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

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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

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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

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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.

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