and provider characteristics on the treatment and outcomes of colorectal cancer. J Natl Cancer Inst 2001; 93: 501–15. 60. Speiser BL, Spratling L. Remote after-loading brachy therapy for the local control of endobronchial carcinoma. Int J Radiat Oncol Biol Phys 1993; 25(4): 579–87.

15 Complications of lung cancer Vincenzo Minotti, Michele Montedoro, Maurizio Tonato Contents Introduction • Infections • Major hemoptysis • Chest pain • Pleural effusion • Superior vena cava syndrome • Cardiac tamponade • Extrathoracic complications • Paraneoplastic syndromes

INTRODUCTION The majority of patients with lung cancer will have troublesome symptoms at some time during the course of their disease due to the disease itself or its complications. Complications in lung cancer patients depend on the location of the tumor, its locoregional spread, and the presence of metastatic growth. Moreover, lung cancer, especially small cell lung cancer (SCLC), is associated with paraneoplastic syndromes more frequently than any other type of cancer is. Clinicians must keep in mind the most frequent complications of lung cancer, since a timely diagnosis and adequate treatment are essential in order to ameliorate symptoms. Although a multitude of signs and symptoms may be manifested by patients with lung cancer, the focus of this chapter will be on the more frequent and severe complications due to intrathoracic growth of tumor and to remote effects that are not related to direct invasion or metastasis (Table 15.1).

INFECTIONS Pulmonary infections frequently complicate the course of patients with lung cancer, and are often the direct cause of death. Infections can be present at the time of cancer diagnosis, complicate the treatment course, and result in death. Causes of infection include bronchial obstruction, aspiration, immunosuppression from radiation and/or chemotherapy, disruption of local host defenses due to tumor invasion, and necrosis of both normal and tumor tissue. To determine the causes of infection, Nagata and colleagues1 reviewed the case records and autopsy data of 304 patients who died of lung cancer. They showed that the local and systemic effects of the lung cancer itself were probably more important than either antineoplastic agents or cortico-

steroids in predisposing the patient to bacterial infections. Perlin and colleagues2 reviewed retrospectively a cohort of 121 lung cancer patients in an attempt to identify the frequency of infection and to determine its impact on the survival of those patients. Infections were documented in 85 patients (70%); the most common organisms were streptococci, Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter aerogenes, and Pseudomonas aeruginosa. The median survival of all infected patients was 4.2 months, which was significantly shorter than that of uninfected patients, who had a median survival of 12.9 months. In the only prospective study done to date, involving 96 consecutive lung cancer patients at diagnosis, Putinati and colleagues3 reported an incidence of secondary respiratory infections in 33 patients (34%). Major pathogens responsible for infection were Haemophilus spp., S. aureus, and P. aeruginosa. In a review, Berghmans et al4 reported 435 episodes of fever and/or infection occurring in 275 patients with lung cancer. The majority of infections involved the upper and lower respiratory tract (56%). Pulmonary infections depend on the particular pattern of growth of the lung cancer. Centrally located tumors produce airway obstruction, which may cause an obstructive pneumonitis, while peripheral large tumor masses occasionally cavitate and present as malignant abscesses. Such patients suffer from typical symptoms of pneumonia, including fever, chills, and a productive cough with streaky hemoptysis. Non-small cell lung cancer (NSCLC), particularly squamous cell carcinoma, may present with a shaggy cavitary opacity, indistinguishable from a conventional anaerobic lung abscess on chest radiograph. Extensive central necrosis is responsible for the cavitary appearance. Several clinical clues may suggest the presence of cancer, including persistent hemoptysis, relative absence of fever and leukocytosis, and radiographic location in a region of the lung with minimal surrounding pneumonitis. A rare and

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Table 15.1 Most frequent and severe complications of lung cancer

• • • • • • • •

Infections Major hemoptysis Chest pain Pleural effusion Superior vena cava syndrome Cardiac tamponade Paraneoplastic syndromes Extrathoracic complications (brain metastases, spinal cord compression)

severe complication of lung cancer is the formation of a tracheo- or broncho-esophageal fistula, which can manifest by paroxysmal violent cough after meals and recurrent aspiration pneumonia. Bronchoscopy is useful to establish a microbiologic diagnosis5 and to search for an underlying lung cancer in patients with atypical resolution of pneumonia by chest radiography. For example, in a study of 115 cases with a clinical profile of chronic bacterial pneumonia, bronchoscopy disclosed newly diagnosed NSCLC in 14% of cases.6 Identification of a definitive etiologic agent is of great importance for rational antimicrobial treatment of pulmonary infections. Because infecting flora can include aerobic Gram − and Gram + species as well as anaerobes, broad-spectrum antimicrobial therapy is warranted, as for postobstructive and aspiration pneumonias, but the duration is typically prolonged (weeks to months).7 Endobronchial obstruction with distal uncontrolled pneumonia or a lung abscess can be treated by endoscopic removal of tumor with laser or, in the case of an abscess, by percutaneous or bronchoscopic drainage of the abscess.

MAJOR HEMOPTYSIS Hemoptysis is the presenting symptom in 7 to 10% of patients with lung cancer. Approximately 20% will have hemoptysis some time during their clinical course. However, massive hemoptysis is a rare event, with 3% having terminal massive hemoptysis. Most patients experience blood-streaked sputum. Santiago and colleagues8 reviewed the records of 264 patients who underwent bronchoscopy for unexplained hemoptysis in order to determine its causes. Bronchogenic carcinoma was the most common cause, accounting for 29%

of the cases. The diagnosis of bronchogenic carcinoma was established endoscopicalIy in 65 (82%) of 78 patients. Four patients with carcinoma had normal chest radiographs. These four patients had centrally located lesions that were diagnosed endoscopicalIy. Massive hemoptysis is arbitrarily defined as expectoration of at least 100 to 600 ml of blood in a 24-hour period, or intrabronchial bleeding at such a rate as to present a threat to life.9 Massive hemoptysis due to lung cancer has a much poorer prognosis than hemoptysis of other etiologies. The mortality of massive hemoptysis may be as high as 59 to 100% in patients with bronchogenic carcinoma.10 Death from hemoptysis is usually attributed to asphyxia rather than to exsanguination. This horrific complication is associated more frequently with central squamous cell carcinoma. These tumors tend to be large and angioinvasive, and to undergo spontaneous necrosis and cavitation. Hemoptysis results from necrosis and destruction of lung parenchymal support for vessels, as well as from neovascularization of the tumor. The initial priority of therapy is to maintain the airway to optimize oxygenation and to stabilize the hemodynamic status.11 Clinically stable patients should be positioned with the bleeding side in a dependent position, to reduce aspiration of blood into the contralateral lung. Supplemental oxygen, sedatives, bed rest, mild cough suppression, and avoidance of excessive thoracic manipulation are helpful. Traditionally, a rigid rather than a flexible bronchoscope is generally preferred with massive bleeding, when the need to remove large clots is anticipated. Because of its larger diameter, a rigid bronchoscope is particularly effective in suctioning, oxygen administration, and airway control. Usually the airway can be protected from blood aspiration by inflating a Fogarty balloon catheter proximal to the bleeding site. The balloon can be left in place while the patient is stabilized and considered for additional therapy. Another approach to protect functional airways involves placing a special endotracheal tube with inflatable distal cuff into the non-bleeding right or left main stem bronchus. The use of a double-lumen tube permits adequate suctioning of blood. However, placement of the tube requires experienced personnel. Urgent surgical intervention should be considered when bleeding is associated with persistent hemodynamic and respiratory failure. In patients who are not candidates for surgery because of severe prognosis, extensive disease, co-morbid conditions, prior pulmonary resection or inadequate pulmonary reserve (predicted postoperative FEV1 less

220 Textbook of Lung Cancer

than 0.8–1l), several non-operative techniques have been reported to control massive hemoptysis. Prolonged tamponade with a Fogarty balloon catheter, ice-saline lavage, and arteriography with therapeutic embolization of bronchial arteries have been reported to be successful in controlling bleeding. However, no prospective comparative trials have been conducted on the efficacy of these various techniques, and it is well known that conservative non-surgical management of massive hemoptysis carries a high mortality rate. Radiation therapy (endobronchial or external beam) and laser therapy may be useful in controlling bleeding lung tumors. Palliative management should also be aimed at reducing awareness and fear. A combination of a parenterally administered strong opioid and a benzodiazepine is usually required.

CHEST PAIN Pain is a significant problem in cancer patients in general and lung cancer patients in particular. Chest pain is reported at presentation in one-quarter to one-half of patients with lung cancer,12 and usually arises via direct invasion or metastatic involvement of pain-sensitive intrathoracic structures (mediastinum, pleura, or chest wall). Marino and colleagues13 reported early thoracic pain in 40% of 164 patients with lung cancer without extrathoracic or distant metastasis. Pain was present on the side of the neoplasm in 80% of the patients.13 Peripheral tumor invading the costal parietal pleura and chest wall gives rise to sharp, intermittent, pleuritic pain. This type of pain may also be caused by obstructive pneumonitis or associated pulmonary embolus.

Brachial plexus (arm and shoulder pain) Sympathetic trunk] (Horner’s syndrome) Subclavian artery and vein

Other patients suffer from a poorly localized, vague, persistent discomfort, sometimes associated with central tumors with mediastinal extension and possible involvement of perivascular and peribronchial nerves. It is important to distinguish the chest pain that accompanies direct contiguous chest wall extension from rib metastases. A characteristic pain syndrome is caused by local extension of an apical lung tumor at the superior thoracic inlet. Such a tumor is called a superior pulmonary sulcus tumor, and the associated pain is known as Pancoast’s syndrome (Figure 15.1). The most common initial symptom is shoulder pain, produced by neoplastic involvement of the brachial plexus, parietal pleura, endothoracic fascia, vertebral bodies, and first, second and third ribs.14 The pain is often severe and unrelenting; while initially confined to the shoulder and scapula, it later radiates down the arm, following an ulnar distribution, reflecting involvement of the C8 and T1 nerve roots. Pulmonary symptoms and signs are conspicuously absent, while arm weakness signifies advanced brachial plexus invasion. With further extension through the intervertebral foramina in 5% of patients initially, but in as many as 25% later in the course of the disease, compression of the spinal cord and paraplegia may result.15 The majority of cases of Pancoast’s syndrome are caused by NSCLC, most commonly squamous, followed by adenocarcinoma and large cell carcinoma. SCLC is only rarely associated with this syndrome. Although in the past a histologic diagnosis was not considered necessary before therapy, the wide variety of diseases that can result in Pancoast’s syndrome (other primary thoracic neoplasms, metastatic and hematologic

Vertebral body Vagus nerve Recurrent nerve (vocal cord paralysis) T4 A tumor of any size with invasion of the mediastinum, or involving heart, great vessels, trachea, (a) esophagus, (b) vertebral body or carina or presence of malignant pleural effusion

Figure 15.1 Schematic of International Staging System definitions for superior sulcus tumors, including Pancoast’s syndrome. (Reproduced with permission from Mountain CF. A new international staging system for lung cancer. Chest 1986; 89: 225S).

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neoplasms, infectious processes, neurogenic thoracic outlet syndrome) now mandates a conclusive diagnosis before definitive treatment is started. The chest radiograph may show an obvious apical mass, but frequently only a subtle increase in density is visible at the apex, and is often missed. Magnetic resonance imaging (MRI) has become the diagnostic modality of choice, because of its superiority to CT in delineating tumor extension to vascular and neural structures, vertebrae, and the spinal canal. Therapeutic modalities for superior sulcus tumors involve combinations of preoperative, intraoperative, and postoperative radiotherapy, and either surgery or radiotherapy alone. Surgical resection after preoperative radiotherapy has been the most common treatment of superior sulcus tumors. However, there is no conclusive scientific evidence to recommend the standard use of preoperative radiotherapy for such tumors. Proponents of these treatment modalities based their recommendations on retrospective data. Standard resection is usually performed by en bloc resection of the tumor, generally by lobectomy, including chest wall, and may also be accompanied by resection of the involved paravertebral sympathetic chain, stellate ganglion, lower trunks of the brachial plexus, and, in some cases, the subclavian artery and portions of the thoracic vertebrae. Contraindications to surgical treatment include extensive involvement of the brachial plexus and paraspinal region, especially the intervertebral foramina, bodies, and laminae of the vertebrae. Radiotherapy at doses of at least 60 Gy (dose range 20–70 Gy) can be used alone as a primary treatment, especially for inoperable superior sulcus tumors, palliating pain in up to 90% of patients.16 The role of intraoperative and postoperative radiotherapy is unclear at present, and they should be used mainly in patients who are found to have unresectable tumors after a surgical attempt.17 Recently, induction chemoradiotherapy has been reported to enhance complete resection rates and improve survival compared with historical controls and is likely to become the new standard treatment for localized superior sulcus tumors.18 Clinical factors associated with improved survival include good performance status, a weight loss of less than 5% of total body weight, and achievement of local control and pain relief after treatment.19 Standard pain management techniques, including stepwise analgesics and radiation therapy, are usually effective in controlling pain initially in many patients. Some patients may require additional measures, including nerve blocks, spinal analgesia, or even palliative surgery.

PLEURAL EFFUSION Approximately 25% of patients with lung carcinoma develop a malignant effusion during the course of their disease. Impaired drainage from the pleural space is the predominant mechanism for the accumulation of fluid associated with malignancy. Tumor cells either seed the mesothelial surface or invade the subserous layer. When the mesothelial surface is involved, tumor cells are abundant in pleural fluid; with subserous involvement, only a few malignant cells are exfoliated into the pleural space. Peripheral tumors, most commonly adenocarcinomas, may directly seed the pleural space. Patients usually present symptoms that compromise their quality of life, including progressive dyspnea, cough, and/or chest pain.20 Symptoms appear to be closely related to the rate of pleural fluid accumulation rather than to the total volume. Accompanying fever is usually a sign of atelectasis and infection. About one-quarter of patients with malignant pleural effusions are asymptomatic. The fluid itself may be serous, serosanguineous, or grossly bloody, and typically it is ipsilateral to the main tumor and of moderate to large volume. The finding of malignant cells in the fluid confirms stage IIIB disease and a relatively poor prognosis. However, not all pleural effusions associated with lung cancer are due to pleural metastasis. Occasionally, fluid formation is only indirectly related to the tumor. Patients are at increased risk for pleural effusions from postobstructive pneumonia, atelectasis, pulmonary emboli, and drug or radiation reactions. In one series, 4 of 73 NSCLC patients with pleural effusion had surgically resectable tumors and survived for intervals ranging from 3 to 14 years.21 The diagnosis should be made on physical examination and confirmed by chest radiograph. The latter may be the only clue to the presence of pleural effusion. Approximately 300 ml of fluid is required for detection of a pleural effusion on a standard posteroanterior chest film. The lateral decubitus chest film is extremely useful in cases of subpulmonic effusion, detecting significantly smaller quantities of pleural fluid. Loculated effusions can be localized with ultrasonography or CT scan. The most definitive and simplest method of identifying a malignant pleural effusion is by cytologic examination. A sample of 250–1000 ml of fresh pleural fluid should be sent to the cytology laboratory for examination. The diagnostic efficacy increases on repeated aspirations, from approximately 50% positivity on initial thoracentesis to 65% on the second sample and to 70% on the third.22 The management of malignant pleural effusions depends on the treatment options of the primary malignancy.

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Systemic treatment may control pleural effusion due to SCLC, although therapeutic thoracentesis may still be required to control symptoms. Patients with SCLC who present ipsilateral effusions as their only manifestation of metastatic spread beyond the primary tumor and regional lymph nodes may have an overall response rate, complete response rate, and survival equivalent to patients staged as having limited disease.23 If effective systemic treatment is not available, treatment is often palliative, usually consisting of sequential thoracentesis or tube thoracostomy with or without sclerotherapy. Therapeutic thoracentesis may improve patient comfort and relieve dyspnea. The subjective response to drainage and the rate of fluid reaccumulation should be monitored. Repeated thoracenteses are reasonable if they achieve symptomatic relief, if fluid reaccumulation is slow, and if the patient’s expected lifespan is very short. Used alone it is not an effective means for preventing recurrence. The mean time to fluid reaccumulation in one series was as short as 4 days, with a 98% recurrence rate at 39 days.24 If life expectancy is reasonable, obliteration of the pleural space, either by parietal pleurectomy or by instillation of sclerosants that cause inflammation and subsequent pleural symphysis, can prevent recurrent accumulation of fluid. The efficacy of chemical pleurodesis depends upon complete evacuation of pleural fluid by tube thoracotomy followed by introduction of an effective sclerosing agent into the pleural space and retention of the agent in the chest for sufficient time to induce an inflammatory fibrosis.25 Several agents have been used for pleurodesis, including talc, tetracycline, doxycycline, bleomycin, and others, with variable efficacy rates.25 In two meta-analyses of trials of adults who underwent pleurodesis for malignant pleural effusion, talc was the most effective sclerosant.26 Talc may be delivered as a slurry by way of a chest tube after drainage or at the time of thoracoscopy, using insufflation. The efficacy of these two approaches was compared in a prospective randomized trial.27 Survival rates and success of the pleurodesis were similar in both arms, but quality of life scores were higher in the group that was treated thoracoscopically. Traditionally, large bore (20–28 Fr) chest tubes have been used for drainage before pleurodesis. In recent years several studies have indicated that small-bore (8–14 Fr) catheter drainage and sclerosis may be comparable in efficacy.28 Another approach involves placement of an indwelling pleural catheter through which the patient can drain pleural fluid in the ambulatory setting. Advantages include the ease of insertion, rapid drainage of

recurrent symptomatic effusion, and minimal hospitalization required for catheter insertion and care.29 A phase III trial compared the efficacy of an indwelling pleural catheter with chest tube and doxycycline sclerotherapy for recurrent symptomatic malignant pleural effusion in 144 patients. The pleural catheter had similar efficacy to doxycycline pleurodesis in relieving symptoms that were secondary to pleural effusion. Patients who were treated with the pleural catheter had a shorter hospital stay.30

SUPERIOR VENA CAVA SYNDROME The principal vascular syndrome associated with extension of lung cancer into the mediastinum is superior vena cava syndrome (SVCS), most commonly caused from compression by a large primary tumor or its mediastinal lymph node metastases, but also from intraluminal thrombosis. Patients characteristically complain of headache, swelling of the face, neck, and upper extremities, or a host of thoracic symptoms, such as dyspnea, cough, chest pain, and dysphagia. Physical examination may show facial edema, neck vein distension, and striking collateral engorgement over the anterior chest wall and upper abdomen. The degree of collateral vein formation reflects the time over which superior vena cava obstruction has developed and the relative anatomic site of the blockade, since obstruction above the azygos vein is better tolerated. Signs of airway obstruction (e.g. stridor) or intracranial pressure (stupor or convulsion) should prompt rapid evaluation and treatment. When typical signs are present, complete SVC obstruction is easily diagnosed. The CT scan is likely to show tumor masses, and can also reveal the presence of thrombi and collateral vessels. Lung cancer accounts for 65–90% of patients with SVCS, with approximately 85% of primary lung tumors occurring on the right, primarily in the right upper lobe or right mainstem bronchus. Among 2000 patients presenting lung cancer, 4% had SVCS.31 By cell type, SCLC predominates as the cause of SVCS, followed by squamous cell carcinoma. In addition to lung cancer, lymphoma, and other malignancies, benign causes of obstruction of the SVC include fibrosing mediastinitis, thrombosis, inflammatory adenopathy, postirradiation fibrosis, and aneurysms. Contrary to prior clinical wisdom, it has been convincingly demonstrated that the SVCS does not constitute a true medical emergency requiring urgent treatment without a tissue diagnosis.32 The immediate causes of

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death directly related to SVC obstruction are airway obstruction and intracerebral hemorrhage. In the absence of significant airway obstruction and signs of severely elevated intracranial pressure, definite diagnosis can be obtained before therapy. An accurate diagnosis is also especially important in view of the diverse etiologic considerations mentioned above. Bronchoscopy and, depending on the clinical circumstances, node biopsy, mediastinoscopy or even thoracotomy can be employed safely and effectively to diagnose lung cancer in this setting. Most patients with SVCS secondary to lung cancer have resolution of symptoms after initiation of radiation or chemotherapy.33 Before instituting radiotherapy in SVCS, general medical maneuvers, including oxygen support, bed rest with elevation of the head of the bed, and corticosteroids, may be used as temporizing measures. Chemotherapy is particularly useful when SVC obstruction is secondary to SCLC, although radiotherapy has been used in selected series. There is no difference in outcome or in time to resolution between the two,34 but chemotherapy offers the advantage of simultaneous management of systemic disease and avoidance of large-field irradiation to the heart and lung. Resolution of the syndrome is prompt (7–10 days), and is achieved in 43–100% of cases.35 If the chemotherapy drugs include vesicants, these should not be injected into the dilated, high-pressure, upper-extremity veins. The right upper extremity should be avoided for any drug administration, since the rate of blood flow is markedly decreased, and thrombosis, phlebitis, and erratic drug distribution are likely. Radiation is generally indicated in the management of the patient with SVCS secondary to NSCLC. Initial treatment with two to four fractions of 300–400 cGy, followed by conventional fractionation to a total dose of 3000–5000 cGy, has been advocated on the basis of limited evidence suggesting a prompter response with this schedule. One study evaluated the efficacy of treating patients with SVCS with a short course of hypofractionated irradiation.36 The study compared a regimen of 8 Gy fractions once a week (to a total dose of 24 Gy) within two weeks, versus a program of delivering only two fractions of 8 Gy (to a totaI dose of 16 Gy) within a week. In both regimens, a good palliative result was established; however, the results of the 24 Gy regimen were superior. Using the 24 Gy regimen, partial responses were obtained in 96% of patients, and 56% achieved complete response. The 16 Gy regimen yielded a complete response in only 28% of patients. Median

overall survival was longer with the higher-dose regimen (nine months), compared with the low-dose regimen (three months). Anticoagulation with heparin may be of benefit in SVCS resulting from intraluminal thrombosis of the SVC. Rapid onset obstruction that causes respiratory compromise must be treated emergently; percutaneous stenting may be the treatment of choice.37 Analysis of 23 retrospective trials that assessed the efficacy of superior vena cava stenting showed that 151 of 159 patients (95%) had relief of SVC obstruction after stenting.38

CARDIAC TAMPONADE Neoplastic cardiac tamponade is one of the true emergencies of clinical oncology. It may appear abruptly and cause death in a patient who otherwise has good shortterm life expectancy. Carcinoma of the lung is associated with the highest frequency of malignant pericardiac effusion, accounting for 37% of reported cases.39 Haskell and French40 reported on 23 patients in whom cardiac tamponade was the initial presentation in malignancy: 7 of these patients had lung cancer. Pericardial involvement arises either from direct extension of the tumor or because of retrograde spread through mediastinal and epicardial lymphatics. Cardiac tamponade may also be caused by postirradiation pericarditis with fibrosis or by encasement of the heart by tumor. The amount of fluid necessary to cause tamponade may be small (less than 200 ml) when the effusion accumulates rapidly or when the pericardium is non-compliant owing to fibrosis. When the pericardial effusion is chronic, over 1 liter may accumulate before causing tamponade. The symptoms of cardiac tamponade are non-specific. The most frequent complaints are apprehension, chest pain, and dyspnea. Occasionally, cough, hoarseness, hiccups, nausea, and abdominal pain are prominent complaints. Elevated jugular venous pressure, tachycardia, and narrow arterial pulse pressure are almost always seen. Pulsus paradoxus, an abnormally large drop in arterial systolic pressure during inspiration (>10 mmHg), is a hallmark of cardiac tamponade. The chest radiograph may show a large globular (‘water bottle’) heart, but cardiac silhouette may appear normal when the effusion has accumulated rapidly or is less than 250 ml. Sinus tachycardia and low voltage (QRS complex < 5 mV) are usually present on a 12-lead electrocardiogram. QRS complex electrical alternans, pathognomonic of cardiac tamponade, is infrequently seen. A pericardial effusion may be quickly and accurately diagnosed by

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echocardiogram. Two-dimensional echocardiography is more sensitive than M-mode, because it displays virtually the entire circumference of the heart. Certain two-dimensional echocardiographic findings help to determine the functional significance of a pericardial effusion. Diastolic right atrial and right ventricular collapse occur early during the development of cardiac tamponade. However, physical examination and noninvasive tests may not elucidate the functional significance of pericardial effusion, particularly in patients with associated cardiopulmonary disease. In such cases, right heart catheterization or diagnostic pericardiocentesis is indicated. Definitive treatment of cardiac tamponade requires decompression of the heart either surgically or by pericardiocentesis. Supportive therapy, including intravenous fluids, pressor agents, and oxygen, is of limited benefit. Acute pericardial tamponade with hemodynamic instability is life threatening, and must be alleviated by prompt fluid removal – most rapidly by pericardiocentesis. If the patient develops cyanosis, dyspnea, shock, or impaired consciousness, a pulsus paradoxus greater than 50% of pulse pressure, or a decrease of more than 20 mmHg in pulse pressure, emergency pericardiocentesis must be performed. If the patient is hemodynamically stable, a more definitive procedure should be performed. Zwischenberger and Bradford41 recommend echocardiography or CT-guided percutaneous tube pericardiotomy to accomplish both diagnosis and therapy at the initial intervention. Once the pericardium has been drained, these authors use doxycyclin or bleomycin for sclerotherapy. If sclerotherapy does not control the effusion, they proceed with subxiphoid pericardiotomy for evacuation of the effusion. A subxiphoid pericardial window can be performed under local anesthesia, and is reported to control the effusion in almost all patients. The high control rate and low incidence of complications with subxiphoid pericardiotomy have also led other investigators to conclude that this procedure can be used instead of pericardiocentesis for initial treatment of cardiac tamponade.42

EXTRATHORACIC COMPLICATIONS Lung cancer frequently metastasizes to distant organs. More than 60% of patients with SCLC, and approximately 30–40% of those with NSCLC, have stage IV metastatic disease. The usual sites of distant metastatic disease include the adrenals, brain, liver, lung and bone, although virtually any organ can be affected. Metastases may

present at the same time as the primary tumor or may occur much later, and they may be single or multiple, clinically silent or requiring urgent diagnosis and treatment. Manifestations resulting from distant metastases depend on the specific organ involved and are similar to those for other kinds of cancer. Brain metastases The most frequent metastatic neurologic complications of lung cancer are metastases to the brain. Clinically diagnosed brain metastases are present at initial presentation in 4–19% of SCLC patients,43 and the incidence rises to 50% in patients not receiving prophylactic cranial irradiation.44 Patients with NSCLC, especially those with adenocarcinoma, often develop brain metastases during the course of their disease.45 Brain metastases may be detected before the primary tumor is found or at the same time (synchronous presentation), but more commonly (80%) the diagnosis of the lung cancer antedates the development of the brain metastases (metachronous presentation). Focal neurologic abnormalities and global deficit of higher mental function are the commonest findings, with headaches being the most frequent symptom at presentation. Headaches occur in approximately 50% of patients with brain metastases, more commonly in those with multiple metastases and with metastases in the posterior fossa. Headeache may be associated with other symptoms characteristic of increased intracranial pressure, such as vomiting, visual blurring and confusion. Focal weakness is the presenting symptom in 20–40% of patients. Deficits of higher mental function (memory problems and mood or personality changes) are reported by onethird of patients, whereas cognitive dysfunction as detected by standard tests of mental status may be present in as many as 75%. Seizures occur in approximately 10% of patients as the first sign of metastases. CT and MRI are the primary radiographic means of evaluating patients suspected of having brain metastases. MRI is more sensitive in detecting multiple lesions, and allows improved visualization of the brainstem. The prognosis for patients with brain metastases is very poor, and depends on their functional and neurologic status, evidence of systemic tumor involvement, and whether the brain metastasis is truly solitary. Twothirds of patients will have improvement in their neurologic signs and symptoms with the use of steroids, but only for a short time (maximum one month). Dexamethasone is the most commonly used glucocorticoid, because it has minimal mineralcorticoid activity as compared with other steroids.

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Conventional dosing with dexamethasone for brain edema is 16 mg/day. Currently there are three treatment options available for patients with a known NSCLC and a solitary intracranial metastasis: surgical resection, whole brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). Most often, some combination of these methods of treatment is preferable. Surgical resection plus postoperative WBRT is currently the treatment of choice for patients with surgically accessible single brain metastases. The data supporting surgery for single brain metastases come from many retrospective studies46 and two randomized prospective trials,47,48 the results of which show that surgical resection is of benefit in selected patients. In the first randomized trial, by Patchell et al,47 patients with known systemic cancer were treated either with biopsy of the suspected brain metastases plus WBRT or with complete surgical resection of the metastases plus WBRT. A statistically significant increase in survival time was found in the surgical group (40 weeks versus 15 weeks). In addition, patients receiving surgery also had a significant decrease in recurrence at this surgical site and an improved quality of life. A second randomized study48 evaluated 63 patients randomized either to complete surgical resection plus WBRT or to WBRT alone. Survival was significantly longer in the surgical group (10 months versus 6 months), and a non-significant trend towards longer duration of functional independence was seen in the surgically treated patients. On the basis of these data, surgery and radiotherapy are usually recommended for good performance status patients with a solitary cerebral metastasis. However, over 50% of isolated brain lesions are not amenable to surgery. SRS is an alternative method able to deliver a highly focused, single dose of radiation to a well-defined, small intracranial target, thus minimizing exposure to the normal surrounding brain. No randomized prospective trials have compared SRS to surgery. Many studies of SRS for patients with intracranial metastases have reported similar median survival times to surgery.49 A retrospective study has demonstrated equal local tumor control rates and equal neurologic death rates between surgery and SRS.50 A prospective but nonrandomized study of patients with lung cancer (both SCLC and NSCLC) demonstrated significantly longer median survival for SRS with or without WBRT over WBRT alone (10.6 months and 9.3 months vs 5.7 months, p <0.0001).51 A randomized study of WBRT alone versus WBRT plus SRS in patients with two to four intracranial metastases showed significantly

improved local control, with a trend toward increased survival for WBRT plus SRS.52 Based on the available data, the appropriate SRS dose following WBRT is 20 Gy in tumors less than 2 cm in size, 18 Gy in tumors 2 to 3 cm in size, and 15 Gy in tumors more than 3 cm. The majority of patients with brain metastases present with multiple lesions, and are not candidates for aggressive local therapy. The mainstay of treatment is palliative WBRT.53 Many studies have compared different radiation schedules and doses. Final results from the Royal College of Radiologists’ trial54 suggest that a hypofractionated course of WBRT could palliate symptoms with minimal toxicity. Patients with NSCLC who are elderly or have a poor performance status could benefit from a short course of treatment. Some studies indicate that chemotherapeutic agents may cross the blood–brain barrier in patients with brain metastases.55 The observed response rate to chemotherapeutic agents was reported to be similar in the brain (16–35%) to other organs.56,57 Two studies on concomitant radiotherapy and chemotherapy for brain metastases in NSCLC reported higher objective response rates (58–76%).58,59 Moreover, both studies demonstrated a neurologic improvement in more than 50% of patients. Whether there is a definitive role for chemotherapy or combined chemoradiotherapy in the treatment of brain metastases in patients with NSCLC will have to be determined by prospective studies, taking into account survival and quality of life as their main endpoints. Patients with SCLC and brain metastases at presentation should be treated with primary chemotherapy. Whether consolidating cranial radiotherapy should be given after a few courses of initial chemotherapy is unclear. In patients who are unfit for chemotherapy or who have brain relapses during or immediately after chemotherapy, some palliative effect can be obtained with a short course of WBRT. As with NSCLC, combined chemoradiotherapy should be considered only in the context of a clinical trial. Spinal cord compression After brain metastases, spinal cord compression (SCC) is the most frequent neurologic complication of lung cancer. Five percent of patients with lung cancer develop SCC, more frequently at an interval after the diagnosis, usually six months.60 In a retrospective study on metastatic SCC secondary to lung cancer, Bach et al61 observed some variations between the different types of lung cancer. In SCLC, 75% of the cases of SCC were diagnosed during the first month after the primary malignant diagnosis was established,

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which contrasts with 12 months for adenocarcinoma and 21 months for squamous subtypes. Lung cancer has a predeliction to metastasize to the spine. The most common mode of SCC is that due to expansion or collapse of the vertebral body (85%) or neural arch. Paraspinal lung cancer may also directly invade the extradural space through the intervertebral foramen, producing SCC without vertebral body involvement. Malignant SCC is a medical emergency, and the key to successful management is early diagnosis and prompt treatment. All too often, the diagnosis is made too late for useful treatment. Those patients who present paraparesis, sensory symptoms, and sphincteric dysfunction usually pose no difficulty in diagnosis. Patients with more subtle presentations must be identified, and an appreciation of the earliest clinical manifestation is therefore essential. Isolated back pain is the initial symptom in 70–95% of patients, and it always antedates diagnosis of SCC by several days to many months. Pain can be local or radicular. Symptoms other than pain suggest compromise of neural structures. Weakness is present in approximately 80% of patients, and may be most evident when it affects proximal muscles of the lower extremity, creating difficulty when climbing stairs or rising from chairs. Non-painful sensory symptoms include paraesthesias, which in SCC usually begin in the feet and gradually ascend, ultimately stopping at a specific level that the patient may indicate. Loss of proprioception, producing ataxia, and sphincteric dysfunction are often late manifestations. Careful neurologic examination usually identifies the neurologic level and establishes the diagnosis.The evaluation of the patient with SCC must be speedy and resolutive. Although 80% of patients show abnormalities on plain spinal radiography, normal spine films do not exclude epidural metastases. MRI is being recognized as the diagnostic method of choice in SCC. Patients diagnosed with epidural cord compression should be treated urgently. Loss of ambulation or sphincter function before treatment is associated with a poor response to treatment and an adverse prognosis. About 80% of patients with little or no ambulatory dysfunction retain the ability to walk. Patients who are paraparetic recover ambulation in 20–60% of cases. Paraplegia improves in response to treatment in no more than 16% of cases.62,63 When the diagnosis of epidural compression has been made, dexamethasone should be administered. There is good evidence that the administration of high-dose steroids (dexamethasone 96 mg intravenous bolus, then 24 mg orally four

times a day for three days, then taper over ten days) improves the postradiation ambulatory rate compared with those who do not receive any steroids.64 However, the utility of moderate-dose steroids (dexamethasone 10 mg intravenous bolus, then 4 mg intravenously, with a taper over two weeks) remains unclear. There is fair evidence that dexamethasone does not need to be given to asymptomatic ambulatory patients with radiographic cord compression who are receiving radiotherapy.65 The decision to proceed with surgery or radiotherapy is based on the individual patient’s specific circumstances. Although based on inconclusive evidence, some general treatment recommendations can be suggested.66,67 Patients who present spinal instability or bony compression of their spinal cord, with no histologic diagnosis, with redevelopment of epidural compression in a previously radiated site, and with neurologic deterioration during radiotherapy, should be considered for surgical resection. Postsurgically ambulatory patients may benefit from postoperative radiotherapy. Other patients can be treated effectively with radiotherapy alone, specifically those with a life expectancy of three months or less, more than one level of simultaneous SCC, paraplegia of greater than 12–24 hours’ duration, and co-morbid conditions that preclude surgery.

PARANEOPLASTIC SYNDROMES Complications of lung cancer that are not related to direct invasion, obstruction, or metastatic effects of the tumor are generally termed paraneoplastic. Paraneoplastic syndromes comprise a group of disorders mediated by the production of circulating factors by, or in response to, lung cancer. These syndromes are numerous and occur in 10–20% of lung cancer patients, and include endocrine, neurologic, cardiovascular, skeletal, and cutaneous manifestations (Table 15.2). In this review, we focus only on the most common syndromes. Paraneoplastic endocrine syndromes Syndrome of inappropriate antidiuretic hormone Syndrome of inappropriate antidiuretic hormone (SIADH) results from inadequate secretion of antidiuretic hormone (ADH, vasopressin), which is almost exclusively associated with small cell histology. Up to 50% of SCLCs have elevated levels of ADH, but fewer than 10% have clinically apparent disease. SCLC is estimated to account for 75% of tumor-associated SIADH.

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Table 15.2 Paraneoplastic syndromes of lung cancer Syndrome

Clinical frequency (%)

Isotype

Endocrine Inappropriate ADH Ectopic ACTH Humoral hypercalcemia

5–10 3–7 10

SCLC SCLC Most frequently with squamous cell types

Neurological Lambert–Eaton Peripheral neuropathy Encephalopathy Myelopathy Cutaneous and musculoskeletal Clubbing/hypertrophic pulmonary osteoarthropathy Dermatomyositis Acanthosis nigricans Vascular and hematologic Hypercoagulable state Thrombophlebitis Non-bacterial thrombotic endocarditis

6 Rare Rare Rare

}

SCLC

10

}

More with adenocarcinoma

}

More with adenocarcinma

Rare Rare 10–15 Uncommon Uncommon

The main features of SIADH are water intoxication and hyponatremia. Diagnostic criteria include: • • • •

hypo-osmotic hyponatremia; inappropriately concentrated urine (urine osmolarity >100 mosmol/kg); euvolemia; normal renal, adrenal, and thyroid function.

The clinical features are related to osmotic water shift that leads to increased intracellular fluid (ICF) volume, specifically brain cell swelling. More often, hyponatremia develops insidiously, and adaptive mechanisms tend to minimize the increase in the ICF volume and its symptoms. Most patients experience minimal symptoms, and are discovered on routine laboratory evaluation when they have hyponatremia. Symptoms most frequently associated with hyponatremia include anorexia, nausea, vomiting, headache, and mildly altered mental status. In severe or rapid-onset hyponatremia, patients may experience symptoms related to cerebral edema, resulting in confusion, irritability, seizures, coma, and, ultimately, respiratory arrest. In evaluating a patient with hyponatremia, the physician must carefully exclude other causes and non-malignant conditions associated with SIADH. The first

step in the diagnostic process is to assess volume status. As SIADH is one of the so-called euvolemic hyponatremic states, the physician must recognize all diseases associated with volume overload, such as congestive heart failure, nephrotic syndrome, and severe liver disease. On the other hand, it is also important to exclude causes of hypovolemic hyponatremia that develops as a consequence of electrolyte-free water retention. Once the patient has been determined to be euvolemic, other causes of hyponatremia associated with a normal extracellular fluid volume must be ruled out, including glucocorticoid deficiency, hypothyroidism, and renal disease. Finally, other causes of SlADH must be excluded before the disorder is accepted as a paraneoplastic syndrome. Well-known non-malignant conditions associated with SIADH include pulmonary infections, central nervous system disorders (e.g. head trauma, space-occupying lesions, and cerebrovascular accidents) and drugs (most commonly chlorpropamide, carbamazepine, tricyclic antidepressants, thiazide diuretics, morphine, cyclophosphamide, and vincristine). List and colleagues68 reviewed 350 cases of SCLC and noted that 40 (11%) met a strict definition of SIADH similar to that outlined above, and 33 of them had the syndrome at initial presentation. Chemotherapy of the associated SCLC is generally associated with

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improvement in the syndrome. SIADH has not been shown to be a negative prognostic factor in terms of response to chemotherapy. In 80% of patients, the serum sodium returns to normal within three weeks of the start of chemotherapy, and this may predate other indices of response. Additional management of the hyponatremia may be necessary while waiting a response to chemotherapy, or when the tumor is resistant to therapy. Supportive measures such as fluid restriction and pharmacologic therapy can be undertaken to treat SIADH. For patients with sodium levels below 130 mmol/l, placement on free-water restriction (500 ml/day) is generally recommended, in addition to treatment of the primary malignancy. In the event that this measure does not bring the serum sodium level above 130 mmol/l, the tetracycline antibiotic demeclocycline (150–300 mg, 6–8 hourly) can be used, which induces nephrogenic diabetes insipidus such that the distal tubule becomes refractory to the effect of arginine vasopressin. In patients with more severe or life-threatening symptoms related to hyponatremia (serum sodium less than 115 mmol/l), treatment consists of intravenous fluids with 0.9% saline (rarely, hypertonic saline) and diuresis with a loop diuretic such as intravenous frusemide (furosemide). The rate of correction of hyponatraemia depends on the absence or presence of neurologic dysfunction. This is, in turn, related to the rapidity of onset and magnitude of the fall of the serum sodium. The rate of correction of the sodium is best limited to 1–2 mmol/l/h, or a maximum of 20 mmol/l/day until a Ievel of 120–130 mmol/l is reached. More rapid correction has been associated with the development of central pontine myelinolysis, which is characterized by flaccid paralysis, dysarthria, and dysphagia. Ectopic adrenocorticotropic hormone syndrome Cushing’s syndrome is due to the chronic effects of an excess of glucocorticoid hormone, most often iatrogenic resulting from therapy with glucocorticoid drugs. Adrenocorticotropic hormone (ACTH)-secreting pituitary microadenomas (Cushing’s disease) account for some 80% of cases of endogenous Cushing’s syndrome. About 15–20% of cases of Cushing’s syndrome are due to ectopic ACTH or corticotropin-releasing hormone (CRH) production. SCLC and bronchial carcinoid tumors account for most of these cases.69 The classic signs and symptoms include truncal obesity, cutaneous striae, moon face, buffalo hump, proximal myopathy and weakness, osteoporosis, diabetes mellitus, hypertension, and personality changes. However, lung cancer

patients with Cushing’s syndrome often do not have the classic clinical finding. The commonest physical findings are edema (83%) and proximal myopathy (61%).70 Myopathy with weakness and muscle wasting is much more common in ectopic ACTH production. Moreover, hyperpigmentation is found in ectopic ACTH production, but not in Cushing’s disease. Most patients will have a hypokalemic alkalosis, and about half will be hyperglycemic. This difference in presentation may be due to the rapid growth of the malignancy, relatively high levels of ACTH, and the fact that patients may not live long enough to develop the more classic features of the syndrome. Cushing’s syndrome occurs in approximately 5% of cases of SCLC, although raised concentrations of immunoreactive corticotropin can be detected in as many as 50%. In a review of more than 500 patients with SCLC, 23 cases (4.5%) of Cushing’s syndrome were identified.70 Thirteen patients had the syndrome at initial diagnosis, and ten developed it at the time of relapse of their disease after therapy. All of these patients had a shorter survival compared with patients without the syndrome. This may be due in part to the observed complications (infections and gastrointestinal ulceration) related to prolonged exposure to high levels of corticosteroids secondary to ectopic ACTH production. The diagnosis of Cushing’s syndrome is best established by 24 hour urine-free cortisol measurements or lowdose dexamethasone suppression testing (0.5 mg every six hours for eight doses).71 The primary therapy of ectopic Cushing’s syndrome secondary to lung cancer is treatment of the underlying tumor. If patients experience significant clinical effects from the hypercortisolism, cortisol production blockers (steroid synthesis inhibitors), such as aminoglutethimide, mitotane, metyrapone, and ketoconazole, are said to be beneficial. Because of its rapid onset of action and favorable toxicity profile, ketoconazole (300–400 mg twice a day) has become the therapy of choice for ectopic ACTH.72 Suppressors of ACTH production, such as the somatostatin analog octreotide,73 have shown some efficacy. Humoral hypercalcemia Hypercalcemia is probably the most common metabolic complication of cancer and, since determination of the serum calcium level became routine, the recognition of patients with hypercalcemia associated with cancer has increased. Hypercalcemia may be related to direct bone destruction or to secretion of a parathyroid hormone (PTH)-related protein or other bone-resorbing substances (cytokines) secreted by the tumor. A PTH-related

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protein that shares an N-terminal sequence with PTH, but has a unique C-terminal portion, has been shown to be responsible for most cases of hypercalcemia of malignancy. Elevated levels of PTH-related protein by radioimmunoassay were found in 30 of 42 patients (71%) with hypercalcemia of malignancy, but only in 3 of 23 patients with cancer (13%) but with normal calcium levels.74 In a study of 200 consecutive patients with untreated bronchogenic carcinoma, the overall frequency of hypercalcemia was 12.5%.75 Of these 25 patients, 14 did not have evidence of bony metastases. Humoral hypercalcemia was most commonly observed in those with squamous cell histology, and was uncommonly observed with adenocarcinoma and SCLC. The symptoms associated with hypercalcemia generally correlate with the magnitude and rapidity of the rise in serum calcium. Mild hypercalcemia is generally asymptomatic. More severe hypercalcemia is frequently associated with neurologic, gastrointestinal and renal symptoms. The neurologic manifestations range from mild drowsiness, progressing to weakness, depression, lethargy, stupor, and coma. Gastrointestinal symptoms may include constipation, nausea, vomiting, anorexia, and peptic ulcer disease. Hypercalcemia-induced nephrogenic diabetes insipidus often results in polyuria, leading to extracellular fluid (ECF) volume depletion and a reduction in the glomerular filtration rate (GFR), which may lead to a further increase in calcium concentration. Cardiovascular effects include shortened QT interval, broadened T wave, heart block, ventricular arrhythmia, and asystole. Individual patients may manifest any combination of these signs and symptoms to varying degrees. Hypercalcemia may be completely reversible with effective treatment of the underlying cancer; it is important to recognize that hypercalcemia per se does not rule out the possibility of curative therapy, including surgery, if indicated. The prognosis for patients with hypercalcemia and no further treatment of the underlying malignancy is extremely poor, with median survivals of 30–45 days.76 The symptoms and the magnitude of the hypercalcemia are key considerations in determining the need for aggressive therapy. If the serum calcium concentration is greater than 14 mg/dl, immediate treatment is indicated, even if symptoms are absent. In the case of mild calcium elevation (<12 mg/dl) in patients with widely metastatic and incurable malignancy, it may be most appropriate to give supportive care only, without specific therapy for the hypercalcemia. Otherwise, most patients with serum calcium values of 12–14 mg/dl should be treated. The approaches

to the management of hypercalcemia can be divided into four specific areas: • • • •

treating the underlying tumor; correcting dehydration; enhancing renal excretion of calcium; inhibiting accelerated bone resorption.

The intravenous administration of isotonic saline is an important component, and is the first step in the management of severe hypercalcemia with associated symptoms. A widely used regimen is to administer 3 l of isotonic saline daily, recognizing that the rate of fluid administration may need to be varied if symptoms and signs of fluid overload appear. The next step is to add a loop diuretic, such as frusemide, that will increase calcium excretion. This initial treatment usually has little effect on calcium levels, effecting a median decrease of only 1.0 mg/dl. Specific therapy to inhibit accelerated bone resorption is often necessary. Bisphosphonates are potent inhibitors of bone resorption that have dramatically changed the therapeutic approach to hypercalcemia. These compounds have poor gastrointestinal absorption, and are best used intravenously. Pamidronate and zoledronate are the most useful of the commercially available compounds. Normalization of serum calcium is obtained after three days (range 1–11 days), and normocalcemia is maintained for a variable length of time (median of one to two weeks). Bisphosphonates are well tolerated; the only clinically detectable side-effect is transient fever in about 20% of the cases. Other inhibitors of osteoclast activity include calcitonin, plicamycin, and gallium nitrate. Calcitonin inhibits bone resorption, increases renal calcium excretion, and has a rapid onset of action. The hypercalcemia effect begins within hours, with a nadir in serum calcium within 12–24 hours, but the effect on calcium concentrations is modest and transient, and calcitonin alone has no place in the treatment of severe hypercalcemia. However, in very severe cases, it is an excellent addition to the lateracting bisphosphonates or plicamycin. Plicamycin (mithramycin) inhibits osteoclastic RNA synthesis. It lowers the serum calcium more quickly than bisphosphonates do, but significant side-effects (raised transaminases, nephrotoxicity with proteinuria, thrombocytopenia, nausea, and local inflammation or cellulitis at sites of extravasation) decrease enthusiasm for this agent unless the calcium concentration needs to be lowered very rapidly. Gallium nitrate also inhibits bone resorption. As with bisphosphonates, it takes several days before a nadir in

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serum calcium is reached, and this lasts about a week. Side-effects are frequent and severe, and include nephrotoxicity, hypophosphatemia, and anemia. The need to treat patients for five days with a continuous infusion and its toxicity limit the use of this compound in the treatment of hypercalcemia. Paraneoplastic neurologic syndromes Paraneoplastic neurologic syndromes have long been recognized, and these disorders are now thought to result from the cross-reaction of antitumor antibodies with antigen also present in neural tissue.77 One such antigen is the nuclear-associated HuD protein, which has been cloned by use of high-titer antibodies from the serum of patients with paraneoplastic syndromes.78 In health, the antigen is expressed only in neural tissue, but is expressed by all SCLCs, perhaps reflecting the apparent neuroendocrine origin of this tumor. Why high titers of anti-HuD antibodies develop in some patients with SCLC is unknown. Neurologic paraneoplastic syndromes include sensory, sensorimotor, and autonomic neuropathies and encephalomyelitis. Neurologic symptoms of encephalomyelitis include dementia (limbic encephalitis), cerebellar degeneration, brain-stem encephalitis, and myelitis. Sensory neuropathy and encephalomyelitis often occur together, and are associated primarily with SCLC. Symptoms may precede the diagnosis of lung cancer by many months, or they may be the first sign of tumor recurrence. Direct metastatic effects as well as metabolic or infectious processes must be excluded as contributors to the neurologic findings. The severity of neurologic symptoms is not related to tumor bulk; in fact, a primary malignant lesion may be undetected before death, despite disabling symptoms. In a patient with the appropriate neurologic findings, positive anti-Hu antibody, and significant smoking history, a diligent diagnostic evaluation should be undertaken. The most helpful diagnostic test is probably CT of the chest, with careful attention to mediastinal or hilar nodes. Fluorodeoxyglucose (FDG)-PET scanning has also been used with some success.79 Lambert–Eaton myasthenic syndrome The neurologic syndrome most commonly recognized is the Lambert–Eaton myasthenic syndrome, reported to occur in up to 6% of cases of SCLC. Clinically, this syndrome is characterized by muscle weakness, hyporeflexia, and autonomic dysfunction due to impaired release of acetylcholine from the cholinergic nerve terminals. Symptoms are most pronounced in the pelvic

girdle and thigh muscles, making it difficult for patients to climb stairs or get out of a bathtub. Other symptoms, such as dysarthria, dysphagia, diplopia, and ptosis, may occur. It is distinguished from myasthenia gravis by the absence or minor involvement of bulbar or extraocular muscles. Standard electromyography characteristically demonstrates a reduced amplitude of the compound muscle action potential, which increases immediately after 10–15 seconds of maximal voluntary contraction, or during high-frequency nerve stimulation, while there is a steady decrease in classic myasthenia. The manifestations of the disease may occur as long as two to four years before the diagnosis of SCLC. The syndrome is thought to result from autoantibodymediated impairment of presynaptic neuronal calcium channel activity, which impairs the nerve stimulusinduced release of acetylcholine.80 Treatment-induced remission of the SCLC may cause attenuation or remission of the syndrome in some patients. The use of acetylcholinesterase inhibitors is of limited benefit. 3,4Diaminopyridine enhances the release of acetylcholine, and has been shown to be effective in treating both the motor and the autonomic deficits of the syndrome.81 Immunosuppressive treatment may provide benefit, but its effects are usually delayed and incomplete. Many patients become severely debilitated from their motor dysfunction, regardless of the status of their lung cancer. Paraneoplastic cerebellar degeneration Paraneoplastic cerebellar degeneration (PCD) is a disorder that is charaterized by ataxia, nystagmus, diplopia, dysarthria, and dysphagia. It is most often associated with SCLC, and 44% of patients have elevated anti-Hu antibodies. Individuals with anti-Hu antibodies are more likely to be women, have extracerebellar manifestations (encephalomyelopathy or sensory neuropathy), have severe disability, and have localized or undetected tumor at the time of death. Less that one half of patients with PCD have abnormal neuroradiologic studies. Pathology reveals inflammatory infiltrates, perivascular lymphocytic cuffing, and loss of Purkinje cells. Neither treatment of the tumor, nor the immune modulating therapy alters the course of PCD. Those with PCD and small cell carcinoma have a shorter survival than those without PCD.82 Progression of neurologic disease is the cause of death in most patients with PCD who have positive anti-Hu antibodies and in a few who are anti-Hu negative.82 Peripheral neuropathy Patients with cancer who suffer from a peripheral neuropathy usually do so from causes other than

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paraneoplastic syndromes (e.g. neoplastic invasion, chemotherapeutic agents, and nutritional and metabolic disorders). Therefore a careful evaluation for other causes of peripheral neuropathy should be made before the disorder is accepted as a paraneoplastic syndrome. One exception is the subacute sensory neuropathy occurring in patients who have the anti-Hu antibody, where the presence of the antibody establishes the diagnosis as a paraneoplastic syndrome and the cancer as highly likely to be SCLC. In about 20% of all patients with a subacutely developing pure sensory neuropathy, cancer is the underlying cause. Subacute sensory neuropathy is usually a rapidly developing severe disorder in which patients lose all modalities of sensation, usually in all four extremities. The disorder is clinically distinguishable from cisplatin sensory neuropathy, because cisplatin neuropathy causes loss of proprioception and spares pain and temperature sensation. Although the disorder may begin in the face or trunk, it commonly begins distally in the extremities and extends proximally. The sensory loss is so severe that patients may be unable to walk, use their hands, or co-ordinate movements. The neurologic symptoms may precede the diagnosis of SCLC by several months.83 Electrodiagnostic tests show absent sensory potentials. Motor nerve conduction and F waves may be entirely normal. The neuropathologic findings include drop-out of neurons in the dorsal root ganglia, inflammatory infiltrates mainly composed of T cells, and anti-Hu antibody on the surface and in the nuclei of the remaining sensory neurons. Other neurologic syndromes Among the other SCLC-associated neurologic syndromes are limbic encephalopathy, necrotizing myelopathy, intestinal dysmotility syndrome, opsoclonus-myoclonus, and cancer-associated retinopathy (CARS). Anti-Hu antibody has been noted in patients with SCLC presenting these rare neurologic paraneoplastic syndromes.84 Limbic encephalopathy is characterized by memory loss and behavioral changes, including dementia, which often antedate the diagnosis of cancer. Necrotizing myelopathy is an unusual neurologic paraneoplastic syndrome, and is characterized by a relatively acute, rapidly ascending paraplegia that culminates in rapid deterioration and death. Intestinal pseudo-obstruction of the bowel is the most well-defined isolated autonomic symptom. Patients may suffer weight loss, refractory constipation, and abdominal distension. Neurologic studies show loss of neurons in the myenteric plexus with inflammatory

infiltrates. Serum antibodies to myenteric and submucosal neural plexus of the jejunum and stomach have been found in patients with SCLC.85 Opsoclonus-myoclonus is another paraneoplastic syndrome commonly associated with SCLC. Neurologic manifestations involve myoclonus, truncal ataxia, and progressive involuntary rapid eye movements. The cerebrospinal fluid reveals increased protein with mild pleocytosis. Imaging studies are often interpreted as normal. Treatment of the SCLC can lead to partial or even complete recovery. CARS is a rare paraneoplastic syndrome and it is most commonly associated with SCLC. CARS is suspected to be caused by autoimmune degeneration of the retinal photoreceptors. The triad of photosensitvity, scotomes, and attenuated retinal arteriole caliber suggests the diagnosis of CARS. The use of steroids has been reported to result in some improvement of visual symptoms.86 Most cases progress to blindness, even with treatment of the cancer. Paraneoplastic cutaneous and musculoskeletal syndromes Digital clubbing and hypertrophic pulmonary osteoarthropathy are the other major paraneoplastic syndromes that are associated with lung cancer, almost exclusively with NSCLC.87 Digital clubbing is characterized by subungual soft tissue thickening, most commonly involving the fingernails, which are often bulbous in appearance (Figure 15.2). Clubbing of the digits is one of the most commonly discussed findings on pulmonary medicine clinical rounds. Etiologic factors include hereditary and both non-pulmonary and pulmonary diseases, including bronchogenic carcinoma. Hypertrophic pulmonary osteoarthropathy (HPO) is less common than digital clubbing, and is usually associated with intrathoracic malignancy, especially lung cancer, and often resembles rheumatoid arthritis (Figure 15.3). It is characterized by painful symmetric polyarthritis that generally involves the ankles, wrists, and knees. HPO is due to proliferative periostitis of the long bones, often with little or no evidence of clubbing. The onset of HPO is often acute, may precede the diagnosis of cancer by months, and usually, but not invariably, is associated with inoperability. The cause of HPO is not known, but may be due to a humoral agent. Patients with HPO frequently have consulted a rheumatologist or orthopedic specialist before the ultimate diagnosis of lung cancer is suspected and a chest radiograph is obtained. In patients who smoke and present arthralgia, HPO must be included in the differential diagnosis. Radionuclide bone scans typically show

232 Textbook of Lung Cancer

nary disease. Weakness usually moves gradually and progressively. Although they do not occur in all patients, muscle tenderness and aches may be very striking. The inflammation characteristically causes elevations of serum levels of aldolase and creatinine kinase, and alternation of liver function tests. Although most patients respond initially to corticosteroids, cytotoxic drugs are sometimes added when steroid toxicity or refractoriness develops.

Figure 15.2 Digital clubbing.

Figure 15.3 Hypertrophic pulmonary osteoarthropathy.

increased uptake at the distal ends of the affected long bones, and this may be confirmed by evidence of new bone formation on plain-film radiographs. The spine is spared. The syndrome may resolve with response of the cancer; however, no effective form of treatment is recognized, including aspirin and non-steroidal antiinflammatory agents. Other cutaneous paraneoplastic syndromes include dermatomyositis, acanthosis nigricans, and hyperkeratosis of the palm and soles. These conditions are rarely seen in patients with lung cancer. Dermatomyositis is a rare but very disabling complication of lung cancer. The patient presents weakness and a characteristic rash. Sometimes the disease presents as a cardiac or pulmo-

Paraneoplastic vascular and hematologic syndromes The association between cancer and venous thromboembolism is well known. Over a hundred years ago, Trousseau reported cases of episodic migratory thrombophlebitis in patients with cancer. The pathogenic mechanisms for the association include hypercoagulability due to activation of clotting by tumor cells, vessel wall injury, and stasis. Occasionally, the thromboembolic event occurs before the diagnosis of cancer, and it has been suggested that deep venous thrombosis may be a predictor of the subsequent diagnosis of cancer. Two studies have noted a significant association between primary venous thrombosis and the subsequent development of cancer.88,89 This link seems particularly strong in patients with recurrent deep venous thrombosis. Lung cancer and other malignancies, especially those of the gastrointestinal tract (e.g. the pancreas), are commonly associated with Trousseau’ s syndrome. Pulmonary embolism has been observed at autopsy in 20% of patients with lung cancer, and may precede the diagnosis of cancer;90 25% of adult patients with acute pulmonary embolism may develop cancer within five years.91 There appears to be a general activation of the clotting system in patients with lung cancer, the clinical consequence much more often being thrombosis rather than bleeding. Disseminated intravascular coagulation (DIC) is another state of hemostatic disarray, characterized by the inappropriate co-existence of enhanced fibrin production and fibrinolysis. DIC has been reported as a complication of many neoplastic disorders, but is most likely to occur in carcinoma of the lung, prostate, breast, and gastrointestinal tract, in melanoma, and in leukemia. In its grossest form, DIC is readily recognized by prolongation of the thrombin time, prothrombin time, and partial thromboplastin time, by a decrease in the concentration of plasma fibrinogen and other clotting factors, by thrombocytopenia and by the presence in serum of antigens reacting with antiserum to fibrinogen or its derivatives. However, apparent DIC, with

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consumption of platelets and clotting factors and bleeding, is rare and is most commonly associated with acute promyelocytic leukemia and adenocarcinoma. Non-bacterial thrombotic endocarditis (NBTE), also known as marantic endocarditis, probably relates to this hypercoagulable state, and is generally defined as vegetations on the heart valves or wall that contain fibrin and platelets, but without evidence of infection. It is particularly associated with bronchoalveolar carcinoma and adenocarcinoma of the lung. At autopsy, the incidence of NBTE in each of these cell types is approximately 7%. The mitral valve is commonly involved, and clinically significant emboli to the central nervous system, kidneys, and coronary arteries have been described in what previously was thought to be a syndrome of only pathologic interest at autopsy.92 Although some patients may have heart murmurs, most do not. Echocardiography picks up vegetations larger than 2 mm. In a review of cerebrovascular complications in patients with cancer, Graus and colleagues93 observed cerebral embolic infarction in 42 of 86 patients with pathologically documented NBTE and careful autopsy examination of the brain. NSCLC was the most common malignancy in this group. Cerebral infarction was symptomatic in 32 (76%) of these patients ante mortem, and was associated with clinical evidence of other systemic emboli in 19 patients. The definitive diagnostic test is cerebral angiography, which shows multiple arterial occlusions. Tumor embolization to the lungs and brain is another cause of emboli in cancer patients, in addition to venous thrombosis and NBTE. Tumor emboli are an unusual clinical event, although autopsy series have reported tumor emboli in up to 23% of solid tumors.94 Lung cancer and breast cancer were the most common malignancies in these patients, but in only one patient was the tumor embolism correctly diagnosed ante mortem. The management of thromboembolic complications in patients with lung cancer is difficult. Typically, such patients are resistant to anticoagulation, especially with warfarin. Long-term administration of subcutaneous low molecular weight heparin (LMWH) may be a more effective approach.95

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16 Quality of life and supportive care Jean-Paul Sculier, Anne-Pascal Meert, Marianne Paesmans, Thierry Berghmans Contents Introduction • Quality of life assessment • Critical care of the lung cancer patient • Symptom management • Management of treatment complications

INTRODUCTION During the last two decades there has been great interest in the patient’s well-being, particularly among oncologists and lung cancer specialists in particular. Quality of life (QoL) assessment is a way to obtain objective data in order to ‘measure’ the patient’s condition and to evaluate the effectiveness of therapies administered to improve his or her situation. Unfortunately, there are considerable methodologic difficulties in designing adequate universal instruments to give a global measurement of QoL. Most of the investigations performed so far in this field have in fact assessed the symptoms of the patient in a semiquantitative way. The specific anticancer treatment is in many situations the obvious solution to control the disease and thus to improve the patient’s condition, but it can be associated with side-effects and complications, may act with some delay, or may not always be applicable or effective. The aim of supportive care is to manage those problems for which anticancer therapy is not effective or sufficient. The field covered by supportive care is very large, from critical care to terminal care, and includes complications management, symptomatic treatment, psychosocial support, and palliative care. In the present chapter we will first review QoL assessment of lung cancer patients with an analysis of the published data, indications and principles of critical care in oncology, management of the most common symptoms related to bronchial neoplasms (dyspnea, pain), and treatment of the usual complications of anticancer treatment (emesis, febrile neutropenia). QUALITY OF LIFE ASSESSMENT Interest in QoL evaluation began in the mid-1980s and has increased in oncology, and in particular for lung cancer patients, due to the disappointing progress made in improving survival – the traditional and true endpoint for phase III clinical trials – especially for advanced

unresectable non-small cell lung cancer (NSCLC). Improvement in evaluation is due to the development of validated instruments for measuring QoL. Up to now there has been no significant improvement in length of survival of these patients, so more attention is being paid to identifying less toxic treatments, achieving better control of symptoms, and generally improving the QoL of the patients. However, the incorporation of QoL assessment in lung cancer clinical trials is a challenge, due to the practical and theoretic difficulties of data collection, data analysis, and interpretation of results. The definition of QoL is clearly a multidimensional concept and agreement was needed on the dimensions to be included for measuring it, although, most often in medical research, the concept is restricted to the dimensions directly related to the disease, its symptoms, and its treatment. Research is then focused on health-related QoL, with inclusion of dimensions like physical function and impairment of physical function due to disease symptoms, occupational function, psychologic or emotional function, and social function. There is an association between this health-related QoL and the Karnofsky performance index, introduced much earlier (in 1949). However, the latter measure is clearly too limited, although worsening in performance status is correlated to a QoL deterioration and to an increase in the lung cancer symptoms. The problem of measuring QoL adequately (by the patient himself as, due to the subjective nature of the concept, external observers are poor raters) has been solved by the development of validated instruments proven to be both reproducible (an unchanged measure has to been obtained when the patient’s condition is stable) and sensitive (able to capture any change in the patient’s condition). In lung cancer, several diseasespecific instruments are available. The most frequently used in advanced NSCLC in recent randomized clinical trials include: •

the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life

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• •

Questionnaire, including a core (QLQ C30) completed by a lung cancer module assessing diseasespecific symptoms and toxicities (QLQ LC13),1 which has the advantage of being translated into many languages; the Lung Cancer Symptom Scale (LCSS);2 and the Functional Assessment of Cancer Therapy– Lung (FACT-L).3

These three tools assess different domains including functional scales – physical, role, cognitive, emotional, social – (5 for QLQ C30, 4 for LCSS, and 5 for FACT-L) and symptom scales (e.g. fatigue, nausea and vomiting, pain). A questionnaire has also been developed in Japanese, called QOL-ACD (QoL questionnaire for cancer patients treated with anticancer drugs).4 Other validated instruments less frequently used include the Rotterdam Symptom Check List (RSCL), the Functional Living Index–Cancer (FLIC), the Hospital Anxiety and Depression Scale (HADS), and the Daily Diary Card (DDC). These questionnaires need to be assessed both at baseline and at several preordained time points during the treatment period and the follow-up. The logistics required for QoL assessments are therefore important and adequate monitoring is necessary to ensure patient compliance in completing the questionnaires. Data analysis also leads to some difficulties, for several reasons. The most important one is that the investigators are faced with significant amounts of missing data, which are most probably related to QoL itself. The missing data are therefore not missing at random but due to a process of information censoring. It has indeed been shown that a progressive worsening in clinical status induces a parallel increase in missing data. This is clearly illustrated in the trials reporting on QoL. Consequently, data analysis is most often restricted to the first weeks of follow-up, when the rate of missing data is not yet too high. One helpful approach to this problem is to look at the time of QoL deterioration and make some assumptions about the QoL of the patients with missing evaluations. Some statistical methods have been developed to deal with this issue of information censoring, but are not yet in frequent use in practice. Another problem is that a QoL assessment generates vast amounts of data due to its multifactorial definition and due to the need to study it over a period of time. To control the rate of false-positive results, significance probabilities have to be adjusted. Another solution is to perform data reduction and to use summary parameters, but this may result in a loss of information when a

patient’s evolution is not going in the same direction on several scales. Nevertheless, QoL proved to be a useful secondary endpoint when assessing the value of chemotherapy versus best supportive care in advanced NSCLC. Indeed, after the results of several meta-analyses showed survival benefit for chemotherapy compared to best supportive care, the issue of the positive balance between survival benefit and chemotherapy toxicity was raised, and none of the trials included in the meta-analyses had been successful in investigating QoL. Some further studies5–12 were therefore conducted in this respect, all including QoL as an endpoint, sometimes even as primary objective (four of them), despite the methodologic difficulties described above. In 5 studies, attention was paid to the problem of information censoring. It was found that at least one parameter of QoL improved in all these series; in particular, symptoms related to lung cancer such as pain or dyspnea were found to be reduced in chemotherapytreated patients. The side-effects of chemotherapy did not cause a significant deterioration in the QoL. The study by Cullen et al,6 which compared MIC (mitomycin C, ifosfamide, cisplatin) versus best supportive care, demonstrated a significant prolongation of life in chemotherapy treatment as well as a significant improvement in QoL in treated patients, and a deterioration with standard treatment. Thus these studies reinforce the case for the use of chemotherapy in patients with advanced NSCLC. QoL is now frequently considered as an endpoint in trials comparing different chemotherapy regimens in advanced NSCLC, and the results of QoL assessments are particularly interesting when no survival benefit is demonstrated (which is indeed not infrequent). In such circumstances, information on the relative merits of different treatments derived from the symptom scales and QoL domains might, in conjunction with evaluation of the side-effects of the treatments, be vital for selecting the best treatment. A recent unpublished review analyzed whether the use of more recent drugs (paclitaxel, docetaxel, vinorelbine, gemcitabine) might be associated with a further improvement in QoL in patients with NSCLC. Among 16 selected studies, 5 were found in which attention to information censoring was paid. Socinski et al13 compared four courses of carboplatin and paclitaxel, given by the same regimen until progression in 230 patients with advanced NSCLC. No effect was found on survival, and QoL demonstrated a similar deterioration in both groups, with time. It was concluded that four courses

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of chemotherapy were as good as a more protracted therapy. Bonomi et al14 compared cisplatin and etoposide to cisplatin combined with paclitaxel in 574 patients. Survival was slightly increased with paclitaxel and QoL was improved, compared to the other arm, at 6 months’ evaluation, but not afterwards. Kelly et al evaluated 408 patients randomized to carboplatin and paclitaxel or to cisplatin and vinorelbine.15 No effect of treatment on survival or QoL was seen. Rosell et al compared carboplatin and paclitaxel to cisplatin and paclitaxel in 618 patients.16 Survival was better with cisplatin, as was the control of symptoms related to lung cancer. Scagliotti et al compared carboplatin plus paclitaxel to cisplatin combined with either gemcitabine or vinorelbine in 607 patients; no differences in survival were observed and no superiority of one of the three treatment arms was noticed in terms of QoL.17 In an additional 11 studies, in which QoL was evaluated without taking into account possible information censorship, a positive effect on survival was seen in 3/11 series and a difference between treatment arms related to QoL was seen in 6/11 studies. At least two other studies reported clearly that chemotherapy improved symptoms of disease, but without any difference being detected between study arms. The regimens that were associated with an improved QoL including better palliation of symptoms, were cisplatin plus paclitaxel in four studies and cisplatin (or carboplatin) plus docetaxel in one series; cisplatin and gemcitabine in one series and gemcitabine and vinorelbine in one series. A final series showed improved clinical benefit with gemcitabine. There was no real QoL assessment; however the considered endpoint was a composite one including treatment effect on symptom control, performance status, and weight. In more recent randomized phase III trials looking at first-line chemotherapy in advanced NSCLC we found two18,19 without detectable survival difference but with a better QoL in one of the tested arms. Paccagnella et al,18 with QoL as primary endpoint, showed that patients reported better improvement on some symptom scales (nausea and vomiting, appetite loss, and constipation) with carboplatin combined with mitomycin and vinblastine compared to the regimen with cisplatin subsitituted for carboplatin. Global QoL was found with Spitzer’s scale, but not with the EORTC scale. Georgoulias et al19 found that a gemcitabine–docetaxel combination significantly improved QoL compared to cisplatin– vinorelbine. For these two studies, QoL might be the key to selecting one of the two treatments for further studies. Three other trials20–22 showed improvement in

survival accompanied by better QoL: Fossella et al in favor of docetaxel–platinum combinations (cisplatin or carboplatin) compared to cisplatin and vinorelbine,20 Kubota et al in favor of docetaxel plus cisplatin compared to cisplatin and vindesine,21 and Rudd et al identified gemcitabine and carboplatin as improving results obtained with MIC.22 A trial published by Cella et al,23 testing two doses of gefitinib in symptomatic patients who had received at least two prior chemotherapy regimens, showed a rapid improvement in symptoms and, interestingly, showed that this symptomatic improvement was associated with tumor response and survival. They suggested that symptom improvement might precede response assessment detected using radiologic tools. However, comparisons between studies are seldom possible as there is as yet no consensus about the frequency of QoL evaluations and about which results to present, usually with selective reporting due to the significant amount of data generated by QoL evaluations. Nevertheless, QoL assessment can play its role in the global interpretation of clinical trial results.

CRITICAL CARE OF THE LUNG CANCER PATIENT Intensive care is becoming more and more important in the management of cancer patients and major cancer hospitals have developed intensive therapy units, not only for surgical patients but also for medical patients. However, there is limited information in the medical literature about intensive care in oncology, especially concerning description of the types of patients admitted in such units. An international inquiry performed in anticancer centers24 has shown that 70% of the cancer hospitals have at least one intensive care unit (ICU) especially devoted to patients with neoplastic diseases. Whether general, surgical, or medical, those units do not depart from the recommended guidelines for intensive care, as far as the number of beds, the nursing staff, and the main critical care techniques performed are concerned. Admission of patients in an ICU is usually based on the following three principles.25 First, the patients have to be ‘salvageable’: patients whose chances of being cured or having their disease put into remission are minimal should not be admitted or should not stay in an ICU. Second, the patient’s ‘autonomy’ must be respected: a patient who refuses intensive supportive therapy because he or she understands the potential poor prognosis of the underlying cancer disease should not be admitted in the ICU. Finally, as medical resources are

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limited, even in highly developed countries, ‘distributive justice’ should be taken into account: patients with the best chances of benefiting from intensive therapy should be admitted in priority. The assumption that patients with active malignant disease should not be admitted to an ICU often predominates in general hospitals and makes it very difficult for oncologists to undertake a fruitful collaboration with intensivists for the management of the critically ill cancer patients. This negative opinion is not supported by scientific data. It results from a bias of many physicians, who refuse critical care to cancer patients although they are willing to provide it to patients with serious non-neoplastic diseases such as advanced heart failure or liver cirrhosis, who do not have a better short- or long-term prognosis.26 Recently, it has been shown that the prognosis of the cancer patient admitted in ICU for a severe complication is not related to the characteristics of the underlying malignancy but only to the physiologic perturbations induced by the complications as measured by severity scores.27–29 These data were confirmed in the only study specifically performed on lung cancer with 57 patients admitted to the ICU.30 There are four main reasons to admit a cancer patient to the intensive care unit:31 (1) postoperative recovery for advantages that are the same as those for any high-risk postoperative patient (availability of continuous hemodynamic monitoring, early identification of cardiovascular and respiratory disturbances, facilities for respiratory support, and constant skilled nursing care); (2) critical complications of the cancer disease and its treatment; these complications are numerous and can be very specific for oncology, and their management has always to take into consideration the presence of a severe chronic underlying disease; (3) intensive anticancer treatment administration and monitoring, useful in various situations such as increased risk for treatment administration related to the patient’s condition, administration of intensive chemotherapy requiring patient monitoring, treatment of unknown toxicity in phase I trial requiring optimal safety conditions of surveillance, and administration of treatment that frequently results in acute severe toxicity; and (4) acute disease (such as myocardial infarction or severe asthma), possibly unrelated to the malignancy or its treatment. Advances in knowledge have been obtained during the last decade in the use of life-threatening support

techniques for oncologic patients. Cardiopulmonary resuscitation has been shown to be as effective in cancer patients as in non-cancer patients.32,33 Mechanical ventilation is associated with a relatively poor outcome,34 particularly if the patient is leukopenic at the time of intubation.35 A major advance in the management of the cancer patient with respiratory failure has been achieved with the development of non-invasive ventilation.36 The ICU mortality in these patients can be reduced by this technique from about 70–80% to 50%.37 Extrarenal expuration by continuous venovenous hemofiltration has also been shown to be effective in cases of acute renal failure occurring in ICU.38 In all these situations, the short-term prognosis is never influenced by the characteristics of the underlying neoplasm.

SYMPTOM MANAGEMENT The signs and symptoms manifested by patients with lung cancer depend on the localization of the tumor, its locoregional spread, and the effects of metastatic growth. Dyspnea, pain, and cough are common symptoms of lung cancer patients, with frequencies of 59%, 48%, and 71%, respectively.2 Pain More than 50% of lung cancer patients will present with pain during the evolution of their disease. The first cause of pain is related to direct tumor involvement, bone destruction, liver metastasis, nerve compression or invasion, or soft tissue infiltration. Pancoast’s syndrome with shoulder pain, brachial plexopathy, and Horner’s sign occurs in apical tumors invading the brachial plexus, the chest wall, and stellate ganglion. Pleural effusion can cause pleuritic pain. Persistent pain after surgery, radiotherapy, or chemotherapy can also occur. Finally, some non-cancer-related causes of pain like infection have to be looked for. Effective management of pain can be achieved in approximately 90% of patients. A pain severity scale from 0 (‘no pain’) to 10 (‘pain as bad as you can imagine’) may be helpful in titrating analgesics. Careful description of the type of pain is also essential. Some cancer lesions, such as bone or epidural metastases, responsible for pain can be treated by radiotherapy, chemotherapy, or sometimes by surgical debulking. Any analgesic medication program should be as simple as possible and non-invasive.39 Except for a minority of patients whose pain is clearly episodic, analgesics should be given around the clock. Treatment is decided

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according to ascending steps. A non-opioid drug (paracetamol) should be used as first step. Non-steroidal antiinflammatory drugs (NSAIDs) are very effective but have a number of side-effects (e.g. gastritis and gastrointestinal bleeding, renal failure). As second step, an opioid for mild to moderate pain (e.g. tramadol, codeine) should be added. The third step includes an opioid for moderate to severe pain (e.g. morphine, hydromorphone, methadone, fentanyl). Oral morphine, as an immediate or sustained-release preparation, is the analgesic of choice for moderate to severe cancer pain. A typical starting dose of immediate-release morphine is 5 to 30 mg every four hours, with a relatively rapid increase if necessary. When an effective dose of short-acting morphine has been established, the required dose for a long-acting preparation can be calculated, with an additional supply of short-acting morphine if necessary. A consistent need for this supplemental morphine will dictate an upward dose adjustment of the sustained-release morphine. Transdermal preparations (e.g. fentanyl) can be more convenient, and with fewer side-effects (e.g. constipation) than morphine,40 but they are more expensive. Constipation is a frequent side-effect of opioids that should be managed prophylactically (increased fiber consumption, mild laxative). Initial nausea and somnolence are also frequent. An anti-emetic should be administered to all patients who are started on opioids. The combination of opioids and paracetamol or NSAID often provides more analgesia than can be accomplished by either class of drugs alone, and thus facilitates the use of lower opioid doses with fewer related side-effects. A co-analgesic (corticoid, tricyclic antidepressant, or anticonvulsant) may be added at each step. Indeed, gabapentine, carbamazepine, valproic acid, clonazepam, and phenytoin can be used to manage neuropathic pain. Tricyclic drugs are useful in a variety of neuropathic pain (dysesthetic or burning pain). Corticosteroid administration can lead to mood elevation, relief of visceral inflammation, and reduction of cerebral or spinal cord edema when there is symptomatic metastasis or spinal cord compression. Bisphosphonate (pamidronate, zoledronate) can be administered alone or as an adjunct to external radiation therapy for bone metastases. Other non-pharmacologic methods exist to manage pain for example cutaneous stimulation, nerve blocks, maintenance of regular activity, avoidance of prolonged immobilization, psychosocial intervention, and education.

including physiologic, psychologic, and social components. It is perceived as one of the most devastating, distressing symptoms. Its major physical evidence is tachypnea. Dyspnea is, with cough, the most commonly reported symptom in lung cancer patients. There are multiple causes of dyspnea and several may co-exist. The most common cause of dyspnea in lung cancer patients is the primary or metastatic disease, but it may also be related to cancer treatment (lung resection, anemia, chemotherapy or radiation-induced lung toxicities) or to non-cancer causes (lung infection, pulmonary embolism, chronic obstructive pulmonary disease, heart failure). Most of the time, the cause can be easily determined by history and physical examination. Chest imaging, oximetry, blood tests, and pulmonary functions are useful in the assessment of dyspnea. The first aim should be to correct the cause when possible and appropriate. Palliative management of dyspnea in the cancer patient is often complex and difficult.39 Oxygen may be helpful. However, there are no large studies available and, except for hypoxemic patients who feel less breathless on oxygen,41 it is difficult to predict which patients will benefit.42 As bronchospasm is one important reversible cause of dyspnea in cancer patients, bronchodilatators (β2-agonists, anticholinergics) and aerosolized steroids are commonly used. Systemic steroids can be used for patients with airflow obstruction, postradio- or chemotherapy pneumonitis, or lymphangitic carcinomatosis. Opioids are efficacious in the management of dyspnea by decreasing the perception of breathlessness. The advised starting morphine dose is 10 mg po or 5 mg sc/4 hours around the clock. If the patient already receives morphine for pain, doses must be increased to relieve dyspnea. Intravenous continuous morphine infusion is optional for terminal patients with severe dyspnea. In this situation, patient and family members should be aware of the risk of hypoventilation and death. Nebulized opioids could also be tried in less severe cases, and with fewer sideeffects, although their efficacy has not been demonstrated. Subcutaneous scopolamine, hyoscine, or atropine can be beneficial in drying up upper airway secretions. Anxiolytics are needed when an anxious component is obvious (lorazepam 0.5–2 mg/day; diazepam 2.5 mg/6 hours) or for intractable dyspnea (midazolam 10 mg iv /day). Finally, environmental issues are important: a calm atmosphere, relaxation, breathing techniques, and psychosocial support can reduce the perception of breathlessness.

Dyspnea Dyspnea is a subjective experience of difficult and uncomfortable breathing. It is a complex symptom

Cough Cough is observed in 70 to 90% of the patients with lung cancer. Involvement of any part of the respiratory system

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can lead to cough, predominantly lung cancer originating in the airways. Radiation- or chemotherapy-induced fibrosis must also be considered when evaluating the causes of cough. Finally, non-cancer causes of cough (e.g. respiratory infection, drugs, heart failure, gastro-esophagal reflux, chronic bronchitis) must also be looked for. The control of cough is of particular importance because it leads to sleep disturbance, shortness of breath, pain, and decreased quality of life. Pharmacologic palliative treatments of cough39 are often disappointing for example non-opioid cough suppressants (e.g. dextromethorphan, levodroproprizine), cromoglycate, bronchodilatators if bronchospasm exists, corticosteroids (in case of radio-induced pneumonitis), and nebulized lidocaine. Narcotics, acting via opioid receptors, are the most efficacious treatment for significant cough. Codeine (15–30 mg/6 hours) and analogs can be tried initially and, if insufficient, morphine (5–10 mg/6 hours) can be administered. Depression and anxiety Psychologic distress including depression is an essential element of the quality of life of a cancer patient. Between 15 and 44% of lung cancer patients experience some form of depression after diagnosis, increasing according to disease extent and associated prognosis. After curative resection, the prevalence of depression is 4 to 8%.43 In unresectable lung carcinoma patients, about 15% of the patients have some degree of suicidal ideation,44 for which predisposing factors are pain and depressive disorder. Female gender, living alone, no children in the role of confidant, nurses as confidants, are predictive factors for psychologic distress in ambulatory lung cancer patients.45 For example, in 52 newly diagnosed lung cancer patients undergoing radio- or chemotherapy, 4% had an affective disorder, 44% expressed feelings of sadness, 29% feelings of fear, 8% feelings of guilt, 13% had considered suicide, and 31% had thoughts of death.46 In the same study, 52% of the patients had insomnia and 19% concentrating difficulties. Anxiety and depression can be related to the announcement of the diagnosis, the numerous investigations, the treatments, the symptoms due to cancer or its treatment, and the fear of death. In the cancer patient, it can be difficult to discriminate between underlying biological/organic and psychologic factors causing depression. Moreover, somatic symptoms of depression can be confused with constitutional symptoms due to the cancer or its treatment (such as fatigue). Supportive conversation and advice must be the firstline treatment, but anxiolytics and antidepressants

could be necessary. Finally, active anticancer treatments play a psychologic role by improving performance status or quality of life, by alleviating symptoms, and by giving hope. Anorexia and weight loss Cancer-associated cachexia/anorexia occurs in almost any late stage cancer, but is particularly common in lung cancer, even at an early stage. Cachexia is a consequence of both decreased food intake (resulting from loss of appetite) and metabolic abnormalities (e.g. release of tumor-induced cytokines). Contributing factors include altered taste, pain, dysphagia, asthenia, and depression. As removal of the underlying causes is rarely possible, supportive measures are required. Control of nausea and vomiting is the first therapeutic step. Nasogastric tube feeding or parenteral alimentation must be discussed case by case, as their efficacy is relative. Forcing patients to eat has no impact on well-being and survival. Patients have to be encouraged to eat frequent, small, enjoyable meals and to take a lot of liquids (often better tolerated than solid food). Most appetite stimulants are not very effective. Steroids (dexamethasone, prednisolone, or methylprednisolone) have some short-term benefit in stimulating appetite, but their impact on weight gain is not defined.47 Due to their side-effects, caution is necessary for prolonged use of steroids. Progestational agents (e.g. megestrol acetate, medroxyprogesterone acetate) stimulate appetite and, at least for megestrol, have a positive impact on weight. In some studies, megestrol acetate was shown to improve quality of life.47 However, the benefit of these drugs must be counterbalanced with an increased risk of thromboembolic episodes. Other drugs have been tested, some with promising results. For example, in a randomized clinical trial, 58 patients with advanced NSCLC were randomized to receive either 10 30-hour adenosine triphosphate (ATP) iv infusions every two to four weeks or no treatment. An inhibition of weight loss and appetite stabilization was noted in the ATP group.48 In contrast, nandrolone, pentoxifylline, and hydrazine sulfate are not effective.49 MANAGEMENT OF TREATMENT COMPLICATIONS The main complications related to the medical treatment of lung cancer are chemotherapy-induced aplasia, mainly neutropenia but also anemia and thrombocytopenia, and vomiting secondary to cisplatin administration.

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Neutropenia The relationship between neutropenia and the risk of severe infections has been established by Bodey et al.50 The risk of developing infectious complications depends on the duration and on the level of the neutropenia. These two variables also predict the severity of the infection. In addition to neutropenia, lung cancer patients are predisposed to infection due to neoplastic bronchial obstruction favoring obstructive pneumonia and by concomitant COPD. The impact of infections on survival in lung cancer patients has not been well established. No statistically significant survival difference was observed between SCLC patients presenting with lung abscess and the others.51 In a very old study, the authors52 observed a significant reduction in median survival in patients with pulmonary infections. Few studies have assessed the type and microbiologic nature of infection in lung cancer patients. Recently, we found that the lung is the predominant site of infection and that, among all microbiologically documented infectious episodes, Gram-negative bacteria were the most prominent pathogens, mainly Escherichia coli, Haemophilus influenzae, Pseudomonas aeruginosa, and Moraxella catarrhalis, although Streptococcus pneumoniae and Staphylococcus aureus were frequently observed (7% and 9%, respectively, of all documented pathogens).53 Few data are today available concerning infection in neutropenic lung cancer patients. In cancer patients from any origin presenting with febrile neutropenia, Gram-negative microorganisms are the most common pathogens, although an increase in Gram-positive bacteria has been demonstrated in recent years. Febrile neutropenia (FN) is a life-threatening complication requiring prompt empiric antibiotic therapy. Guidelines have been published by the Infectious Disease Society of America (IDSA) for the use of antimicrobials in patients with cancer, not specifically addressed for lung cancer, and FN.54 Broad-spectrum β-lactams or carbapenem are suggested as first-line therapy. Outside of specific situations, aminoglycosides (for shock, Gram-negative bacteriemia, etc.) and glycopeptides (for documented resistant Gram-positive infection or clinical signs suggesting infection with resistant Grampositive organisms) are no longer needed routinely in first-line antibiotic combinations, monotherapy being as effective.55,56 Oral antibiotic therapy should be considered for low-risk patients.54 The role of new fluoroquinolones with increased sensitivity against Grampositive pathogens remains to be validated in randomized trials. In any case, given the importance of S. pneumoniae as a pathogen in patients with lung cancer, antibi-

otics should provide adequate coverage for this bacterium.53 Some studies have assessed the role of antibiotic prophylaxis to reduce the incidence of FN in SCLC patients. In this setting, prophylactic cotrimoxazole appeared effective. In pooled results from three studies,57 a global reduction of infection from 36 to 17% was observed, in patients with bacteriemia as well as for non-bacteriemic infectious episodes. In a more recent study by the EORTC,58 163 chemonaive SCLC patients were randomized between prophylaxis with ciprofloxacine (750 mg, bid) plus roxithromycin (150 mg bid) and placebo. Prophylaxis was associated with a statistically significant reduction in the incidence of FN (43% vs 24%, p = 0.007), fewer microbiologically and clinically documented infections, fewer hospitalizations for FN, and a reduction in the number of infectious deaths (6% versus 0%, p = 0.022). Nevertheless, it is not clear at the present time if this strategy has an impact on the overall survival of lung cancer patients undergoing chemotherapy. Another way to reduce the duration of neutropenia and the incidence of FN could be the administration of colony-stimulating factors (CSFs). In a meta-analysis of randomized studies assessing the role of CSF in SCLC,59 we did not observe any favorable impact of CSF on survival, whatever the type of chemotherapy, although dose intensity was generally increased with CSF administration. Yet, a detrimental impact on survival was noted in patients treated with concomitant radiochemotherapy,60 or those receiving high-dose concentrated chemotherapy.61 No significant difference in infection-related mortality was associated with CSF administration. The duration of neutropenia below 500/mm3 was reduced and a statistically significant reduction in the incidence of FN was noted in two-thirds of the trials. No meaningful conclusions could be drawn from two small randomized studies performed in NSCLC. CSF administration has also been tested in addition to antibiotics in established FN. Although a shorter time to neutrophil recovery was evident, overall mortality was not influenced significantly.62 These results did not support the routine use of CSF, either for preventing FN or in addition to antibiotics for the treatment of FN, in patients with lung cancer. Vaccination against S. pneumoniae and influenza viruses might be another way to prevent infections in lung cancer patients. Few data are currently available. In a small study, the majority of the patients responded fully to influenza vaccination.63 Pneumococcal vaccination was unsuccessful to prevent infection in a small

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randomized study,64 but the number of patients was limited and new vaccines have since been developed. Nevertheless, vaccination should be considered for lung cancer patients as such treatment is well tolerated and could have a beneficial impact on infection at a low cost. Anemia Platinum-based chemotherapy, as well as other agents, is frequently associated with anemia. Guidelines from the Cancer Care Ontario Program (www.cancercare. on.ca) recommend the use of erythropoietin (EPO) to reduce the incidence of symptomatic anemia in patients receiving platinum-based chemotherapy, but also for myelosuppressive regimens that do not contain platinum derivatives. In a recent meta-analysis, the transfusion requirement was reduced by 33% with EPO administration,65 without significantly higher toxicity. A beneficial effect on survival was suggested (hazard ratio 0.81). Currently, three EPOs are marketed: epoietin alpha, r-huEPo, and darbepoietin alpha. All three have demonstrated their efficacy in lung cancer patients. Today, there is no evidence that the effectiveness of these drugs is different.66 Recommended initial dosages are either 150 IU/kg three times a week or 40 000 IU once a week for epoietin alpha and r-huEPO, and the equivalent weekly dose of 100 µg (USA) or 150 µg (Europe) for darbepoietin alpha. Thrombocytopenia Severe, potentially lethal bleeding is a frequent problem in oncology. However, platelet transfusion requirement is ten times less frequent in solid tumors than in hematologic patients. Half of the incidents of bleeding are confined to the skin or mucosa. Risk factors for lifethreatening bleedings in thrombocytopenic patients are concomitant infection, invasion of main vessels, as it can be seen in lung cancer, and coagulation disorders. Randomized trials conducted in the 1970s have shown the effectiveness of a prophylactic transfusion policy on the occurrence of bleeding. The threshold below which platelets have to be transfused has also been the subject of randomized trials. A level of 10 000 platelets/mm3 has been shown to be as safe as 20 000/mm3, with the advantage of requiring significantly fewer platelet transfusions in the absence of fever or infection, in the absence of bleeding, and when invasive procedures were not planned. There are no specific data for solid tumors and we could only extrapolate these results to the lung cancer patients.

Nausea and vomiting It was the development of cisplatin-based therapy for lung cancer patients which initiated a strong stimulus for the control of nausea and vomiting. The initial regimens that were able to control severe emesis caused by highdose cisplatin consisted of high doses (2–4 mg/kg) of metoclopramide in association with dexamethasone and lorazepam. These regimens were complicated by a significant number of side-effects, such as extrapyramidal motor disturbances. The introduction of the ‘setrons’, 5-HT3 antagonists, made anti-emetic therapy in patients treated with cisplatin much easier. Once again, the addition of corticosteroids increased the effectiveness of all the setrons. However, setrons are essentially active in acute emesis, and did not demonstrate a superior efficacy in delayed emesis compared with dexamethasone plus metoclopramide. The selective NK1 antagonist, aprepitant, is more effective for controlling delayed emesis after cisplatin compared to 5-HT3 antagonists. Different guidelines have been reported for the prevention and treatment of chemotherapy-induced nausea and vomiting. As well as the recommendations made by ASCO67 and by the Cancer Care Ontario Program (www. cancercare.on.ca), a combination of 5-HT3 antagonist plus a corticosteroid is recommended for the prevention of acute emesis induced by chemotherapy with high emetogenic potential. For patients receiving cisplatin, a corticosteroid plus metoclopramide (or domperidone) and eventually a 5-HT3 antagonist are recommended for the prevention of delayed emesis. The role of aprepitant is not yet well delineated, although the consensus from the Multinational Association of Supportive Care in Cancer suggests its use in addition to a 5-HT3 antagonist and dexamethasone for acute emesis and to dexamethasone for delayed emesis.68 In lung cancer patients, caution must be used with aprepitant, which is an inhibitor of CYP3A4 and could thus theoretically increase the concentrations of drugs metabolized this way, including the chemotherapeutic agents frequently administered in these patients: docetaxel and paclitaxel, etoposide, ifosfamide, vinorelbine, vincristine, and vinblastine (www. merck.com/product/hcp.html).

REFERENCES 1. Aaronson NK, Ahmedzai S, Bergman B et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85: 365–76.

244 Textbook of Lung Cancer 2. Hollen PJ, Gralla RJ, Kris MG, Potanovich LM. Quality of life assessment in individuals with lung cancer: testing the Lung Cancer Symptom Scale (LCSS). Eur J Cancer 1993; 29A (Suppl 1): S51–8. 3. Cella DF, Tulsky DS, Gray G et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 1993; 11: 570–9. 4. Morita S, Kobayashi K, Eguchi K et al. Influence of clinical parameters on quality of life during chemotherapy in patients with advanced non-small cell lung cancer: application of a general linear model. Jpn J Clin Oncol 2003; 33: 470–6. 5. Helsing M, Bergman B, Thaning L, Hero U. Quality of life and survival in patients with advanced non-small cell lung cancer receiving supportive care plus chemotherapy with carboplatin and etoposide or supportive care only. A multicentre randomised phase III trial. Joint Lung Cancer Study Group. Eur J Cancer 1998; 34: 1036–44. 6. Cullen MH, Billingham LJ, Woodroffe CM et al. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol 1999; 17: 3188–94. 7. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 1999; 91: 66–72. 8. Thongprasert S, Sanguanmitra P, Juthapan W, Clinch J. Relationship between quality of life and clinical outcomes in advanced non-small cell lung cancer: best supportive care (BSC) versus BSC plus chemotherapy. Lung Cancer 1999; 24: 17–24. 9. Anderson H, Hopwood P, Stephens RJ et al. Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer – a randomized trial with quality of life as the primary outcome. UK NSCLC Gemcitabine Group. Non-Small Cell Lung Cancer. Br J Cancer 2000; 83: 447–53. 10. Ranson M, Davidson N, Nicolson M et al. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2000; 92: 1074–80. 11. Roszkowski K, Pluzanska A, Krzakowski M et al. A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC). Lung Cancer 2000; 27: 145–57. 12. Shepherd FA, Dancey J, Ramlau R et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinumbased chemotherapy. J Clin Oncol 2000; 18: 2095–103. 13. Socinski MA, Schell MJ, Peterman A et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV nonsmall-cell lung cancer. J Clin Oncol 2002; 20: 1335–43. 14. Bonomi P, Kim K, Fairclough D et al. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 2000; 18: 623. 15. Kelly K, Crowley J, Bunn PA Jr et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung

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Quality of life and supportive care 245 32. Sculier JP, Markiewicz E. Cardiopulmonary resuscitation in medical cancer patients: the experience of a medical intensivecare unit of a cancer centre. Support Care Cancer 1993; 1: 135–8. 33. Vitelli CE, Cooper K, Rogatko A, Brennan MF. Cardiopulmonary resuscitation and the patient with cancer. J Clin Oncol 1991; 9: 111–15. 34. Sculier JP, Berghmans T, Lemaitre F, Vallot F. La ventilation artificielle chez les patients atteints de cancer. Rev Mal Resp 2001; 18: 137–54. 35. Vallot F, Paesmans M, Berghmans T, Sculier JP. Leucopenia is an independent predictor in cancer patients requiring invasive mechanical ventilation: a prognostic factor analysis in a series of 168 patients. Support Care Cancer 2003; 11: 236–41. 36. Azoulay E, Alberti C, Bornstain C et al. Improved survival in cancer patients requiring mechanical ventilatory support: impact of noninvasive mechanical ventilatory support. Crit Care Med 2001; 29: 519–25. 37. Meert AP, Close L, Hardy M et al. Noninvasive ventilation: application to the cancer patient admitted in the intensive care unit. Support Care Cancer 2003; 11: 56–9. 38. Berghmans T, Meert AP, Markiewicz E, Sculier JP. Continuous venovenous haemofiltration in cancer patients with renal failure: a single-centre experience. Support Care Cancer 2004; 12: 306–11. 39. Kvale PA, Simoff M, Prakash UB. Lung cancer. Palliative care. Chest 2003; 123: 284S–311S. 40. van Seventer R, Smit JM, Schipper RM et al. Comparison of TTS-fentanyl with sustained-release oral morphine in the treatment of patients not using opioids for mild-to-moderate pain. Curr Med Res Opin 2003; 19: 457–69. 41. Bruera E, de Stoutz N, Velasco-Leiva A et al. Effects of oxygen on dyspnoea in hypoxaemic terminal-cancer patients. Lancet 1993; 342: 13–14. 42. Booth S, Wade R, Johnson M et al. The use of oxygen in the palliation of breathlessness. A report of the expert working group of the Scientific Committee of the Association of Palliative Medicine. Resp Med 2004; 98: 66–77. 43. Uchitomi Y, Mikami I, Nagai K et al. Depression and psychological distress in patients during the year after curative resection of non-small-cell lung cancer. J Clin Oncol 2003; 21: 69–77. 44. Akechi T, Okamura H, Nishiwaki Y, Uchitomi Y. Predictive factors for suicidal ideation in patients with unresectable lung carcinoma. Cancer 2002; 95: 1085–93. 45. Akechi T, Kugaya A, Okamura H et al. Predictive factors for psychological distress in ambulatory lung cancer patients. Support Care Cancer 1998; 6: 281–6. 46. Ginsburg ML, Quirt C, Ginsburg AD, MacKillop WJ. Psychiatric illness and psychosocial concerns of patients with newly diagnosed lung cancer. CMAJ 1995; 152: 701–8. 47. Desport JC, Blanc-Vincent MP, Gory-Delabaere G et al. Standards, options and recommendations for the use of appetite stimulants in oncology. Bull Cancer 2000; 87: 315–28. 48. Agteresch HJ, Rietveld T, Kerkhofs LG et al. Beneficial effects of adenosine triphosphate on nutritional status in advanced lung cancer patients: a randomized clinical trial. J Clin Oncol 2002; 20: 371–8. 49. Desport JC, Gory-Delabaere G, Blanc-Vincent MP et al. Standards, options and recommendations for the use of

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appetite stimulants in oncology (2000). Br J Cancer 2003; 89: S98–100. Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966; 64: 328–40. Hansen SW, Aabo K, Osterlind K. Lung abscess in small cell carcinoma of the lung during chemotherapy and corticosteroids: an analysis of 276 consecutive patients. Eur J Resp Dis 1986; 68: 7–11. Perlin E, Bang KM, Kassim OO. The impact of pulmonary infections on the survival of lung cancer patients. Cancer 1960; 66: 593–6. Berghmans T, Sculier JP, Klastersky J. A prospective study of infections in lung cancer patients admitted to the hospital. Chest 2003; 124: 114–20. Hughes WT, Armstrong D, Bodey GP et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2003; 34: 730–51. Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam–aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ 2004; 328: 668. Vardakas KZ, Samonis G, Chrysanthopoulou SA et al. Role of glycopeptides as part of initial empirical treatment of febrile neutropenic patients: a meta-analysis of randomised controlled trials. Lancet Infect Dis 2005; 5: 431–9. Klastersky J. Les complications infectieuses du cancer bronchique. Rev Mal Resp 1998; 15: 451–9. Tjan-Heijnen VC, Postmus PE, Ardizzoni A et al. Reduction of chemotherapy-induced febrile leucopenia by prophylactic use of ciprofloxacin and roxithromycin in small-cell lung cancer patients: an EORTC double-blind placebo-controlled phase III study. Ann Oncol 2001; 12: 1359–68. Berghmans T, Paesmans M, Lafitte JJ et al. Role of granulocyte and granulocyte-macrophage colony-stimulating factors in the treatment of small-cell lung cancer: a systematic review of the literature with methodological assessment and meta-analysis. Lung Cancer 2002; 37: 115–23. Bunn PAJ, Crowley J, Kelly K et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group [published erratum appears in J Clin Oncol 1995; 13 (11): 2860]. J Clin Oncol 1995; 13: 1632–41. Pujol JL, Douillard JY, Riviere A et al. Dose-intensity of a fourdrug chemotherapy regimen with or without recombinant human granulocyte-macrophage colony-stimulating factor in extensive-stage small-cell lung cancer: a multicenter randomized phase III study. J Clin Oncol 1997; 15: 2082–9. Clark OA, Lyman GH, Castro AA et al. Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a metaanalysis of randomized controlled trials. J Clin Oncol 2005; 23: 4198–214. Anderson H, Petrie K, Berrisford C et al. Seroconversion after influenza vaccination in patients with lung cancer. Br J Cancer 1999; 80: 219–20. Klastersky J, Mommen P, Cantraine F, Safary A. Placebo controlled pneumococcal immunization in patients with bronchogenic carcinoma. Eur J Cancer Clin Oncol 1986; 22: 807–13.

246 Textbook of Lung Cancer 65. Bohlius J, Langensiepen S, Schwarzer G et al. Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis. J Natl Cancer Inst 2005; 97: 489–98. 66. Schwartzberg LS, Yee LK, Senecal FM et al. A randomized comparison of every-2-week darbepoietin alfa and weekly epoietin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer. Oncologist 2004; 9: 696–707.

67. Gralla RJ, Osoba D, Kris MG et al. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. American Society of Clinical Oncology. J Clin Oncol 1999; 17: 2971–94. 68. Kris MG, Hesketh PJ, Herrstedt J et al. Consensus proposals for the prevention of acute and delayed vomiting and nausea following high-emetic-risk chemotherapy. Support Care Cancer 2005; 13: 85–96.

17 The cost and cost-effectiveness of lung cancer management William K Evans, Christopher J Longo Contents Introduction • Types of economic evaluation • Methodologic issues • Other considerations • The cost of lung cancer management • Estimating the costs of lung cancer in Canada • The cost-effectiveness of lung cancer treatment • Lung cancer economics and health-care policy • Conclusion

INTRODUCTION Lung cancer is the second most common cancer in men and women in North America, and the leading cause of cancer death among both sexes in the industrialized world. In 2007, it is estimated that lung cancer will be responsible for the deaths of over 180 000 individuals in North America.1,2 In the last decade there has been a marked increase in the incidence of lung cancer in women.3 Worldwide, the problem of lung cancer is escalating as the developing world succumbs to the promotional activities of the tobacco industry. The resulting worldwide epidemic of lung cancer is a major public health concern, not only because of the enormous loss of life and the great morbidity it causes, but also because of the large economic burden it places on health-care systems and society in general. Brown et al4 have extensively analyzed the economic burden of cancer in the United States based largely on 1990 data sources. The total direct healthcare expenditures for cancer were estimated to be US$ 27.5 billion, including the costs of hospital care ($17.9 billion), physician services ($6.6 billion), nursing services ($1.3 billion), drugs ($1.1 billion), and other ($0.5 billion). Soni5 more recently estimated the total direct health-care expenditures for cancer at $62.2 billion (2004) using the Medical Expenditure Panel Survey (MEPS). Although the data from Soni on cancer expenditures are more current than those available in Brown’s publication no breakdown across types of health services was described. Indirect costs were estimated by Brown et al4 to be $58.7 billion as a result of mortality costs and $9.9 billion due to morbidity costs. Morbidity costs are measured by lost income due to disability and absenteeism from work. In total, the direct and indirect costs of cancer were estimated to total US$96.1 billion. The percentage of health expenditure dedicated to cancer appears to have changed very little in the

interval from 1963 to 1995. Although the percentage due to cancer increased from a low of 4.35% in 1963 to a high of 6.01% in 1980, more recent figures from Soni5 based on the MEPS data suggest the percentage of health expenditures dedicated to cancer in 2004 had increased to 6.9%. Based on expenditure data from the 1996 Surveillance, Epidemiology, and End Results (SEER) database, Brown has made estimates of the direct medical care costs for all cancers and for the four most common tumor types in the United States. Expenditures were estimated to be $6.0 billion for breast cancer, $5.7 billion for colorectal, $4.7 billion for lung, and $4.6 billion for prostate cancer. These four tumor types, which together make up approximately 50% of all cancer cases, accounted for 49.5% of the total direct costs of cancer ($21 billion of $42.4 billion). In California, a study of the long-term costs of treatment estimated that the cost per case for the common cancers ranged from a high of US$64 000 for ovarian cancer to a low of $29 000 for prostate cancer.6 Breast, colon, and lung cancer were estimated to incur long-term costs of $35 000, $42 000, and $33 000, respectively. From these analyses, it can be readily appreciated that the cost of lung cancer care will be high in industrialized countries where there is a high incidence of lung cancer and adequate resources to provide stateof-the-art clinical care. The impact of such a large economic burden on the health-care systems of developing countries could easily overwhelm the financial ability of a country to provide other types of appropriate care. Even in wealthy nations, fiscal constraint is increasingly causing physicians and health-care administrators to critically examine the value of healthcare interventions and the efficiency of health-care delivery systems. This concern about the value for money expended is particularly relevant to the problem of lung cancer,

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where, despite recent advances, the overall prognosis of the disease remains poor.3 New treatments for lung cancer, particularly for early stage resected disease and locally advanced disease, add expense but also improve survival. However, the reputation of the disease as one with a poor prognosis can be a barrier to the adoption of new therapies. Economic evaluations of the new treatment interventions for lung cancer can shed light on their relative cost-effectiveness compared with other health-care interventions. An understanding of the cost components of care can also help to inform health-care providers on how to deliver treatments in the most efficient fashion. This chapter will describe some of the economic analyses that have been conducted on lung cancer management throughout the world, particularly in the United States and Canada. Although it is not possible to easily extrapolate health economic evaluations directly from one health-care system to another, there are lessons that can be learned from a review of these studies. Physicians have typically had little training and only passing interest in health economics, and, therefore, may be relatively unaware of the types of health economic analysis that can be done and their application to lung cancer. Therefore, prior to presenting data from studies evaluating the economic burden of lung cancer, the cost components of lung cancer management, and the cost-effectiveness of treatment, we will first provide some information on the types of economic evaluation and costing methodologies that are commonly employed. TYPES OF ECONOMIC EVALUATION There are four types of commonly used economic evaluations (Table 17.1). Each involves a comparison

of the costs and consequences of alternative interventions. The main difference between each of these evaluations is in the method used to measure the consequences. Cost-minimization analysis Also called a ‘cost analysis’, cost-minimization analysis is the simplest form of economic evaluation. This type of study assumes that the outcomes or effectiveness of the interventions are equal. Resource utilization is the only significant difference between the options. The direct costs associated with each intervention are compared, and the least costly strategy is the preferred choice. No assessment of the consequences of treatment is required. Although there are some examples of cost minimization in the oncology literature, including studies of staging procedures,7,8 radiotherapy techniques,9–11 and systemic therapy,12 this type of economic evaluation is not common because cancer treatments rarely produce equivalent survival or quality of life benefits. Cost-effectiveness analysis If the interventions being assessed are not of equal effectiveness, a more sophisticated analysis is required. Cost-effectiveness analysis includes a comparison of outcomes, as well as costs. In this form of analysis, the effectiveness of alternatives is measured in natural units, such as life years gained, cases successfully treated, or cases averted. These outcomes are then related to the direct costs of the procedure by calculating ratios of cost per unit of effectiveness, such as cost per life year gained. Typically the results are described as an incremental cost-effectiveness ratio (ICER), since the analysis is a comparative one, and presents both the incremental costs and the incremental benefits.

Table 17.1 Types of economic analyses

Cost-minimization analysis Cost-effectiveness analysis Cost–utility analysis

Cost–benefit analysis

Compares strategies of equal effectiveness to determine which is least expensive Compares ratios of the incremental cost over the incremental effectiveness of alternative strategies Compares ratios of the incremental cost over the incremental utility; a utility is a measure of the value attributed to a health state, usually measured in quality adjusted life years (QALYs) Assigns monetary value to the health benefits of an intervention; if the cost/benefit ratio is <1, the intervention is attractive

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Cost-effectiveness analysis has the advantage of being easily understood. As a result, it is the most common approach to economic evaluation in health care.13 However, its value is limited by the fact that only one measure of effectiveness can be related to the cost of the interventions. A cost per life year gained looks at survival, but not at toxicity, inconvenience, or effects on quality of life. These are also important considerations in cancer treatment. For example, surgery for the primary treatment of a specific cancer can be compared to radiation in terms of its costs per life year gained, but this may lead to an invalid conclusion if their effects on quality of life are very different. Therefore, cost-effectiveness analysis can help choose between similar treatments for a specific disease, but cannot help in choices across dissimilar treatments and conditions. More recently, new methodologies such as ‘net health benefits’ or ‘net monetary benefits’ have been introduced into cost-effectiveness analysis for health care.14 These newer methodologies provide a more appropriate way to deal with situations where costeffectiveness ratios might be misleading, as when both costs and effects are negative and the resulting ratio is positive. Standard cost-effectiveness formulas do not deal with this scenario well, whereas the ‘net benefit’ approach is straightforward. Cost–utility analysis A cost–utility analysis is similar to a cost-effectiveness analysis, but it incorporates mortality and morbidity data into a single multidimensional measure, usually as a quality adjusted life year (QALY).15 The QALY is a measure of the quantity of life gained by a treatment, weighted by the quality of that life. This is relevant in oncology because many anticancer treatments are inconvenient and have substantial toxicities that impair quality of life. Because the QALY is not disease-specific, it also allows comparisons between the relative efficiency of health-care interventions for different conditions. Quality of life is approximated by a utility, which is a measure of preference for a given health state rated on a scale where 0 equals death and 1 equals perfect health. Theoretically, a utility is most accurately determined using a ‘standard gamble’ exercise, where a subject in a particular health state finds the balance between the chance of returning to perfect health and the risk of possibly dying in the process. Other techniques such as time trade-off and direct rating on visual analog scales have also been employed.16 Alternatively, instruments such as the Health Utilities

Index17 and the EuroQoL18 can be administered alongside standard gamble exercises in order to relate their scores to utilities. However, most quality of life instruments have not undergone such testing. An approach often used to integrate quality and quantity of life calculates the quality-adjusted time with and without symptoms or toxicity (Q-TWiST).19 It is particularly useful when looking at interventions that will have health effects persisting beyond the duration of treatment, such as adjuvant chemotherapy. There is controversy about whether utilities should be derived from patients, their families, health-care workers, or lay societal ‘jurors’ given detailed scenarios describing the health state. Recent guidelines favor the latter as being most consistent with the societal perspective in an economic analysis.20 However, there is concern that people without relevant disease experience may not fully understand the health (disease) state. Any of these approaches to defining utilities is defensible, as long as it is clearly identified in the report of the study. Cost–benefit analysis Cost–benefit analysis (CBA) differs in how it values consequences of health-care programs. CBA values programs in monetary terms, thus allowing a direct comparison of a program’s incremental costs with its incremental consequences. The result is either a net cost or a net benefit of the program. One common application of this methodology is to convert the quality-adjusted life year in the denominator of an analysis into a monetary equivalent to arrive at the absolute benefit of the intervention. An intervention is ‘cost beneficial’ if the benefits (measured in currency) are greater than the actual costs. Because these analyses always produce a monetary outcome, it is relatively easy to compare different potential uses of resources. However, placing a monetary value on the often intangible outcomes of health care, in particular the value of a life, is problematic. As a result, true cost–benefit analyses are rare. Each of these analytic techniques has its place. While cost–utility analysis is ideal for comparing toxic treatment options, a cost-effectiveness analysis may be adequate when deciding between two diagnostic strategies.

METHODOLOGIC ISSUES As the primary purpose of a cost-effectiveness analysis is to introduce a consideration of resource consumption

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into medical decision-making, an economic evaluation begins by identifying all the consequences of adopting one intervention over another.21 This involves identifying the resources used (medical care services, the cost of informal care-giving, and other non-direct medical care costs) and the effects of the treatment intervention on the health state. Both direct and indirect health-care costs should be considered. The term direct health-care cost refers to resource use that is directly attributable to the medical intervention or treatment regimen. In health economics, the term indirect refers to gains or losses in productivity related to the illness. Because indirect costs in accounting terminology refer to overhead or fixed costs of production, some health economists recommend the use of the term ‘productivity cost’ to define the indirect cost associated with the morbidity or mortality of an illness.21 Assessment of costs Depending on the perspective taken, the resource costs in an economic analysis can include: •

•

•

•

direct treatment costs: the resources used by the health sector to provide treatment (e.g. healthcare provider time, drugs, equipment, diagnostic tests, overhead); direct non-treatment costs: the resources used by patients and family to gain access to and participate in treatment, such as travel, parking, and accommodation near a cancer treatment center. Often these are measured by having patients complete diaries of their out-of-pocket expenses. indirect costs: costs such as lost work time for the patient or caregiver, or the time of volunteers assisting with treatment; intangible costs: the costs of anxiety, uncertainty, or pain caused by the treatment itself. These have proven difficult to measure. Techniques, such as ‘willingness to pay’ have been developed to capture these ‘costs’, but can be affected by each subject’s own economic circumstances.

The choice of time horizon for an economic evaluation is important to ensure that the analysis has considered all relevant resource utilization. If a new treatment intervention has an impact on the natural history of a disease, it can affect ‘downstream’ costs. For example, when analyzing the cost of treating lung cancer, up-front costs include the cost of physician visits, diagnostic tests and procedures, hospitalization, as well as drugs and dispensing fees. Downstream costs include the costs for treatment of long-term compli-

cations and terminal care. One of these downstream costs, hospitalization for terminal care, has been found in the Canadian health-care system to be the largest single component of the management of cancer over the entire course of the illness.22 Interventions that can affect terminal care can have important impacts on the lifetime costs of the disease23,24 that might be missed if the time horizon only included the active phase of disease treatment. In addition to ensuring that all relevant resource use has been considered, it is important to assess whether the resource use has been quantified accurately and valued credibly, and to know whether the analysis is based on costs or charges. Charges for health care are influenced by market forces, government regulations, and taxation laws,25 and often bear little resemblance to actual incremental resource costs.26 Medicare providers in the United States are required to provide cost-to-charge ratios that can be used to estimate costs. However, it is not clear how accurate these ratios are. Another consideration is whether resource utilization data have been collected prospectively or retrospectively. Prospectively collected data, such as those gathered during a clinical trial, are more likely to be complete and to allow for timely availability of economic data to help decision-makers after an important clinical result is found. However, the prospective collection of data may be expensive. Furthermore, care in clinical trials is often more resource intense than in routine practice. For example, trials usually take place in expensive tertiary care teaching hospital settings, and involve more frequent monitoring of blood tests and use of imaging studies. As a result, retrospective data or prospective data collected outside a clinical trial can also be used effectively in many circumstances. It is often necessary to estimate costs through the use of a combination of empirical data and modeling. Resource utilization data such as the number of hospital days might be derived from a clinical trial. These data might then be adjusted to reflect anticipated usual care. Last, the costs can be allocated to the resources consumed to calculate the cost of delivering the intervention. By separating resource utilization from cost, local variations in costs or charges can be assessed.

OTHER CONSIDERATIONS Setting Economic evaluations are relatively specific to the health-care system in which they are performed.

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Countries such as Canada have single-payer, universal health-care systems in which the government funds virtually the entire system. In contrast, health care in the United States is funded by multiple payers, primarily private insurers, and providers compete for contracts to manage the care of groups of individuals. A third type of system, common in European countries, provides universal health care, but with patients responsible for a co-payment. Extrapolating the results of a study from one healthcare environment to another involves more than simply adjusting the figures by the exchange rate. Costs for a health-care intervention may be affected by differences in (1) demographics and disease incidence, (2) clinical practice patterns, and (3) relative prices. Practice patterns may be influenced by the availability of alternative treatments and diagnostic tests, as well as incentives to professionals and institutions (e.g. salary versus fee for service).27 There have been few studies reported to date addressing this issue. Drummond et al assessed misoprostal for the prevention of NSAIDinduced ulcers simultaneously in four countries (Belgium, France, UK, USA) using identical methodology. They found misoprostol to be more cost-effective in the United States despite the fact that the drug was 36% more expensive there, because it averted surgical procedures which were relatively more costly.28 Copley-Merriman et al29 made similar observations when they found that the treatment of advanced NSCLC with gemcitabine monotherapy saved more money in the United States compared to standard etoposide/cisplatin (excluding chemotherapy drug costs) than in Germany or Spain because it averted more costly hospitalization and anti-emetic use.

is said to be ‘sensitive’ to that variable. If not, it is ‘robust’. The question becomes not whether all estimates of resource use and survival were accurate, but whether any errors would have a meaningful impact on the results. One of the challenges facing economists is estimating an appropriate range for sensitivity analysis for parameters that have a high degree of uncertainty. If patient level data are available, the use of 95% confidence intervals can be employed to determine the ‘best case’ and ‘worst case’ scenarios. In cases where confidence intervals are not available, one form of sensitivity analysis involves the use of non-parametric bootstrapping to derive confidence intervals for the ‘incremental cost-effectiveness ratio’ (ICER).30–32 Bootstrapping resamples from the original data to build an estimate of the sampling distribution, allowing the calculation of confidence intervals and hence a plausible range of values. Transparency A concern with many economic papers is a lack of transparency in the description of methods and assumptions. Transparency refers to how easy it is to see exactly what the authors of a study have done. After reading the results of an economic analysis, the reader should not be left with the impression that the study was done in a ‘black box’. For optimal transparency, it is best to report disaggregated data on costs, resource use, and quality of life.33 Ideally, the numerator and denominator of cost-effectiveness ratios should be reported separately. Costs should be shown in the format: quantity⫻unit price⫽cost

Sensitivity analysis and uncertainty Sensitivity analyses assess the effect of varying the estimates of resource use (such as the number of treatments of a new drug, the number of hospital days for treatment administration or for palliative care) and effectiveness (e.g. the length of survival gained, utility estimates) over a range of plausible possibilities. No matter how accurately costs and benefits have been quantified and valued, it is likely that certain assumptions will be required. Skeptics often attack these assumptions to dismiss a study. The choice of which parameters to include in a sensitivity analysis is dependent on two factors: how much confidence the researcher has in the reported parameter, and the impact changing this parameter has on the final outcome. If altering the value of key parameters significantly changes the outcome of the study, the analysis

while effectiveness measures should be separated from their utility weightings. Obviously, it is important to know the currency and year of the costs. However, reports should also identify instances of price adjustment, such as the use of the consumer price index to inflate prices from another time period, or the date and exchange rate used to translate costs from other countries. Discounting Costs and benefits that occur in the future should be adjusted, or discounted, to their present value. This is because of ‘time preference’. We generally prefer to incur benefits sooner rather than later and costs later rather than sooner. Thus, future costs and benefits have less weight than current costs and benefits, and

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are usually accounted for by multiplying them by a constant discount rate with the formula: 1 (1 + r )n where r is the discount rate, and n is the number of years.33 Such adjustment favors therapeutic procedures that provide immediate benefit, while rendering preventive and screening programs, which require immediate expenditure for future benefits, less attractive. There is a lack of consensus over what the appropriate discount rate should be. American guidelines suggest 3%,20 while Canadian guidelines have recommended 5%34 and British recommendations have been 6%.35 The choice of discount rate can seriously affect the results of an evaluation,36 and so should be subject to sensitivity analysis. Also there is debate as to whether benefits and costs should be discounted at the same rate, as empirical studies have demonstrated that people do not have the same preferences for future health benefits as for future costs.37–40 Assessing effectiveness Health-care benefits can be measured as: • • •

direct benefits: monetary savings in treatmentrelated resource utilization; indirect benefits: increased productivity; and intangible benefits: alleviation of pain and suffering associated with health improvements.

As described previously, the type of study (costeffectiveness, cost–utility, etc.) will determine the type of benefit considered. Large, randomized controlled trials or meta-analyses provide good measures of clinical effectiveness. However, extrapolation of economic and clinical data to routine practice is not always straightforward. Controlled clinical trials usually test the efficacy of a procedure under strictly defined ‘ideal world’ conditions. Differences in the demographic characteristics of the population, variations in clinical practice, and availability of resources may mean that the procedure is less effective in routine clinical management.41 For example, we might expect an elderly patient with multiple co-morbidities to have a very different experience with chemotherapy for advanced lung cancer than the highly selected patients studied in most clinical trials. A clinician must decide whether his patient is likely to derive the same benefits as the patients included in the study.

Similarly, the toxicity of therapy may differ between the experimental and normal practice settings. The complication rate reported in a trial of complex therapy given to highly selected patients in a tertiary care setting might not be the same as that seen when the treatment is moved into general practice. As a result of the costs associated with these complications, the treatment might prove to be more expensive than predicted by the economic model. When survival is the outcome of interest, it is important to accurately quantify the magnitude of this benefit. Because survival distributions are skewed, the median survival is most often reported in cancer trials. However, this measure may disregard important information when trying to determine the average benefit a patient can expect from a therapy. For example, an intervention that results in some cures will create a long tail on the survival curve that contributes to the number of life years gained. Such an intervention can be highly cost-effective, even if there is little or no increase in the median survival time. As a result, economic evaluations should use the area between the survival curves to determine the average benefit from treatment. Assessing cost-effectiveness The cost-effectiveness ratio (CE) is the incremental cost of an intervention divided by its incremental benefits, as given by the formula: CE ⫽

C1 ⫺ C 2 ($) E1 ⫺ E 2 (eg. time )

where C represents the cost of each intervention and E represents their effectiveness. Many people use thresholds to decide whether an intervention is cost-effective. Canadian authors have proposed that interventions costing less than $20 000 per QALY be considered cost-effective.42 Americans tend to set the threshold at approximately $50 000 per QALY.25 However, these cut-off points are a