Lung Cancer Therapy Annual 4

LUNG CANCER THERAPY ANNUAL 4

LUNG CANCER THERAPY ANNUAL 4 Heine H Hansen, MD, FRCP Professor of Medical Oncology The Finsen Center, National University Hospital Copenhagen, Denmark Paul A Bunn Jr, MD Grohne/Stapp Professor and Director University of Colorado Cancer Center Denver, Colorado, USA With contributions from

Karen Kelly, MD (Chapter 7) Christiane Thienelt, MD (Chapter 7) Praveena Solipuram, MD (Chapter 7) University of Colorado School of Medicine Denver, Colorado, USA

LONDON AND NEW YORK

© 2005 Taylor & Francis, an imprint of the Taylor & Francis Group First published in the United Kingdom in 2005 by Taylor & Francis, an imprint of the Taylor & Francis Group, 2 Park Square, Milton Park, Abingdon, Oxon OX14 4RN Tel.: +44 (0)20 7017 6000 Fax.: +44 (0)20 7017 6699 E-mail: [email protected] Website: www.tandf.co.uk/medicine This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to http://www.ebookstore.tandf.co.uk/.” 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 Cataloging-in-Publication Data Data available on application ISBN 0-203-35719-1 Master e-book ISBN

ISBN 0-203-68958-5 (OEB Format) ISBN 1-84184-370-9 (Print Edition) Distributed in North and South America by Taylor & Francis 2000 NW Corporate Blvd Boca Raton, FL 33431, USA Within Continental USA Tel: 800 272 7737; Fax: 800 374 3401 Outside Continental USA Tel: 561 994 0555; Fax: 561 361 6018 E-mail: [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 E-mail: [email protected] Composition by Wearset Ltd, Boldon, Tyne and Wear

Contents

Preface

vii

1 Introduction

1

2 Epidemiology

4

3 Prevention, early detection, and screening

8

4 Histopathology

15

5 Staging, staging procedures, and prognostic factors

22

6 Treatment of small cell lung cancer

58

7 Treatment of non-small cell lung cancer

65

8 Mesothelioma

105

9 Summary

117

Index

122

Preface

The purpose of this fourth edition of the Lung Cancer Therapy Annual remains the same as that of the previous editions, namely to brief the oncology community about current developments in lung cancer by reviewing recent literature, with emphasis on therapeutic aspects, and to offer an update of the impact that this information will have on the day-today management of lung cancer patients. Special thanks are due to Dr Christiane Thienelt and Dr Praveena Solipuram, who coauthored part of Chapter 7. The editors gratefully acknowledge the cooperation and help of Robert Peden of Taylor & Francis. The interest and help of the publisher is greatly appreciated. Heine H Hansen, MD Paul A Bunn Jr, MD

1 Introduction

Globally, the incidence of lung cancer continues to rise drastically, in parallel with increased tobacco consumption. In September 2003, Ezzali et al1 estimated that in 2000, 4.83 million (uncertainty range 3.94–5.93 million) premature deaths, including 850000 from lung cancer, would have been caused by tobacco worldwide. In North America and northwestern Europe, the incidence of lung cancer has decreased over the last 10–15 years in males, whereas the incidence continues to rise in females and adolescents. The picture in eastern and southern Europe is markedly different, with a continuous increase also occurring among men, although the incidence is also rising drastically among women. A similar situation is seen elsewhere, for example in China, South America, and India, with cigarette sales rising steadily in parallel with the pursuit of new conquests by the tobacco industry, especially in developing countries. It has been known for more than 70 years that lung cancer is largely preventable,2 but the effort to inform the public remains on a low level in many countries. Recently, however, many organizations have strengthened their efforts against tobacco. This development has been spearheaded by the World Health Organization, with attempts to develop the world’s first international tobacco control treaty.3 Most countries, particularly in South East Asia and Africa, support a strong convention that would halt this public health disaster. However, a few key countries have been obstructing progress, including Germany, Europe’s largest tobacco manufacturer, and Japan, whose government is the majority shareholder in the world’s third largest tobacco transnational company. The medical establishment of the UK, represented by the leaders of the 18 Royal Colleges of Medicine and their faculties, jointly attacked the UK government for not introducing legislation to ban smoking in public places.4 Fortunately, such bans have been, or are now being, established in many countries, such as in major parts of the USA and Canada, Thailand, India, Malaysia, Norway, Ireland, and the Netherlands.4–6 The Framework Convention on Tobacco Control was finally adopted by the World Health Assembly on May 21, 2003.7 In addition, medical associations, including the American Society of Clinical Oncology (ASCO) and the International Association for the Study of Lung Cancer (IASLC), have published policy statements on tobacco control.8,9 The background to a global approach to tobacco policy has been published by Gray,10,11 including suggestions for future action. In the meantime, important new information concerning the biology of lung cancer,12 including new treatment approaches,13–17 has been published, resulting in a more optimistic therapeutic approach using a combination of the three major treatment

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modalities—surgery, chemotherapy, and radiotherapy—applied concurrently or sequentially in early-stage disease. In addition, second-and third-line treatments have now been developed showing benefit for patients both with non-small cell and with small cell lung cancer. These developments have been presented in review articles,18–20 in reports of guidelines,21–23 in supplements to regular issues of international journals,24–26 at the World Conference on Lung Cancer organized by the IASLC in Vancouver with 1800 abstracts and 3000 participants from 71 countries,27,28 and in textbooks on lung cancer.29–31

REFERENCES 1. Ezzati M, Lopez AD. Estimates of global mortality attributable to smoking in 2000. Lancet 2003; 362: 847–52. 2. Müller FH. Tabakmissbrauch and Lungen Carcinom. Z Krebsforsch 1939; 49:57–85. 3. Gilmore AB, Collin J. The world’s first international tobacco control treaty. BMJ 2002; 325:846–7. 4. Editorial. How do you sleep at night, Mr. Blair? Lancet 2003; 362:1865. 5. Ashraf H. Malaysia steps up anti-tobacco legislation. Lancet 2002; 360: 627. 6. Sharma DC. India bans tobacco advertising and smoking in public places. Lancet 2004; 363:135. 7. Kapp C. WHO approves historic tobacco accord. Lancet 2003; 361: 1793. 8. ASCO’s Public Issues Committee. American Society of Clinical Oncology policy statement update: tobacco control—reducing cancer incidence and saving lives. J Clin Oncol 2003; 21:2777–86. 9. IASLC Tokyo Declaration on Tobacco. Lung Cancer 2001; 31: 355–9. 10. Gray N. A global approach to tobacco policy. Lung Cancer 2003; 39:113–17. 11. Gray N, Kozlowski LT. More on the regulation of tobacco smoke: how we got here and where next. Ann Oncol 2003; 14:353–7. 12. Minna JD, Fong K, Zochbauer-Muller S, Gazdar AF. Molecular pathogenesis of lung cancer and potential translational application. Cancer J 2002; 8(Suppl 1):S41–6. 13. Bunn PA. Novel targeted agents for the treatment of lung cancer. Am Soc Clin Oncol Educational Book 2002:683–92. 14. Hoang T, Traynor AM, Schiller JH. Novel therapies for lung cancer. Surg Oncol 2002; 11:229– 41. 15. Dy GK, Adjei AA. Novel targets for lung cancer therapy: Part I. J Clin Oncol 2002; 20:2881– 94. 16. Dy GK, Adjei AA. Novel targets for lung cancer therapy: Part II. J Clin Oncol 2002; 20:3016– 28. 17. Kukunoor R, Shah J, Mekhail T. Targeted therapy for lung cancer. Curr Oncol Rep 2003; 5:326–33. 18. Spiro SG. Lung cancer—Where are we today? Am J Respir Crit Care Med 2002; 166:1166–96. 19. Hansen HH. An update on management of lung cancer. Acta Oncol 2002; 41:500–6. 20. Booton R, Jones M, Thatcher N. Lung Cancer 7: Management of lung cancer in elderly patients. Thorax 2003; 58:711–20 21. Depierre A, Lagrange JL, Theobald S et al. Summary report of the standards, options and recommendations for the management of patients with non-small-cell lung carcinoma (2000). Br J Cancer 2003; 89(Suppl 1):S35–49. 22. Diagnosis and management of lung cancer: ACCP evidence-based guidelines. Chest 2003; 123(Suppl): S1–332.

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23. Van Houtte P: IASLC Workshop. Progress and Guidelines in the Management of Non-Small Cell Lung Cancer. Lung Cancer 2003; 42(Suppl 1):S1–92. 24. Demedts M, Nackaerts K, Vansteenkiste J, Verleden G (eds). Respiratory Oncology: A Clinical Update. Eur Respir Rev 2002; 12: Review 84, 111–217. 25. Zielinski C, Krainer M, Hirsch FR (eds). European Consensus Conference on Medical Treatment of Non-Small Cell Lung Cancer. Lung Cancer 2002; 38(Suppl. 3): S1–81. 26. Sharma AK, Edelman MJ (eds) Head and Neck Cancer/Lung Cancer. Curr Treat Opt Oncol 2003; 4:3–89. 27. Extended abstracts of the 10th World Conference on Lung Cancer, 10–14 August, Vancouver, Canada. Lung Cancer 2003; 41(Suppl 3): S1–122. 28. Abstracts of the 10th World Conference on Lung Cancer, 10–14 August, Vancouver, Canada. Lung Cancer 2003; 41(Suppl 2): S1–314. 29. Fossella FV, Putnam JBJ, Komaki R (eds). Lung Cancer. MD Anderson Cancer Care Series. New York: Springer-Verlag 2003. 30. Sculier J-P, Frey WA (eds). Malignant Tumors of the Lung. New York: Springer-Verlag, 2003. 31. Ginsberg RJ. Lung Cancer. American Cancer Society Atlas of Clinical Oncology. Hamilton, Ontario: BC Decker, 2001.

2 Epidemiology

Lung cancer remains a major public health problem and the commonest malignant cause of death. A direct relationship between the tar yield of cigarettes and development of lung cancer has been recognized for years, and over the last few decades smokers have massively shifted from high-nicotine cigarettes to lower-yield brands in the belief that such cigarettes are safer or less addictive—led on by misleading and even harmful labelling. In a study from Switzerland with 494 smokers or ex-smokers participating, the participants estimated that one would have to smoke two light cigarettes or four ultralight cigarettes in order to inhale the same amount of nicotine as that in one regular cigarette. Most participants (60%) answered that the risk of lung cancer was the same but 27% answered that the risk was lower in smokers of light cigarettes than in smokers of regular cigarettes.1 The risk of lung cancer among smokers has been evaluated by Bach et al,2 based on data on 18172 subjects enrolled in a large randomized trial of lung cancer prevention. It was observed that the risk of lung cancer varied greatly among participants in the study, from 15% for a 68-year-old man who has smoked two packs per day for 50 years and continues to smoke, to 0.8% for a 51-year-old woman who smoked one pack per day for 28 years before quitting 9 years earlier. Another epidemiologic study from the USA included 37078 women aged 55–69 years. In 1986, mailed questionnaires were used to collect detailed smoking history, and ageadjusted lung cancer incidence through 1999 was analyzed according to years of smoking abstinence.3 The results indicated that, compared with the never smokers, former smokers had an elevated lung cancer risk up to 30 years after smoking cessation for all former smokers. However, a beneficial effect of smoking cessation was also observed among recent and distant former smokers. The risk of adenocarcinoma remained elevated up to 30 years for both former heavier and former lighter smokers. With these results, it is not surprising that much emphasis lately has been given to smoking cessation intervention programs in order to prevent tobacco-related morbidity and mortality, including lung cancer.4 Evidence-based clinical practice guidelines for smoking cessation, including editorials on pharmacologic therapy for nicotine addiction, have also been developed.5,6 Smoking cessation results in a reduction in the risk of all major histologic types of lung cancer, as demonstrated by Khuder and Mutgi.7 The highest reduction was in small cell and squamous cell carcinoma. Several articles have

Epidemiology

5

also urged physicians to assist patients quit smoking, including patients with lung cancer.8,9 In a matched case-control design, based on 201 lung cancer patients, Cox et al10 showed that nicotine dependence treatment is effective for patients with a diagnosis of lung cancer and that the majority of lung cancer patients were motivated to stop smoking. Other prevention measures include changes in air pollution. On the basis of data from Xuanwei County, Yunnan Province, China, Lan et al11 showed that changing from unvented to vented stoves appears to reduce the incidence of lung cancer. As far as other epidemiologic factors are concerned, reports on the association between alcohol consumption and the risk of lung cancer have been inconsistent. Djoussé et al12 reevaluated this issue based on 4973 subjects from the original population-based Framingham Study cohort. After adjustment for age, sex, pack-years of smoking, smoking status, and year of birth in a multivariable conditional logistic regression model, alcohol consumption was not statistically significantly associated with the risk of lung cancer. Similarly, previous cohort studies have found an elevated risk of lung cancers among rock and slag wool production workers. In a large European study of 196 lung cancer cases occurring among men who worked in seven plants in northern Europe, Kjærheim et al13 were not able to provide evidence of a carcinogenic effect on the lung of rock and slag wool under conditions of exposure in the production industry during the last four to five decades. Tobacco smoking was, as expected, an important predictor of risk, but there were no indications of a confounding effect from tobacco on the association between rock and slag wool and lung cancer. There were also no indications of a confounding effect from other occupational exposures, such as polycyclic aromatic hydrocarbons and silica, whereas for asbestos there was moderate negative confounding. Finally, one study has demonstrated an increased incidence of primary lung tumors (both ipsilateral and contralateral) in patients with breast cancer receiving extensive postmastectomy irradiation of the chest wall and regional lymph nodes.14,15 Similar observations have been published from Sweden.16 Large variations do occur in the epidemiology of lung cancer and great changes have also taken place over the last decade in various parts of the world, including changes in the distribution among cell types. In Europe, Janssen-Heijnen and Coebergh17 used the EUROCARE database and data from the Eindhoven Cancer Registry to clarify this issue. The study confirmed that the incidence of lung cancer among men in Denmark, Finland, Germany, Italy, the Netherlands, Switzerland, and the UK has been decreasing since the 1980s, while the age-adjusted rate for men in other European countries increased, at least until the 1990s. Among women, the peak incidence had not been reached in the 1990s. The proportion of adenocarcinomas has been increasing over time; the most likely explanation is the shift to low-tar filter cigarettes, expos-ing the peripheral part of the lung, where adenocarcinoma occurs, to a disproportionally higher amount of smoke carcinogens. Similar trends have been reported, specifically in Scotland and Poland.18,19 With respect to recent and future directions for lung cancer mortality in Europe, Brennan and Bray20 demonstrated that the incidence of lung cancer among women in Ireland and the UK has started to decrease and is projected to continue falling. Trends in women younger than 55 years indicate that rates in Danish women will peak in the next decade, whereas lung cancer rates among Dutch women are likely to continue increasing,

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as are the rates among women in eastern Europe. In Hungarian women, the lung cancer rates are likely to increase and will surpass the current high rate observed in Denmark. In the USA, Jemal et al21 have also found an increase in lung cancer in young men and women—mainly adenocarcinomas, which is most likely related to the increase in the smoking of filter versus non-filter cigarettes. The socioeconomic patterns of lung cancer mortality changed dramatically in the USA between 1950 and 1998.22 Men aged 25–64 years and those aged 65 years or older in higher socioeconomic groups generally had higher lung cancer mortality than did those in lower socioeconomic groups during 1950–1964 and 1950–1980, respectively. Socioeconomic differences in lung cancer mortality began to reverse and widen by the early 1970s for younger men and by the mid-1980s for older men. In 1998, lung cancer mortality was 56% higher for younger men and 38% higher for older men in the lowest socioeconomic group than for the same age ranges in the highest socioeconomic group. Lung cancer mortality among older women in all socioeconomic groups increased sevento eightfold between 1950 and 1998, with higher mortality in higher socioeconomic groups. These data may be useful for monitoring socioeconomic disparities in cancer mortality and for identifying potential cancer control interventions. In south Asia (India, Pakistan, and Bangladesh), a slight increase in lung cancer has been observed among women.23 In China, the pattern indicates an increase in all age groups and in both sexes, in both urban and rural areas.24 The increase is not surprising, considering that the annual consumption of cigarettes in China increased from 500 billion in 1980 to 1800 billion in 1996 and that two-thirds of men now become smokers before the age of 25 years.

REFERENCES 1. Etter J-F, Kozlowski LT, Perneger TV. What smokers believe about light and ultralight cigarettes. Prev Med 2002; 39:92–8. 2. Bach PB, Kattan MW, Thornquist MD et al. Variations in lung cancer risk among smokers. J Natl Cancer Inst 2003; 95:470–8. 3. Ebbert JO, Yang P, Vachon VM et al. Lung cancer risk reduction after smoking cessation: observations from a prospective cohort of women. J Clin Oncol 2003; 21:921–6. 4. Hurt RD, Ebbert JO. Preventing lung cancer by stopping smoking. Clin Chest Med 2002; 23:27– 36. 5. Anderson JE, Jorenby DE, Scott WJ, Fiore MC. Treating tobacco use and dependence. Chest 2002; 121: 932–41. 6. DeGraff AC. Pharmacologic therapy for nicotine addiction. Chest 2002; 122:392–4. 7. Khuder SA, Mutgi AB. Effect of smoking cessation on major histologic types of lung cancer. Chest 2001; 120:1577–83. 8. Larkin M. Physicians urged to help patients quit smoking. Lancet 2002; 359:1041. 9. Dresler CM. Is it more important to quit smoking than which chemotherapy is used? Lung Cancer 2003; 39: 119–25. 10. Cox LS, Patten CA, Ebbert JO et al. Tobacco use outcomes among patients within lung cancer treated for nicotine dependence. J Clin Oncol 2002; 20:3461–9. 11. Lan Q, Chapman RS, Schreinemachers DM et al. Household stove improvement and risk of lung cancer in Xuanwei, China. J Natl Cancer Inst 2002; 94:826–35. 12. Djoussé L, Dorgan JF, Zhang Y et al. Alcohol consumption and risk of lung cancer; the Framingham Study. J Natl Cancer Inst 2002; 94:1877–82.

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13. Kjærheim K, Boffetta P, Hansen J et al. Lung cancer among rock and slag wool production workers. Epidemiology 2002; 13:445–53. 14. Deutsch M, Land SR, Begovic M, Wieand HS et al. The incidence of lung carcinoma after surgery for breast carcinoma with and without postoperative radiotherapy. Cancer 2003; 98:1362–8. 15. Buchholz TA. Lung carcinoma development after radiotherapy for breast carcinoma. Cancer 2003; 98:1331–3. 16. Prochazka M, Granath F, Ekbom A et al. Lung cancer risks in women with previous breast cancer. Eur J Cancer 2002; 38:1520–5. 17. Janssen-Heijnen MLG, Coebergh J-WW. The changing epidemiology of lung cancer in Europe. Lung Cancer 2003; 41:245–58. 18. Harkness EF, Brewster DH, Kerr KM et al. Changing trends in incidence of lung cancer by histologic type in Scotland. Int J Cancer 2002; 102: 179–83. 19. Radzikowska E, Glaz P, Roszkowski K. Lung cancer in women: age, smoking, histology, performance status, stage, initial treatment and survival. Population-based study of 20561 cases. Ann Oncol 2002; 13: 1087–93. 20. Brennan P, Bray I. Recent trends and future directions for lung cancer mortality in Europe. Br J Cancer 2002; 87:43–8. 21. Jemal A, Travis WD, Tarone RE et al. Lung cancer rates convergence in young men and women in the United States: analysis by birth cohort and histologic type. Int J Cancer 2003; 105:101–7. 22. Singh GK, Miller BA, Hankey BF. Changing area socioeconomic patterns in U.S. cancer mortality 1950–1998: Part II—Lung and colorectal cancers. J Natl Cancer Inst 2002; 94:916– 25. 23. Smith LK, Peake MD, Botha JL. Recent changes in lung cancer incidence for south Asians; a population based register study. BMJ 2003; 326: 81–2. 24. Yang L, Parkin DM, Li L, Chen Y. Time trends in cancer mortality in China: 1987–1999. Int J Cancer 2003; 106:771–83.

3 Prevention, early detection, and screening

As with the situation described in the last edition of this Annual, recent new information from clinical trials on prevention has been scarce while chemoprevention of lung cancer per se has been the subject of a few review articles.1–3 One of the new potential strategies to inhibit the development of invasive cancer in those who are at risk of developing lung cancer is to use chemopreventive agents that either block the DNA damage that initiates carcinogenesis or arrest or reverse the progression of premalignant cells in which such damage has already occurred. One group of compounds for which in vivo anticarcinogenic activity was predicted on the basis of their abilities to induce expression of carcinogen detoxification enzymes includes anethole dithiolethione (ADT) and Oltipraz, which are members of the dithiolethione class of organosulfur compounds. Lam et al4 performed a randomized, double-blind, placebo-controlled, phase IIb clinical trial to determine the efficacy and safety of ADT as a chemopreventive agent in smokers with premalignant lesions in their bronchial epithelia. One hundred and twelve current and former smokers with a smoking history of at least 30 pack-years and at least one site of bronchial dysplasia identified by an autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive placebo or ADT at 25 mg orally thrice daily for 6 months. Each subject then underwent a follow-up bronchoscopy-directed biopsy. Changes in histopathologic grade and nuclear morphometry index (MI) were used as the primary and secondary endpoint biomarkers, respectively. One hundred and one subjects had a follow-up bronchoscopy. In the lesion-specific analysis, the rate of progression of preexisting dysplastic lesions by two or more grades and/or the appearance of new lesions was statistically significantly lower in the ADT group (8%) than in the placebo group (17%) (p<0.001). In the person-specific analysis, the disease progression rate was statistically significantly lower in the ADT group (32%) than in the placebo group (59%) (p=0.013). The two treatment groups did not differ statistically significantly in terms of nuclear MI. Among individuals with an abnormal nuclear MI before treatment, the progression rate in the ADT group (41%) was substantially lower than in the placebo group (60%), although the difference was not statistically significant. Adverse events were mostly minor gastrointestinal symptoms that resolved with dose reduction or discontinuation of the medication. The authors concluded that, in smokers, ADT is a potentially efficacious chemoprevention agent for lung cancer. Another compound that might have potential chemopreventive properties in former smokers is 9-cis-retinoic acid, which in patients with previous cancer of the head and

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neck region has reduced the incidence of second primary tumors and decreased locoregional relapse. Retinoids have been shown to restore retinoic acid receptor β (RARβ) expression in the bronchial epithelium. Loss of this receptor is considered a biomarker of preneoplasia. Retinoids can restore expression of this receptor and, presumably, halt the progression of carcinogenesis. The study by Kurie et al5 was designed to investigate whether either of two retinoid-based regimens, 9-cis-retinoic acid (RA) or 13-cis-RA plus α-tocopherol (AT), could reverse RARβ expression loss in former smokers after 3 months of treatment. Former smokers were defined as individuals who had smoked at least 20 pack-years and had ceased smoking for at least 1 year before study entry. Individuals were randomly assigned to receive 3 months of daily oral 9-cisRA (100 mg), 13-cis-RA (1 mg/kg)+AT (1200 IU), or placebo. Bronchoscopy and biopsy at six predetermined sites of the bronchial tree were performed before treatment and at 3 and 6 months thereafter. Specimens were evaluated for squamous metaplasia, dysplasia and RARβ expression. A total of 177 assessable subjects completed at least 3 months of therapy and underwent at least the baseline and 3-month bronchoscopic evaluations with biopsies. RARβ was detected in 69.7% of all baseline biopsy samples, and metaplasia was evident in 6.9% of all baseline samples from 240 subjects. Restoration of RARβ expression (p=0.03) and reduction of metaplasia (p=0.1) were found in the 9-cis-RA group. After adjustment for years of smoking, packs/day smoked, and metaplasia, treatment with 9-cis-RA, but not with 13-cis-RA+AT, led to a statistically significant increase in RARβ expresion compared with placebo (p=0.03). With respect to early detection and the use of molecular diagnostics in highrisk populations, these topics were treated at a workshop in June 2001 at the Roy Castle International Centre for Lung Cancer Research, with the participation of experts in the clinical, epidemiologic and molecular pathology of lung cancer, and a consensus report was published in the fall of 2002.6 A summary of the role played by sputum cytology for the detection of early lung cancer, including lung cancer identification in high-risk groups, has been published by Petty.7 Attention has recently been given to the value of autofluorescence bronchoscopy (AFB), based on a study from France with 244 consecutive patients.8 The study was undertaken in order to define the population in which the rate of detection is higher using AFB, as an adjunct to standard white-light bronscoscopy (WLB). The patients included were symptomatic smokers or patients who had previously been treated for lung cancer or head and neck cancers. They all underwent WLB and AFB and all patients with endoscopic abnormalities underwent biopsies. In a lesion-by-lesion analysis, 92 lowgrade lesions, 42 high-grade lesions (i.e. moderate dysplasia, severe dysplasia, and carcinoma in situ), and 39 invasive carcinomas were diagnosed. There was no effect of age, gender, or age at smoking initiation on the prevalence of preinvasive or invasive lesions. The 10 patients who had previously undergone surgery for lung cancer and exhibited high-grade preinvasive lesions had a history of carcinoma of the epidermoid histologic type (p=0.01). These patients displayed multiple lesions in the bronchial tree (mean number of lesions 1.8 per patient). In current smokers, the prevalences of highgrade and invasive lesions were both related to the number of pack-years of smoking (p=0.01) and to the duration of smoking (p=0.01). In contrast, the prevalence of preinvasive lesions in former smokers was related to a history of epidermoid carcinoma.

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In a study from Belgium, Meert et al9 demonstrated that the epidermal growth factor receptor (EGFR) expression rate changes with the stage of the bronchial lesion, increasing from normal epithelium to carcinoma in situ and microinvasive tumors with a statistically significant difference between mild versus severe dysplasia. The study included 13 normal bronchial epithelia, 19 hyperplasias, 16 metaplasias, 10 mild dysplasias, 1 moderate dysplasia, 10 severe dysplasias, 14 carcinomas in situ and 11 microinvasive tumors. As an adjunct to cytologic diagnosis using bronchial lavage, Dikmen et al10 examined telomerase activity determined with a polymerase chain reaction (PCR)-based telomeric repeat amplification protocol (TRAP) assay. A total of 29 bronchial lavage samples were collected from patients in whom the diagnosis was confirmed with cytologic and/or histologic examinations. Patients were classified as lung cancer patients (group 1, n=22) and patients with benign disease (group 2, n=7). Cytologic examination was diagnostic in 12 (54.5%) of 22 patients in group 1, and in all 7 patients of group 2 (p=0.063). Telomerase activity was positive in 16 (72.7%) of group 1 patients, while it was positive in only 1 (14.3%) sample in group 2. The sensitivity rate of cytologic examination when combined with telomerase activity (81.8%) was significantly greater than that of cytologic examination alone (54.5%) (p=0.031). Telomerase activity in bronchial lavage is thus a highly sensitive diagnostic biomarker for malignancy and a potential complementary diagnostic technique to cytologic examination in the diagnosis of lung cancer. However, larger definite studies are needed to validate this promising result using telomerase activity as a marker of tumor detection, including genetic testing and fluorescence bronchoscopy. An interesting study has been published by Phillips et al,11 who evaluated volatile organic compounds (VOCs) in the breath as tumor markers in lung cancer. Alkanes and monomethylated alkanes are oxidative stress products that are excreted in the breath, the catabolism of which may be accelerated by polymorphic cytochrome P450-mixed oxidase enzymes that are induced in patients with lung cancer. One hundred and seventyeight bronchoscopy patients and 41 healthy volunteers from five academic pulmonary medicine services in the USA and the UK were included. Breath samples were analyzed to determine alveolar gradients of C4–C20 alkanes and monomethylated alkanes. Patients with primary lung cancer were compared with healthy volunteers. Of the 178 patients, 87 had lung cancer. A predictive model employing nine VOCs identified primary lung cancer with a sensitivity of 89.6% (60 of 67 patients) and a specificity of 82.9% (34 of 41 patients). Compared with healthy volunteers, patients with primary lung cancer had abnormal breath test findings that were consistent with the accelerated catabolism of alkanes and monomethylated alkanes. A predictive model employing nine of these VOCs demonstrated sufficient sensitivity and specificity to be considered as a screen for lung cancer in a high-risk population such as adult smokers, according to Phillips et al.11 Again, further larger studies are needed to validate the information from this preliminary report. There is continuing debate about the potential value of screening for lung cancer, as evidenced by several review articles from both the USA and Europe,12–15 followed by editorials, comments, and letters to editors.16–21 In addition, there have been a number of articles concerning the economic, legal, and ethical rationales for lung screening trials using computed tomography (CT) screening.22–27 A number of questions arise when

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setting up clinical trials in this area: Does spiral CT scanning work? How is the test performed optimally? How are patients managed once abnormalities on the CT scan have been observed? Reports have also emerged from major centers such as the Mayo Clinic (Rochester, Minnesota), Cornell University (New York), and Denver (Colorado), and from Japan, where there has been longstanding interest in lung cancer screening projects. These include results from pilot studies.28–36 The initial Mayo Lung Project trial from the 1970s has been reanalyzed with 20-year follow-up by Strauss.28 The Mayo Lung Cohort comprised 9192 randomized individuals and has been interpreted as negative because it failed to demonstrate a significant mortality reduction among those randomized to chest X-ray and cytology. In contrast, survival data suggest that screening is highly effective. Strauss28 reanalyzed the trial in an effort to identify predictors of lung cancer incidence and mortality and to determine whether survival or mortality was unbiased. The results demonstrate that, in addition to age and smoking, randomization to screening predicted increased lung cancer incidence (hazard ratio 1.3; 95% confidence interval 1.06–1.60). Predictors of mortality were similar, except that randomization to screening was not significant. Survival was significantly superior in the experimental population. The higher incidence in the experimental group accounts for the mortality/survival discrepancy. Both lead-time and length biases can be excluded, because survival from randomization was superior in the experimental population. Over-diagnosis is eliminated because resection was the only significant multivariate predictor of survival. Overall, 50% of resected and 0% of unresected cases were cured. The data support the initiation of a randomized control trial in the USA comparing screening with chest X-ray versus low-dose spinal CT scan. The study will have the ability to detect a 20% difference in lung cancer mortality.29 From the same institution, Swensen et al31 reported on the evaluation of low-dose spiral CT and sputum cytology in screening for lung cancer in 1520 individuals aged 50 years or older who had at least 20 pack-years of smoking in a prospective cohort study. One year after baseline scanning, 2244 uncalcified lung nodules were identified in 1000 participants. Twenty-five cases of lung cancer were diagnosed. CT alone detected 23 cases and sputum cytology alone detected 2 cases. The cell types were 6 squamous cell carcinomas, 15 adeno-or broncheoalveolar carcinomas, 1 large cell carcinoma and 3 small cell carcinoma. Twenty-two patients underwent curative surgical resection. Seven benign nodules were resected, resulting in a very high false-positive rate. In a feasibility study by Garg et al,34 preliminary results of a randomized controlled trial with low-dose spiral CT for lung cancer screening have been published. Subjects were recruited to undergo either low-dose spiral CT or observation. Subjects were from a high-risk group with known chronic obstructive pulmonary disease (COPD) and sputum atypia and from a moderate-risk group randomly selected from the general population of a US Veterans’ Administration medical center in Colorado. All subjects were 50–80 years of age with 30 or more pack-years of cigarette smoking and had not undergone chest CT during the previous 3 years. At the time of publication, 304 eligible subjects had been contacted and 239 (79%) had agreed to participate in the trial. One hundred and nineteen (88%) of the 136 subjects in the high-risk group and 120 (71%) of the 168 subjects in the moderate-risk group agreed to randomization. Of the first 92 subjects examined with CT, 22 (40%) of 55 in the high-risk group and 8 (22%) of 37 in the

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moderate-risk group had one to six non-calcified nodules that required follow-up (p=0.07). In all but three subjects, nodules were small than 5 mm. Two of the three larger nodules were malignancies. One of the studies from Japan was a large study carried out from April 1998 to August 2000.35 CT screening was performed as part of the annual health examination on a total of 7956 individuals. Of those participants, 5568 were rescreened 1 year later. When a non-calcified solitary pulmonary nodule (SPN) 8 mm or larger was detected on CT screening, a detailed CT scan was carried out approximately 1 month later. During the baseline screening, a total of 2865 non-calcified SPNs were detected among the 7956 participants. Primary lung cancer was confirmed histologically in 40 patients (41 lesions). The prevalence was 0.44% of all participants from the baseline, and 0.07% from the repeated screening. Of the 41 tumors, 35 were stage I. Current or former smokers represented only 17 of 40 cases. The detection rate was rather high in female participants. In their discussion, the authors emphasized that females and non-smoking subjects should be included in the baseline screening.35 The purpose of the other Japanese study was to evaluate the efficacy of annual chest X-ray screening for lung cancer based on a case-control study comparing 121 case subjects with lung cancer who died of lung cancer from 1992 to 1997 with a total of 536 controls matched to case subjects by gender, year of birth, address, and smoking habits.36 The smoking-adjusted odds ratio of lung cancer death for those subjects screened within 12 months prior to diagnosis versus those not screened was 0.68, suggesting that 20–30% of deaths attributed to lung cancer (especially adenocarcinoma) might be prevented by annual chest X-ray. A retrospective review has been performed of the value of systematic postoperative radiologic follow-up in patients with non-small cell lung cancer (NSCLC).37 One hundred and twenty-four patients with resected NSCLC underwent annual CT examination of the chest with interval chest radiography every 4 months for 2 years and every 6 months for 3 additional years. Second primary lung cancer (SPLC) was diagnosed in 19 (15.3%) of 124 patients. The probability of developing an SPLC was 2.1% per patient per year. All patients were asymptomatic. SPLC was potentially resectable in 18 patients (94.7%). Fourteen patients (73.7%) ultimately underwent resection of SPLC by limited resection (n=13) or completion pneumonection (n=1). Of 14 patients with SPLC treated surgically, 9 were without evidence of disease at a median of 20 months (range 4–56 months), while 2 died of unrelated causes but without evidence of disease at 7 and 35 months. The use of annual CT scanning thus results in an early recognition of SPLC, and subsequent intervention will salvage a significant proportion of these patients.

REFERENCES 1. Soria J-C, Kin ES, Fayette J et al. Chemoprevention of lung cancer. Lancet Oncol 2003; 4:659– 69. 2. Kim ES, Khuir FR. Chemoprevention of lung cancer. Curr Oncol Rep 2002; 4:341–6. 3. van Zandwijk N, Hirsch FR. Chemoprevention strategies for non-small cell lung cancer. Curr Opin Oncol 2002; 14:185–90. 4. Lam S, MacAulay C, le Riche JC et al. A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia. J Natl Cancer Inst 2002; 94:1001–9.

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5. Kurie JM, Lotan R, Lee JJ et al Treatment of former smokers with 9-cis-retinoic acid reverses loss of retinoic acid receptor-β expression in the bronchial epithelium: results from a randomized placebo-controlled trial. J Natl Cancer Inst 2003; 95:206–14. 6. Field JK, Brambilla C, Caporaso N et al. Consensus statements from Second International Lung Cancer Molecular Biomarkers Workshop: a European strategy for developing lung cancer molecular diagnostics in high risk populations. Int J Oncol 2002; 21:369–73. 7. Petty TL. Sputum cytology for the detection of early lung cancer. Curr Opin Pulm Med 2003; 9:309–12. 8. Moro-Sibilot D, Jeanmart M, Lantuejoul S et al. Cigarette smoking, preinvasive bronchial lesions, and autofluorescence bronchoscopy. Chest 2002; 122:1902–8. 9. Meert A-P, Verdebout J-M, Martin B et al. Epidermal growth factor receptor expression in preinvasive and early invasive bronchial lesions. Eur Respir J 2003; 21:611–15. 10. Dikmen E, Kara M, Dikmen G et al. Detection of telomerase activity in bronchial lavage as an adjunct to cytological diagnosis in lung cancer. Eur J Cardio-Thorac Surg 2003; 23: 194–200. 11. Phillips M, Cataneo RN, Cummin ARC et al. Detection of lung cancer with volatile markers in the breath. Chest 2003; 123:2115–23. 12. Ellis JRC, Gleeson FV. New concepts in lung cancer screening. Curr Opin Pulm Med 2002; 8:270–4. 13. Mulshine JL, Smith RA. Lung Cancer 2: screening and early diagnosis of lung cancer. Thorax 2002; 57: 1071–8. 14. Truong MT, Munden RF. Lung cancer screening. Curr Oncol Rep 2003; 5:309–12. 15. Reich JM. Improved survival and higher mortality. The conundrum of lung cancer screening. Chest 2002; 122:329–37. 16. Grannis FWJ. Lung cancer screening. Conundrum of contumacy? Chest 2002; 122:1–2. 17. Ost D, Shah RD, Fein D, Fein, AM. To screen or not to screen—a volatile issue in lung cancer. Chest 2003; 123:1788–92. 18. Hall FM. Screening for lung cancer; been there and done that. Radiology 2002; 224:928–31. 19. Heffener JE, Silverstri G. CT screening for lung cancer—Is smaller better? Am J Respir Care Med 2002; 165: 433–7. 20. Marcus, P.M. Lung cancer screening, once again. Chest 2002; 122:3–4. 21. Hakama, M. Screening for lung cancer. J Clin Oncol 2002; 20:3931–3. 22. Woloshin S, Schwartz LM, Welch HG. Tobacco money: up in smoke? Lancet 2002; 359:2108– 11. 23. Henschke CI. A defence of the New York early lung cancer project. Lancet 2003; 361:1138. 24. Mulshine JL, Smith RA, Field JK, Hirsch FR. Tobacco money: up in smoke? Lancet 2002; 360:1979–81. 25. Hillman BJ. Economic, legal, and ethical rationales for the ACRIN national lung screening trial of CT screening for lung cancer. Acad Radiol 2003; 10:349–50. 26. Grannis Jr FW. Lung cancer screening—Who will pick up the tab? Chest 2002; 121:1388–90. 27. Baldwin J. New study questions marketing of spiral CT scanning to consumers. J Natl Cancer Inst 2003; 95: 50–9. 28. Strauss GM. The Mayo Lung Cohort: a regression analysis focusing on lung cancer incidence and mortality. J Clin Oncol 2002; 20:1973–83. 29. Jett JR. Screening for lung cancer: no longer a taboo subject. J Clin Oncol 2002; 20:1959–61. 30. Swensen SJ. CT screening for lung cancer. AJR 2002; 179:833–6. 31. Swensen SJ, Jett JR, Sloan JA et al. Screening for lung cancer with low-dose spiral computed tomography. Am J Respir Crit Care Med 2002; 165: 508–13. 32. Yankelevitz DF, Kostis WJ, Henschke CI et al. Overdiagnosis in chest radiographic screening for lung carcinoma. Cancer 2003; 97:1271–5. 33. Henschke CI, Yankelevitz DF, Libby D, Kimmel M. CT screening for lung cancer: the first ten years. Cancer J 2002; 8(Suppl 1):S47–54.

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34. Garg K, Keith RL, Byers T et al. Randomized controlled trial with low-dose spiral CT for lung cancer screening: feasibility study and preliminary results. Radiology 2002; 225:506–10. 35. Nawa T, Nakagawa T, Kusano S et al. Lung cancer screening using low-dose spiral CT. Results and baseline and 1-year follow-up studies. Chest 2002; 122:15–20. 36. Nakayama T, Baba T, Suzuki T et al. An evaluation of chest X-ray screening for lung cancer in Gunma Prefecture, Japan: a population-based case-control study. Eur J Cancer 2002; 38:1380– 7. 37. Lamont JP, Kakuda JT, Smith D et al. Systematic postoperative radiologic follow-up in patients with non-small cell lung cancer for detecting second primary lung cancer in stage IA. Arch Surg 2002; 137:935–9.

4 Histopathology

The 1999 histologic classification of malignant lung and pleural tumors, published by the World Health Organization (WHO) on the basis of recommendations by the Pathology Panel of the International Association for the Study of Lung Cancer (IASCL), is listed in Table 4.1. It contains the morphologic codes of the International Classification of Diseases for Oncology (ICD-O) and the Systemized Nomenclature of Medicine (SNOMED).1 A major change from the 1981 classification was the introduction of the concept of neuroendocrine tumors of the lung, which has been refined by the recognition of large neuroendocrine carcinomas and modifications of the criteria for atypical carcinoids. Neuroendocrine tumors are defined as a distinct subset of tumors that share certain morphologic, ultrastructural, and immunohistochemical characteristics. The major categories of morphologically identifiable neuroendocrine tumors are small cell carcinoma (SCLC), large cell neuroendocrine carcinoma, typical carcinoids, and atypical carcinoids. The criteria for diagnosis of these tumors are given in Table 4.2. A number of publications have shed additional light on this topic. The incidence and prognosis of histologic subtypes of neuroendocrine tumors in the lung were elucidated in a population-based study in Denmark by Skuladottir et al.2 This was the first populationbased study of the demographics of patients with neuroendocrine tumors grouped by histologic subtype. A cancer registry-based analysis of patients in Denmark in whom bronchial neuroendocrine tumors were diagnosed in 1978–97 was performed and the patients were followed up to 31 December 1999. Typical carcinoid was diagnosed in 105 patients, atypical carcinoid in 192, large cell neuroendocrine carcinoma in 50, and small cell carcinoma in 11998. The recorded incidence of neuroendocrine tumors other than small cell carcinoma increased by twofold among men and by threefold in women during the study period, while the incidence of small cell carcinoma decreased among men and levelled off among women. The prognosis of patients with bronchial neuroendocrine tumors varied with the degree of malignancy; the 5-year survival rate ranged from 87% for patients with typical carcinoids, to 44%, 15%, and 2% for patients with atypical carcinoids, large cell neuroendocrine carcinoma, and small cell carcinoma, respectively. The findings by Skuladottir et al2 support the pathologic categorization of neuroendocrine tumors into three grades of malignancy.

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Table 4.1 Histologic classification of lung and pleural tumorsa 1. Epithelial tumors 1.3 Malignant 1.3.1 Squamous cell carcinoma Variants:

8070/3

1.3.1.1

Papillary

8052/3

1.3.1.2

Clear cell

8084/3

1.3.1.3

Small cell

8073/3

1.3.1.4

Basaloid

8083/3

1.3.2 Small cell carcinoma Variant: 1.3.2.1

Combined

8041/3 8045/3

1.3.3 Adenocarcinoma

8140/3

1.3.3.1

Acinar

8550/3

1.3.3.2

Papillary

8260/3

1.3.3.3

Bronchioloalveolar carcinoma

8250/3

1.3.3.3.1

Non-mucinous

8252/3

1.3.3.3.2

Mucinous

8253/3

1.3.3.3.3

Mixed mucinous and non-mucinous or indeterminate cell type

8254/3

1.3.3.4

Solid adenocarcinoma with mucin

8230/3

1.3.3.5

Adenocarcinoma with mixed subtypes

8255/3

1.3.3.6

Variants: 1.3.3.6.1

Well-differentiated fetal adenocarcinoma

8333/3

1.3.3.6.2

Mucinous (‘colloid’) adenocarcinoma

8480/3

1.3.3.6.3

Mucinous cystadenocarcinoma

8470/3

1.3.3.6.4

Signet ring adenocarcinoma

8490/3

1.3.3.6.5

Clear cell adenocarcinoma

8310/3

1.3.4 Large cell carcinoma Variants: 1.3.4.1

Large cell neuroendocrine carcinoma 1.3.4.1.1

8012/3 8013/3

Combined large cell neuroendocrine carcinoma

1.3.4.2

Basaloid carcinoma

8123/3

1.3.4.3

Lymphoepithelioma-like carcinoma

8082/3

1.3.4.4

Clear cell carcinoma

8310/3

Histopathology

1.3.4.5

17

Large cell carcinoma with rhabdoid phenotype

1.3.5 Adenosquamous carcinoma

8014/3 8560/3

1.3.6 Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements 1.3.6.1

Carcinomas with spindle and/or giant cells

8030/3

1.3.6.1.1

Pleomorphic carcinoma

8022/3

1.3.6.1.2

Spindle cell carcinoma

8032/3

1.3.6.1.3

Giant cell carcinoma

8031/3

1.3.6.2

Carcinosarcoma

8980/3

1.3.6.3

Pulmonary blastoma

8972/3

1.3.6.4

Others

1.3.7 Carcinoid tumour

8240/3

1.3.7.1

Typical carcinoid

8240/3

1.3.7.2

Atypical carcinoid

8249/3

1.3.8 Carcinomas of salivary gland type 1.3.8.1

Mucoepidermoid carcinoma

8430/3

1.3.8.2

Adenoid cystic carcinoma

8200/3

1.3.8.3

Others

1.3.9 Unclassified carcinoma

8010/3

a

Modified from Travis WD, Colby TV, Corrin B et al (eds). Histological Typing of Lung and Pleural Tumours. WHO International Histological Classification of Tumours. Berlin: SpringerVerlag, 1999:22–3.

With respect to the classification and the criteria for the diagnosis of neuroendocrine tumors, Ullmann et al,3 on the basis of a study of 218 neuroendocrine tumors and 50 nonsmall cell lung cancers (NSCLC), illustrated the benefit of chromosomal analysis as a supplement to the diagnosis of bronchopulmonary carcinoids. Loss of 11q was the most frequent aberration in atypical forms of bronchopulmonary carcinoids (55%), but was observed only twice in typical carcinoids (13%). Deletion of 3p was seen only in atypical carcinoids. The subgroup, pulmonary large cell neuroendocrine carcinoma (LCNEC), was subjected to specific analysis in three articles—one from the Netherlands and two from Japan.4–6 All three studies indicated that, in terms of prognosis, LCNEC is distinctively different from other types of NSCLC, with a very poor prognosis even for early-stage disease. The prognosis of stage I LCNEC was poorer than that of the same stage of other types of NSCLC, as shown by Takei et al.5 Iyoda et al6 found that typical carcinoids and atypical carcinoids were not related to smoking and, unlike large cell carcinomas, neuroendocrine features were found in younger patients without a male predominance.

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Also, according to Hiroshima et al,7 the presence of neuroendocrine differentiation in adenocarcinoma of the lung predicts a poorer prognosis than for patients with adenocarcinoma without neuroendocrine differentiation, based on data from 90 patients with adenocarcinoma of the lung measuring 3 cm or less (T1N0M0 or T2N0M0). A comparison in terms of survival between classic large cell carcinoma and large cell carcinoma with neuroendocrine features is shown in Table 4.3. Another subtype of adenocarcinoma of the lung that has attracted increased interest is bronchioloalveolar carcinoma (BAC), which has increased in incidence over recent years, partly because of the increase in adenocarcinoma in general. In a study including 1158 patients submitted to surgical resection for NSCLC in the period 1993–99, Rena et al8 found that 28 patients (2.4%) had stage I peripheral pure BAC and 80 (6.9%) had stage I peripheral adenocarcima. Comparing the two groups, no differences were detected between smokers during BAC and adenocarcinoma patients. Relapse of disease was less frequent in BAC than in adenocarcinoma patients (14.2% vs 33.7%) and recurrent disease developed intrathoracically with higher frequency in BAC patients (75% vs 33.3%). Both 5-year disease-free and long-term survival rates were significantly higher in patients affected by BAC (81% vs 51% and 86% vs 71%, respectively) (p<0.05). Overall, the subtype of adenocarcinoma termed BAC is characterized by less aggressive clinical behavior than similar-stage adenocarcinoma.

Table 4.2 Criteria for diagnosis of neuroendocrine (NE) tumoursa Tumor

Descriptionb

Typical carcinoid

A tumor with carcinoid morphology and <2 mitoses per 2 mm2 (10 HPF), lacking necrosis and 0.5 cm or larger

Atypical carcinoid

A tumor with carcinoid morphology with 2–10 mitoses per 2 mm2 (10 HPF) or necrosis (often punctate)

Large cell neuroendocrine carcinoma

1. A tumor with a neuroendocrine morphology (organoid nesting, palisading, rosettes, trabeculae) 2. High mitotic rate; ≥11 per 2 mm2 (10 HPF), median of 70 per 2 mm2 (10 HPF) 3. Necrosis (often large zones) 4. Cytologic features of a non-small cell lung cancer (NSCLC): large cell size, low nuclear-to-cytoplasmic ratio, vesicular or fine chromatin, and/or frequent nucleoli. Some tumors have fine nuclear chromatin and lack nucleoli, but qualify as NSCLC because of large cell size and abundant cytoplasm 5. Positive immunohistochemical staining for one or more neuroendocrine markers (other than neuron-specific enolase) and/or neuroendocrine granules by electron microscopy

Small cell carcinoma

1. Small size (generally less than the diameter of three small resting lymphocytes) 2. Scant cytoplasm

Histopathology

19

3. Nuclei: finely granular nuclear chromatin, absent or faint nucleoli 4. High mitotic rate (≥11 per 2 mm2) (10 HPF), median of 80 per 2 mm2 (10 HPF) 5, Frequent necrosis, often in large zones a

Modified from Travis WD, Colby TV, Corrin B et al (eds). Histological Typing of Lung and Pleural Tumours. WHO International Histological Classification of Tumours. Berlin: SpringerVerlag, 1999. b For an explanation of HPF (high-power field) and mitosis counting, see page 10 of Travis et al.

Table 4.3 Overall and disease-free survival for classic large cell carcinomas and forge cell carcinomas with neuroendocrine features Overall survival Tumora

Median survival (months)

CLCC

5-year survival rate (%)b 25

4.84 (31.9–64.9)

16.5

3.23 (20.5–44.1)

LCNEC

19

35.3 (20.8–49.8)

LCCND

8

22.2 (0–49.4)

LCCNM

14

27.3 (1.0–54.5)

Large cell carcinomas with NE featuresc

Disease-free survival Tumora

Median survival (months)

5-year survival rate (%)b

CLCC 24

43.3 (27.8–58.8)

LCNEC

11.5

25.4 (14.8–36.0)

LCCND

12.5

27.4 (14.3–40.5)

LCCNM

6

22.2 (0–49.4)

Large cell carcinomas with NE featuresc

a

CLCC, classic large cell carcinoma; NE, neuroendocrine; LCNEC, large cell NE carcinoma; LCCND, large cell carcinoma with NE differentiation; LCCNM, large cell carcinoma with NE morphology. b 95% confidence interval in parentheses. c Combining LCNEC, LCCND, and LCCNM.

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A retrospective study by Ebright et al9 analyzed 100 consecutive surgically treated patients at the Memorial Sloan-Kettering Cancer Center in New York with adenocarcinomas exhibiting various degrees of BAC features, and it was concluded that the clinical pattern and pathologic stage, but not the degree of invasion on histologic examination, predict survival. A special subtype of BAC has been described by some investigators as pneumonic-type adenocarcinoma (P-ADC) of the lung; it is characterized by aerogenous propagation and a pneumonia-like consolidation on X-ray or CT scan without concomitant bacterial pneumonia or obstructive pneumonia. Fifty-two patients with this subtype were diagnosed in a 4-year period in a study by Wislez et al.10 The median survival after diagnosis was 10.5 months. With respect to the distinction between lung carcinomas and mesotheliomas of the pleura, studies have been performed using various immunohistochemical markers employing a number of new commercial antibodies. These markers have been compared with others that are already commonly used for this purpose in order to determine which are at present the best for discriminating between these malignancies, using a large panel of immunohistochemical markers. Ordónez11 concluded that calretinin, cytokeratin 5/6, and WT1 were the best positive markers for differentiating epithelioid malignant mesothelioma from pulmonary adenocarcinoma. The best discriminators among the antibodies considered to be negative markers for mesothelioma are carcinoembryonic antigen (CEA), MOC31, Ber-EP4, BG-8, and B72.3. Ordónez11 recommended a panel of four markers (two positive and two negative) selected on the basis of availability and whether they yield good staining results in a given laboratory. These results are supported by an immunohistochemical analysis of 596 tumors of the lung by Miettinen and Sarlomo-Rikala12 and Abutaily et al.13 In the future, gene expression ratios may be a useful tool in distinguishing adenocarcinoma of the lung from mesothelioma, as indicated by preliminary results by Gordon et al.14 Among the rarer tumors of the lung, pulmonary blastoma and pulmonary lymphoepithelioma-like carcinomas have been reviewed partly based on groups of patients from one institutiton and partly on a review of the literature.15,16

REFERENCES 1. Travis WD, Colby TV, Corrin B et al. Histological Typing of Lung and Pleural Tumours. WHO International Histological Classification of Tumours, 3rd edn. Berlin: Springer-Verlag, 1999. 2. Skuladottir H, Hirsch FR, Hansen HH, Olsen JH. Pulmonary neuroendocrine tumors: incidence and prognosis of histological subtypes. A population-based study in Denmark. Lung Cancer 2002; 37:127–35. 3. Ullmann R, Petzmann S, Klemen H et al. The position of pulmonary carcinoids within the spectrum of neuroendocrine tumors of the lung and other tissues. Genes Chromosomes Cancer 2002; 34:78–85. 4. Hage R, Seldenrijk K, de Bruin P et al. Pulmonary large-cell neuroendocrine carcinoma (LCNEC). Eur J Cardio-Thorac Surg 2003; 23:457–60. 5. Takei H, Asamura H, Maeshima A et al. Large cell neuroendocrine carcinoma of the lung: a clinicopatho logic study of eighty-seven cases. J Thorac Cardiovas Surg 2002; 124: 285–92. 6. Iyoda A, Hiroshima K, Baba M et al. Pulmonary large cell carcinomas with neuroendocrine features are high-grade neuroendocrine tumors. Ann Thorac Surg 2002; 73:1049–54.

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7. Hiroshima K, Iyoda A, Shibuya K et al. Prognostic significance of neuroendocrine differentiation in adenocarcinoma of the lung. Ann Thorac Surg 2002; 73:1732–5. 8. Rena O, Papalia E, Ruffini E et al. Stage I pure bronchioloalveolar carcinoma: recurrences, survival and comparison with adenocarcinoma of the lung. Eur J Cardio-Thorac Surg 2003; 23:409–14. 9. Ebright MI, Zakowski ME, Martin J et al. Clinical pattern and pathologic stage but not histologic features predict outcome for bronchioloalveolar carcinoma. Ann Thorac Surg 2002; 74:1640–7. 10. Wislez M, Massiani M-A, Milleron B et al. Clinical characteristics of pneumonic-type adenocarcinoma of the lung. Chest 2003; 123:1868–77. 11. Ordónez NG. The immunohistochemical diagnosis of mesothelioma. Am J Surg Pathol 2003; 27:1031–51. 12. Miettinen M, Sarlomo-Rikala M. Expression of calretinin, thrombomodulin, keratin 5, and mesothelin in lung carcinomas of different types. Am J Surg Pathol 2003; 27:150–8. 13. Abutaily AS, Addis BJ, Roche WR. Immunohistochemistry in the distinction between malignant mesothelioma and pulmonary adenocarcinoma: a critical evaluation of new antibodies. J Clin Pathol 2002; 55: 662–8. 14. Gordon GJ, Jensen RV, Hsiao L-L et al. Translation of microarray data into clinically relevant cancer diagnostic tests using gene expression ratios in lung cancer and mesothelioma. Cancer Res 2002; 62:4963–7. 15. Robert J, Pache J-C, Seium Y et al. Pulmonary blastoma: report of five cases and identification of clinical features suggestive of the disease. Eur J Cardio-Thorac Surg 2002; 22: 708–11. 16. Chang Y-L, Wu C-T, Shih J-Y, Lee Y-C. New aspects in clinicopathologic and oncogene studies of 23 pulmonary lymphoepithelioma-like carcinomas. Am J Surg Pathol 2002; 26: 715– 23.

5 Staging, staging procedures, and prognostic factors

Clinical staging of lung cancer helps to determine the extent of disease and to stratify patients into similar prognostic and therapeutic categories. For lung cancer patients, an important goal is to separate patients with potentially resectable disease from those who are unresectable. The most recent staging system for lung cancer was published in 1997 (Table 5.1; Figures 5.1–5.5), replacing the 1986 classification. This staging system is now under revision by an International Staging Committee established by the International Association for the Study of Lung Cancer (IASLC), and cooperation between this Committee, the Union Internationale Contre le Cancer (UICC), the American Joint Committee for Cancer (AJCC), and the Japan Lung Cancer Society has been established. Accrual from data centers around the world is taking place, with more than 30000 patients already being registered by the IASLC Committee.1 Several problems exist with the present staging system, especially within stage III, as evidenced by two reports.2,3 In a study by Kameyama et al,2 including 429 patients with non-small cell lung cancer (NSCLC) who underwent resection, a special analysis was performed for patients with stage IIIA (n=73) or stage IIIB (n=79). No difference in survival between patients with T3 and T4 disease was observed, and this seemed to affect the prognosis of patients with stage IIIA or IIIB disease. However, when those with T3 and T4 disease were classified into different groups on the basis of TNM descriptors, differences in survival became evident. Kameyama et al2 concluded that a multicenter study is necessary to evaluate the TNM classification, such as that taking place under the auspices of the IASLC Staging Committee.

Table 5.1 Revised (1997) TNM stage classification for lung canceraa Stage

TNM classificationb

Occult

TXN0M0

0

TISN0M0

IA

T1N0M0

IB

T2N0M0

Staging, staging procedures, and prognostic factors

IIA

T12N1M0

IIB

T2N1M0, T3N0M0

IIIA

T3N1M0, T1N2M0, T2N2M0, T3N2M0

IIIB

T4(any N)M0, (any T)N3M0

IV

(any T)(any N)M1

23

a

Adpoted from Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111: 1710–17. b Satellite tumor nodule(s) in ipsilateral primary tumor lobe(s) is designated T4. Separate tumor nodule(s) in ipsilateral non-primary tumor lobe(s) is designated M1.

Figure 5.1 Stage I disease. Reproduced, with permission, from Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111: 1710–17.

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Figure 5.2 Stage IIA disease. Adapted with permission, from Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111: 1710–17. In another study on a group of patients receiving radiotherapy with or without concomitant chemotherapy, Ball et al3 analyzed a total of 231 patients for whom the T and N stages were known. They observed that even though there is evidence that T stage is an independent prognostic factor in patients with NSCLC treated surgically, it did not appear to be of value in this series of patients treated with radiotherapy with or without concomitant chemotherapy. Another topic that has been subjected to evaluation has been the impact of tumor size. Since 1974, a tumor size of 3 cm in diameter has been regarded as the prognostic threshold in the staging of bronchogenic carcinoma. López-Encuentra et al,4 from the Spanish Society of Pneumology and Thoracic Surgery, analyzed 1020 cases treated surgically with complete resection from 1993 to 1997. Four prognostic groups with different tumor sizes were identified: 0–2 cm (n=147), 2.1–4 cm (n=448), 4.1–7 cm (n=336), and over 7 cm (n=89). The study did not find the 3 cm value to be a prognostic threshold, but it did identify the above-mentioned four tumor size groups to have an

Staging, staging procedures, and prognostic factors

25

impact on survival. Again, these data will be pooled with data from other cooperative groups by the IASLC Staging Committee.

Figure 5.3 Stage IIB disease. Adapted with permission, from Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111: 1710–17. Lymph node size evaluated by computed tomography (CT) is also a parameter for the evaluation of metastatic involvement in patients with NSCLC. Prenzel et al5 analyzed 256 patients, comparing preoperative CT scans with morphometric study of hilar and mediastinal lymph nodes. A total of 2891 lymph nodes were present in the 256 specimens examined. The conclusion of the study was that lymph node size is not a reliable parameter, since, of 139 patients with no metastatic lymph node involvement, 101 (77%) had at least one lymph node that was more than 10 mm in diameter. Of 127 patients with metastatic lymph node involvement, 12% had no lymph node that was less than 10 mm.

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Independent radiologic evaluation of the CT scans of 80 patients yielded a sensitivity of 57.1% and a specificity of 80.6%. In another study evaluating hilar and mediastinal lymph nodes removed during surgery, Osaki et al6 analyzed the lymph nodes for micrometastasis using immunohistochemistry with the biclonal anti-cytokeratin (CK) antibody AE1/AE3. In addition, bone marrow aspirates from 115 patients were immunocytochemically stained with the monoclonal anti-CK antibody CK2. CK-positive cells were detected in 42 (1.7%) of 2432 lymph nodes, in 32 (27.8%) of 115 patients, and in 32 (27.8%) of 115 bone marrow aspirates. The patients with CK-positive cells in the lymph nodes had a poor prognosis by both univariate (p=0.008) and multivariate (p=0.01) analyses, whereas the presence of CK-positive cells in the bone marrow did not allow prediction of survival (p=0.32). The prognostic impact of lymph node micrometastasis was independent even after adjusting for the status of bone marrow micrometastasis.

Figure 5.4 Stage IIIA disease. Adapted with permission, from Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111: 1710–17.

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Figure 5.5 Stage IIIB disease. Reproduced with permission, from Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111: 1710–17.

STAGING PROCEDURES AND PROGNOSTIC FACTORS Non-small cell lung cancer With respect to staging, chest radiography and CT scanning are the conventional imaging procedures, and have now been complemented by positron emission tomography (PET) using [18F]fluorodeoxyglucose (FDG). Invasive procedures have included bronchoscopy, mediastinoscopy, transbronchial needle biopsy, transthoracic needle biopsy, mediastinal transthoracic needle biopsy and core lymph node methods, such as intraoperative sentinel lymph node mapping. There have been a number of reviews of various concepts in the staging of NSCLC,7–17 especially the role of PET scanning, including a study with questionnaires to 292 physicians who referred patients to PET scanning.18 Altogether, 744 consecutive patients with known or suspected lung cancer were evaluated and questionnaires on 274 patients were returned. Overall, physicians reported that PET caused them to change their decision on clinical stage in 44% of all patients: the disease was upstaged in 29% and downstaged in 15%. PET resulted in intermodality management changes in 39% of patients, whereas 15% had an intramodality change. Similar observations have been made by Herder et al19 on the basis of a cohort of 164 patients referred for PET in a 2-year period. PET thus has already had a major impact on the staging and management of lung cancer.

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With regard to specific evaluation of the effectiveness of PET in the preoperative assessment of patients with lung cancer and the surgical staging of NSCLC, several studies have been performed.20 Similarly, studies have focused on the use of PET in the non-surgical treatment of NSCLC. In a pivotal randomized study by van Tinteren et al,21 188 patients from nine hospitals were randomly assigned before surgery (mediastinoscopy or thoracotomy) to either conventional workup (CWU) or conventional workup and PET (CWU-PET). Patients were followed up for 1 year. Thoracotomy was regarded as futile if the patient had benign disease, explorative thoracotomy, pathologic stage IIIA-N2/IIIB, or postoperative relapse or death within 12 months of randomization. Eighteen patients in the CWU group and 32 in the CWU-PET group did not have thoracotomy. In the CWU group, 39 (41%) patients had a futile thoracotomy, compared with 19 (21%) in the CWU-PET group (relative reduction 51%, 95% confidence interval 32–80%; p=0.003). van Tinteren et al21 concluded that the addition of PET to conventional workup prevented unnecessary surgery in one out of five patients with suspected NSCLC. The value of PET in this clinical situation was highlighted in a subsequent editorial by Coleman.22 Similar conclusions were reached by Lardinois et al.23 Integrated PET-CT was performed in 50 patients with proven or suspected NSCLC. Tumor staging was significantly more accurate with integrated PET-CT than with CT alone (p=0.001). It is also noteworthy that node staging was significantly more accurate with integrated PETCT than with PET alone. In metastasis staging, integrated PET-CT increased the diagnostic certainty in two of eight patients. FDG-PET imaging has been applied to the bronchioloalveolar carcinoma (BAC) subtype of adenocarcinoma. Yap et al24 reevaluated the results of preoperative FDG-PET and concluded that the diagnostic performance of wholebody FDG-PET is similar in most patients with lesions with a BAC pattern and in those with other NSCLC. However, PET is less accurate in patients with rare BAC tumors that have no invasive component. A comparison of FDG-PET with mediastinal lymph node staging in patients with suspective NSCLC was performed by Graeter et al.25 In a 4-year period, 102 patients underwent both PET and mediastinoscopy for radiologically suspected mediastinal lymph node disease. Benign lesions were diagnosed in 15 of the 102 patients. In 87 patients, malignant disease was proven by histology, and bronchogenic carcinoma was found in 82. Of 469 nodal stations analyzed, 84 were proven malignant by histology. In PET analysis, 79 true-positive and 304 true-negative samples were found. Five lymph node stations were false-negative and 81 samples were false-positive. False-positive findings in PET were frequently seen in inflammatory lung disease. The sensitivity of PET was 94.1% and the specificity was 79%, with a diagnostic accuracy of 81.6%. The positive predictive value of PET was 49.3% and the negative predictive value was 98.4%. Graeter et al25 concluded that in patients with positive PET scan results, histologic verification appears necessary for exact lymph node staging. In view of the negative predictive value, mediastinoscopy can be omitted in patients with bronchogenic carcinoma whose PET scan results are negative. Similar conclusions were reached by Kernstine et al26 based on a 5-year retrospective analysis of 239 patients who underwent surgical mediastinal nodal sampling by mediastinoscopy and PET.

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The value of FDG-PET has also been established in the selection of patients with stage IIIA for combined-modality treatment, as shown by both Hoekstra et al27 and Eschmann et al,28 based on prospective studies in 57 patients and 101 patients, respectively. The results were compared with conventional staging, including mediastinoscopy, CT, and, in the latter study, also bone scan and abdominal ultrasonography. Results from both studies indicate that a substantial group of patients are understaged if PET scans are not applied, with upstaging in 30% in the former study and the occurrence of distant metastases in 25 of 101 patients, all previously unknown, in the latter study. Furthermore, PET findings changed further treatment in 29% in the study by Eschmann et al.28 Similar findings with high sensitivity of FDG-PET to detect extracranial metastases were observed by MacManus et al,29 who also correlated the findings of PET scanning with survival. With respect to extrapulmonary manifestations of disease, Gupta et al30 showed the important clinical role of FDG-PET imaging in patients with lung cancer and suspected malignant pleural effusion. FDG-PET imaging correctly detected the presence of malignant pleural effusion and malignant pleural involvement in 16 of 18 patients and excluded malignant effusion or pleural metastatic involvement in 16 of 17 patients in a study comparing PET and CT scanning with pleural cytology and positive pleural biopsies (31 and 3, respectively). With respect to the evaluation of lymph nodes in the mediastinum, Sioris et al31 compared CT and systematic lymph node dissection in 49 patients with NSCLC. Preoperative clinical and CT findings were compared with surgical-pathologic findings. Lymph nodes with a shortest diameter of more than 1 cm on CT were considered abnormal, but did not contraindicate surgery. The clinical T category was correct in 71% and the N category in 55%. The sensitivity for detecting N2 disease was 67% and the specificity was 81%. Sioris et al31 concluded that clinical TNM and staging based on CT scans are inaccurate and that the sensitivity for detecting N2 disease is poor, especially on a node-by-node basis. Preoperative exclusion of N2 metastases is quite reliable, but a positive finding should always be verified. Systematic mediastinal lymph node dissection remains necessary to detect N2 inaccessible to mediastinoscopy. Another procedure to identify lymph node metastases in primary NSCLC is the use of intraoperative sentinel lymph node mapping, as described by Liptay et al,32 Schmidt et al,33 and Nomori et al,34 with a subsequent commentary by Liptay35 on the article by Nomori et al. All three studies, which included 100, 31, and 46 patients, respectively, clearly indicated that the use of sentinel lymph node identification by technetium-99m tin colloid resulted in accurate sentinel node readings in more than 80% of the patients when the intraoperative readings of the lymph nodes were compared with histopathologic findings after lymph node dissection. There is thus growing experience with the sentinel lymph node technique, and the results of the above-mentioned studies confirm the promise of this staging tool to identify those most likely to benefit from adjuvant therapies. These findings await broader application in patients with resectable lung cancer in order to refine the sentinel node mapping technique and patient selection criteria. As to invasive procedures, the experience with transesophageal endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) has been evaluated by investigators from the USA, Japan, and Europe, and the topic has also been reviewed in detail with comparison of CT, PET, and endoscopic ultrasonography.36–39 The authors concluded that no single

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imaging method alone was conclusive in evaluating potential mediastinal involvement in apparently operable lung cancer under routine clinical conditions.36,37 Because FNA can be performed at the time same as EUS, this combination emerged as the most useful technique for the evaluation of even very small mediastinal metastases of lung cancer. Other invasive procedures used for staging include transbronchial needle biopsies and mediastinal transthoracic needle and core lymph node biopsy. The latter method was analyzed in a retrospective study including 89 patients with mediastinal lymphadenopathy (>1.5 cm in short-axis diameter) by CT.40 Mediastinal transthoracic FNA was used alone in 39 of 89 patients, or with core biopsy in 50 or 89 patients prior to medianoscopy. Transthoracic FNA with or without core biopsy was diagnostic in virtually all mediastinal nodal stations in 78% of cases with mediastinal adenopathy or masses, and Zwischenberger et al40 concluded that it should precede mediastinoscopy in the staging of lung cancer or the workup of mediastinal masses. Of the above-mentioned methods, PET has also been applied for radiotherapy planning, but only in a small study of 11 patients.41 Preliminary data indicate that the incorporation of PET data improves the definition of the primary lesion by including positive lymph nodes into the planning target volume and that the PET data reduce the likelihood of geographic misses. However, outcome analysis in survival, disease-free survival, morbidity, and secondary effects of radiation from larger studies is needed to evaluate the cost-effectiveness and overall utility of this approach for future planning of radiotherapy for NSCLC. In a response assessment after radical therapy or chemoradiotherapy, MacManus et al42 demonstrated that PET was superior to CT, based on a study with 73 patients who underwent PET and CT scans before and after the abovementioned treatment. As mentioned above, the current staging of NSCLC is based on the TNM system, but data on molecular biological substaging are accumulating rapidly and several biological staging models have been suggested. In addition, the first report on the detection of circulating tumor DNA and gene transcripts in plasma at diagnosis and during follow-up of lung cancer patients has been published, and these might emerge as valuable noninvasive diagnostic tools for discriminating patients from unaffected individuals and for detecting early recurrence during follow-up.43–45 Also, carcinoembryonic antigen (CEA) messenger ribonucleic acid (mRNA) in circulating cells has been explored to identify patients at a greater risk of metastasis in a small study by Castaldo et al46 comparing 32 lung cancer patients monitored for 24 months with 19 healthy controls. Among 17 positive patients, 12 developed metastases within 9 months of mRNA analysis. Other prognostic factors have been reviewed by Brundage et al47 and Kasimir-Bauer et 48 al, who emphasized that the breadth of prognostic factors studied is extensive, that the scope of factors evaluated in individual studies is inappropriately narrow, and that these studies are typically statistically underpowered and remarkably heterogeneous with regard to their conclusions. Larger studies with clinically relevant modeling are required to address the usefulness of newly available prognostic factors in defining the management of patients with NSCLC. A number of articles have provided prognostic information on a variety of tumor markers: classical ones such as CEA and CYFRA 21–1;49,50 molecular biological markers, including DNA content determined by flow cy tome try;51 vascular endothelial growth factor (VEGF) expression;52,54 various proteases and adhesion molecules

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potentially involved in angiogenesis and metastasis;55–63 immunohistochemical evaluation or use of microarrays in the evaluation of a number of genes;64–68 c-ErbB-2 expression;68,69 Bcl-2;70 p16, p53, Ki67, and cyclin D expression;71–75 telomerase activity;76 and various receptors, especially tyrosine kinase receptor proteins, such as epidermal growth factor receptors (EGFRs),77–80 including meta-analyses81,82 and a discussion of how to target the EGFR in NSCLC.83 Other parameters, such as various glycoprotein subgroups (e.g. CEACAM 1),84,85 carbonic anhydrase IX expression (a novel surrogate marker of tumor hypoxia),86 and cyclooxygenase-2 mRNA expression,87 have also been evaluated as predictors of survival. The first studies using tissue microassay analysis to evaluate the biology of NSCLC have also emerged.88 Small cell lung cancer FDG-PET imaging has also been evaluated in patients with small cell lung cancer (SCLC), but with much fewer patients included in the studies.89,90 In addition, the prognostic value of FDG-PET imaging has been determined.91 In one of the studies applying FDG-PET in the initial staging of 42 patients and for restaging after chemotherapy or radiotherapy in 20 patients, the PET findings were correlated with clinical and radiologic findings (CT of the chest and abdomen, bone scan, and CT or magnetic resonance imaging (MRI) of the brain).89 For 12 of the 42 patients (29%), PET results changed the patient’s management. In 8 patients (19%), PET resulted in a change of radiotherapy because of detection of previously unknown tumor foci. Adjuvant radiochemotherapy was cancelled in 3 patients. In 1 patient, PET excluded extensive disease, thus permitting surgical resection of the tumor. In the other study, by Chin et al,90 the design was quite similar, with a comparison of FDG-PET with conventional staging procedures, with 18 patients being included. Overall, staging by FDG-PET agreed with conventional staging in 83% of the patients, including 8 extensive and 7 limited cases. FDG-PET showed more extensive disease in 2 of the 3 patients for whom FDG-PET and conventional staging disagreed. Fukuchi et al92 reported that FDGPET is particularly useful in detecting bone marrow metastasis, also in patients with negative 99mTc-HMDP bone scans. Based on a larger study by Pandit et al,91 with FDG-PET in 46 patients, overall survival in PET-positive scans was significantly worse than that in PET-negative cases (p=0.0108), which is not surprising. In summary, the usefulness of FDG-PET imaging in SCLC is still under evaluation and large prospective studies of consecutive patients are needed, involving comparison of whole-body FDG-PET with conventional imaging methods, MRI, and bone marrow examinations with immunohistochemical and polymerase chain reaction (PCR) analysis of neuroendocrine markers, as summarized in a commentary by Lassen.93 Studies to detect SCLC cells in the peripheral blood, bone marrow, and pleural effusion using preprogastrin-releasing pep tide (preproGRP)-specific nested reverse transcriptase (RT)-PCR94 or chromogranin A gene transcripts95 have been carried out. The former method was tested in 32 patients with SCLC, 39 patients with NSCLC, 28 patients with non-malignant pulmonary disease, and 20 healthy volunteers.94 PreproGRP mRNA was detected in 16 of 32 blood samples, in 2 of 11 marrow samples, and in all

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pleural effusion samples. Blood samples gave positive results in 11 of 19 patients with extensive disease, compared with 5 of 13 patients with limited disease. In contrast, only 1 blood sample (2.6%) from a patient with lung adenocarcinoma gave a positive result among patients with NSCLC. No other samples from patients with NSCLC or from patients with non-malignant diseases and healthy volunteers were positive. As to the classical prognostic factors, Bremnes et al96 confirmed, in a study of 436 patients in a multivariate Cox model, that gender, extent of disease, performance status, weight loss, platelet count, lactate dehydrogenase (LDH), and non-specific enolase (NSE) are all independent prognostic factors. Pujol et al97 obtained similar results in a smaller group of patients with 148 untreated SCLC cases, including CYFRA 21–1 and chromogranin A as additional diagnostic determinants. Among the new prognostic factors, VEGF has been estimated, in two studies, either in serum or immunohistochemically on biopsy specimens. These two studies included 70 and 75 patients with SCLC, respectively.98,99 Other factors involved in angiogenesis, such as basic fibroblast growth factor (bFGF), have been determined by Ruotsalainen et al100 in 103 patients with SCLC at the time of diagnosis. Again, a multivariate model of survival was applied and a high pretreatment serum bFGF level was associated with poor overall survival. Finally, the tyrosine kinase receptor c-Kit was determined in biopsies from 102 and 193 patients with SCLC by Micke et al101 and Potti et al.102 Positive c-Kit expression was observed in roughly one-third of the patients, and in the study by Micke et al it was found to be a new prognostic factor. This information is of value, and clinical studies aiming at targeting c-Kit (e.g. with the selective tyrosine kinase inhibitor imatinib (STI571, Gleevec/Glivec)), either alone or in combination with conventional therapy, are clearly warranted.

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51. Otsuka H, Funai S, Azumi T et al. Ability of bivariate cytokeratin and deoxyribonucleic acid flow cytometry to determine the biologic aggressiveness of resectable non-small cell lung cancer. J Thorac Cardiovasc Surg 2003; 124:293–8. 52. Kishiro I, Fuse D, Yoshida T et al. Clinical significance of vascular endothelial growth factor in patients with primary lung cancer. Respirology 2002; 7:93–8. 53. Arinaga M, Noguchi T, Takeno S et al. Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with non-small cell lung carcinoma. Cancer 2003; 97:457–64. 54. Trapé J, Buxó J, Pérez de Olaguer JP. Serum concentrations of vascular endothelial growth factor in advanced non-small cell lung cancer. Clin Chem 2003; 49:523–5. 55. Meert A-P, Paesmans M, Martin B et al. The role of microvessel density on the survival of patients with lung cancer: a systematic review of the litterature with meta-analysis. Br J Cancer 2002; 87:694–701. 56. Jäger R, List B, Knabbe C et al. Serum levels of the angiogenic factor pleiotrophin in relation to disease stage in lung cancer patients. Br J Cancer 2002; 86:858–63. 57. Inoshima N, Nakanishi Y, Minami T et al. The influence of dendritic cell infiltration and vascular endothelial growth factor expression on the prognostic of non-small cell lung cancer. Clin Cancer Res 2002; 8: 3480–6. 58. Marchetti A, Tinari N, Buttitta F et al. Expression of 90K (Mac-2 BP) correlates with distant metastasis and predicts survival in stage I non-small cell lung cancer patients. Cancer Res 2002; 62:2535–9. 59. Laack E, Köhler A, Kugler C et al. Pretreatment serum levels of matrix metalloproteinase-9 and vascular endothelial growth factor in non-small-cell lung cancer. Ann Oncol 2002; 13:1550–7. 60. Sienel W, Hellers J, Morresi-Hauf A et al. Prognostic impact of matrix metalloproteinase-9 in operable non-small cell lung cancer. Int J Cancer 2003; 103:647–51. 61. Chen JJW, Yao P, Yuan A et al. Up-regulation of tumor interleukin-8 expression by infiltrating macrophages: its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer. Clin Cancer Res 2003; 9:729–37. 62. Joensuu H, Anttonen A, Eriksson M et al. Soluble syndecan-1 and serum basic fibroblast growth factor are new prognostic factors in lung cancer. Cancer Res 2002; 62:5210–7. 63. Bremnes RM, Veve R, Gabrielson E et al. High-throughput tissue microarray analysis used to evaluate biology and prognostic significance of the E-cadherin pathway in non-small-cell lung cancer. J Clin Oncol 2002; 20:2417–28. 64. Brabender J, Usadel H, Metzger R et al. Quantitative O6-methylguanine DNA methyltransferase methylation analysis in curatively resected non-small cell lung cancer: associations with clinical outcome. Clin Cancer Res 2003; 9:223–7. 65. Katakura H, Tanaka F, Oyanagi H et al. Clinical significance of nm23 expression in resected pathologic-stage I, non-small cell lung cancer. Ann Thorac Surg 2002; 73:1060–4. 66. Volm M, Koomogi R, Mattern J, Efferth T. Expression profile of genes in non-small cell lung carcinomas from long-term surviving patients. Clin Cancer Res 2002; 8:1843–8. 67. Wigle DA, Jurisica I, Radulovich N et al. Molecular profiling of non-small cell lung cancer and correlation with disease-free survival. Cancer Res 2002; 62:3005–8. 68. Nakamura H, Saji H, Ogata A et al. Correlation between encoded protein overexpression and copy number of the HER2 gene with survival in non-small cell lung cancer. Int J Cancer 2003; 103:61–6. 69. Bakir K, Ucak R, Tuncögür B, Elbeyli L. Prognostic factors and c-erbB-2 expression in nonsmall cell lung carcinoma. Thorac Cardiovasc Surg 2002; 50:55–8. 70. Martin B, Paesmans M, Berghmans T et al. Role of Bcl-2 as a prognostic factor for survival in lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 2003; 89:55– 64.

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71. Hirabayashi H, Ohta M, Tanaka H et al. Prognostic significance of p27KIP1 expression in resected non-small cell lung cancers: analysis in combination with expressions of p16INK4A, pRB, p53. J Surg Oncol 2002; 81:177–84. 72. Cheng Y-L, Lee S-C, Harn H-J et al. Prognostic prediction of the immunohistochemical expression of p53 and p16 in resected non-small cell lung cancer. Eur J Cardio-Thorac Surg 2003; 23:221–8. 73. Bubb RS, Komaki R, Hachiya T et al. Association of Ki-67, p53, and bcl-2 expression of the primary non-small-cell lung cancer lesion with brain metastatic lesion. Int J Radiat Oncol Biol Phys 2002; 53: 1216–24. 74. Ratschiller D, Heighway J, Gugger M et al. Cyclin D1 overexpression in bronchial epithelia of patients with lung cancer is associated with smoking and predicts survival. J Clin Oncol 2003; 21:2085–93. 75. An Q, Liu Y, Gao Y, Huang J et al. Detection of p16 hypermethylation in circulating plasma DNA of non-small cell lung cancer patients. Cancer Letters 2002; 188:109–14. 76. Wang L, Soria J-C, Kemp BL et al. hTERT expression is a prognostic factor of survival in patients with stage I non-small cell lung cancer. Clin Cancer Res 2002; 8:2883–9. 77. Hirsch FR, Varella-Garcia M, Franklin WA et al. Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas. Br J Cancer 2002; 86:1449–56. 78. Hirsch FR, Varella-Garcia M, Bunn PA Jr et al. Epidermal growth factor receptor in non-smallcell lung cancer carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 2003; 21: 3798–807. 79. Kinch MS, Moore M-B, Harpole DH. Predictive value of the EphA2 receptor tyrosine kinase in lung cancer recurrence and survival. Clin Cancer Res 2003; 9:613–18. 80. Gong Y, Hirano T, Kato Y et al. Phosphorylated tyrosine-containing proteins in primary lung cancer correlates with proliferation and prognosis. Br J Cancer 2002; 86:1893–8. 81. Meert A-P, Martin B, Delmotte P et al. The role of EGF-R expression on patients survival in lung cancer: a systematic review with meta-analysis. Eur Respir J 2002; 20:975–81. 82. Meert A-P, Martin B, Paesmans M et al. The role of HER-2/neu expression on the survival of patients with lung cancer: a systematic review of the literature. Br J Cancer 2003; 89: 956–65. 83. Herbst RS, Bunn PA Jr. Targeting the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res 2003:9:5813–24. 84. Laack E, Nikbakht H, Peters A et al. Expression of CEACAM1 in adenocarcinoma of the lung: a factor of independent prognostic significance. J Clin Oncol 2002; 20: 4279–84. 85. Plunkett TA, Ellis PA. CEACAM1: a marker with a difference or more of the same? J Clin Oncol 2002; 20: 4273–5. 86. Swinson DE, Jones JL, Richardson D et al. Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer. J Clin Oncol 2003; 21:473–82. 87. Brabender J, Park J, Metzger R et al. Prognostic significance of cyclooxygenase 2 mRNA expression in non-small cell lung cancer. Ann Surgery 2002; 235:440–3. 88. Zhukov TA, Johanson RA, Cantor AB et al. Discovery of distinct protein profiles specific for lung tumors and premalignant lung lesions by SELDI mass spectrometry. Lung Cancer 2003; 40:267–79. 89. Kamel EM, Zwahlen D, Wyss MT et al. Whole-body 18F-FDG PET improves the management of patients with small cell lung cancer. J Nucl Med 2003; 44:1911–17. 90. Chin R Jr, McCain TW, Miller AA et al. Whole body FDG-PET for the evaluation and staging of small cell lung cancer: a preliminary study. Lung Cancer 2002; 37:1–6. 91. Pandit N, Gonen M, Krug L, Larson SM. Prognostic value of [18F]FDG-PET imaging in small cell lung cancer. Eur J Nucl Med Mol Imag 2002; 30:78–84. 92. Fukuchi K, Yamaguchi M, Hayashida K, Ishida Y. Discrepancy between Tc-99m HMDP bone scan and F-18 FDG positron emission tomographic images in a patients with small cell lung cancer. Clin Nucl Med 2003; 28:232–3.

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93. Lassen U. Commentary—FDG-PET imaging in small cell lung cancer: any value? Lung Cancer 2002; 37:7. 94. Saito T, Kobayashi M, Harada R et al. Sensitive detection of small cell lung carcinoma cells by reverse transcriptase-polymerase chain reaction for prepro-gastrin-releasing peptide mRNA. Cancer 2003; 97: 2504–11. 95. Bégueret H, Vergier B, Bigueret J et al. Detection of circulating cells expressing chromogranin A gene transcripts in patients with lung neuroendocrine carcinoma. Eur J Cancer 2002; 38:2325–30. 96. Bremnes RM, Sundstrom S, Aasebø U et al. The Norwegian Lung Cancer Study Group. The value of prognostic factors in small cell lung cancer: results from randomised multicenter study with minimum 5 year follow-up. Lung Cancer 2003; 39:303–13. 97. Pujol J-L, Quantin X, Jacot W et al. Neuroendocrine and cytokeratin serum markers as prognostic determinants of small cell lung cancer. Lung Cancer 2003; 39:131–8. 98. Mall JW, Schwenk W, Philipp AW et al. Serum vascular endothelial growth factor levels correlate better with tumour stage in small cell lung cancer than albumin, neuron-specific enolase or lactate dehydrogenase. Respirology 2002; 7:99–102. 99. Fontanini G, Faviana P, Lucchi M et al. A high vascular count and overexpression of vascular endothelial growth factor are associated with unfavorable prognosis in operated small cell lung carcinoma. Br J Cancer 2002; 86:558–63. 100. Ruotsalainen T, Joensuu H, Mattson K, Salven P. High pretreatment serum concentration of basic fibroblast growth factor is a predictor of poor prognosis in small cell lung cancer. Cancer Epidemiol Biomark Prev 2002; 11:1492–5. 101. Micke P, Basrai M, Faldum A et al. Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications. Clin Cancer Res 2003; 9:188–94. 102. Potti A, Moazzam N, Ramar K et al. CD117 (c-KIT) overexpression in patients with extensive-stage small-cell lung carcinoma. Ann Oncol 2003; 14:894–7.

6 Treatment of small cell lung cancer

The treatment of small cell lung cancer (SCLC) has been the subject of several reviews, ranging from guidelines developed by the American College of Chest Physicians to a full supplement on the treatment of SCLC,1–4 and in addition the progress in the treatment of SCLC during the last three decades has been highlighted in a historical overview.5 With regard to the overall management of SCLC, in Lung Cancer Therapy Annual 3, we described, on the basis of an abstract presentation, the results of a study from North America analyzing survival trends in patients with limited-stage SCLC from randomized clinical trials performed by cooperative groups in North America, initiated between 1972 and 1982 and completed by 1996. These data have now been published in full, demonstrating meaningful improvements in survival, with doubling of the 5-year survival rate of patients with limited-stage SCLC listed in the US Surveillance, Epidemiology, and End Results Program (SEER) database.6 Similar results have been obtained from a French region in a study analyzing data in the period 1981–83 including 787 patients.7 The median survival time increased for the overall population from 6.6 months in 1981–83 to 11.3 months in 1993–94 (p=10−5), for patients with limited disease from 9.2 months to 14.0 months (p=0.002), and for those with extensive disease from 3.5 months to 9.6 months (p=10−5). Long-term treatment results are also available from the Saskatchewan Cancer Centre in Canada.8 Between 1981 and 1998, 1447 new cases of SCLC were diagnosed, 244 of which were limited-stage and were treated with curative intent. They were followed to the end of February 2002. A parametric log-normal statistical model was retrospectively validated to determine whether long-term survival rates could be estimated several years earlier than is possible using the standard life-table actuarial method. The results showed that the survival time of the uncured group followed a log-normal distribution. The estimated 10-year cause-specific survival rate was 13% according to the log-normal model, while a Kaplan-Meier calculation gave 15% ± 3%. The data also showed that absence of mediastinal lymphadenopathy and higher chest radiotherapy dose were significant prognostic factors on multivariate analysis (p<0.05). Among the 163 patients given prophylactic cranial irradiation (PCI), a higher biologically effective dose to the brain did not improve survival or decrease the incidence of brain metastases. In Japan, a pattern-of-care study (PCS) was conducted as a nationwide survey of radiotherapy for patients with SCLC between September 1988 and March 2001.9 It was shown that age stratification had no impact on the variables of radiotherapy such as total

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dose and field size. Overall, only 37% of patients received chemotherapy and thoracic radiotherapy concurrently, with the proportion of patients being 44%, 27%, and 25% of the younger, intermediate, and elderly groups, respectively. The overall survival rate at 3 years was 26% for the entire group, 30% in the younger group, 28% in the intermediate group, and 9% in the elderly group. At the Christie Hospital in Manchester, UK, a retrospective review was performed in patients who received cyclophosphamide-doxorubicin-etoposide chemotherapy in the period 1994–98.10 The investigation compared patients treated on and off trial with the same standard-arm treatment regimen. Sixty patients were treated in one of the two randomized trials and 46 patients were treated off trial. Analysis of the data demonstrated that survival was no different for patients participating in a randomized trial compared with a group of patients similarly treated who were not eligible for trial or who declined randomization.

SURGERY In the very rare case of SCLC presenting as stage I or II disease, surgery is indicated provided that it is followed by postoperative chemotherapy. Overall, the 5-year survival rate is about 35–40%, with patients with no nodal metastases faring better than those who are node-positive. The role of local treatment, including surgery, in the current management of limitedstage SCLC was reviewed by Eberhart and Korfee,11 who discussed various strategies to improve local control. They also presented their own experience with the inclusion of surgery in an aggressive combined-modality protocol for patients with limited-stage SCLC. They incorporated both surgery and hyperfractionated accelerated radiotherapy into a chemotherapy program given preoperatively. Patients with up to stage IIIa disease were included. Forty-six patients were treated in the trial from 1991 to 1995, of whom 24 patients were surgically treated, and in 23 patients the tumor was completely resected at final thoracotomy. The long-term survival outcome data were updated, with the median follow-up of the patients still alive being 107 months in January 2003, and the actuarial 5- and 10-year survival rates being 39% and 35%, respectively. The 22 patients who had had initial disease involvement to the mediastinum (central T3N2 disease) had 5- and 10year actuarial survival rates of 44% and 41%, respectively. Only randomized trials will elucidate whether these curative treatment approaches should be incorporated as part of standard treatment. Fortunately, such studies have been initiated in both Japan and Germany.12

RADIOTHERAPY Chest irradiation Radiotherapy of the chest is indicated in cases of limited SCLC because it increases survival and local control. The effects of age and comorbidity of treatment on outcomes for radiotherapy in patients with limited SCLC were analyzed in a communitive-based

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population study from the Vancouver region by Ludbrook et al.13 A retrospective review was performed on 174 patients with limited SCLC referred to the British Columbia Cancer Agency, Vancouver Island Centre, between January 1991 and December 1999. Patients and treatment characteristics, disease response, relapse, and survival were compared among three age cohorts: less than 65 years (n=55), 65–74 years (n=76), and 75 years or older (n=43), and according to Charlson comorbidity scores 0, 1, and 2 or more. Multivariate analysis was performed to identify independent prognostic factors associated with treatment response and survival. Among the results, it is noteworthy that combined-modality chemo/radiotherapy was given in 86%, 66%, and 40% of patients aged less than 65, 65–74, and 75 or older, respectively (p<0.0001). The use of thoracic irradiation was comparable among the age cohorts, but the use of chemotherapy varied significantly, with less intensive regimens, fewer cycles, and lower total doses with advancing age (p<0.05). PCI was used in 41 patients, only 3 of whom were older than 70. Treatment toxicity and relapse patterns were similar across the age cohorts. The overall 2-year survival rates were significantly lower with advancing age: 37%, 22%, and 19% (p=0.003), with corresponding median survivals of 17, 12, and 7 months among patients aged less than 65, 65–74 and 75 years or older. Independent prognostic factors favorably associated with survival were good performance status, normal lactate dehydrogenase (LDH), absence of pleural effusion, and four or more cycles of chemotherapy. A number of issues regarding radiotherapy in patients with limited-stage SCLC remains to be resolved, such as fractionation, timing, combination with other treatment modalities, and dose and volume of irradiation. Phase II trials have explored the routine use of approximately 60 Gy once-daily thoracic irradiation for patients with limited-stage SCLC based on an analysis of 65 patients seen over the period 1991 and 1999 at Duke University, North Carolina, USA.14 PCI was administered to 17 patients and thoracic irradiation was given as a continuous course once daily in 1.8–2 Gy fractions to approximately 60 Gy (range 58–66 Gy). The results show that the 3-year actuarial rates of local failure, progression-free survival, and overall survival were 40%, 25%, and 23%, respectively. One case of acute grade 3 esophagitis developed. Ten late complications occurred. The importance of appropriately powered phase III prospective randomized trials of radiation dose or radiation dose intensification for limited-stage SCLC has also been emphasized by Roof et al15 on the basis of a retrospective analysis of 84 patients treated at Massachusetts General Hospital, USA between 1987 and 2000. Takada et al,16 from the Japan Clinical Oncology Group, published the final results of a randomized trial focusing on thoracic irradiation. The purpose of the study was to evaluate the optimal timing for thoracic radiotherapy (TRT) in limited-stage SCLC, with patients being randomized to sequential TRT or concurrent TRT. A total of 231 patients were enrolled, and TRT consisted of 45 Gy over 3 weeks (1.5 Gy twice daily). All patients received four cycles of cisplatin plus etoposide every 3 weeks (sequential arm) or 4 weeks (concurrent arm). TRT was begun on day 2 of the first cycle of chemotherapy in the concurrent arm and after the fourth cycle in the sequential arm. The analysis of the results of this study revealed that concurrent radiotherapy yielded better survival than sequential radiotherapy (p=0.097 by log-rank test). The median survival time was 19.7 months in the sequential arm versus 27.2 months in the concurrent arm. The 2-, 3-, and 5year survival rates for patients who received sequential radiotherapy were 35.1%, 20.2%,

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and 18.3%, respectively, as opposed to 54.4%, 29.8%, and 23.7%, respectively, for the patients who received concurrent radiotherapy. Hematologic toxicity was more severe in the concurrent arm, while severe esophagitis was infrequent in both arms, occurring in 9% of the patients in the concurrent arm and 4% in the sequential arm. The study strongly suggests that cisplatin plus etoposide and concurrent radiotherapy is more effective than cisplatin plus etoposide and sequential radiotherapy for the treatment of limited-stage SCLC. In order to decrease the incidence and grade of esophagitis secondary to twice-daily chest irradiation with concurrent chemotherapy, Arquette et al17 studied 34 patients treated with amifostine. They concluded that there was no reduction in toxicity, and the results thus differ from those on the use of amifostine in non-small cell lung cancer, in which there is evidence of a protective effect of amifostine on the esophagus. With regard to the newer agents, the efficacy of irinotecan (CPT-11) and cisplatin was tested with concurrent split-course radiotherapy in limited-disease SCLC by Oka et al.18 Seventeen patients were enrolled at three dose levels of irinotecan/cisplatin. The overall response rate obtained was 93.8%, including 4 patients with complete response and 11 with partial response among 16 evaluable patients. Ofra et al concluded that this combined modality is tolerable and recommended the treatment for further clinical trials. The combination of topotecan and paclitaxel alternating with etoposide and cisplatin and thoracic irradiation was explored in patients with limited disease, but with inconclusive results because only 18 patients were included in the study.19 Finally, an interesting retrospective review was carried out by Videtic et al20 on 215 patients with limited-stage SCLC treated between 1989 and 1999 at the London Regional Cancer Centre, Ontario, Canada. Treatment consisted of six cycles of alternating cyclophosphamide-doxorubicin-vincristine and etoposide-cisplatin. Thoracic radiotherapy was concurrent with etoposide and cisplatin. Patients were known smokers, with their smoking status recorded at the start of chemo/radiotherapy. Of 215 patients, smoking status was recorded for 186 (86.5%), with 79 (42%) continuing to smoke and 107 (58%) abstaining during chemo/radiotherapy. The median survival for former smokers was greater than for continuing smokers (18 months vs 13.6 months), with a 5year actuarial overall survival rate of 8.9% versus 4%, respectively (log-rank p=0.0017). Continuing smokers did not have a greater incidence of toxicity-related treatment breaks, but those who continued to smoke and also experienced a treatment break had the poorest overall survival (median 13.4 months; log-rank p=0.0014). Videtic et al20 concluded that limited-stage SCLC patients who continue to smoke during combination chemo/radiotherapy have poorer survival rates than those who did not. Accordingly, treating phycisians need to ask their patients about their smoking status before initiating treatment and should be prepared to make recommendations regarding means of smoking cessation for patients to achieve this goal. Prophylactic cranial irradiation PCI decreases the overall rate of brain metastases in limited-stage SCLC achieving complete remission and, according to a meta-analysis, gives an absolute survival benefit of 5.4% in the 3-year survival rate, with 15.3% in the control group and 20.7% in the treatment group.21 PCI is therefore considered part of the standard treatment of patients

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with SCLC in complete remission. The meta-analysis is based on several studies performed in the 1970s and 1980s and includes two parallel randomized studies with a total of 511 patients with SCLC, coordinated by the Institut Gustave-Roussy.22 In those studies, patients were randomly assigned to either PCI (24 Gy in eight fractions and 12 days) or no PCI. Patterns of failure were analyzed according to total event rates and isolated first site of relapse using a competing risk approach. Five hundred and five patients were analyzed. The 5-year cumulative rate of brain metastasis as an isolated first site of relapse was 37% in the control group and 20% in the PCI group (p<0.001). The overall 5-year rates of brain metastasis were 59% and 43%, respectively (relative risk 0.50; p<0.001). The 5-year overall survival rates were 15% in the control group and 18% in the PCI group (relative risk 0.84; p=0.06). Potential long-term neuropsychologic adverse effects remain of concern in patients receiving PCI, and radiation-induced reactive oxygen intermediates and reactive nitrogen intermediates appear to play a major role in mediating this toxicity.23 Hypoxia results in a significant increase in erythropoietin (EPO) mRNA in mouse brain, and, in two models, the administration of EPO improves performance function and prevents cognitive impairment. Senzer23 therefore suggested the use of EPO as a neurocognitive protectant in patients with SCLC receiving PCI, and the preliminary design for such a study has already been presented.

SYSTEMIC TREATMENT Chemotherapy remains the keystone in the treatment of SCLC, as emphasized in the many review articles on lung cancer. The most frequently used combination remains etoposide with a platinum compound, often cisplatin. Overall results have been somewhat at a standstill over the past few years, and unfortunately there have been only a few reports in the recent literature with regard to new treatment approaches, using either new agents or new combinations, in SCLC.

COMBINATION CHEMOTHERAPY—PHASE II TRIALS The results of a number of phase II trials including untreated patients with extensive disease have been published, including a couple of review articles dealing with specific drug combinations24–33 (Table 6.1). Among the new agents, gemcitabine, topotecan, and paclitaxel have been tested as three-drug combinations, or as two-drug combinations, given with known active agents, such as etoposide and platinum-compounds. In addition, alternating regimens have been exploited incorporating topotecan, either as a single agent or together with paclitaxel. The vast majority of these studies have resulted in response rates of 50%, with the highest being 77%, with overlapping 95% confidence intervals. With respect to median survival, the results are 10–12 months, with 1-year survival rates ranging from 37% to 49%. Further developments lie ahead to determine the potential impact of many of these combinations in the overall management of patients with SCLC.

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RANDOMIZED TRIALS—CHEMOTHERAPY The results of randomized trials and the use of chemotherapy in advanced SCLC are presented in Table 6.2. Two of the studies presented34,36 were reviewed in Lung Cancer Therapy Annual 3 based on published abstracts. Important studies are by Sundstrøm et al34 from Norway, who investigated whether chemotherapy with etoposide and cisplatin (EP) is superior to cyclophosphamide, epirubicin, and vincristine (CEV) in SCLC. The study is a national study covering the majority of patients with SCLC diagnosed in Norway, and it is thus more representative than many other studies. Based on survival data, the results clearly indicate superiority of the EP combination over CEV. The 2- and 5-year survival rates in the EP arm were 14% and 5% (p=0.0004), which were significantly higher than those in the CEV arm (6% and 2%). Among limited-disease patients, the median survival was 14.5 months in the EP arm versus 9.7 months in the CEV arm (p=0.001). The 2-and 5-year survival rates were 25% and 10% in the EP arm, compared with 8% and 3% in the CEV arm (p=0.0001). For extensive-disease patients, there was no significant survival difference between the treatment arms. In addition to chemotherapy, patients with limited disease received thoracic radiotherapy concurrent with chemotherapy cycle 3, and those achieving complete remission during the treatment period received PCI. In a commentary, Johnson35 concluded that the results should alter practice patterns—at least in countries where anthracycline-based therapy still predominates. The other article that has now been published as a full paper compared paclitaxeletoposide-carboplatin (TEC) versus carboplatin-etoposide-vincristine in patients with SCLC.36 Altogether, 614 patients from Germany were included and both groups were well balanced with respect to stage, with 50% stage I–IIIb patients and 50% stage IV patients in each group. A total of 608 patients were evaluable for all endpoints. The hazard ratio (HR) of death for patients receiving the standard treatment with carboplatinetoposide-vincristine was statistically significantly higher than that for patients receiving the experimental treatment (HR 1.22, 95% confidence interval (CI) 1.03–1.45; p=0.024). Progression-free survival was also statistically significantly shorter for patients in the standard arm relative to that for patients in the experimental arm (HR 1.21; 95% CI 1.03– 1.42). There were no differences in the response rates and there was less frequent hematologic toxicity in the experimental arm than in the standard arm. In an editorial, Laskin et al37 raised the question of whether TEC should supplant EP as the regimen of choice in SCLC. These results are in contrast to those from two other studies, one by the US Intergroup38 and another by the Greek Lung Cancer Cooperative,39 who also conducted a prospective randomized trial of paclitaxel-etoposide-cisplatin (TEP) versus EP. In the US trial with enrollment of nearly 600 patients with extensive disease, failure-free survival favored patients in the TEP arm, similarly to the study by Reck et al,38 but the median survival was not statistically significant different between the two arms (10.35 months vs 9.86 months; p=0.27). In contrast to the German study, the Greek study included only

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Table 6.1 Combination chemotherapy in untreated SCLC patients: phase II trials Treat ment

No. of No. of patients respondersa

Response Median 1-year Comments Ref rate (%)b survival survival (months) rate CR PR Total (%)

Cisplatin+gemci tabine+ etoposide

54

10

29

Paclitaxel+ topotecan

17

0

Topotecan+ etoposide

23

Cisplatin+ Etoposide alternating with topotecan

72.2 (56.5– 85.0)

10

9

9 53 (28–77)

–

– –

27

4

4

8

34.7 (14– 55)

11.5

48 –

28

36

5

18

23 64 (48–79)

–

49 Presented in Lung Cancer Therapy Annual 3 based on abstact (Table 6.4 and ref 47)

29

Etoposide+ Cisplatin alternating with topotecan+ paclitaxel

44

4

30

34 77 (62–89)

10.5

37 –

30

Cisplatin+ topotecan

11

2

6

8 73 (39–94)

–

– –

31

Paclitaxel followed by topotecan

43

2

22

24

55.8 (39.9– 70.9)

10.8

Paclitaxel+ ifosfamide+ carboplatin

35

5

19

24

71

9.5

a b

39

CR, complete response; PR, partial response. 95% confidence interval in parentheses.

37.5 Includes both limited-and extensivestage disease

26

41 Median progressionfree survival 8.5 months

32

43 –

33

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Table 6.2 Randomized trials of chemotherapy in advanced SCLC Treatment

Cisplatin 75 mg/m2 day 1, etoposide 100 mg/m2 day 1 and 200 mg/m2 p.o. days 2–4 q3wks×5

No. of No. of patients responders

Response Median Survival Comments Ref rate (%) survival rate (%) (months) CR PR Total 1- 2- 5yr yr yr

218

–

–

–

–

LD 14.5

– 14

6 Presented in Lung Cancer Therapy Annual 3 based on abstract (Table 6.5 and ref 53)

Cyclophosphamide 1000 mg/m2 i.v., epirubicin 50 mg/m2 i.v., and vincristine 2.6 mg/m2 i.v. q3wks×5

218

–

–

–

–

Paclitaxel 175 mg/m2 i.v. day 4, etoposide phosphate 125 mg/m2 i.v. days 1– 3 q3wks, and carboplatin AUC 5 i.v. day 4

306

–

–

–

Vincristine 2 mg i.v. days 1, 8, etoposide phosphate 159 mg/m2 days 1–3 q3wks, and carboplatin AUC 5+i.v. day 1

309

–

–

–

Cisplatin 25 mg/m2 day 1 wkly for 9 wks irinotecan 90

30

2 23

25

34

LD 9.7

–

5

2

81.8 (CR 19.3)

–

–

–

– Presented in Lung Cancer Therapy Annual 3 based on abstract (Table 6.5 and ref 62)

36

76.3 (CR 16.6)

–

–

–

– Prophylactic granulocyte colony-

40

Vs

Vs

84

8.9 –

–

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mg/m2 day 1 in wks 1, 3, 5, 7, 9, and etoposide 60 mg/m2 days 1–3 in wks 2, 4, 6, 8

stimulating factor was provided for both arms

vs Cisplatin 60 mg/m2 day 1, irinotecan 60 mg/m2 days 1, 8, 15, and etoposide 50 mg/m2 days 1–3 q 4 wks

30

5 18

23

77

12.9 –

–

–

Topotecan 1.5 mg/m2 days 1–5 q3wks

40

–

–

25

62.5 (CI 49–75)

18.5 –

–

– Randomization 41 to continuous infusion was discontinued because of inactivity

20

–

–

3 15 (CI 1– 29)

12.5 –

–

–

vs Topotecan 1.3 mg/m2 over 72 h q4wks

CR, complete response; PR, partial response; CI, 95% confidence interval; LD, limited-stage disease.

133 patients with limited and extensive disease, and had to be stopped because of excessive toxicity and mortality in the TEP arm. The data from the US and Greek studies have dampened enthusiasm for adopting a three-drug TEC or TEP induction regimen for SCLC, and Laskin et al37 have concluded that, by and large, the addition of a third drug to an EP regimen has not substantially improved the outcome in patients with SCLC, irrespective of how the drug is incorporated. The last two randomized trials are rather small in numbers, including only 60 patients in each trial. The purpose of the study by Sekine et al40 was to evaluate the toxicity and antitumor effect of cisplatin, irinotecan, and etoposide combinations on two schedules with administration either weekly (arm A) or every 4 weeks (arm B). Complete and partial response rates were 7% and 77%, respectively, in arm A and 17% and 60%, respectively, in arm B. Similarly, the median survival favored the 4-week schedule (12.9 months vs 8.9 months). The Japanese investigators will pursue these observations by performing a large phase III trial with one of the arms being an every-4-week schedule. In the trial with 40 patients by Schaefer et al,41 the purpose was to assess the anti-tumor activity and toxicity of two different schedules of topotecan, using either the daily schedule with topotecan being administered intravenously at 1.5 mg/m2 daily for 5 days every 3 weeks or the continuous-infusion schedule, with topotecan administered intravenously at a dosage of 1.3 mg/m2 per day over 72 hours every 4 weeks. Randomization to the continuous-infusion schedule was discountinued due to inactivity,

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47

with only 3 of 20 patients (15%) responding to continuous infusion, while 25 of 40 patients (62.5%) responded to the daily intravenous schedule of topotecan.

INTENSITY OF TREATMENT The topic of chemotherapy dose and dose intensity in SCLC has been comprehensively reviewed by Tjan-Heijnen et al,42 who considered 20 randomized studies published in the period 1980–2001 in which dose or dose intensity of chemotherapy in SCLC were the only variables tested. The studies were categorized as follows: (1) number of cycles (treatment duration); (2) dose per cycle; (3) interval between cycles (dose densification); and (4) a combination of these variables. The results indicated the following. (1) With treatment duration reduced to 3–6 cycles, the median survival time (MST) was 2 months shorter, most evidently in patients showing a (complete) response to initial chemotherapy. (2) Improved survival was observed in two out of five high-dose studies. (3) Survival was increased by 0.6–6.2 months in all four densification studies. (4) Survival was not improved in studies that used dose-escalation and/or dose-densification in combination with a reduced number of cycles. The sample sizes were too small to be conclusive in most of the individual trials. The median of the MSTs in the 20 trials taken together was 9.8 months for the standard arms and 11.5 months for the intensified arms (i.e. more cycles, higher dose per cycle, and/or shorter intervals). After omitting the two trials with reduced number of cycles in the so-called ‘high-dose’ arm, the medians of the MSTs were 8.7 months and 11.5 months, respectively. There was only a slight improvement (1%) in 2year survival rate for all trials taken together. However, when only high-dose and dose-densified chemotherapy trials were taken into account, the difference in median 2-year survival rate became 19% (12% vs 31%). Tjan-Heijnen et al42 concluded that intensification of chemotherapy in SCLC still deserves further research. Further light on this issue has been shed by Ardizzoni et al43 from the EORTC Lung Cancer Group. They randomized untreated SCLC patients to standard CDE (cyclophophamide 1000 mg/m2 and doxorubicin 45 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1–3 every 3 weeks for five cycles) or intensified CDE (cyclophosphamide 1250 mg/m2 and doxorubicin 55 mg/m2 on day 1 and etoposide 125 mg/m2 on days 1–3, with granulocyte colony-stimulating factor (G-CSF) 5 µg/kg/day on days 4–13 every 2 weeks, for four cycles). The projected cumulative dose was almost identical on the two arms, whereas the projected dose intensity was nearly 90% higher on the intensified arm. Two hundred and forty-four patients were enrolled. The first 163 patients were also randomized (2×2 factorial design) to prophylactic antibiotics or placebo to assess their impact on preventing febrile leukopenia. The actually delivered dose intensity on the intensified arm was 70% higher than on the standard arm. Intensified CDE was associated with more grade 4 leukopenia, grade 4 thrombocytopenia, anorexia, nausea, and mucositis. The objective response rate was 79% for the standard arm and 84% for the intensified arm (p=0.315). The median survivals were 54 weeks and 52 weeks, and the 2year survival rates were 15% and 18%, respectively. In conclusion, the 70% increase of CDE actual dose intensity did not translate into an improved outcome in SCLC. In a commentary, Galani et al44 raised the question of whether the end of the road of dose

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intensification in SCLC has been reached. They argued that the evidence from other solid tumors would suggest this, even though there are studies where a significant improvement in clinical outcome has been achieved with increased dose density, for example by reducing the interval between cycles from 4 to 3 weeks.45 In a Letter to the Editor, Munck46 argued that the design of the Ardizzoni study was suboptimal, with an insufficient duration of chemotherapy in the intensified arm counteracting a possible positive effect of dose intensity. In addition to these large randomized trials, a small phase II trial including 32 patients has been presented by Hand et al,47 using intensive chemotherapy administered on an outpatient basis, with a modified combination of ifosfamide, carboplatin, and etoposide; this combination was also used by Oelmann et al.48 As expected, response rates above 75% were obtained in these two studies, but both are too small for one to draw firm conclusions concerning efficacy compared with standard therapy. Intensive chemotherapy with whole blood stem cell support and concurrent chest radiotherapy in SCLC has been explored by Calderoni et al49 in 18 patients with limited SCLC, using intensive sequential single-agent (ifosfamide, carboplatin, etoposide, and paclitaxel (ICE-T)) chemotherapy with the support of unprocessed stem cell-enriched whole blood and G-CSF and concomitant bifractionated chest radiotherapy (60 Gy). The treatment was delivered in a short time of 10 weeks. After a 3-year median follow-up, the 2-year progression-free and overall survival rates were 54% and 63%. Calderoni et al49 concluded that this short and intensive chemo/radiotherapy regimen is well tolerated and produces promising results in terms of survival. The use of stem cell-enriched whole blood should be investigated in larger randomized studies. A similar study has been reported by Yoshizawa et al50 with peripheral blood stem cell support and concurrent thoracic radiotherapy combined with combination chemotherapy using ifosfamide, carboplatin, and etoposide plus G-CSF. Among 23 patients, an astonishing complete response was observed in 19 of 23 (82%) patients (95% CI 61.2–95.0), with 2-year progression-free and overall survival rates of 75% and 77%, respectively.

PREVENTION OF TOXICITY In order to prevent chemotherapy-induced febrile leukopenia, the European Organization for Research and Treatment of Cancer (EORTC) Lung Cancer Group investigated the impact of prophylactic antibiotics during chemotherapy for SCLC.51 The study was described in detail in Lung Cancer Therapy Annual 3 and has now been followed up with an economic evaluation examining the cost and effect of patients taking antibiotics (ciprofloxacin and roxithromycin) versus placebo.51 A total of 244 patients were included in the study and medical resource utilization was documented prospectively in 33 patients from one center in the Netherlands and 49 patients from one center in Germany. In the main trial, prophylactic antibiotics reduced the incidence of febrile leukopenia, hospitalization due to febrile leukopenia, and use of therapeutic antibiotics by 50%. In Germany, the incidence of febrile leukopenia was not reduced by prophylaxis. This resulted in an average cost difference of only 35 Euros in favour of prophylaxis (not significant). In the Netherlands, prophylaxis reduced the incidence of febrile leukopenia by nearly 50% (which is comparable to the results of the main trial), resulting in a cost

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difference of 2706 Euros (95% CI 810–5948 Euros), demonstrating savings in favor of prophylactic antibiotics of nearly 45%. Sensitivity analyses indicate that with an efficacy of prophylaxis of 50% and with expected costs of antibiotic prophylaxis of 500 Euros or less, cost savings will be achieved over a broad range of baseline risks for febrile leukopenia, i.e. a risk greater than 10–20% for febrile leukopenia per cycle. The authors recommend the use of phophylactic antibiotics in patients at risk for febrile leukopenia during chemotherapy. At present, there are no data available that support the routine use of antibiotics. The role of G-CSF in the treatment of SCLC has been elucidated by Berghmans et al,52 who performed a systematic review of the randomized trials published on this topic. Since 1991, 12 studies were eligible, including a total of 2107 randomized patients. They were divided into three groups: (1) maintenance of dose intensity when chemotherapy was given at conventional doses and time intervals (seven trials); (2) accelerated chemotherapy with increased dose intensity by reducing the delay between chemotherapy cycles (five trials); (3) concentration of chemotherapy over an overall shorter duration with a lower number of cycles (one trial). Berghmans et al52 concluded that the published data do not support the routine use of G-CSF in the treatment of SCLC, which is also the key message in a commentary by Trillet-Lenoir et al,53 who pinpointed the methodologic problems involved in performing meta-analyses, including the problem of obtaining data from the pharmaceutical industry.

SPECIAL TOPICS Relapsed SCLC More than 90% of patients with SCLC relapse after initial treatment, and the overall expected survival post relapse is rather short, as pointed out by Murray54 in a review of second-line chemotherapy for SCLC, and also by Lima and Chiappori,55 who focus particularly on the role of topotecan in this situation. Results of clinical trials concerning second-line chemotherapy in previously treated SCLC patients are given in Table 6.3.56–61 Only the study by Sculier et al,56 from the European Lung Cancer Working Party, is randomized, comparing cisplatin-etoposide combination chemotherapy with or without carboplatin as second-line therapy for SCLC. Sixty-five eligible patients were randomized: 31 for CE (cisplatin 20 mg/m2 and etoposide 100 mg/m2 on days 1–3) and 34 for CCE (carboplatin 200 mg/m2 on day 1, cisplatin 30 mg/m2 on days 2–3, and etoposide 100 mg/m2 on days 1–3). The best response rates were 29% (95% CI 13–45%) and 47% (95% CI 30–64%) for CE and CCE, respectively, with median survival times of 4.3 and 7.6 months. Toxicity was tolerable and comparable between the study arms. CCE thus appears to be associated with a high objective response rate, and the phase II randomized study design suggests that a comparison between the two regimens in a phase III trial would be interesting, but Sculier et al56 point out that it would probably be difficult to perform for reasons of accrual. Of the other trials, the overall response rate for gemcitabine as a single agent was only 12%,57 while for a combination of gemcitabine and vinorelbine it was 10%.58 The

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remaining three studies included irinotecan—in two studies given with ifosfamide or carboplatin and in one with a combination of cisplatin and topotecan. The median survival after second-line treatment in all three studies was rather constant (6.1–7.2 months), while the response rate varied from 24% to 68%, with overlapping 95% confidence intervals. Treatment of elderly patients and poor-prognosis SCLC A special group of SCLC patients consists of elderly patients and those who have decreased organ functions and performance at the time of diagnosis. It is estimated that 25% of patients with SCLC are 70 years of age or older and 10–15% of patients present with poor performance status. The treatment of SCLC in the elderly has been extensively reviewed by Weinmann et al62 and a single phase II study has also appeared from Gridelli et al.63 Twenty-eight patients were enrolled in this study, using a combination of carboplatin (AUC 5 according to Calvert, day 1) plus vinorelbine (25 mg/m2 days 1 and 8) with G-CSF (lenograstim) support every 3 weeks. The median age was 70 years and the treatment was remarkably toxic, with three patients dying while on treatment. Eleven patients (39.3%, 95% CI 21.5–59.4%) had an objective response, which was complete in two cases. The

Table 6.3 Chemotherapy in previously treated SCLC patients—phase II trials Treatment

No. of patients

No. of respondersa

Response rate (%)b

Comments

Ref

CR PR Total 2

Cisplatin 20 mg/m days 1–3 and etoposide 100 mg/m2 days 1–3 Cisplatin 30 mg/m2 days 2–3, etoposide 100 mg/m2 days 1–3, and carboplatin 200 mg/m2 day 1

26

0

9

9

29 (13–45) Median survival 4.3 months

56

vs 33

3

13

16

47 (30–64) 7.6 months

Gemcitabine 1000 mg/m2 i.v. days 1, 8, 15 q4wks

42

0

5

5

12 (3–26) Objective response in 1 patient with refractory SCLC (5.6%) and 4 with sensitive SCLC (16.7%)

57

Gemcitabine 1000 mg/m2 and vinorelbine 20 mg/m2 days 1, 8, 15 q28d

28

0

3

3

11(2–28) None of the 17 patients with refractory disease responded vs 3 of 12 with sensitive disease

58

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(25%) 2

Irinotecan 80 mg/m days 1, 8, 15 q4wks and ifosfamide 1.5 g i.v. days 1–3 q4wks

34

2

16

18

53 (29–65) Median survival after second-line treatment 7.2 months

59

Irinotecan 50 mg/m2 days 1,8, q3wks and carboplatin (AUC 5 mg/min/ml)

22

0

15

15

68 (45–86) Median survival after second-line treatment 6.5 months. Response rate in sensitive patients 68.2%

60

68 (sensitive)

1

19

20

29 (19–42) Median survival 6.4 months

61

Cisplatin 20 mg/m2 day 1 q3wks and topotecan 0.75 mg/m2 days 1–5 q3wks

vs 42 (resistant)

a b

0

10

10

24 (12–39) 6.1 months

CR, complete response; PR, partial response. 95% confidence interval in parentheses.

median survival was 7.9 months. It was concluded that the combination is poorly tolerated and should not be pursued further in this group of patients. The same combination but without G-CSF support was assessed in 58 patients with SCLC having poor prognostic features by MacKay et al.64 Similar toxicity was obtained, with a total of three toxic deaths, all from sepsis complicating neutropenia. Seventy percent experienced grade 3 or 4 neutropenia and 6 (11%) grade 3 or 4 thrombocytopenia. The overall response rate was 55% (95% CI 42–68)%, with 6 patients having a complete response. The median time to progression was 18 weeks and the median overall survival was 26 weeks. Patients with brain metastases Brain metastases are observed in 20% of patients with SCLC at the time of first diagnosis and in 18% at autopsy. The benefit of whole-brain irradiation in these patients is local control, but most of them die from the systemic disease after a median survival of less than 6 months. Even after the use of whole-brain irradiation, some patients progress with symptomatic brain metastases. Korfel et al65 explored the efficacy of topotecan in such a setting using a dose of 1.25–1.5 mg/m2 as a 30-minute infusion for 5 consecutive days every 3 weeks. All 30 patients were pretreated with chemotherapy (14 with one regimen and 16 with at least two regimens), and 8 patients had prior whole-brain irradiation (7 in the prophylactic and 1 in the palliative setting). Concomitant systemic metastases were recorded in 24 patients at the time of brain relapse. Cerebral metastases responded in 33% of patients (10 of 30:3 complete and 7 partial responses). It was noteworthy that a response was achieved in 4 of 8 patients pretreated with whole-brain irradiation. The systemic response rate was 29%.

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Other treatment modalities Increased expression of metalloproteinases is associated with poor prognosis in SCLC. Based on this information, Shepherd et al66 undertook a trial to determine whether adjuvant treatment with the metalloproteinase inhibitor marimastat could prolong survival in patients with SCLC responding after chemotherapy. SCLC patients in complete or partial remission were eligible. They were stratified by radiotherapy, stage, and cooperative group to receive marimastat 10 mg or placebo orally twice daily for up to 2 years. Five hundred and thirty-two patients were eligible and the median time to progression for marimastat patients was 4.3 months, compared with 4.4 months for placebo patients (p=0.81). The median survivals for marimastat and placebo patients were 9.3 months and 9.7 months, respectively (p=0.90). Dose modifications for musculoskeletal toxicity were registered in 90 patients (33%) on the marimastat arm, and 98 (32%) permanently stopped marimastat because of toxicity. The data clearly demonstrate that marimastat after induction therapy for SCLC did not result in improved survival and had a negative impact on quality of life. Other new therapeutic approaches include the use of anti-BEC2 antibodies and various vaccines against other targets in SCLC, such as GM2, Focusyl, GM1, Globo H, and polysialic acid, as summarized by Krug.67 A pilot trial of G3139 (a bcl-2 antisense oligonucleotide) and paclitaxel in patients with chemorefractory SCLC has been performed by Rudin et al,68 including 12 patients who were given G3139 by continuous intravenous infusion over 7 days at a fixed dose of 3 mg/kg/day. No objective responses were observed, but two patients had stable disease. Plasma G3139 levels were determined and were found to be highest in the patient with prolonged stable disease, suggesting that individual variation in metabolism and clearance of the antisense oligonucleotide may influence activity. Other neuroendocrine tumors Among the various neuroendocrine neoplasms of the lung, Hage et al69 have given a general update regarding pulmonary carcinoid tumors in a review article, while the role of surgery has been presented in two retrospective, simple-institution reviews—one from Italy70 and the other from Turkey.71 In the Italian study, 126 patients were assessed for surgery and 65% had typical and 35% atypical carcinoid tumors. Recurrent tumors developed in 5.5% of patients with typical carcinoids versus 19.5% with atypical subtypes and the overall survival rate at 15 years was 74%, with prognosis being related to stage and to histologic subtype, with better survival for typical carcinoid tumors. Similar results were described by Kurul et al,71 who analyzed 83 patients with carcinoid tumors who underwent thoracotomy over a 25-year period. The outcomes and patterns of failure in bronchial carcinoid tumors have been described by Kaplan et al,72 reviewing charts of 241 patients from the MD Anderson Cancer Center, Texas, USA. Thirty-four patients had no follow-up, leaving a study population of 206, of whom 62 had atypical carcinoid and 144 typical carcinoid tumors. Again, stage-for-stage the outcome is worse for patients with atypical carcinoid tumors than for those with typical carcinoid tumors. Locoregional failure is common after curative resection, even for early-stage atypical carcinoid tumors, and another observation was that second cancers are common in patients with carcinoid tumors.

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A frequent metastatic site in patients with carcinoid tumors is the liver, and Filosso et al73 have demonstrated that long-term survival can be obtained using octreotide administered at a dose of 1500 µg/day subcutaneously. They reported that 7 patients had been treated and were alive and well at 51, 36, 24, 24, 23, 19, and 16 months after the diagnosis of liver metastases. Finally, Zacharias et al74 have shed further light on a group of patients with large cell neuroendocrine carcinomas and large cell carcinomas with neuroendocrine morphology. Twenty-one cases with with these histologic types had been identified in the files of the Royal Brompton Hospital, London, UK between 1986 and 1999. All patient data were reviewed, and complete followup was achieved with 20 of these patients. Of the 21 identified, 20 underwent resection, with systematic nodal dissection in 18. There was no in-hospital mortality. Of those patients fully staged by systematic nodal dissection, 9 were stage I, 5 were stage II, and 4 were stage III. The median follow-up was 25 months (range 2–120 months). At the time of review, 11 patients were alive and free of disease. The 5-year actuarial survival rate for the entire group was 47%: 88% for stage I patients and 28% for stage II and III patients.

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52. Berghmans T, Paesmans M, Lafitte JJ et al. Role of granulocyte and granulocyte-macrophage colony-stimulating factors in the treatment of small-cell lung cancer: a systematic review of the literature with methodological assessment and meta-analysis. Lung Cancer 2002; 37:115–23. 53. Trillet-Lenoir V, Piedbois P, Buyse M. The role of colony stimulating factors in small cell lung cancer. Why the question is still unsolved. Lung Cancer 2002; 37:125–6. 54. Murray N. Second-line chemotherapy for small-cell lung cancer. J Clin Oncol 2003; 21:667– 71. 55. Lima CMR, Chiappori A. Treatment of relapsed small-cell lung cancer—a focus on the evolving role of topotecan. Lung Cancer 2003; 40:229–36. 56. Sculier JP, Lafitte JJ, Lecomte J et al. A phase II randomised trial comparing cisplatinetoposide combination chemotherapy with or without carboplatin as second-line therapy for small-cell lung cancer. Ann Oncol 2002;13:1454–9. 57. Masters GA, Declerck L, Blanke C et al. Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin Oncol 2003; 21:1550–5. 58. Hainsworth J, Burris HA III, Erland JB et al. Combination therapy with gemcitabine and vinorelbine in the treatment of patients with relapsed or refractory small cell lung cancer: a phase II trial of the Minnie Pearl Cancer Research Network. Cancer Invest 2003; 21:193–9. 59. Ichiki M, Gohara R, Rikimaru T et al. Combination chemotherapy with irinotecan and ifosfamide as secondline treatment of refractory or sensitive relapsed small cell lung cancer: a phase II study. Chemotherapy 2003; 49:200–5. 60. Hirose T, Horichi N, Ohmori T et al. Phase II study of irinotecan and carboplatin in patients with refractory or relapsed small cell lung cancer. Lung Cancer 2003; 40:333–8. 61. Azdizzoni A, Tjan-Heijnen VCG, Postmus PE et al. Standard versus intensified chemotherapy with granulocyte colony-stimulating factor support in small-cell lung cancer: a prospective European Organization for Research and Treatment of Cancer—Lung Cancer Group phase III trial—08923. J Clin Oncol 2002; 20: 3947–55. 62. Weinmann M, Jeremic B, Bamberg M, Bokemeyer C. Treatment of lung cancer in elderly. Part II: Small cell lung cancer. Lung Cancer 2003; 40: 1–16. 63. Gridelli C, Rossi A, Barletta E et al. Carboplatin plus vinorelbine plus GCSF in elderly patients with extensive-stage small-cell lung cancer: a poorly tolerated regimen. Results of multicentre phase II study. Lung Cancer 2002; 36:327–32. 64. MacKay HJ, O’Brien M, Hill S et al. A phase II study of carboplatin and vinorelbine in patients with poor prognosis small cell lung cancer. Clin Oncol 2003; 15:181–5. 65. Korfel A, Oehm C, von Pawel J et al. Response to topotecan of symptomatic metastases of small-cell lung cancer also after whole-brain irradiation: a multicentre phase II study. Eur J Cancer 2002; 38: 1724–9. 66. Shepherd FA, Giaccone G, Seymour L et al. Prospective, randomized, double-blind, placebocontrolled trial of marimastat after response to firstline chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada—Clinical Trials Group and the European Organization for Research and Treatment of Cancer. J Clin Oncol 2002; 20:4434–9. 67. Krug LM. Small cell lung cancer: targeting minimal residual disease. Lung Cancer 2003; 41(Suppl 3):S55 68. Rudin CM, Otterson GA, Mauer AM et al. A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer. Ann Oncol 2002; 13:539–45. 69. Hage R, Brutel de la Riviére A, Seldenrijk CA, van den Bosch JMM. Update in pulmonary carcinoid tumors: a review article. Ann Surg Oncol 2003; 10:697–704. 70. Filosso PL, Rena O, Donati G et al. Bronchial carcinoid tumors: surgical management and long-term outcome. J Thorac Cardio Surg 2002; 123:303–9. 71. Kurul IC, Topcu S, Tastepe I et al. Surgery in bronchial carcinoids: experience with 83 patients. Eur J Cardio-Thorac Surg 2002; 21:883–7.

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72. Kaplan B, Stevens CW, Allen P et al. Outcomes and patterns of failure in bronchial carcinoid tumors. Int J Radiat Oncol Biol Phys 2003; 55: 125–31. 73. Filosso PL, Ruffini E, Oliaro A et al. Long-term survival of atypical bronchial carcinoids with liver metastases, treated with octreotide. Eur J Cardio-Thorac Surg 2002; 21: 913–17. 74. Zacharias J, Nicholson AG, Ladas GP, Goldstraw P. Large cell neuroendocrine carcinoma and large cell carcinomas with neuroendocrine morphology of the lung: prognosis after complete resection and systematic nodal dissection. Ann Thorac Surg 2003; 75:348–52.

7 Treatment of non-small cell lung cancer

SYSTEMIC TREATMENT OF STAGE I–IIIA NSCLC Introduction The majority of relapses following complete surgical resection of early-stage non-small cell lung cancer (NSCLC) are in distant metastatic sites, providing a rationale for systemic therapy that has been recognized for many years. The high rates of distant spread account for much of the poor survival following surgical therapy. For example, Canadian statistics published in 2003 are similar to those for other developed countries. The overall 5-year survival rate in Canada was 14%, with rates of 72% in stage I and 48% in stage II.1 There are several obstacles to the successful use of adjuvant (postoperative) or neoadjuvant (preoperative) therapy in these patients, however. The median age of lung cancer patients in the USA is 68 years. These patients frequently have comorbid cardiac and pulmonary disease and have relatively high rates of death from these causes. Second primary cancers occur at a rate of about 2% per year following complete surgical resection, and the second cancers are often fatal. A large US intergroup study of postoperative therapy confirmed the high rate of second primary cancers: 1.8% per year.2 The median time to detection of a second primary tumor was about 40 months. These non-cancer deaths are highlighted by the fact that smoking cessation is associated with improved survival. Many studies in both small cell lung cancer (SCLC) and NSCLC have confirmed the value of smoking cessation. A study from Boston showed that continued cigarette smoking by patients receiving concurrent chemo/radiotherapy for limited-stage SCLC is associated with decreased survival.3 The median survival was 18 months for former smokers, compared with 13.6 months for continuing smokers. These non-cancer deaths are the likely cause of the increased death rates observed in metaanalyses of postoperative radiotherapy4 and postoperative alkylating agent therapy.5 These issues must be kept in mind as the results of adjuvant and neoadjuvant studies are considered. Postoperative chemotherapy The results of several large randomized trials of postoperative chemotherapy have been published,6–8 and are summarized and compared with the meta-analysis5 in Table 7.1. In

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the Adjuvant Lung Project of Italy (ALPI) trial reported by Scagliotti et al,6 1089 patients with completely resected stage I–IIIA NSCLC were randomized to receive adjuvant chemotherapy consisting of MVP (mitomycin C-vindesine-cisplatin) or no chemotherapy. Centers could elect to add chest radiotherapy to patients in both groups. The time-to-progression analysis favored the chemotherapy group (hazard ratio, HR=0.89), but the differences were not significant. The overall survival advantage with chemotherapy was minor (HR=0.96) and there were no significant differences in survival. There were fewer cancer-related deaths but more non-cancer-related deaths in the chemotherapy arm. Compliance with the MVP chemotherapy combination was similar to that in the meta-analysis and was in the 50–60% range. These results were not as favorable as those in the meta-analysis. The Big Lung Trial from the UK randomized NSCLC patients of all stages to receive or not receive chemotherapy.7 The results of a subset analysis in patients with stage IIIIA are summarized in Table 7.1. In this study, centers were allowed to select one of four different chemotherapy combinations (mitomycin C-vindesine-cisplatin, mitomycin C-ifosfamide-cisplatin, vinorelbine-cisplatin, or vindesine-cisplatin). In this study, there was no advantage for the chemotherapy with respect to time to progression or survival (HR=1.0). There was more toxicity and more non-cancer deaths in the chemotherapy arm. Compliance with chemotherapy was not high. The results of the largest study reported to date, the International Adjuvant Lung Trial (IALT), were presented at both the American Society of Clinical Oncology (ASCO) Annual Meeting and the International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in 2003.8 The sample size for this trial was determined by the results of the meta-analysis, and 1867 patients with stage I–IIIA NSCLC were randomized to receive or not receive adjuvant chemotherapy. Centers had the option of selecting one of four two-drug chemotherapy combinations consisting of cisplatin combined with etoposide, vinorelbine, vindesine, or vinblastine. Centers could also opt to give or not give postoperative radiotherapy to patients in both groups. Compliance with the chemotherapy regimens was superior to compliance in other trials, with 8% of patients receiving no chemotherapy and 16% a reduced amount. Overall, 76% received the majority of the prescribed chemotherapy. Patients randomized to receive chemotherapy had a significantly improved time to progression (HR=0.84, p=0.003) and survival (HR=0.86, p=0.03). The absolute improvement in survival at 5 years was 4.1%. The toxic death rate was 0.8%. Although there were more non-cancer-related deaths in the chemotherapy arm, the increase was not as great as in the other trials, suggesting that these newer two-drug combinations may be better tolerated than older cisplatincontaining combinations, especially those with three drugs. The results of this trial were quite similar to those reported in the meta-analysis. It is difficult to understand how to best interpret these differing results. It is likely that any advantage of chemotherapy is small. The small advantage, by itself, could lead to both positive and negative results, especially in underpowered studies. It is also likely that the results are influenced by the selection of the chemotherapy combination and the delivery of postoperative radiotherapy. Studies have indicated that most of the older three-drug combinations produce equivalent or inferior survival compared with newer two-drug combinations (Table 7.2) and more toxicity and more toxic deaths.9–14 These non-cancer deaths are especially important in the postoperative setting, as discussed

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above in the introduction. Postoperative radiotherapy can also negatively impact survival, as shown in the Cochrane review.4 This is potentially an even greater negative factor when combined with chemotherapy.

Table 7.1 Ongoing and completed randomized cisplatin-based adjuvant chemotherapy trials in stage I–IIIA NSCLC Study

Therapy

Metaanalysis5

Surgery alone

688

NR

56

49

Surgery+CT

706

NR

60+

54

Surgery alone

540

28.9

48

47

Surgery+MVP

548

36.5

55.2

48

Surgery alone

189

NR

NR

NR

Surgery+CT

192

NR

NR

NR

Surgery alone

945

30

47

40.4

Surgery+CT

932

42

52

44.5

ALPI

BLT

6

7

IALT

8

No. of patients

MTP MS (months)

5-YS Survival (%) HR

Survival p

0.87

0.08

0.96

NS

1.0

NS

0.86

<0.03

ALPI, Adjuvant Lung Project of Italy; IALT, International Adjuvant Lung Cancer Trial; BLT, Big Lung Trial; MTP, median time to progression; 5-YS, 5-year survival rate; CT. chemotherapy; HR, hazard ratio; MVP, mitomycin C-vinblastine-cisplatin; NR, not reported; NS, not significant.

If the advantage of postoperative chemotherapy is small and influenced by the choice of therapy, when should it be offered and which chemotherapy? We believe it should

Table 7.2 Randomized trials comparing MIC MVP, or NIP with a two-drug platinum-based combination in advanced NSCLC Study

Therapy

No. of patients

MS (months)

1-YS (%)

p

Crino et al9

GC MIC

153 154

8.6 9.6

33 34

NS

Alberola et al10

GC GVC GV→IV

187 188 187

9.4 7.9 8.3

35 31 31

NR

Rudd et al11

GCb MIP

212 210

10.2 6.5

38 28

0.0043

Tan et al12

NP

133

10.2

38

NR

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NIP

126

8.3

33

Melo et al

GC1 MVP GC2 VC

62 62 62 62

9.4 9.4 9.6 9.0

NR NR NR NR

0.05 0.04 NR

Bonomi et al14

Cb EP MVP

87 174 174

6 5 4.3

NR NR NR

0.08

13

MS, median survival; 1-YS, 1-year survival rate; GC, gemcitabine-cisplatin; MIC, mitomycin Cifosfamide-cisplatin; GVC, gemcitabine-vinorelbine-cisplatin; GV→IV, gemcitabine-vinorelbine followed by ifosfamide-vinorelbine; GCb, gemcitabine-carboplatin; MIP, mitomycin C-ifosfamidecisplatin; NP, vinorelbine-cisplatin; NIP, vinorelbine-ifosfamide-cisplatin; VC, vinorelbinecisplatin; MVP, mitomycin C-vinblastine-cisplatin; Cb, carboplatin; EP, etoposide-cisplatin; NS, not significant; NR, not reported.

only be considered for stages IB-IIIA with good performance status (PS 0–1) and no lifethreatening comorbid conditions. We believe a two-drug combination such as those employed in IALT should be offered and that postoperative radiotherapy should not be used in conjunction with postoperative chemotherapy. Postoperative UFT-based therapy Several Japanese trials have evaluated the role of postoperative UFT therapy (uracil plus tegafur), and the results of two such randomized trials have been reported. The results of the North-East Japan Study Group for Lung Cancer Surgery have been reported by Endo et al15 and are summarized in Table 7.3. This study randomized 221 patients with completely resected stage I or II NSCLC to receive UFT daily for 2 years or no further therapy. The overall 5-year survival rates were 79% for the UFT group and 75% for the control group, but the survival advantage was not statistically significant. The mean total dosages of UFT were about 75% of that prescribed. A large study has been reported by the Japanese Lung Group.16 This study was confined to patients with stage I adenocarcinoma. As shown in Table 7.3, the 5-year survival rate was 85.4% in the control group and 87.9% in the UFT group. The survival differences were of the same magnitude as in the trial by Endo et al,15 but the differences were statistically significant (p=0.035), perhaps due to the larger sample size. A subset analysis was performed, and the time to progression and survival advantage was largely confined to the stage IB (T2N0) subset. Postoperative ubenimex therapy Ubenimex (Bestatin) is an inhibitor of aminopeptidases that has immunostimulant and antiangiogenic properties. Several randomized trials of ubenimex from Japan have yielded conflicting results—some positive and some negative. The results of the NK421 Lung Cancer Surgery Group trial have been reported by Ichinose et al.17 This trial was confined to patients with resected stage I squamous cell cancer who were randomized to

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receive either ubenimex (30 mg) or placebo daily by mouth for 2 years. The 5-year overall survival rate was 81% in the ubenimex group and 74% in the placebo group (p=0.033). The conflicting nature of the results between this and other trails suggests that additional trials are needed to determine whether ubenimex should become a standard therapy.

Table 7.3 Results of adjuvant studies reported in 2003 using UFT or ubenimex Study

Therapy

Endo et al15

Surgery UFT

110 109

30 22

Kato et al16

Surgery UFT

488 491

NR NR

85.4 0.71 0.035 87.9

198 202

37 29

74 0.51 0.033 81

Ichinose et al17 Surgery Ubenimex

No. of patients

Recurrence rate (%)

5-YS (%)

HR p 75 0.90 79

NS

UFT, uracil plus tegafur; 5-YS, 5-year survival rate; HR, hazard ratio; NR, not reported; NS, not significant.

Preoperative neoadjuvant chemotherapy A major advantage of preoperative chemotherapy is the improved compliance. There are many phase II and III trials using platinum-based combinations that show a higher compliance rate with preoperative compared with postoperative chemotherapy. Most of these studies also show acceptable rates of surgical morbidity and mortality following the preoperative therapy. Altorki et al18 have presented the results of a phase II trial employing a combination of celecoxib, paclitaxel, and carboplatin prior to surgery in 29 patients with stage IB–IIIA NSCLC. Compliance with the combination was 100% for paclitaxel-carboplatin and 90% for celecoxib. The clinical response rate was 65%, with a 17% rate of complete responses. There were no complete pathologic responses, but 24% had a near-pathologic response. Altorki et al18 indicated that they believe the results might be superior to those reported in a phase II neoadjuvant study of paclitaxelcarboplatin alone.19 The results appear similar to these authors. While only a randomized trial can prove whether the addition of celecoxib improves results over chemotherapy alone, such trial is more reasonable in stage IV patients than in stage I–II patients. Randomized trials of neoadjuvant chemotherapy are ongoing in the USA and Europe. Prognostic factors in stage I–II NSCLC Several studies have evaluated prognostic factors in clinical stage I–II patients. A Japanese study showed that nodal involvement, high carcinoembryonic antigen (CEA) and large tumor size were poor risk factors.20 A US study from the Cancer and Leukemia Group B (CALGB) used a multivariate analysis to show that T classification and level of N1 involvement were significant prognostic factors.21 The overall 5-year survival rate for

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patients with pN1 was 40%. A study from Hungary showed that for bronchioloalveolar carcinoma (BAC), females had superior survival. Multiple nodules in a lobe did not worsen survival, but mixed adenocarcinoma features did worsen survival.22 A study from South Korea23 indicated that reduced expression of E-cadherin and β-catenin were associated with tumor dedifferentiation and poor survival, consistent with the results of Bremnes et al.24 An Italian study suggested that epidermal growth factor receptor (EGFR) overexpression correlated with poor survival.25 However, another study showed no adverse effect of high EGFR expression on survival.26 Patient follow-up It is difficult to recommend routine follow-up studies for resected NSCLC patients because there are few studies. Follow-up spiral computed tomography (CT) scans make sense because of the high rates of second primary cancers and the low dose of radiation delivered by spiral CT. Chiu et al27 compared annual follow-up with spiral CT compared with chest X-ray and conventional CT. They reported that spiral CT was of considerable value in detecting recurrence and far more valuable than chest X-rays. Additional studies are clearly needed.

STAGE IIIB (MALIGNANT PLEURAL EFFUSION)/STAGE IV NSCLC The standard therapy for patients with advanced NSCLC is cytotoxic chemotherapy. Numerous trials have shown that chemotherapy can improve survival, enhance quality of life, and be cost-effective. Although no combination regimen is clearly superior to another, the results of randomized trials of a variety of combinations have answered important questions about chemotherapy for patients with advanced disease. Phase III platinum doublets Older studies clearly demonstrated that a cisplatin doublet produced a survival advantage over single-agent cisplatin, but no published data were available comparing a newer single agent with a novel platinum doublet. Three more recent studies have addressed this issue (Table 7.4). The CALGB study compared paclitaxel with paclitaxel plus carboplatin.28 The combination produced a higher response rate (29% versus 17%; p<0.001). Median survival by log-rank analysis favored the doublet arm at 8.8 months compared with 6.7 months, but this was not statistically significant. The two smaller trials—of gemcitabine versus gemcitabine with carboplatin and of docetaxel versus docetaxel plus cisplatin—produced somewhat similar results, with one trial showing a significant survival prolongation with the doublet and the other showing a trend in favor of the doublet.29,30 Another approach, taken by Monnier et al,31 examined the value of a single novel agent (docetaxel) versus a different doublet (vinorelbine-cisplatin). One hundred patients were enrolled in each arm. The response rate was higher with the doublet, but the median

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and 1-year survivals were comparable. Overall, a platinum-based doublet regimen appears to be slightly more efficacious than a single agent in PS 0–1 patients. Additional studies compared various platinum-based doublets (Table 7.4). The final results from one of the largest trials conducted have been published by Fosella et al.32 In this trial, known as TAX 326, approximately 1200 patients were randomized to two experimental arms—docetaxel plus cisplatin or docetaxel plus carboplatin—or to the control arm of vinorelbine and cisplatin. Efficacy results revealed a higher response rate and an improved survival for docetaxel plus cisplatin (31.6% and 11.3 months) compared with vinorelbine plus cisplatin (23.9% and 10.1 months; p=0.04), but no significant benefit was demonstrated for docetaxel plus carboplatin versus vinorelbine plus cisplatin. Both docetaxel regimens were better tolerated, and led to an improved quality of life (QoL) compared with the vinorelbine regimen.32

Table 7.4 Phase III platinum doublet chemotherapy studies in advanced-stage NSCLC Authors

No. of patients

Treatment Overall response rate (%)

Median survival (months)

Survival rate (%) 1-yr

2yr

1 versus 2 Lillenbaum et al28

277 Paclitaxel 225 mg/m2 d1 q3wks

17 (12– 23)

6.7 (5.8–7.8)

33 (28– 39)

6.7

29 (24– 36)

8.8 (8.8–9.9)

37 (32– 43)

8.8

12

9

32

5

120 Gemcitabine 1250 mg/m2 d1, 8+ carboplatin AUC 5 d1 q3wks

30

10

44

17

132 Docetaxel 100 mg/m2 d1

18

8

40

18

147 Docetaxel 100 mg/m2 d1+ cisplatin 80 mg/m2 d2+rhu GCSF 5 µg/kg s.c. d3–8 q3wks

35

10

45

16

100 Docetaxel 100 mg/m2 d1 q3wks

23

10.4

versus 284 Paclitaxel 225 mg/m2 d1+ carboplatin AUC 6, d1 q3wks Sederholm et al29

147 Gemcitabine 1250 mg/m2 d1, 8 q21d versus

Georgoulias et al30

versus

Monnier et

43 NR

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al31 versus 101 Vinorelbine 25 mg/m2/wk+ cisplatin 100 mg/m2 q4wks 2 versus 2 Fosella et al32

Kubota et al33

38

10.7

39 NR

408 Docetaxel 75 mg/m2, d1+ cisplatin 75 mg/m2, d1 q3wks

31.6a 11.3mb (27.1– (10.1–12.4) 36.4)

3.46 (42– 51)

21 (16 – 25)

406 Docetaxel 75 mg/m2, d1+ carboplatin AUC 6, d1 q3wks

23.9 (19.8– 28.3)

9.4 (8.7–10.6)

38 (33– 43)

18 (18 – 22)

404 Vinorelbine 25 mg/m2/wk+ cisplatin 100 mg/m2 d1 q4wks

24.5a (20.4– 29.0)

10.1b (9.2–11.3) 9.9 (9.0–11.3)

41 (36– 46)

14 (10 – 18)

37c

11.3d

48

24

151 Cisplatin 80 mg/m2 d1+ vindesine 3 mg/m2 d1, 8, 15 q4weeks

21

9.6

43

12

602 Cisplatin 80 mg/m2 d1+ irinotecan 60 mg/m2 q4wks

30

NR

NR

NR

31

NR

NR

NR

28

NR

NR

NR

31

NR

NR NR

30.5

9

NR NR

25

9

NR NR

151 Docetaxel 60 mg/m2 d1+ cisplatin 80 mg/m2 d1 q4wks versus

Ohe et al34

versus Carboplatin AUC 6 d1+ paclitaxel 200 mg/m2 d1 versus Cisplatin 80 mg/m2 d1+ gemcitabine 1000 mg/m2 d1, 8 q3wks versus Cisplatin 80 mg/m2 d1+ vinorelbine 25 mg/m2 d1, 8 q3wks Martoni et al35

133 Vinorelbine 25 mg/m2 d1, 8+ cisplatin 75 mg/m2 d1 q3wks versus 131 Gemcitabine 1200 mg/m2 d1, 8+ cisplatin 75 mg/m2 d1 q3wks

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Zatloukal et al36

87 Gemcitabine 1200 mg/m2 d 1, 8+ cisplatin 80 mg/m2 d1 q3wks

66

41.4 (31–51.7)

8.75 (6.7–10.5)

NR (0.22– 0.44)

33

89 Gemcitabine 1200 mg/m2 d1, 8+ carboplatin AUC 5 iv d1 q3wks

29.2 (19.8– 38.7)

7.97 (6.9–11.4)

36 NR (0.26– 0.47)

300 Carboplatin AUC 4+ vinorelbine 25 mg/m2 d1, 8 q21d 3 cycles

NR

7

24

8

NR

8

26

8

37 (31–45)

10

38

N R

210 Mitomycin C 6 mg/m2 d1+ ifosfamide 13 mg/m2 d1+ cisplatin 50 mg/m2 d1 q3wks

40

6.5

28 (22– 35)

N R

62 Mitomycin C 6 mg/m2 d1+ vinblastine 6 mg/m2 d1+ cisplatin 100 mg/m2 d1 q28d

27

6.4

NR

N R

37.1

9.0e

NR

N R

48.4f

9.4g

NR

N R

48.4f

9.6g

NR

N R

versus

Andresen et al38

versus Carboplatin AUC 4+ vinorelbine 25 mg/m2 d1, 8 q21d 6 cycles 2 versus 3 Rudd et al39

212 Gemcitabine 1200 mg/m2 d1, 8+ carboplatin AUC 5 d1 q3wks versus

Melo et al40

versus 62 Cisplatin 100 mg/m2 d1+ vinorelbine 30 mg/m2 d1, 8, 15 q28d versus 62 Cisplatin 100 mg/m2 d1+ gemcitabine 1000 mg/m2 d1, 8, 15 q28d versus 62 Cisplatin 100 mg/m2 d15+ gemcitabine 1000 mg/m2 d1, 8, 15 q28d Confidence intervals in parentheses. NR, not reported. p-values: a0.29; b0.04; c<0.01; d0.014; e0.05; f0.016; g0.04.

Kubota et al33 have reported their results comparing an old doublet, vindesine-cisplatin (VdsC), with the newer docetaxel-cisplatin combination (DC). The DC arm demonstrated significant improvements compared with the VdsC arm in overall response rates (37% vs 21%, respectively; p<0.01) and median survival times (11.3 vs 9.6 months, respectively; p=0.014). The 2-year survival rate was 24% for DC, compared with 12% for VdsC. QoL

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was also shown to be significantly better in the DC arm than in the VdsC arm (p=0.020). Toxicity was predominantly hematologic and was more severe in the VdsC arm. The Japanese have also completed accrual to their four-arm cooperative study (FACS) that was designed to compare overall survival of three platinum-based combinations with their standard of cisplatin plus irinotecan.34 A preliminary report on response rate and toxicity was presented at ASCO 2003. The objective tumor response rates were essentially equal in all arms: 30% (irinotecan-cisplatin), 31% (paclitaxel-carboplatin), 28% (gemcitabine-cisplatin), and 31% (vinorelbine-cisplatin). The frequency of grade 3 or greater neutropenia was lower in the gemcitabine arm; however, grade 3 or greater thrombocytopenia was higher in this arm. Differences in non-hematologic toxicity included higher grade 2 or greater sensory neuropathy in the paclitaxel group and an increased incidence of grade 2 or greater diarrhea in the irinotecan arm. Martoni et al35 have reported the results from a randomized trial combining vinorelbine or gemcitabine with the same dose of cisplatin (75 mg/m2). Approximately 130 patients were accrued to each arm. The response rates were (30.5% and 25%, respectively, time to progression (TTP) was 5 months in both arms, and overall survival (OS) was 9 months in both arms. Both combinations were well tolerated. Grade 3–4 neutropenia occurred in 30% of patients receiving vinorelbine and 17% of patients receiving gemcitabine (p=0.03). Significant thrombocytopenia developed more frequently in the gemcitabine arm (10%) than in the vinorelbine arm (1%; p=0.002). Non-hematologic toxicity was generally mild, but a slightly higher incidence of neurotoxicity (31% vs 21%) and arm phlebitis (7% vs 2%) occurred in the vinorelbinecisplatin group (p=NS). Although the TAX 326 trial did not directly compare the docetaxel arms, the question of cisplatin versus carboplatin resurfaced. Zatloukal et al36 compared gemcitabine plus cisplatin with gemcitabine plus carboplatin and showed no significant difference in efficacy between the two arms, with median survivals of 8.75 months for the cisplatin regimen and 8 months for the carboplatin regimen. An Italian group37 evaluated the potential impact of substituting carboplatin for cisplatin in the MVP (mitomycin Cvinblastine-carboplatin) regimen Patients were randomized to MVP or MVC (mitomycin C-vinblastine-cisplatin). The response rates were 43.1% and 38.6% (p=0.59), and the median survival times were 10.2 months and 7.2 months for the cisplatin and carboplatin arms, respectively (p=0.39). The global QoL evaluated by the Spitzer questionnaire suggested an advantage for the MVC regimen (p=0.05). When evaluated with the European Organization for Research and Treatment of Cancer (EORTC) questionnaire, there was significantly less nausea and vomiting (p=0.0001), appetite loss (p=0.01), insomnia (p=0.03), constipation (p=0.01), and peripheral neuropathy (p=0.01) in favor of the carboplatin regimen, and a trend for less hair loss (p=0.05). Carboplatin can be substituted for cisplatin without jeopardizing efficacy and is less toxic. One randomized phase III trial has addressed the issue of cycle number. Andresen et al38 compared 3 cycles versus 6 cycles of carboplatin with vinorelbine in 300 patients. The overall median survival was approximately the same in both arms (28 weeks vs 32 weeks) and the 1- and 2-year survival rates were similar (24% vs 26% and 8% vs 8%). Controversy continues over the number of cycles of chemotherapy to be administered in the first-line setting. Current ASCO guidelines suggests a maximum of 6 cycles, but there are accumulating data (including the present study) that 3–4 cycles is sufficient.

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Finally, two trials have compared a new doublet with an older, commonly used triplet. Rudd et al39 chose to study gemcitabine and carboplatin versus MIC (mitomycin Cifosfamide-cisplatin), while in a smaller trial Melo et al40 evaluated vinorelbine or gemcitabine with cisplatin versus MVP. Both trials revealed the doublets to be more efficacious and less toxic. Phase III trials evaluating non-platinum-containing regimen It was hypothesized that non-platinum regimens with newer agents would be more tolerable and show more efficacy. Early studies demonstrated that toxicity was slightly decreased with this approach but that efficacy and QoL were similar. Results from additional studies are presented in Table 7.5. The Hellenic Cooperative Oncology Group41 have published their results comparing paclitaxel and carboplatin with paclitaxel and gemcitabine. No difference in median survival (10.4 months vs 9.8 months, respectively) or 1-year survival rate (41.7% vs 41.4%, respectively) was observed. Gridelli et al42 from Italy and Canada conducted a randomized trial comparing a cisplatinbased regimen with either gemcitabine or vinorelbine versus the non-platinum regimen of gemcitabine plus vinorelbine. The primary endpoint in this trial was QoL, which was similar in both arms. Survival, although not significant, was slightly inferior in the nonplatinum arm. Kakolyris et al43 compared the efficacy and toxicity of docetaxelgemcitabine versus that of vinorelbine-cisplatin. Two hundred and fifty-one chemotherapy-naive patient entered the study. Preliminary results indicated that both regimens were effective in NSCLC, with response rates of 29% and 36% and median survivals of 9 and 11.5 months, respectively. The cisplatin regimen was more toxic. A phase III trial undertaken by Wachters et al44 compared the efficacy and QoL of 240 patients randomized to gemcitabine-cisplatin (CG) or gemcitabine-epirubicin (EG). There were no significant differences in median overall survival (43 weeks for CG and 36 weeks for EG) or tumor response rates (46% and 36%, respectively). In the EG arm, granulocytopenia occurred more frequently, leading to more febrile neutropenia. Also, elevation of serum aminotransferases, mucositis, fever, and decline in left ventricular ejection fraction (LVEF) were more common in the EG arm. In the CG arm, more patients experienced elevated serum creatinine levels, sensory neuropathy, nausea, and vomiting. Global QoL did not differ between the arms. Another Greek trial45 compared paclitaxel plus carboplatin with a non-platinum-based doublet of paclitaxel and vinorelbine. Overall response rates (54.5% vs 47.3%), median survivals (11.3 months vs 9.4 months), and 1-year survival rates (42.5% vs 36.5%) were not statistically different. In the USA, a study undertaken by the Coalition of National Cancer Cooperative Groups46 reported preliminary response rates in their trial designed to compare the efficacy of a non-platinum doublet of paclitaxel and gemcitabine against the most commonly used platinum-based regimens: paclitaxel plus carboplatin and gemcitabine plus carboplatin. Response rates in 472 patients were 32.4%, 39%, and 34.7%, respectively. Gemcitabine plus carboplatin produced a higher incidence of grade 3–4 myelosuppression, but was associated with less alopecia and less neurosensory and musculoskeletal toxicity.

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Overall, non-platinum doublets demonstrate a favorable toxicity profile and similar QoL when compared with platinum-containing regimens. However, some studies suggest that non-platinum regimens may be slightly inferior in terms of efficacy. Phase III trials evaluating triple-drug regimens The concept that the addition of a third agent to a standard doublet regimen could improve overall survival with acceptable toxicity has continued to be evaluated in a limited number of studies (Table 7.6). The Southwest Oncology Group (SWOG)47 elected to examine paclitaxel and carboplatin with or without the addition of tirapazamine, a hypoxic cell sensitizer that showed encouraging results in one randomized phase III trial when added to cisplatin. The trial was closed early by the data safety and monitoring board because of lack of efficacy of the triplet arm. Furthermore, a significant increase in toxicity was noted on the three-drug arm. A second randomized trial48 compared a non-platinum doublet, gemcitabine-vinorelbine, with gemcitabinevinorelbine-cisplatin. Gemcitabine plus vinorelbine produced a higher response rate of 32% versus 21% for the triplet. Survival times were similar between the two groups. Paccagnella et al49 randomized 218 patients to paclitaxel-carboplatin or paclitaxelcarboplatin-gemcitabine. The primary endpoint of the study was response rate, which was higher with the triplet regimen: 38% versus 20% (p=0.0073) for the standard regimen. Median survival and 1- and 2-year survival rates favored the three drugs: 11 months, 44%, and 18%, compared with 9.2 months, 34%, and 10% for paclitaxel-carboplatin. Significantly more patients developed hematologic toxicity with the triplet. The Spanish Lung Cancer Group50 compared gemcitabine-cisplatin with a cisplatin-based triplet and with a unique non-platinum sequential doublet.23 In this large trial, the response rate was significantly inferior for the sequential doublet, but no differences in median survival were observed between the three arms. Toxicity was highest for the triplet regimen. In conclusion, randomized phase III trials continue to support the use of a platinumbased doublet as first-line therapy for the majority of patients with stage IV NSCLC. Non-platinum doublets may be used if toxicity is of concern. Triple-drug combinations produce increased toxicity without any survival gain, and are not recommended. Randomized phase II trials Several randomized phase II trials have continued to explore doublet regimens (Table 7.7). One trial51 compared two novel agents—gemcitabine or paclitaxel plus cisplatin— with the older regimen of cisplatin and etoposide. Survival favored both newer regimens. Two studies compared novel cisplatin regimens with a non-platinum doublet. In the trial by Tsai et al,52 the non-platinum regimen produced lower responses, but toxicity was lower and QoL was comparable to that in the cisplatin arms. Preliminary results from the second trial revealed no difference in objective responses between gemcitabinecarboplatin and vinorelbine-gemcitabine.53 Two trials examined alternative dosing and schedules in an effort to further reduce toxicity and perhaps increase efficacy.54,55 While the trial by Chen et al,56 which evaluated weekly dosing of both agents, produced similar efficacy results, the progression-free survival favored the vinorelbine-cisplatin arm: 70 weeks, versus 46

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weeks for the paclitaxel-cisplatin arm (p=0.00046). Masters et al55 were interested in decreasing the problematic thrombocytopenia that develops with gemcitabine and carboplatin, and evaluated alternative schedules. The every-28-day schedule produced less thrombocytopenia. The every-21-day schedule produced a higher response rate, but this did not translate into a survival advantage. Modifications in dose and schedules have not significantly impacted survival or toxicity. One randomized phase II trial took a unique approach to delineate the role of docetaxel in the first- and second-line setting.56 As described in Table 7.7, six cycles of a doublet regimen were followed by single-agent maintenance. Upon progression, patients crossed over to the other single-agent arm. The authors concluded that upfront docetaxel

Table 7.5 Phase III platinum vs non-platinum regimens in advanced-stage NSCLC Authors

No. of patients

Treatment

Overall response rate (%)

Median survival (months)

Survival rate (%) 1-yr 2-yr

Kosmidis et al41

2

252 Paclitaxel 200 mg/m d1+ carboplatin AUC 6 d1 q3wks

28 (22–34)

10.4 (8.8–12)

41.7

17

257 Paclitaxel 200 mg/m2 d1+ gemcitabine 1000 mg/m2 d1, 8 q3wks

35 (29–41)

9.8 (8.0–11.7)

41.4

15.2

250 Gemcitabine 1200 mg/m2 d1, 8 or Vinorelbine 30 mg/m2 d1, 8+ cisplatin 80 mg/m2 d1 q3wks

30 (24–35)

9.5 (8.75–11.25)

37

NR

251 Gemcitabine 1000 mg/m2d1, 8+ vinorelbine 25 mg/m2 d1, 8 q3wks

25 (20–31)

8 (7.5–9.750

31

NR

134 Gemcitabine 1000 mg/m2 d1, 8+ docetaxel 100 mg/m2 d8+ rhuG-CSF 150 µg/m2 d9–15

28.9

9

NR

NR

36

11.5

NR

NR

versus

Gridelli et al42

versus

Kakolyris et al43

versus 117 Vinorelbine 30 mg/m2 d1, 8+ cisplatin 80 mg/m2 d8+ rhG-CSF 150 µg/m2 d9–15 q3wks

Authors

No of

Treatment

Overall

Median

Survival

Treatment of non-small cell lung cancer

patients

71

response rate (%)

survival (months)

rate (%) 1-yr 2-yr

Wachters et al44

Stathopoulos et al45

110 Gemcitabine 1125 mg/m2 d1, 8+ epirubicin 100 mg/m2 d1 q3wks

46

10.75

NR

NR

114 Gemcitabine 1125 mg/m2 d1, 8+ cisplatin 100 mg/m2, d1 q3wks

36

9

NR

NR

54.5

11.3

42.5

NR

111 Paclitaxel 135 mg/m2 d1+ vinorelbine 25 mg/m2 d1 q2wks

47.3

9.4

36.5

NR

102 Gemcitabine 1000 mg/m2 d1, 8+ carboplatin AUC 5.5 d1 q3wks

32.4

NR

NR

NR

39

NR

NR

NR

34.7

NR

NR

NR

118 Paclitaxel 175 mg/m2 d1+ carboplatin AUC 6 d1 q3wks versus

Treat et al46

versus 105 Gemcitabine 1000 mg/m2 d1, 8+ paclitaxel 200 mg/m2 d1 q3wks versus 98 Paclitaxel 225 mg/m2 d1+ carboplatin AUC 6 d1 q3wks Confidence intervals in parentheses. NR, not reported.

Table 7.6 Phase III triplet chemotherapy studies in patients with advanced-stage NSCLC Authors

No. of patients

Treatment

Overall response rate (%)

Median survival (months)

Survival rate (%) 1yr

Williamson et al47

187 Carboplatin AUC 6 d1+ paclitaxel 225 mg/m2 d1

27

9

NR

2-yr NR

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72

q21d versus 190 Carboplatin AUC 6 d1+ paclitaxel 225 mg/m2 d1+ tirapazamine 260–330 mg/m2 d1 q3wks

18

7

NR

NR

166 Gemcitabine 1250 mg/m2 d1, 8+ vinorelbine 30 mg/m2 d1, 8 q3wks

32

8

26

NR

172 Cisplatin 50 mg/m2 d1, 8+ gemcitabine 1250 mg/m2 d1, 8+ vinorelbine 30 mg/m2 d1, 8 q21d

21

7

28

NR

218a Paclitaxel 200 mg/m2 d1+ carboplatin AUC 6 d1 q21d

20

9.2

34

9.7

38b

11

44

18.2

Esteban et al48

versus

Paccagnella et al49

versus Paclitaxel 200 mg/m2 d1+ carboplatin AUC 6 d1+ gemcitabine 1000 mg/m2 d1, 8 q21d

Authors No. of patients

Treatment

Overall response rate (%)

Median survival (months)

Survival rate (%) 1-yr 2-yr

Alberola et al50

2

182 Cisplatin 100 mg/m d1+ gemcitabine 1250 mg/m2 d1, 8 q3wks

42 (8.1– 10.5)

9.3

38

13

41 (7–9.4)

8.2

33

16

27c (6.9–9.2)

8.1

34

11

versus 188 Cisplatin 100 mg/m2 d1+ gemcitabine 1000 mg/m2 d1, 8+ vinorelbine 25 mg/m2 d1, 8 q3wks versus 187 Gemcitabine 1000 mg/m2 d1, 8+ vinorelbine 30 mg/m2 d1, 8 q3wks, then vinorelbine 30 mg/m2 d1, 8+ ifosfamide 3 mg/m2 d1 q3wks Confidence intervals in parentheses.

Treatment of non-small cell lung cancer

73

a

Total number of patients. p=0.0073. c p=0.003. b

Table 7.7 Randomized phase II trials Authors

Ciuleanu et al51

No. of patients

Treatment

118 Cisplatin 80 mg/m2 d1+ gemcitabine 1250 mg/m2 d1, 8

Overall response rate (%)

Median survival (weeks)

1-yr overall survival rate (%)

26

41

39

33

35

34

Cisplatin 80 mg/m2 d1+ etoposide 120 mg/m2 d1– 3 q21d

35

28

14

120 Cisplatin 80 mg/m2 d1.5+ vinorelbine 20 mg/m2 d1, 8, 15

45

38

24

47.5

40.4

47

27.5

34.4

32

26.3

NR

NR

27.8

NR

NR

versus Cisplatin 80 mg/m2 d1+ paclitaxel 175 mg/m2 d1 versus

Tsai et al52

versus Cisplatin 80 mg/m2 d1.5+ gemcitabine 1000 mg/m2 d1, 8, 15 versus Vinorelbine 20 mg/m2 d1, 8, 15+ gemcitabine 1000 mg/m2 d1, 8, 15 q28d Horio et al53

74 Carboplatin AUC 5 d1+ gemcitabine 1000 mg/m2 d1, 8 q21d versus Vinorelbine 25 mg/m2 d1, 8+ gemcitabine 1000 mg/m2 d1, 8 q21d

Authors No. of patients

Treatment

Overall response rate (%)

Median survival (weeks)

1-yr overall survival rate (%)

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Chen et al54

142 Cisplatin 60 mg/m2 d1, 5+ paclitaxel 66 mg/m2 d1, 5

74

38.6

46.8

49

38.6

70

60.2

23

34.8

33.7

40

29.2

33.5

34

33.2

37a

26

36

36b

versus Cisplatin 60 mg/m2 d1, 5+ vinorelbine 23 mg/m2 d1, 8, 15 q28 Masters et al55

100 Carboplatin AUC 5 d8+ gemcitabine 1100 mg/m2 d1, 8 q28d versus Carboplatin AUC 5 d1+ gemcitabine 1000 mg/m2 d1, 8 q21d

Douillard et al56

233 (A1) Cisplatin 100 mg/m2+ docetaxel 75 mg/m2×6 cycles, followed by gocetaxel 75 mg/m2 q21d versus (B1) Cisplatin 100 mg/m2+ vinorelbine 30 mg/m2 d1, 8 q21d×6 cycles, followed by vinorelbine 30 mg/m2 d1, 8 q21d

Authors

Belani et al57

No. of patients

Treatment

390 Paclitaxel 100 mg/m2 wkly×3+ carboplatin AUC 6 d1 q28d

Overall response rate (%)

Median survival (weeks)

1-yr overall survival rate (%)

32

49

47

24

31

31

Paclitaxel 150 mg/m2/wk cycle 1 (100 mg/m2/wk cycle 2)+ carboplatin AUC 6×6 wks q8wks

18

40

41

80 Pemetrexed 500 mg/m2 d1+ carboplatin AUC 6 d1

33

NR

NR

versus Paclitaxel 100 mg/m2+ carboplatin AUC 3 wkly×3 q28d versus

Scagliotti et al58

versus

Treatment of non-small cell lung cancer

Pemetrexed 500 mg/m2 d1+ oxaliplatin 120 mg/m2 d1 q21d

75

29

NR

NR

NR, not reported. a 17%/13% survival rates at 2 and 3 years. b 10%/6% survival rates at 2 and 3 years.

plus cisplatin was superior because the 3-year survival rate was 13%, versus 6% for vinorelbine plus cisplatin, and that docetaxel in the second-line setting was more tolerable. Another large, multicentric, randomized trial compared three different regimens using weekly paclitaxel and carboplatin.57 Three hundred and ninety patients were randomized, and responders were then assigned to weekly paclitaxel or observation. The best responses were seen with paclitaxel 100 mg/m2 weekly 3 weeks out of 4 and carboplatin AUC 6. This regimen has been compared with the 21-day schedule. Finally, Scagliotti et al58 compared pemetrexed (Alimta) plus carboplatin with pemetrexed plus oxaliplatin in 80 patients. Reported response rates were similar at 33% versus 29%. Grade 3–4 neutropenia occurred in 26% of patients on the pemetrexedcarboplatin arm and 7% on the pemetrexed-oxaliplatin arm, which is lower than with other platinum combinations. Taxane-platinum phase II doublets The theme of the majority of these trials was low-dose weekly regimens, as shown in Table 7.8. Both trials with paclitaxel and carboplatin59–60 reported high response rates of 54.7% and 58.2% with prolonged median survivals, suggesting that this strategy should be pursued further. The small trials with weekly docetaxel plus cisplatin,61,62 however, reported lower response rates. Two trials substituted carboplatin for cisplatin.63,64 In a very large phase II trial with 171 patients,64 a 46% response rate was observed, with a promising prolonged survival of 69 weeks. Grade 3 and 4 neutropenia occurred in 18% of patients, grade 3 and 4 anemia was observed in 6%, and peripheral neuropathy was seen in 3%. The remaining trial65 employed oxaliplatin with paclitaxel. Efficacy was similar to that with other platinum-based regimens. Overall, only the largest phase II trial with docetaxel and carboplatin produced encouraging results; however, it is unlikely that these data will be pursued in a randomized phase III trial because docetaxel plus carboplatin is considered a standard regimen. Gemcitabine-platinum doublets Two cisplatin-based trials evaluated novel doses and schedules (Table 7.9). The first trial administered both drugs weekly66 and the second bimonthly.67 The response rate was high on the bimonthly schedule but no increase in survival resulted. Three trials explored the increasingly popular gemcitabine-carboplatin regimen.68–70 The highest response rate (50%) was seen with the fixed 2-hour infusion rate of gemcitabine, with a median survival of 46 weeks. Prolonged infusions of gemcitabine result in increased levels of the active metabolite, which may account for the high response rate seen in this trial. Oxaliplatin was also combined with gemcitabine in one small study involving 25

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patients.71 The response rate was low (20%). No phase II gemcitabine-platinum doublet produced a meaningful benefit over current regimens.

Table 7.8 Taxane-platinum phase II doublets Authors

No. of patients

Treatment

Overall response rate (%)

Median survival (weeks)

1-yr overall survival rate (%)

Thulfaut et al59

53 Carboplatin 200 mg/m2 or AUC 2+ paclitaxel 100 mg/m2 weekly

54.7

50

52.8

Yamaguchi et al60

46 Carboplatin AUC 6 d1+ paclitaxel 70 mg/m2 weekly d1, 8, 15 q21d

58.2

44

NR

Amenedo et al61

41 Cisplatin 40 mg/m2 d1, 2+ docetaxel 85 mg/m2 d1 q21d

48 (33–63)

42

NR

Minato et al62

37 Cisplatin 80 mg/m2 d1+ docetaxel 35 mg/m2 d1, 8, 15 q28d

43.2

NR

NR

Kimura et al63

39 Carboplatin AUC 5.5 d1+ docetaxel 60 mg/m2 d1 q21d

35.9

53

53.8

171 Carboplatin AUC 5.5 d1+ docetaxel 100 mg/m2 d1 q28d

46.1 (51–87)

69

NR

34 (19.6–51.4)

36.8 (24–49.6)

37a

Zarogoulidis et al64 Mauer et al65

36 Oxaliplatin 130 mg/m2 d1+ paclitaxel 175 mg/m2 d1 q21d

Confidence intervals in parentheses. NR, not reported. a 21% at 2 years

Table 7.9 Gemcitabine-platinum doublets Authors

No. of patients

Treatment

Overall response rate (%)

Median survival (weeks)

1-yr overall survival rate (%)

Richardet et al66

39 Cisplatin 30 mg/m2 d1, 8, 15+ gemcitabine 800 mg/m2 d1, 8, 15 q28d

28

41

NR

PerezHoyos et al67

41 Cisplatin 50 mg/m2 d1, 15+ gemcitabine 2500 mg/m2 d1, 15 q28d

48.8 (33.3–64.2)

35

47

Treatment of non-small cell lung cancer

77

Domine et al68

44 Carboplatin AUC 5 d1+ gemcitabine 1200 mg/m2 d1, 8 2-hr q21d

50 (32–65)

46

NR

Kortsik et al69

60 Carboplatin AUC 5 d1+ gemcitabine 1000 mg/m2 d1, 8 q21d

33.3 (21.7–46.7)

36

NR

Iglesias et al70

40 Gemcitabine 1000 mg/m2 d1, 8+ carboplatin AUC 5 d1 or [d8]

25

40.7 [29.1]

27.8 [33.3]

Crino et al71

25 Oxaliplatin 130 mg/m2 d1+ gemcitabine 1000 mg/m2 d1, 8 q21d

20

NR

NR

Confidence intervals in parentheses. NR, not reported.

Vinorelbine-platinum doublets Table 7.10 summarizes the continuing experience with vinorelbine.72–77 Several trials evaluated the oral formulation, which has shown similar efficacy to its intravenous counterpart, and two trials combined vinorelbine with carboplatin. The results are comparable to those with current regimens. Irinotecan-platinum doublets Trials exploring irinotecan-platinum combinations in NSCLC are primarily being conducted in Japan and Europe, as listed in Table 7.11. All four studies giving irinotecan and cisplatin administered the agents at different doses and schedules.78–81 The first two weekly regimens78,79 produced similar response rates of 33% and 35% and median survivals of 56 and 59 weeks. The one modest size trial incorporating a 21-day schedule80 reported an impressive 61% response rate with a 62-week median survival. This trial incorporated an aggressive antidiarrheal program consisting of oral sodium bicarbonate, magnesium hydroxide, basic water, and ursodeoxycholic acid for 4 days after each irinotecan administration. Late diarrhea developed in only 3% of courses (7 of 233). The final trial alternated cisplatin and irinotecan with docetaxel,81 and showed no improvement in outcome compared with current therapies. The one study that combined irinotecan with carboplatin followed by paclitaxel82 resulted in only a 23% response rate. Non-platinum doublets Two randomized phase II trials incorporated a non-platinum arm, namely gemcitabine plus vinorelbine, and are discussed above. To date, non-platinum doublets have not shown superiority over platinum-based regimens and (although this is controversial) may be slightly inferior. The tolerability of these non-platinum combinations suggests that they may have benefit in other treatment areas such as second-line therapy and treatment of the elderly and poor-risk population.

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Phase II triplet regimens A large number of trials have evaluated the tolerability and efficacy of three-drug combinations, as summarized in Table 7.12. Cisplatin plus gemcitabine was the core regimen in most of these trials.83–90 Response rates varied widely, from a low of 20% to a high of 72%. A few trials reported median survivals, which were comparable to those with doublets. However, triplet chemotherapy regimens seem to cause a greater incidence of febrile neutropenia in comparison with doublet regimens. Interestingly, two smaller trials with docetaxel91,92 both documented high objective response rates of 57.1% and 55%, with equally promising median survivals of 65 weeks and 56 weeks. In the first trial91 45% of patients developed grade 3 and 4 neutropenic fever, while in the second trial,92 which included granulocyte colony-stimulating factor (G-CSF) prophylaxis, 12% of patients developed febrile neutropenia. A novel combination of paclitaxel, carboplatin, and vinorelbine plus G-CSF93 produced a high response rate, median survival, and 1-year survival rate without any septic deaths. Grade 3 and 4 leukopenia was observed in 33% of patients. The majority of the three-drug regimens discussed produced higher objective response rates, with some demonstrating an improvement in survival. However, previously conducted phase III

Table 7.10 Vinorelbine-platinum doublets Authors No. of patients

Treatment

Jassem et al72

56 Cisplatin 100 mg/m2 d1+ vinorelbine 25 mg/m2 d1+ vinorelbine 60 mg/m2 p.o. d8, 15, 22 q28d

Chen et al73

Overall response rate (%)

Median survival (weeks)

1-yr overall survival rate (%)

33

36

NR

43 Cisplatin 50 mg/m2+ vinorelbine 30–35 mg/m2 q2wks

27.9

37 (28–46)

NR

Mori et al74

45 Cisplatin 80 mg/m2 d1+ vinorelbine 25 mg/m2 d1, 8 q21d

48.9

NR

NR

Ramlau et al75

49 Cisplatin 80 mg/m2 d1+ vinorelbine 60–80 mg/m2 p.o. d1, 8 q21d

26.5

40

NR

O’Brien et al76

52 Carboplatin AUC 5 d1+ vinorelbine 25 mg/m2 d1+ vinorelbine p.o. 60 mg/m2 d8 q21d

18

37.2

NR

Couture et al77

53 Carboplatin AUC 6 or [AUC 5 d1]+ vinorelbine 25 mg/m2 d1, 8 q21d

61 [30]

25 [36]

10 [46]

Confidence intervals in parentheses. NR, not reported.

Treatment of non-small cell lung cancer

79

Table 7.11 Irinotecan-platinum doublets Authors

No. of Treatment patients

Overall response rate (%)

Median survival (weeks)

1-yr overall survival rate (%)

Hino et al78

39 Cisplatin 30 mg/m2 d1, 8, 15+ irinotecan 60 mg/m2 d1, 8, 15 q28d

33 (20–49)

56

56

Nakanishi et al79

65 Cisplatin 20 mg/m2 d1, 8, 15+ irinotecan 90 mg/m2 d1, 8, 15 q28d

35 (21.2–43.4)

NR

58.6

Takeda et al80

54 Cisplatin 60 mg/m2 d1+ irinotecan 75 mg/m2 d1, 8 q21d

61.1 (46.9–74.1)

62 (8.7–23.4)

NR

Charoentum et al81

22 Cisplatin 75 mg/m2 d1+ irinotecan 200 mg/m2 d1, alternating with docetaxel 75 mg/m2 d22 q6wks×3 cycles

36

41.6

45

Osterlind et al82

49 Carboplatin AUC 5 d15+ irinotecan 60 mg/m2 d1, 8, 15 q21d×2–4 cycles, then paclitaxel 120 mg/m2/wk×3 q28d×2 cycles

23

NR

NR

Confidence intervals in parentheses. NR, not reported.

Table 7.12 Phase II triplets Authors

No. of patients

Treatment

Overall response rate (%)

Median survival (weeks)

1-yr overall survival rate (%)

Sorensen et al83

104 Cisplatin 100 mg/m2 d1+ paclitaxel 180 mg/m2 d1+ gemcitabine 1000 mg/m2 d1, 8 q21d

55

55

NR

Cappuzzo et al84

36 Cisplatin 50 mg/m2 d1, 8+ gemcitabine 1000 mg/m2 d1, 8+ paclitaxel 125 mg/m2 d1, 8 q21d

72

NR

NR

33a Cisplatin 40 mg/m2+ gemcitabine 1000 mg/m2 d1, 8+ vinorelbine 20 mg/m2 d1, 8 q21d

20

35

36

Doweik et al85

Lung cancer therapy annual 4

80

Bourgeois et al86

60 Cisplatin 100 mg/m2 d15+ gemcitabine 1500 mg/m2 d1, 15+ ifosfamide 3 g/m2 d1 q28d

23b

40

44

Ballesteros et al87

37 Cisplatin 30 mg/m2 d1, 8+ gemcitabine 800 mg/m2 d1, 8+ docetaxel 36 mg/m2 d1, 8 q21d

45.9 (29.8–62)

36.8

NR

Depasquale Ceratti et al88

41 Cisplatin 50 mg/m2d1, 8+ gemcitabine 1000 mg/m2 d1, 8+ paclitaxel 125 mg/m2 d1, 8 q21d

62.8

NR

NR

Tsalic et al89

37 Vinorelbine 25 mg/m2 d1, 8+ gemcitabine 1000 mg/m2 d1, 8+ cisplatin 80 mg/m2 d2 q21d

63

NR

NR

Martins et al90

40 Cisplatin 80 mg/m2 d1+ gemcitabine 1500 mg/m2 d1+ vinorelbine 25 mg/m2 d1, 8 q28d

54 (37–71)

NR

NR

Bessho et al91

49 Cisplatin 60 mg/m2 d1+ docetaxel 60 mg/m2 d1+ irinotecan 60 mg/m2 d2 q21d

57.1 (43.1–71.1)

65

62.4

Kosmas et al92

40 Carboplatin AUC 5 d1+ docetaxel 80 mg/m2 d1+ ifosfamide 3.5g/m2 d1+ G-CSF d3–7 q21d

55 (54–81)

56

55

Friedman et al93

44 Vinorelbine 25 mg/m2 d1, 8, 15+ paclitaxel 135 mg/m2 24-hr infusion d1+carboplatin AUC 6 d2+G-CSF q21d

68.2

69

65.9

Confidence intervals in parentheses. NR, not reported. a 25 chemonaive and 8 pretreated patients. b Stage IV patients.

trials have not shown a survival benefit for a triplet regimen and toxicity was clearly worse, dampening the enthusiasm for pursuing further trials with three-drug combinations. Two additional studies, not shown in the table, evaluated the sequential administration of three or four agents.94,95 The first study94 gave cisplatin 80 mg/m2 and paclitaxel 175 mg/m2 every 3 weeks for two cycles, followed by vinorelbine 30 mg/m2 for two cycles, followed by gemcitabine 1000 mg/m2 weekly for 2 of 4 weeks for two cycles. Fifty-one

Treatment of non-small cell lung cancer

81

patients were evaluated. The addition of vinorelbine increased the response rate from 18% to 41%, while the subsequent administration of gemcitabine did not lead to more responses. The overall median survival was 42 weeks, with a 49% 1-year survival rate. Rytter et al95 evaluated 46 patients who had received gemcitabine 1000 mg/m2 on days 1 and 8 with carboplatin AUC 5 on day 8 every 3 weeks for three cycles, followed by paclitaxel 80 mg/m2 weekly for three cycles. The overall response rate to all therapy was 48%, with a median survival of 37 weeks. As has been seen with other studies testing a sequential design, no benefit was achieved. Numerous phase II trials with a variety of chemotherapy combinations have failed to show significantly superior efficacy in comparison with current treatment regimens, suggesting a plateau effect with chemotherapy. Newer cytotoxic agents with different mechanisms of action and alternative treatment strategies are needed.

TREATMENT OF ELDERLY AND POOR-PERFORMANCESTATUS PATIENTS Randomized phase III trials have shown that elderly patients achieved a survival benefit from chemotherapy and that therapy is tolerable. Further supporting the role of chemotherapy for the elderly are retrospective subset analyses from two large randomized phase III trials, Eastern Cooperative Oncology Group (ECOG) 1594 and TAX 326, as displayed in Table 7.13.96,97 While TAX 326 used an age cutoff of 65, both trials enrolled a significant number of elderly patients. As shown, no difference in efficacy was observed between the younger and older populations in the ECOG analysis, and no difference in efficacy for older patients compared with the entire study group was noted in the TAX 326 study, with elderly patients living 8–12 months. Grade 4 toxicities in ECOG 1594 were 71% in the older cohort compared with 66% in the younger group (p=0.14). In the TAX 326 study, no numbers were given, but the authors stated that there was a moderately higher incidence of grade 3–4 asthenia, infection, and pulmonary toxicity in all three treatment arms administered to the elderly patients. Elderly patients treated with docetaxel plus cisplatin had more grade 1–4 diarrhea (54% vs 23%) and peripheral edema (36% vs 18%) than elderly patients treated with vinorelbine and cisplatin. Crino et al98 also reported on a subset analysis from their randomized phase III trial comparing gemcitabine-cisplatin, paclitaxel-carboplatin, and vinorelbine-cisplatin in untreated patients with advanced NSCLC. A total of 606 patients were enrolled into the study. Crino et al reported that, with respect to age, time to treatment failure was shorter in the patients aged 70 or more, at 3.3 months, compared with 4.4 months for younger patients (p=0.025), but all other efficacy parameters and toxicity were similar among the age groups. Finally, an age analysis was performed on a randomized phase II trial comparing three different weekly schedules of paclitaxel and carboplatin (Table 7.13).99 Twenty-eight percent of patients enrolled were age 70 or older. As one might have predicted, there was comparable efficacy and tolerability between the age groups.

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Table 7.13 Randomized phase II/III chemotherapy trials that included elderly patients Authors

Study

Langer et al96

ECOG 1594

Fossella et al97

TAX 326

Ramalingam et al99

Weekly PC

Lilenbaum et al28

Age No. of patients

Median survival (months)

1-yr overvall survival rate (%)

≥70

227 (25%)

25

8.25

35.2

<70

912 (75%)

22

8.15

32.8

401 (33%)

NR

12/9.9/9.0

a

52/41/38a

1218 (67%)

NR

11.3/10/9.4a

46/41/38a

≥70

111 (28%)

NR

49/26/63b

50/19/52b

<70

292 (72%)

NR

48/33/40b

46/35/38b

≥70

155 (38%)

21

6.5

32

<70

406 (62%)

29

8.0

34

≥65 All pts

CALGB 9730

Response rate (%)

PC, Paclitaxel-carboplatin; NR, not reported. a Treatment arms: docetaxel-cisplatin/vinorelbine-cisplatin/docetaxel-carboplatin b Treatment arms: paclitaxel weekly×3-carboplatin AUC 6 d1/paclitaxel-carboplatin weekly×3/paclitaxel-carboplatin weekly×6.

The most compelling results from a US trial confirming the role of chemotherapy in elderly patients came from a prospective analysis of CALGB 9730, which compared single-agent paclitaxel with paclitaxel plus carboplatin (Table 7.13).28 An impressive 38% of patients registered on the trial were elderly. As shown, the elderly patients lived almost as long as the younger patients (6.5 months versus 8.0 months, respectively, which was not statistically different). In comparing the elderly patients treated with single-agent paclitaxel (n=78) with those treated with the doublet of paclitaxel plus carboplatin (n=77), the doublet produced a response rate of 36%, a median survival of 8 months, and a 1-year survival rate of 35%, which was not statistically different when compared with 21%, 5.8 months and 31%, respectively, for monotherapy. Toxicity was higher for the doublet arm, but no toxic deaths occurred. In summary, these analyses provide additional support for offering cytotoxic chemotherapy to elderly patients. Furthermore, they suggest that some platinum-based doublets can be given without a significant increase in toxicity. Numerous phase II trials evaluating predominantly doublet regimens in the elderly have been completed (Table 7.14). Three trials included only patients with good performance status (PS).100–102 The docetaxel-cisplatin regimen produced an impressive 52% response rate with no grade 4 toxicity, while the vinorelbine-carboplatin regimen

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was modestly active and associated with neutropenia.100,101 Oral vinorelbine demonstrated limited single-agent antitumor activity but was well tolerated.102 The majority of trials in the untreated elderly population included patients with a PS of 0–2 (Table 7.14).103–110 Drug dose is a critical issue in the elderly population, in which a balance between efficacy and tolerability is paramount. Quoix et al103 randomized patients to two different schedules of gemcitabine.

Table 7.14 Phase II chemotherapy trials in the elderly Authors

No. of Treatment PS patients

Response Median 1-yr Grade 4 rate (%) survival overall toxicities (%) (months) survival rate (%)

Niho et al100

33 Docetaxel 20 mg/m2 d1, 8, 15+ cisplatin 25 mg/m2 d1, 8, 15 q4wks

0–1

52 (31–67)

13.3

62

None

Lecaer et al101

40 Carboplatin AUC 5, d1+ vinorelbine 25 mg/m2 d1, 8 q4wks

0–1

20

NR

NR

38 (neutropenia/no. of cycles)

Gatzemeier et al102

56 Vinorelbine p.o. 60–80 mg/m2 wkly

0–1

10.7 (2.6–18.8)

8.2

NR

31 (neutropenia grade 3–4/ no. of cycles)

Quoix et al103

81 Gemcitabine 0–2 1000 mg/m2 d1, 8, 15 q4wks

14.3

5.1

NR

NR

6.8

NR

NR

versus Gemcitabine 28.2 1125 mg/m2 d1, 8 q3wks Moscetti et al104

30 Cisplatin 60–100 mg/m2 d2+ gemcitabine 1000–1250 mg/m2, d1, 8 q21d

0–2

44

NR

74

21 (neutropenia grade 3–4)

Berardi et

48 Gemcitabine

NR

31.8

9

34

10 (neutropenia

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al105

84

1000 mg/m2 d1, 8, 15+ cisplatin 35 mg/m2 d1, 8, 15 q28d

grade 3–4) 42 (thrombocytopenia grade 3–4) 15 (anemia grade 3–4)

Maestu et al106

88 Gemcitabine 1250 mg/m2 d1, 8+ carboplatin AUC 4 q21d

0– 2

37.5

9

34

13 (neutropenia grade 3–4/no. of cycles) 15 (anemia grade 3–4/no. of cycles) 5 (thrombocytopenia grade 3–4/no. of cycles)

Jatoi et al107

49 Carboplatin AUC 2 d1, 8, 15+ paclitaxel 50 mg/m2 d1, 8, 15 q28d

0– 2

14 (4.7–32.5)

NR

31

4 (allergic reactions)

Pujol et al108

38 Paclitaxel 90 mg/m2 d1, 8, 15+ carboplatin AUC 6, d1 q28d

0– 2

47

NR

NR

5 (neutropenia grade 3–4) 3 (thrombocytopenia )

Kanat et al109

24 Cisplatin 60 mg/m2 d1+ etoposide 120 mg/m2 d1–3 q4wks

0– 2

12.5

12

38

17 (neutropenia grade 3–4) 4 (thrombocytopenia )

Maestu et al110

43 Gemcitabine 1750 mg/m2d1, 15+ vinorelbine 30 mg/m2 d1, 15 q21d

0– 29.4 2 (14.1–44.7)

NR

NR

5 (neutropenia grade 3–4/no. of cycles)

Confidence intervals in parentheses. NR, not reported. PS, performance status.

Efficacy favored the every-3-week regimen (a 28.2% response rate with a median survival of 6.8 months) over the 4-week regimen (a 14.3% response rate and a median survival of 5.1 months). The remaining seven trials104–110 investigated various doublets, and were primarily platinum-based regimens. Response rates ranged from 12.5% to 37.5%, with two trials reporting median survivals of 9 months and one trial quoting a 12

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months’ median survival. Significant toxicities were hematologic but modest. This evidence corroborates the data from randomized phase III trials discussed above that elderly patients are candidates for combination therapy. Performance status is a well-known independent prognostic marker, and PS 2 patients fair poorly; therefore PS 2 patients have also been excluded from receiving chemotherapy because of substantial toxicity without any survival gain. Limited data are available suggesting that PS 2 patients may have a small survival advantage with chemotherapy. Thus, ECOG attempted to reevaluate the role of chemotherapy in this group of PS 2 patients by including them in the ECOG 1594 trial, but after 68 patients enrolled, accrual was suspended due to excessive toxicities, including 5 deaths. However, in the final analysis of these patients, there was no difference in the incidence of the worst grade of toxicity or toxic deaths compared with the PS 0–1 patients.111 This led ECOG to conduct a trial (ECOG 1599) with attenuated doses of chemotherapy, specifically in PS 2 patients. Paclitaxel plus carboplatin was chosen for the study because it was the least toxic regimen in ECOG 1594, and gemcitabine plus cisplatin was selected because it produced the longest survival time. In an analysis of this trial, both arms produced encouraging median survivals of 6 and 7 months with acceptable toxicity profiles (Table 7.15).112 The CALGB prospectively readdressed the role of cytotoxic chemotherapy for PS 2 patients by including them in their randomized phase III trial CALGB 9730 described above. They found that while their overall survival was shorter than good-PS patients, PS 2 patients were able to tolerate both the single agent and a platinum doublet.28 Median survival favored the doublet: 4.7 months versus 2.4 months for single-agent paclitaxel. The data suggest that doublet therapy should be investigated in the PS 2 population. Several trials have now been conducted in the PS 2 patient population and in a subset of patients defined as poor-risk, which includes the elderly or anyage patient with a PS of 2–3 (Table 7.15).96,113–120 The largest trial, with 263 patients, evaluating single agents and combination regimens, reported longer survivals with the non-platinum doublets.117 In summary, PS 2 patients should be offered chemotherapy, but it is unclear if a combination regimen is superior to a single agent. More trials specifically designed for PS 2 patients are needed.

SECOND-LINE THERAPY IN NSCLC Second-line therapy with docetaxel is considered the standard of care for patients with advanced lung cancer failing upfront therapy, with a 7% objective response rate and a 7month median survival in randomized trials. Improving efficacy in this salvage setting has become a popular arena to explore with both single agents and combination regimens. Table 7.16 lists the phase II trials of single agents. Several studies have examined weekly schedules of the taxanes without any evidence of significant increase in antitumor activity as compared with phase II trials of the cyclic schedules, although hematologic toxicity was lower.121–131 Two studies examined the role of taxane-like agents—one a novel analog and the other an epithilone.126,127 Both demonstrated superior efficacy compared with paclitaxel in preclinical models; however, in these pilot studies, antitumor activity was modest. The newer agents rebeccamycin (a topoisomerase I and II inhibitor),

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Table 7.15 Phase II trials in poor-risk patients with advanced NSCLC Authors

Langer et al112

No. of Treatment patients

51 Carboplatin AUC 6 d1+ paclitaxel 200 mg/m2 d1 q3wks

Criteria Response Median 1-yr Grade 4 rate (%) survival overall toxicities (%) (months) survival rate (%) PS 2

47 Cisplatin

21

6.8

NR

26 (neutropenia grade 3–4)

10

6.1

NR

11 (neutropenia grade 3–4)

versus 5 (thrombocytopenia grade 3–4)

Gemcitabine 1000 mg/m2, d1, 8+ cisplatin 60 mg/m2 d1 q3wks Baka et al113

174 Gemcitabine 1000 mg/m2 d1, 8, 15 q28d

PS≥2

NR

Arm A =6.5

13

NR

NR

Arm B =5.5

5

NR

10

5.8

18

15 (neutropenia) 10 (thrombocytopenia)

9

8.6

NR

None

versus Gemcitabine 1500 mg/m2 d1, 8 q21d Thomas et al114

18a Gemcitabine 1000 mg/m2 d1, 8+ carboplatin AUC 5, d1 q21d followed by paclitaxel 80 mg/m2 wkly×6

PS 2–3

Buccheri et al115

45a Gemcitabine 1250 mg/m2 wkly×3 q4wks

Poor risk

Treatment of non-small cell lung cancer

Poor risk

28

263 Gemcitabine Poor risk 1200–1600 mg/m2 d1, 8, 15 q4wks

NR

4.9 NR

NR

6.6

NR NR

Gemcitabine NR 1000–1200 mg/m2 d1, 8+vinorelbine 25–30 mg/m2 d1, 8 q3wks

9.7

NR NR

Gemcitabine NR 1000–1200 mg/m2 d1, 8+paclitaxel 80–1000 mg/m2 d1, 8 q3wks

9.4

NR NR

Amadio et al118

Poor risk 27 Vinorelbine 25 mg/m2 d1, 8+ gemcitabine 1000 mg/m2 d2, 9 q21d

37

NR NR

4.5 (neutropenia)

Bodkin et al119

25 CT-2103 175 mg/m2 d1 q21d

Poor risk

8

7.8 (PS NR 0–1) 5.4 (PS 2)

8 (neuropathy)

Shehadeh et al120

13 Celecoxib 400 mg Poor risk p.o. bid+ docetaxel 36 mg/m2/wk ×3–4 wks

23

NR NR

None

Hainsworth et al116

Comella et al117

64 Gemcitabine 800 mg/m2 d1, 8, 15+docetaxel 30 mg/m2 d1 8, 15 q28d

87

7

30

11 (neutropenia grade 3–4)

NR

versus Paclitaxel 100– 140 mg/m2 d1, 8, 15 q4wks versus

versus

PS, performance status; NR, not reported. a Poor risk: elderly or any age with PS 2–3

karenitecin (a lipophilic camptothecin) and BBR3464 (a novel bifunctional platinum compound) did not show significant activity.128–130 Finally, in patients who received a non-platinum regimen initially, single-agent carboplatin produced a similar response as docetaxel.131 Two randomized phase II trials were conducted to address the optimal

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docetaxel regimen as salvage therapy for NSCLC.132,133 As shown in Table 7.17, no difference in response rates and survival were seen. The weekly infusions produced less hematologic toxicity, but increased non-hematologic toxicity was observed in the Spanish study by Camps et al.132 A smaller trial134 administered a unique dose and schedule of docetaxel in both arms. Although the response rate and hematologic toxicity were less in the weekly schedule, overall survival and QoL favored the 3-week regimen. One large phase III monotherapy trial has been completed comparing docetaxel with the experimental agent pemetrexed (Alimta), a novel multitargeted antifolate.135,136 In this trial, response rates, median survival, and overall survival were similar between the two arms. Toxicity favored the pemetrexed arm, with significantly less neutropenia. Two randomized trials explored the role of a two-doublet regimen versus a single agent in the second-line setting.137,138 In the first trial, a non-platinum strategy was employed (gemcitabine plus irinotecan versus irinotecan) and in the second trial, a platinum-based design was used (irinotecan plus cisplatin versus cisplatin). Both trials showed higher response rates for the doublet but no survival advantage. As expected, toxicities were increased with the two-drug combinations. Several smaller phase II studies have evaluated a variety of non-platinum doublets, as shown in Table 7.18.139–149 Response rates ranged from 6% to 39% and median survivals were between 4.5 months and 9.3 months in 8 of the 11 studies. In summary, single-agent docetaxel remains the standard of care in the second-line setting. Pemetrexed offers a less toxic equivalent to standard docetaxel and is awaiting US Food and Drug Administration (FDA) consideration for approval. The toxicity of cyclic docetaxel may be reduced by weekly scheduling, but one study suggests that survival may be compromised with this approach. Newer cytotoxic agents at the doses and schedules tested did not demonstrate sufficient activity in this setting. Although twodrug combinations

Table 7.16 Phase II studies of single agents for second-line treatment of NSCLC Authors

No. of patients

Treatment

Suzuki et al121

32 Paclitaxel 80 mg/m2/wk 6 of 8 weeks

Buccheri et al122

38 Paclitaxel 100 mg/m2/wk+

VazquezEstevez et al123

37 docetaxel 50 mg/m2 d1, 14 q28d

Vidal et al124 Bota et al125

Response rate (%)

Median survival (months)

1-yr overall survival rate (%)

17

NR

NR

15.8

14.5

NR

24 (11–38)

4

NR

38 Paclitaxel 80 mg/m2 wkly

34

10

NR

29 Paclitaxel 100 mg/m2 wkly×12

38

NR

NR

Treatment of non-small cell lung cancer

Felip et al126

51 BMS-18447 60 mg/m2 q21d

Vansteenkiste et al127

52 BMS-247550 32 mg/m2 d1 q21d

89

16

NR

NR

13.5

NR

NR

11.7

NR

NR

5

10

42

17 Rebeccamycin 140 mg/m2 d1–5 q3wks

0

14

41

Herndon et al129

21 Karenitecin 1 mg/m2 d1–5 q21d

5

5.4

NR

Scagliotti et al130

27 BBR3464 0.9–1 mg/m2 d1 q21d

7.4

NR

NR

Fernandez et al131

22 Carboplatin AUC 6 d1 q21d

9

NR

NR

versus 60 BMS-247550 6 mg/m2 d1–5 q21d Cortas et al128

19 Rebeccamycin 500 mg/m2 d1 q3wks versus

Confidence interval in parentheses. NR, not reported.

Table 7.17 Randomized trials of second-line therapies for NSCLC Authors

Camps et al132

No. of patients

Treatment

91 Docetaxel 75 mg/m2 d1 q3wks

Response rate (%)

Median survival (months)

1-yr overall survival rate (%)

11

6.3

NR

88 Docetaxel 36 mg/m2 wkly 6 of 8 weeks

8.9

6.1

NR

62 Docetaxel 75 mg/m2 d1 q3wks

NR

6.3

NR

63 Docetaxel 40 mg/m2 wkly 6 of 8 weeks

NR

5.5

NR

43 Docetaxel 66 mg/m2 d1 q3wks

13.6

8.35

45

versus

Breton et al133

versus

Chang et al134

versus

Lung cancer therapy annual 4

Docetaxel 33 mg/m2 d1, 8 q3wks Hanna et al135

90

28.6

6.9

28

9.1 (5.9–13.2)

8.3

29.7

8.8 (5.7–12.8)

7.9

29.7

71a Gemcitabine 1000 21 mg/m2 d1, 8+ (10.83– irinotecan 300 mg/m2 31.10) d8 q3wks versus

9

NR

64a Irinotecan 300 mg/m2 d1 q3wks

8

NR

9

40.5

9

31.2

264 Pemetrexed 500 mg/m2 d1 q21d versus 274 Docetaxel 75 mg/m2 d1 q21d

Kouroussis et al137

Vassilis et al138

5.5 (0.55–11.46)

69b Irinotecan 100 24 mg/m2 d1+ (13.64– irinotecan 110 mg/m2 34.09) d8+ cisplatin 80 mg/m2 d1 q3wks versus 62b Cisplatin 80 mg/m2 d1 q3wks

p=0.017 8.3

Confidence intervals in parentheses. NR, not reported. a Taxane and platinum failures. b Taxane and gemcitabine failures. Confidence interval in parentheses. NR, not reported.

Table 7.18 Combination regimens for secondline NSCLC Authors

No. of patients

Treatment

Response rate (%)

Median survival (months)

1-yr overall survival rate (%)

Pectasides et al139

41 Irinotecan 150 mg/m2 d1, 15+ vinorelbine 25 mg/m2 d1, 15 q28d

15

7.8

37

Sande et al140

47 Irinotecan 130 mg/m2 d1+ docetaxel 50 mg/m2 d1 q3wks

11

7.4

NR

Pectasides et al141

50 Irinotecan 150 mg/m2 d1, 15+ gemicitabine 1500 mg/m2 d1, 15 q28d

16

8.1

36

Treatment of non-small cell lung cancer

Tsavaris et al142

33 Gemicitabine 1500 mg/m2 d1, 15+ irinotecan 180 mg/m2 d1, 15 q28d

Tsao et al143

32 Vinorelbine 20 mg/m2 d1, 8+ docetaxel 60 mg/m2 d8 q3wks

Hatabay et al144

91

18

7

20

6

NR

NR

27 Docetaxel 75 mg/m2 d1+ carboplatin AUC 5 d1 q3wks

33

NR

NR

Montalar et al145

28 Gemcitabine 1000 mg/m2 d1, 15+ vinorelbine 25 mg/m2 d1, 15 q28d

39

4.5 NR

Bernardo et al146

26 Docetaxel 30 mg/m2 d1, 8+ gemcitabine 800 mg/m2 d1, 8 q21d

15

9 NR

Chang et al147

41 Docetaxel 30 mg/m2 d1, 8, 15+ epirubicin 60 mg/m2 d15 q28d

12

NR NR

VillalonaCalero et al148

39 Docetaxel 36 mg/m2/wk×3+ capecitabine 625 mg/m2 p.o. bid d5–18, q4wks

29 (14–44)

NR NR

Domine et al149

39 Irinotecan 150 mg/m2 d1+ gemcitabine 1500 mg/m2 d1 q2wks

31 (17–47.6)

9.3 NR

Confidence intervals in parentheses. NR, not reported.

produced acceptable response rates, survival was not significantly prolonged. Thus, it appears that cytotoxic chemotherapy may have also reached a plateau in the salvage setting. This provides an excellent opportunity to explore the biologically based therapies.

TARGETED THERAPIES IN ADVANCED LUNG CANCER At the forefront of promising agents are the epidermal growth factor receptor (EGFR) inhibitors. In two randomized phase II trials after failure of prior chemotherapy (IDEAL 1 and IDEAL 2), gefitinib (Iressa) was administered orally at 250 mg or 500 mg a day to 200 patients in each study.150,151 IDEAL 2 required patients to have received two previous regimens, whereas IDEAL 1 required only one previous regimen. The results were similar between the trials (Table 7.19). Importantly in this palliative setting, 35–43% of patients in both trials reported symptom improvement. The 250 mg dose was less toxic than the 500 mg dose, with rash and diarrhea being the most common side-effects. Based

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on the data from these two studies, gefitinib 250 mg/day has been approved by the regulatory authorities of several countries as salvage therapy for lung cancer. At ASCO 2004, Ochs et al reported a retrospective analysis of the gefitinib expanded access program, showing a 29.9% 1-year survival rate in over 21000 patients.152 A prospective randomized trial testing gefitinib 250 mg/day in advanced lung cancer has accrued over 1500 patients, and results are expected in January 2005. Meanwhile, a similar agent, erlotinib, was compared with placebo in over 700 previously treated patients. Reports of a few other targeted agents evaluated in the salvage setting are listed in Table 7.19. Pivanex, a differentiating agent, demonstrated a hint of activity without any report of myelosuppression.153 A logical approach is to integrate these agents with docetaxel. Kim et al154 administered cetuximab, a monoclonal antibody to EGFR, with docetaxel to 54 patients. The response rate was 25.6%, with a median survival of 7.5 months. Grade 3 rash attributed to cetuximab occurred in 20% of patients. Preliminary results from the combination of docetaxel and celecoxib have also been reported.155 The response rate was low, at 4.5%, but the time to progression of 19 weeks and the median survival of 9.8 months were encouraging. No significant increase in toxicity was noted with the addition of celecoxib to docetaxel. Finally, one randomized trial156 evaluated gemcitabine plus the oral histone deacetylase inhibitor CI-994 or placebo as second-line therapy for NSCLC. No difference in response rate, progression-free survival, or median survival was observed between the two groups. Patients receiving CI-994 reported more toxicity. As our understanding of how to evaluate these new agents evolves, we should expect to see an increase in the number of studies evaluating targeted therapies as monotherapy, in combination with cytotoxic drugs, and in combination with other targeted agents in the second- and third-line setting.

Table 7.19 Targeted therapy in the salvage setting Authors

No. of patients

Treatment

Response rate (%)

Median survival (months)

1-yr overall survival rate (%)

Fukuoka et al150

103 Gefitinib 250 mg/d p.o.

18.4

7.6

35

(IDEAL 1)

106 Gefitinib 500 mg/d p.o.

19

8.0

29

Kris et al152

102 Gefitinib 250 mg/d p.o.

12

6.5

27

(IDEAL 2)

114 Gefitinib 500 mg/d p.o.

9

5.9

24

5

7.3

24

2

Keer et al153

39 Pivanex 2.34 g/m /d p.o. d1–3 q3wks

Kim et al154

54 Docetaxel 75 mg/m2 d1+ cetuximab 400 mg/m2 d–7 then 250 mg/m2 wkly q3wks

25.6

7.5

NR

Nugent et

22 Docetaxel 75 mg/m2 d1+

4.5

9.8

NR

Treatment of non-small cell lung cancer

al155 Von Pawel et al156

93

celecoxib 400 mg p.o. bid q3wks

(0–23)

89 Gemcitabine 1000 mg/m2 d1, 8, 15+ CI 994 60 mg/m2/d p.o. d1–21 q4wks versus

3.5

6.3

NR

Gemcitabine 1000 mg/m2 d1, 8, 15+ placebo p.o. d1–21 q4wks

3.8

6.2

NR

Confidence intervals in parentheses. NR, not reported.

The exciting results produced with targeted therapies in the salvage setting have unfortunately not been reproduced in the first-line setting in combination with chemotherapy (Table 7.20). Two large randomized phase III trials administering gefitinib with gemcitabine and cisplatin (INTACT 1)157 or paclitaxel and carboplatin (INTACT 2)158 failed to show any benefit with the addition of gefitinib. Two similar trials substituting erlotinib for gefitinib (TALENT and TRIBUTE) are also reported to be negative. Another targeted agent, affinitak, a protein kinase Cα (PKCα) inhibitor, was also shown to be ineffective when given with paclitaxel and carboplatin.159 Thus, concurrent administration of a targeted agent with combination cytotoxic chemotherapy is not recommended. Studies with single-agent chemotherapy are ongoing. Preclinical and early-phase clinical trials are needed to further explore their interactions. In contrast to the EFGR tyrosine kinase inhibitors described above, cetuximab, a monoclonal antibody to the external domain of the EGFR, may have activity in combination with chemotherapy. Three phase II trials combining cetuximab with various platinum-based doublets have been completed in chemotherapy-naive patients (Table 7.20).160–162 The most intriguing results were seen from the small randomized trial by Gatzemeier et al.160 In a preliminary analysis of the first 72 patients, a higher response rate was observed for the cetuximab arm: 53%, versus 32% for the control arm. Based on these results, a randomized phase III trial is planned in Europe. The two multicenter US trials161,162 produced encouraging median survivals of 10 months and 16 months. A Southwest Oncology Group (SWOG) phase II trial will evaluate cetuximab given concurrently or sequential with paclitaxel and carboplatin. Two hundred patients will be enrolled. For patients with bronchioloalveolar carcinoma (BAC), two trials support the role of an EGFR tyrosine kinase inhibitor as first- or second-line treatment (Table 7.20).163,164 In untreated patients, both trials reported similar response rates of 19% and 26%. Median survival has not been reached in one study,163 but the SWOG study164 reported 12 months. Benefit was also observed in the treated patients, with a 12% response rate and 13 months’ median survival. In conclusion, targeted therapies are impacting survival in patients with advanced lung cancer. We are optimistic that biologically based treatment approaches will continue to improve survival not only in the advanced-disease setting but also in earlier stages of disease as we continue to explore these options.

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Table 7.20 Phase II and III trials with targeted agents Authors

Giaccone et al157

No. of patients

Regimen

Response rate (%)

365 +Gefitinib 250 mg/d versus

50.2

9.86

41

365 +Gefitinib 500 mg/d versus

49.7

9.92

43

44.8

11.07

45

345 +Gefitinib 250 mg/d versus

9.8

41

347 +Gefitinib 500 mg/d versus

8.7

37

9.9

42

307 Paclitaxel 175 mg/m , d1+ carboplatin AUC 6, d1 q3wks versus

36

9.7

42

309 Paclitaxel 175 mg/m2, d1+ carboplatin AUC 6, d1+ affinitak 2 mg/kg CIV 150 mg/d×2 wks q3wks

37

10

41

32.3 (18.6–49.9)

NR

NR

53.3 (36.1–69.8)

NR

NR

29

15.7

NR

2

Paclitaxel 225 mg/m , d1+ carboplatin AUC 6 d1 q3wks

345 +Placebo Lynch et al159

Gatzemeir et al160

1-yr overall survival rate (%)

Gemcitabine 1250 mg/m2d1, 8+ cisplatin 80 mg/m2 d1 q3wks

363 +Placebo Herbst et al158

Median survival (months)

2

36 Cisplatin 80 mg/m2, d1+ vinorelbine 25 mg/m2, d1, 8 q3wks versus 36 Cisplatin 80 mg/m2, d1+ vinorelbine 25 mg/m2, d1, 8+ cetuximab 400 mg/m2, wk−1, then 250 mg/m2 wkly q3wks

Kelly et al161

31 Paclitaxel 225 mg/m2, d1+ carboplatin AUC 6, d1+ cetuximab 400 mg/m2

Treatment of non-small cell lung cancer

95

wk−1, then 250 mg/m2 wkly q3wks Robert et al162

Miller et al163 West et al164

35 Gemcitabine 100 mg/m2 d1, 8+ carboplatin AUC5, d1+ cetuximab 400 mg/m2 wk 1 then 250 mg/m2 wkly q3wks

29

10.3

NR

26

NR

NR

102b Gefitinib

19

12

NR

35c 500 mg/d

9

13

NR

54a Erlotinib 150 mg/d

Confidence intervals in parentheses. NR, not reported. a Patients with bronchioloalveolar carcinoma (BAC). b Includes untreated and treated patients c Remaining patients treated at 250 mg/d dose

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115. Buccheri G, Ferrigno D. Front-line weekly chemotherapy with gemcitabine for unfit and/or elderly patients with non-small cell lung cancer (NSCLC). Lung Cancer 2003; 41:S228. 116. Hainsworth JD, Erland JB, Barton JH et al. Combination treatment with weekly docetaxel and gemcitabine for advanced non-small-cell lung cancer in elderly patients and patients with poor performance status: results of a Minnie Pearl Cancer Research Network phase II trial. Clin Lung Cancer 2003; 5:33–8. 117. Comella G, Comella P, De Cataldis G et al. Gemcitabine plus vinorelbine (GV) or paclitaxel (GT) vs gemcitabine (G) or paclitaxel (T) alone in elderly or unfit non-small cell lung cancer (NSCLC) patients. SICOG 9909 phase III trial [2529]. Proc Am Soc Clin Oncol 2003; 22: 629. 118. Amadio P, Priolo D, Antonelli S et al. Vinorelbine (VNB) and gemcitabine (gem) in unfit or elderly patients (pts) affected by advanced non small cell lung cancer (NSCLC): May sequential administration improve results? Lung Cancer 2003; 41:S239. 119. Bodkin D, Neubauer M, Bolton M. Phase 2 study of first line chemotherapy using CT-2103 (XYOTAX) in patients with non-small-cell lung cancer who are >69 years of age or who have performance status (PS)=2. Lung Cancer 2003; 41:S242. 120. Shehadeh N, Kalemkerian G, Wozniak A et al. Preliminary results of a phase II study of celecoxib and weekly docetaxel in elderly (≥70 yrs) or PS2 patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2003; 22:686. 121. Suzuki R, Taniguchi H, Kondoh Y et al. Second line weekly paclitaxel in resistant or relapsed non-small cell lung cancer (NSCLC) treated with docetaxel and carboplatin. Proc Am Soc Clin Oncol 2002; 21: 325a. 122. Buccheri G, Ferrigno D, Giordano M. Second line chemotherapy with paclitaxel in advanced non-small cell lung cancer, relapsing or refractory to a combination chemotherapy containing cis-platinum (P). Lung Cancer 2003; 42:S228. 123. Vazquez-Estevez S, Huidobro G, Amenedo M et al. Biweekly docetaxel as second-line treatment in advanced or metastatic non-small-cell lung cancer (NSCLC). A phase II study of the Galician Lung Cancer Group. Proc Am Soc Clin Oncol 2003; 22:685. 124. Vidal O, Albert A, Campos J et al. Low-dose weekly paclitaxel as second-line treatment for advanced non-small cell lung cancer (NSCLC): a phase II study. Proc Am Soc Clin Oncol 2002; 21:320a. 125. Bota S, Paillotin D, Ozenne G et al. Second line weekly paclitaxel in patients with non-small cell lung cancer (NSCLC) refractory to platinum based chemotherapy: a multicenter phase II trial. Proc Am Soc Clin Oncol 2003; 22:696. 126. Felip E, Camps C, Sanchez J et al. BMS-184476 as second-line treatment in non-small-cell lung cancer patients: results of a multicenter phase II trial. Proc Am Soc Clin Oncol 2002; 21:305a. 127. Vansteenkiste J, Breton J-L, Sandler A et al. A randomized phase II study of epothilone analog BMS-247550 in patients (pts) with non-small cell lung cancer (NSCLC) who have failed first-line platinum-based chemotherapy. Proc Am Soc Clin Oncol 2003; 22:626. 128. Cortas T, Ness A, Chapman R et al. Randomized phase II trial of 2 different administration schedules of rebeccamycin analogue (RA) as 2nd line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2003; 22:668. 129. Herndon J, Miller A, Zhang C et al. Phase II trial of karenitecin in patients with refractory non-small cell lung cancer (NSCLC): CALGB 30004. Proc Am Soc Clin Oncol 2003; 22:673. 130. Scagliotti G, Novello S, Crinò L et al. Phase II trial of BBR3464, a novel, bifunctional platinum analog, as second line treatment of non-small cell lung cancer patients. Lung Cancer 2003; 42:S223. 131. Fernández Y, Esteban E, Fra J et al. Activity of carboplatin in patients with advanced nonsmall cell lung cancer (NSCLC) previously treated with chemotherapy but not platinum based. Lung Cancer 2003; 42: S100.

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132. Camps C, Massuti B, Jimenez A et al. Second-line docetaxel administrated every 3 weeks versus weekly in advanced non-small-cell lung cancer (NSCLC): a Spanish Lung Cancer Group (SLCG) phase III trial. Proc Am Soc Clin Oncol 2003; 22:625. 133. Breton J-L, Gervais R, Ducolone A et al. Three-weekly docetaxel 75 mg/m2 versus weekly docetaxel 40 mg/m2 in patients with pretreated nonsmall-cell lung cancer (NSCLC): a randomised phase II study. Ann Oncol 2002; 13:145–6. 134. Tsai C-M, Chiu C-H, Wang G-S et al. A phase II randomized trial of weekly versus 3-weekly docetaxel as second line treatment for non-small cell lung cancer. Lung Cancer 2003; 41: S230. 135. Hanna N, Shepherd F, Rosell R et al. A phase III study of pemetrexed vs docetaxel in patients with recurrent non-small cell lung cancer (NSCLC) who were previously treated with chemotherapy. Proc Am Soc Clin Oncol 2003; 22:622. 136. Manegold C, Gervais R, Aigner K et al. Pemetrexed vs. docetaxel: a phase III study in patients with advanced non-small cell lung cancer (NSCLC) who were previously treated with cehmotherapy. Eur J Cancer 2003; 1: S22. 137. Kouroussis C, Agelidou A, Apostolopoulou F et al. Second-line treatment with irinotecan (CPT-11) and gemcitabine (GEM) versus CPT-11 in patients with advanced NSCLC pretreated with taxanes and cisplatinum: preliminary results of a multicenter randomized phase II study. Proc Am Soc Clin Oncol 2002; 21:304a. 138. Vassilis G, Agelidou A, Syrigos K et al. Second-line treatment with irinotecan (CPT-11) and cisplatin (CDDP) versus CDDP alone in patients with advanced NSCLC pretreated with taxanes and gemcitabine: final results of a multicenter randomized phase II study. Proc Am Soc Clin Oncol 2003; 22:626. 139. Pectasides D, Fountzilas G, Rigopoulos A et al. An outpatient second-line chemotherapy (CT) with irinotecan and vinorelbine in patients with non-small cell lung cancer (NSCLC) previously treated with cisplatin-based chemotherapy: a phase II study of Hellenic Cooperative Oncology Group. Proc Am Soc Clin Oncol 2002; 21:327a. 140. Sande J, Verdirame J, Hillman S et al. A phase II study of irinotecan and docetaxel in patients with recurrent non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2002; 21:324a. 141. Pectasides D, Farmakis D, Nikolaou M et al. An out-patient chemotherapy (CT) with irinotecan and gemcitabine in patients (pts) with non-small cell lung cancer (NSCLC) previously treated with cisplatin-based chemotherapy: a phase II study. Proc Am Soc Clin Oncol 2003; 22:676. 142. Tsavaris N, Kosmas C, Makatsoris T et al. Bi-weekly gemcitabine (Gem) and irinotecan (CPT-11) second-line chemotherapy in non-small cell lung cancer (NSCLC) failing prior taxane plus platinum-based regimens. Proc Am Soc Clin Oncol 2003; 22:677. 143. Tsao A, Kim E, Nazario A et al. Phase II study of vinorelbine and docetaxel in the treatment of advanced non-small cell lung cancer as frontline and second-line therapy. Proc Am Soc Clin Oncol 2003; 22:691. 144. Hatabay N, Ece F. Docetaxel and Carboplatin as a second line chemotherapy in advanced nonsmall cell lung cancer. Lung Cancer 2003; 41: S95. 145. Montalar J, López-Tendero P, Diaz-Bedveridge R, et al. Gemcitabinevinorelbine as second line chemotherapy in advanced non-small cell lung cancer previously treated with paclitaxelcarboplatin. Lung Cancer 2003; 41:S95. 146. Bernardo M, Sousa M, Nunes O et al. Docetaxel and gemcitabine as second-line treatment in advanced non-small cell lung cancer. Lung Cancer 2003; 41:S96. 147. Chang J, Tsao T, Chen C-H et al. Phase II study of epirubicin in combination with weekly Taxotere for patients with advanced NSCLC who have failed or relapsed after the frontline platinum-based chemotherapy. Lung Cancer 2003; 41: S103. 148. Villalona-Calero M, Kindwall-Keller T, Soong R et al. Phase II study of docetaxel in combination with capecitabine in patients with previously treated non-small cell lung cancer (NSCLC). Lung Cancer 2003; 41:S144.

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149. Domine M, Provencio M, Garcia Gomez R et al. CPT-11 gemcitabine as a second line chemotherapy in small cell lung cancer (SCLC). A multicentric phase II trial. Eur J Cancer 2003; 1:S235. 150. Fukuoka M, Yano S, Giaccone G et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003; 21:2237–46. 151. Kris MG, Natale RB, Herbst RS et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003; 290:2149–58. 152. Ochs J, Grous JJ, Warner KL. Final survival and safety results for 21,064 non-small-cell lung cancer (NSCLC) patients who received compassionate use gefitinib in a U.S. expanded access program (EAP). J Clin Oncol 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition) Vol 22, No 145 (July 15 Supplement) 2004:7060. 153. Keer H, Reid T. Pivanex activity in refractory non-small cell lung cancer: a phase II study. Proc Am Soc Clin Oncol 2002; 21:314a. 154. Kim E, Muer A, Iran H et al. A phase II study of cetuximab, an epidermal growth factor receptor (EGFR) blocking antibody, in combination with docetaxel in chemotherapy refractory/resistant patients with advanced non-small cell lung cancer: final report. Proc Am Soc Clin Oncol 2003; 22:642. 155. Nugent F, Graziano S, Levitan N et al. Docetaxel and COX-2 inhibition with celecoxib in relapsed/refractory non-small cell lung cancer (NSCLC): promising progression-free survival in a phase II study. Proc Am Soc Clin Oncol 2003; 22: 671. 156. Von Pawel J, Shepherd F, Gatzmeier U et al. Randomized phase 2 study of the oral histone deacetylase inhibitor CI-994 plus gemcitabine (Gem) vs placebo (PBO) plus Gem in second-line nonsmall cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2002; 21:310a. 157. Giaccone G, Herbst RS, Manegold C et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1. J Clin Oncol 2004; 22:777–84. 158. Herbst RS, Giaccone G, Schiller JH et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 2004; 22:785–94. 159. Lynch T, Raju R, Lind M. Randomized phase 3 trial of chemotherapy and antisense oligonucleotide LY 900003 (ISIS 3521) in pts with advanced NSCLC: initial report. Proc Am Soc Clin Oncol 2003; 22: 623. 160. Gatzemeier U, Rosell R, Ramlau R et al. Cetuximab (C225) in combination with cisplatin/vinorelbine vs cisplatin/vinorelbine alone in first line treatment of pts with EGFR positive advanced NSCLC. Proc Am Soc Clin Oncol 2003; 22:642. 161. Kelly K, Hanna N, Rosenberg A et al. A multi-centered phase I/II study of cetuximab in combination with paclitaxel and carboplatin in untreated patients with stage IV non-small cell lung cancer. Proc Am Soc Clin Oncol 2003; 22:644. 162. Robert F, Blumenschein G, Dicke K et al. Phase Ib/IIa study of antiepidermal growth factor receptor (EGFR) antibody, cetuximab, in combination with gemcitabine/carboplatin in patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2003; 22:643. 163. Miller V, Patel J, Shah N et al. The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in bronchioloalveolar carcinoma (BAC): preliminary results of a phase II trial. Proc Am Soc Clin Oncol 2003; 22: 619. 164. West H, Franklin W, Gumerlock P et al. ZD1839 (Iressa) in advanced bronchioloalveolar carcinoma (BAC): a preliminary report of SWOG S0126. Lung Cancer 2003; 41:S56.

8 Mesothelioma

Pleural mesothelioma has been increasing constantly in all industrialized countries over the last decade despite abolished or restricted use of asbestos fibers. The reasons for the increase are the delay between exposure and disease, which is thought to be 30 years or more, and indirect exposure, as reviewed by Hillerdal.1 Usually patients with mesothelioma have been exposed to asbestos fibers in their occupation, but non-occupational environmental exposure is also common. In the region of Anatolia in Turkey, the soil mixtures contain asbestos and the villagers in these mainly agricultural regions use this soil as a whitewash or plaster material (white stucco) for walls, as insulation and waterproofing, for floors and roofs, for baby powder, and also in pottery. In a study from this region including 1886 villagers, Metintas et al2 observed that the risk of mesothelioma is 88.3 times greater in men and 799 times greater in women, respectively, in comparison with world background incidence rates of mesothelioma. Women are more susceptible not only to pleural malignant mesothelioma than men, but also to malignant peritoneal mesothelioma. The study also showed that the latency time was the same for both sexes, namely 59.2 years.3 With respect to model-based predictions, it has been estimated that the maximum incidence will occur between the years 2015 and 2030 in Western Europe, but sooner in the USA, where asbestos use ceased earlier.4 Consistent with these models, the incidence of pleural mesothelioma has been increasing in those countries for which data are available, including Sweden. Asbestos imports to Sweden were drastically reduced in 1976, which coincided with the maximal use of asbestos in many industrialized countries. The difference in the phasing of asbestosis, however, was that in Sweden the use of asbestos was almost completely abolished whereas in many Western European countries the use has tailed on to the 1990s. In this regard, it is noteworthy that mesothelioma incidence seems to be leveling off in Sweden, as reported by Hemminki and Li.5 In Norway, the risk of pleural mesothelioma is still increasing among men and also among women, but at a much lower rate. The rates are determined by age and by birth cohorts, with the highest incidence being in the cohorts born up to around 1935. After this, the risks seem to stabilize.6 According to the most recent classification by the World Health Organization/International Association for the Study of Lung Cancer (WHO/IASLC) of lung and pleural tumors, the latter can be classified as epitheloid (50%), sarcomatoid, or desmoplastic biphasic mesothelioma. Studies have shown that epithelial tumors have a

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better prognosis than the others, which has also been confirmed in an analysis of survival of mesothelioma cases in the Italian National Mesothelioma Register.7 Based on survival data for 429 mesothelioma cases, the Cox proportional hazard model gave an adjusted relative risk for the fibrous histotype of 2.96 (95% confidence interval (CI) 1.28–6.81; p=0.012) compared with cases with unspecified morphology; for epithelioid and biphasic morphologies, the risk was less than unity. There was no significant difference in survival for cases with confirmed exposure (occupational, household, or environmental) or without. Differentiation between malignant mesothelioma and other forms of cancer, particularly adenocarcinoma, is often difficult, as also shown by Iwatsubo et al,8 who evaluated the number of mesothelioma cases from cause-of-death statistics. Histochemistry and immunochemistry remain important tools in the differentiation, as summarized by the WHO/IASLC Pathology Panel (Table 8.1). Data from Gulyás and Hjerpe9 suggest that proteoglycans and WTI may also be useful diagnostic markers distinguishing adenocarcinoma, epitheloid mesothelioma and benign mesothelioma. Other useful markers are desmin and epithelial membrane antigen (EMA), as demonstrated by Attanoos et al.10 With respect to detailed staging, a new system was developed by the International Mesothelioma Interest Group in 1995 (Table 8.2). Radiography of the chest and computed tomography (CT) remain the key procedures when determining the extent of the disease and for evaluation of the diaphragm and mediastinum. Radiologic manifestations tend to be those of pleural effusions and/or pleural thickening. Pleural effusions are initially investigated by thoracocentesis, but the positive diagnosis by pleural fluid cytology is rather low. Pleural biopsy in the presence of pleural effusion has traditionally been performed without image guidance, but thoracoscopic biopsy is needed in detecting malignant pleural disease, including mesothelioma. In recent years, new imaging techniques have been developed for the diagnosis and staging of malignant pleural mesothelioma, as reviewed by Eibel et al.11 In addition, new data have emerged concerning the value both of chest CT and of cervical medianoscopy in the preoperative assessment of patients with mesothelioma in the pleural cavity, including preliminary data on [18F]fluorodeoxyglucose (18F-FDG) imaging. Schouwink et al12 performed CT scans of the chest and cervical mediastinoscopy in 43 patients with proven unilateral malignant pleural mesothelioma. The CT scans were reviewed by one radiologist and two chest physicians. At cervical mediastinoscopy, the lymph node samples were taken from stations Naruke 2, 3, 4, and 7. CT and cervical mediastinoscopy results were compared with final histopathologic findings obtained at thoracotomy or, if this was not performed, at cervical mediastinoscopy. CT scanning revealed pathologic enlarged lymph nodes with a shortest diameter of at least 10 mm in 17 of 43 patients (39%). There was histopathologic evidence of lymph node metastases at cervical mediastinoscopy in 11 of these patients (26%). This resulted in sensitivities of 60% and 80%, specificities of 71% and 100%, and diagnostic accuracies of 67% and 93% for CT and cervical mediastinoscopy, respectively. Schouwink et al12 concluded that cervical mediastinoscopy is a valuable diagnostic procedure for patients with mesothelioma who are considered candidates for surgically based therapy.

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Table 8.1 Immunohistochemistry of pleural lesionsa,b Diagnostic problem

Keratins CEA B72.3 Leu- BER- EMA (LMW/HMW) M1 EP4 HMFG-2

Vimentin Actin

I Mesothelial hyperplasia vs

+−++

−

−

−

−

−/+

−/+

−

Epithelioid +−++ mesothelioma vs

−/+

−/+

−/+

−/+

+(membrane)

+

−/+

Metastatic +−++ carcinoma (usually adenocarcinoma)

+

+

+

+

+(cytoplasmic) −/+

−

II Fibrous pleuritis vs

+

−

−

−

−

−/+

+

+

Sarcomatoid + mesothelioma vs

−

−

−

−/+

−/+

+

−/+

−

−

−

–

−

+

*

Sarcoma (primary or metastatic)

−/+

LMW, low molecular weight; HMW, high molecular weight; CEA, carcinoembryonic antigen; EMA, epithelial membrane antigen; HMGF, human milk fat globulin;. −, Negative; +/−, occasionally positive; −/+, usually negative; *, depends on subtype; +, usually positive. a Until recently, there has been no immunohistochemical stain that is positive in mesotheliomas and negative in other lesions. HBME-1, calretinin, and thrombomodulin have shown some promise as mesothelioma-specific antibodies, but none is as yet widely accepted. b Adopted from Banks DE, Wang M-I, Parker JE. Asbestos exposure, astestosis, and lung cancer. Chest 1999; 115:320–2 .

Table 8.2 International TNM staging system for diffuse malignant pleural mesothelioma according to the International Mesothetlioma Interest Groupa T1 T1a: Tumor limited to the ipsilateral parietal pleura, including mediastinal and diaphragmatic pleura. No involvement of the visceral pleura T1b: Tumor involving the ipsilateral parietal pleura, including mediastinal and diaphragmatic pleura. Scattered foci of tumor also involving the visceral pleura T2 Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura), with at least one of the following features: •

involvement of the diaphragmatic muscle

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confluent visceral pleural tumor (including the fissures) or extension of tumor from visceral pleural into the underlying pulmonary parenchyma

T3 Describes locally advanced but potentially resectable tumor. Tumor involving all of the ipsilateral pleural surfaces with at least one of the following features: •

involvement of the endothoracic fascia

•

extension into the mediastinal fat

•

solitary, completely resectable focus of tumor extending into the soft tissue of the chest wall

•

non-transmural involvement of the pericardium

T4 Describes locally advanced, technically unresectable tumor. Tumor involving all of the ipsilateral pleural surfaces with at least one of the following features: •

diffuse extension or multifocal masses of tumor in the chest wall, with or without local rib destruction

•

direct transdiaphragmatic extension of tumor in the peritoneum

•

direct extension of tumor to the contralateral pleura

•

direct extension of tumor in one or more mediastinal organs

•

direct extension of tumor into the spine

•

tumor extending through to the internal surface of the pericardium with or without a pericardial effusion; or tumor involving the myocardium

N: lymph nodes

M: metastases

Nx

Regional lymph nodes cannot be assessed

Mx

Presence of metastases cannot be assessed

N0

No regional or hilar

M0

No distant metastases

N1

Ipsilateral or hilar lymph nodes positive

M1

Distant metastases

N2

Mediastinal or ipsilateral internal mammary lymph nodes positive

N3

Contralateral mediastinal, supraclavicular or contralateral internal mammary lymph nodes positive

Stage III

T3 (anyN) M0

Stage Stage IA

T1aN0M0

Stage IB

T1bN0M0

(any T) N1M0 (any T) N2M0

Stage II

T2N0M0

Stave IV

T4 (any N) (any M), (any T) N3 (any M), or (any T) (any N) M1

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a

Adapted from Travis WD, Colby TV, Corria B et al (eds). Histological Typing of Lung and Pleural Tumours. WHO International Classification of Tumours, 3rd edn. Berlin: Springer-Verlag. 1999.

In another study, by Gerbaudo et al,13 15 consecutive patients with CT scan evidence of pleural thickening, fluid, plaques, or calcification underwent 18F-FDG imaging, and the results of 18F-FDG-coincidence imaging (CI) scans were compared with CT and with histopathologic diagnosis. Of 15 patients, 11 had histologically proven malignant mesotheliomas. The primary tumors were detected in all 11 patients by 18F-FDG-CI and absence of disease was confirmed in the 4 patients who were disease-free. Thirty-four lesions were biopsied; among these, 29 were found to be positive for tumor. 18F-FDG-CI was true-positive in 28 lesions, true-negative in 4, false-negative in 1, and false-positive in 1 (inflammator pleuritis). For biopsied lesions, the overall sensitivity, specificity, and accurracy for 18F-FDG-CI were 97%, 80%, and 94%, respectively, compared with 83%, 80%, and 82% for CT. These preliminary results suggest that 18F-FDG-CI appears to be an accurate method to diagnose and to define the extent of disease in patients with diffuse malignant pleural mesothelioma. The results are preliminary and promising, but are based on a relatively small sample size. More studies comparing 18F-FDG-CI with surgical mediastinal staging are needed to define correctly the role of CI in patients with malignant mesothelioma. In addition to histology and stage, a number of other prognostic factors have been established for malignant pleural mesothelioma, such as gender, performance status, age, weight loss, pain, thrombocytosis, previous therapy, and biological markers such as Cyfra and TPA, as reviewed by Baas.14 Cyclooxygenase-2 (COX-2) expression can now be added to the list, based on data by Edwards et al.15 Also, expression of glycoprotein 90K has been shown to be an important prognostic factor in a study by Strizzi et al.16 The study by Edwards et al15 was based on immunohistochemical evaluation of tissue from 30 epithelioid, 10 biphasic, and 8 sarcomatoid tumors. Multivariate analysis was performed and a high COX-2 expression was an independent predictor of poor prognosis. COX-2 expression also contributed to both the European Organization for Research and Treatment of Cancer (EORTC) and the Cancer and Leukemia Group B (CALGB) prognostic scoring systems. Results suggest that COX-2 expression is not only a prognostic factor, but also a potential therapeutic target in malignant mesothelioma using COX-2 inhibitors alone or in combination with existing treatment modalities. Expression of glycoprotein 90K using enzyme-linked immunoassay (ELISA) was applied in order to measure 90K in pleural effusions and ser a from patients with malignant mesothelioma (n=28), lung cancer (n=14), and benign pleural disease (n=15).16 Kaplan-Meier univariate analysis showed increased survival probability for mesothelioma patients with serum 90K level above 7.3 µg/ml. The mean 90K level was significantly higher (p<0.05) in pleural effusions of mesothelioma patients (11.0±6.6 µg/ml) than in lung cancer patients (6.1±3.2 µg/ml) or those with benign pleural disease (6.2±5.0 µg/ml). Finally, Gordon et al17 used gene expression ratios to predict outcome among patients with mesothelioma. With data collected from 17 mesothelioma patients, they developed an expression ratio-based test capable of identifying 100% (17 of 17) of the samples used to train the model. This test remained highly accurate (88%, 15 of 17) after cross-validation. This four-gene expression ratio test predicted statistically

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significantly (p=0.0035) treatment-related patient outcome in mesothelioma independently of the histologic subtype of the tumor. This technique could have an impact in the future on the clinical treatment of mesothelioma by allowing the preoperative identification of patients with widely divergent prognoses. Further studies using microarrays on larger groups of patients with multiple mesothelioma are awaited with great interest.

TREATMENT Treatment of malignant mesothelioma remains disappointing regardless of the type of therapy employed. Within the last few years, the tendency has been to combine various treatment modalities, especially in patients with localized disease, as with other malignant disorders of the lung. The topic has been the subject of a number of review articles.18–22 The prospect for new modalities, such as molecular and biologic therapies, has also been highlighted,23 including the results of both preclinical and early clinical research on targeting of vascular endothelial growth factor (VEGF), the epidermal growth factor receptor (EGFR), and the platelet-derived growth factor receptor (PDGFR).24 In addition, experience in the treatment of malignant mesothelioma from a single center has been reported, including 302 patients referred to Hairmyres Hospital in Scotland in the period 1989–98.25 The various treatment modalities have also been reviewed in depth. Surgery, such as extrapleural pneumonectomy (EPP), remains the treatment of choice with curative intent in patients presenting with localized disease.26–28 Numerous studies have shown that the mortality rate in the modern era is approximately 5% or less in specialized centers and in selected patients. The mean survival after EPP ranges from 9 to 19 months and the 2-year survival rate between 20% and 40%, depending on stage. More recently, EPP has been combined with intraoperative photodynamic therapy (PDT),29 and hemithoracic radiation and intensity-modulated radiotherapy have also been explored as novel approaches combined with EPP for malignant pleural mesothelioma.30–33 For hemithoracic radiation, a total dose of 54 Gy delivered in 30 fractions of 180 cGy was used, with the target volume being the entire hemithorax, including the pleural folds and the thoracotomy and chest tube incision sites. This approach appears to improve local control, but the impact on overall survival is uncertain because of a lack of randomized trials.30 With respect to systemic therapy, cautious optimism has recently replaced a longstanding therapeutic nihilism with regard to the treatment of patients with mesothelioma, as summarized in several review articles.18–22,34 The topic has also been the subject of a study by Berghmans et al,35 who evaluated the methodologic quality of published papers relating to chemotherapy or immunotherapy in malignant mesothelioma, and who aggregated, for trials having a similar methodology, the response rates in order to identify the most active chemotherapeutic drugs and regimens. Cisplatin was identified as the most active single-agent regimen and the combination of cisplatin and doxorubicin had the highest response rate (28.5%; p<0.001). The latter combination is suggested by Berghmans et al35 as the control arm for future randomized phase III trials. Among the new agents tested, pemetrexed has been of special interest, showing encouraging results in phase II and III trials, especially when combined with platinum

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compounds.36 One of the reasons for this activity may be the presence of a novel concentrated high-affinity transport activity, which may represent another pathway by which physiologic folates are transported into human mesothelioma cell lines.37 Results using single agents, such as temozolomide,38 docetaxel,39 pegylated-liposomal doxorubicin,40 a new platinum compound (ZD0473),41 raltitrexed,42 and pemetrexed43 are presented in Table 8.3. The latter two compounds showed response rates of 20.8% and 14.1%, respectively, with 5 of 24 and 9 of 56 patients, respectively, achieving a partial response. The experience with combination chemotherapy is shown in Table 8.4.44–47 Overall, the response rates are higher than with single agents, varying from 14% to 31% with overlapping 95% CI. The lowest response rate was observed for the only combination that did not include a platinum compound as one of its two components (epirubicin and gemcitabine).47 The highest response rates were obtained for cisplatin and gemcitabine combinations and for pemetrexed and carboplatin (32% and 33%, respectively).44,45 In the study with cisplatin and gemcitabine (52 patients), the median survival from start of treatment was 11.2 months and, furthermore, vital capacity and global quality of life improved significantly in responding patients.44 Combination chemotherapy has also been combined with 41°C whole-body hyperthermia and intrathoracic chemohyperthermia, resulting in response rates and median survival times similar to those of the other phase II trials without hyperthermia.48 Finally, the results of the first large randomized trial using chemotherapy in patients with malignant pleural mesothelioma have been reported (Table 8.5).49 The study was initiated in March 1999 and 456 patients were randomized to receive either cisplatinpemetrexed (cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 every 21 days) or cisplatin monotherapy in the control group. The combination of pemetrexed and cisplatin resulted in superior median survival and response rate compared with cisplatin alone, with the median survival being 12.1 months versus 9.3 months in the control arm. The study also showed that the addition of folic acid and vitamin B12 significantly reduced the toxicity of the combination without adversely affecting survival time. Quality of life and pulmonary function tests were also evaluated in this study.50 The Lung Cancer Symptom Scale components of dyspnea (p=0.004) and pain (p=0.017) were significantly improved in the pemetrexed-treated patients, and similarly lung function was improved as measured by vital capacity (p=0.006) and forced expiratory volume (FEVl) at cycle 6 (p=0.001). Because of these very promising data, pemetrexed and cisplatin will most likely be considered standard frontline therapy for patients with pleural mesothelioma.51

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Table 8.3 Single-agent chemotherapy for mesothelioma: phase II trials Treatment

Dose/schedule No. of No. of patients respondersa

Response Comments rate (%)b

Ref

CR PR Total 2

Temozolomide 200 mg/m /day p.o. d1–5 q28d

27

0

1

1

4 (0.1–19) –

38

Docetaxel

100 mg/m2 i.v. q3wks

29

0

3

3

10 (2–27) Median duration of response 126 days

39

Pegylatedliposomal doxorubicin

55 mg/m2 i.v. q4wks

14

0

0

1

7 (0.1–34) Included 2 patients with peritoneal mesothelioma

40

ZD0473

120–150 mg/m2 i.v. q3wks

43

0

0

0

0 (0–8) All patients had received prior chemotherapy

41

Raltitrexed

3 mg/m2 i.v. q3wks

24

0

5

5

20.8 (7– – 42)

42

Pemetrexed

500 mg/m2 i.v. q3wks

56

0

9

9

14.1 (7– Median 28) survival 10.7 months

42

a b

CR, complete response; PR, partial response. 95% confidence intervals in parentheses.

Table 8.4 Combination chemotherapy for Mesothelioma—phase II trials Treatment

No. of patients

No. of respondersa

Response Comments rate (%)b

Ref

CR PR Total Cisplatin+gemcitabine

52

0

17

17

33 (20–46) Median survival 11.2 months plus quality-of-life and pulmonary function studies

44

Raltitrexed+oxaliplatin

15 (pretreated)

0

3

3

20 (17–20) Median survival 31 weeks

45

Mesothelioma

113

35 (untreated)

0

11

11

Pemetrexed+carboplatin

25

0

8

8

32 (15–54) Included pharmacokinetic study

46

Epirubicin+gemcitabine

26

0

4

4

14 (2–30) 1-year survival

47

a b

20 (17–49) Median survival 44 weeks

CR, complete response; PR, partial response. 95% confidence intervals in parentheses.

Table 8.5 Combination chemotherapy for mesothelioma: randomized trials Treatment

No. of Response patients rate (%)

Median survival (months)

Time to progression (months)

Pemetrexed 50 mg/m2 i.v.+ cisplatin 75 mg/m2 i.v. both on day 1 q3wks

226

41.3a

12.1b

5.7c

Cisplatin 75 mg/m2 i.v.

222

16.7

9.3

3.9

a

p=0.0001. p=0.02. c p=0.001. b

Another randomized trial is ongoing in the UK by the British Thoracic Society, with its focus on symptom control. Palliation as reported by patients has previously been described for two regimens: mitomycin C, vinblastine, and cisplatin (MVP) or vinorelbine (N). The study, which is planned for 840 patients, compares active symptom control only (ASC) with ASC+MVP and ASC+N. The primary endpoint is survival, but in addition the standard quality-of-life questionnaire for mesothelioma is included.52 During the first year, 230 patients have been registered, of whom 109 have been randomized; altogether 20 centers in the UK are contributing to this study. The first results are expected during 2005 (at the earliest).

REFERENCES 1. Hillerdal G. Asbestos-related pleural disease including diffuse malignant mesothelioma. Eur Respir Mon 2002; 22:189–203. 2. Metintas S, Metintas M, Ucgun I, Oner U. Malignant mesothelioma due to environmental exposure to asbestos. Chest 2002; 122:2224–9. 3. Smith DD. Women and mesothelioma. Chest 2002; 122:1885–6. 4. Vogelzang NJ. Emerging insights into biology and therapy of malignant mesothelioma. Semin Oncol 2002; 29(6 Suppl 18):35–42. 5. Hemminki K, Li X. Mesothelioma incidence seems to have leveled off in Sweden. Int J Cancer 2003; 103: 145–6.

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6. Ulvestad B, Kjaerheim K, Møller B, Andersen Aa. Incidence trends of mesothelioma in Norway, 1965–1999. Int J Cancer 2003; 107:94–8. 7. Marinaccio A, Nesti M. Analysis of survival of mesothelioma cases in the Italian register (ReNaM). Eur J Cancer 2003; 39:1290–5. 8. Iwatsubo Y, Matrat M, Michel E, et al. Estimation of the incidence of pleural mesothelioma according to death certificates in France. Am J Ind Ed 2002; 42:188–99. 9. Gulyás M, Hjerpe A. Proteoglycans and WTI as markers for distinguishing adenocarcinoma, epithelioid mesothelioma, and benign mesothelium. J Pathol 2003; 199:479–87. 10. Attanoos RL, Griffin A, Gibbs AR. The use of immunohistochemistry in distinguishing reactive from neoplastic mesothelium. A novel use for desmin and comparative evaluation with epithelial membrane antigen, p53, platelet-derived growth factor-receptor, P-glycoprotein and Bcl-2. Histopathology 2003; 43: 231–8. 11. Eibel R, Tuengerthal S, Schoenberg SO. The role of new imaging techniques in diagnosis and staging of malignant pleural mesothelioma. Curr Opin Oncol 2003; 15:131–8. 12. Schouwink JH, Kool LS, Rutgers EJ et al. The value of chest computed tomography and cervical mediastinoscopy in the preoperative assessment of patients with malignant pleural mesothelioma. Ann Thorac Surg 2003; 75:1715–19. 13. Gerbaudo VH, Sugarbaker DJ, BritzCunningham S et al. Assessment of malignant pleural mesothelioma with 18F-FDG dual-head gamma-camera coincidence imaging: comparison with histopathology. J Nucl Med 2002; 43:1144–19. 14. Baas P. Predictive and prognostic factors in malignant pleural mesothelioma. Curr Opin Oncol 2003; 15: 127–30. 15. Edwards JG, Faux SP, Plummer SM et al. Cyclooxygenase-2 expression is a novel prognostic factor in malignant mesothelioma. Clin Cancer Res 2002; 8:1857–62. 16. Strizzi L, Muraro R, Vinale G et al. Expression of glycoprotein 90K in human malignant pleural mesothelioma: correlation with patient survival. J Pathology 2002; 197: 218–23. 17. Gordon GJ, Jensen RV, Hsiao L et al. Using gene expression ratios to predict outcome among patients with mesothelioma. J Natl Cancer Inst 2003; 95:598–605. 18. Parker C, Neville E. Lung cancer management of malignant mesothelioma. Thorax 2003; 58:809–13. 19. Pass HI. E-56. Multimodality approaches for malignant pleural mesothelioma. Lung Cancer 2003; 41(Suppl 3):S71. 20. Giaccone G. Pleural mesothelioma: combined modality treatments. Ann Oncol 2002; 13:217– 25. 21. Smythe WR. Current therapy for malignant mesothelioma. Curr Oncol Rep 2002; 4:305–13. 22. Khalil MY, Mapa M, Shin HJC, Shin DM. Advances in the management of malignant mesothelioma. Curr Oncol Rep 2003; 5:334–41. 23. Kindler HL. E-44. Systemic therapy for mesothelioma: old and new. Lung Cancer 2003; 41(Suppl 3):S54 24. Masood R, Kundra A, Zhu S et al. Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-C autocrine loops. Int J Cancer 2003; 104:603–10 25. Aziz T, Jilaihawi A, Prakash D. The management of malignant pleural mesothelioma; single centre experience in 10 years. Eur J Cardio-Thorac Surg 2002; 22:298–395. 26. Zellos L, Sugarbaker DJ. Current surgical management of malignant pleural mesothelioma. Curr Oncol Rep 2002; 4:354–60. 27. van Ruth S, Baas P, Zoetmulder FAN. Surgical treatment of malignant mesothelioma. Chest 2003; 123: 551–61. 28. Waller DA. The role of surgery in diagnosis and treatment of malignant pleural mesothelioma. Curr Opin Oncol 2003; 15:139–43. 29. Bonnette P, Heckly GB, Villette S, Fragola A. Intraoperative photodynamic therapy after pleuropneumonectomy for malignant pleural mesothelioma. Chest 2002; 122: 1866–7.

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30. Yajnik S, Rosenweig KE, Mychalczak B et al. Hemithoracic radiation after extrapleural pneumonectomy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2003; 56:1319–26. 31. Ahamad A, Stevens CW, Smythe WR et al. Intensity-modulated radiotherapy: a novel approach to the management of malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2003; 55:768–75. 32. Forster KM, Smythe WR, Starkschall G et al. Intensity-modulated radiotherapy following extrapleural pneumonectomy for the treatment of malignant mesothelioma: clinical implementation. Int J Radiat Oncol Biol Phys 2003; 55:606–16. 33. Senan S. Indications and limitations of radiotherapy in malignant pleural mesothelioma. Curr Opin Oncol 2003; 15:144–7. 34. Tomek S, Manegold C. Chemotherapy for malignant pleural mesothelioma. Curr Opin Oncol 2003; 15: 148–56. 35. Berghmans T, Paesmans M, Lalami Y et al. Activity of chemotherapy and immunotherapy on malignant mesothelioma; a systematic review of the literature with meta-analysis. Lung Cancer 2002; 38:111–21. 36. Manegold C, Aisner J. Pemetrexed for diffuse malignant pleural mesothelioma. Semin Oncol 2002; 29(2 Suppl 5):30–5. 37. Wang Y, Zhao R, Chattopadhyay S, Goldman ID. A novel folate transport activity in human mesothelioma cell lines with high affinity and specificity for the new-generation antifolate, pemetrexed. Cancer Res 2002; 62:6434–7. 38. van Meerbeeck JP, Baas P, Debruyne C et al. A phase II EORTC study of temozolomide in patients with malignant pleural mesothelioma. Eur J Cancer 2002; 38:779–83. 39. Vorobiof DA, Rapoport BL, Chasen MR et al. Malignant pleural mesothelioma: a phase II trial with docetaxel. Ann Oncol 2002; 13:412–15. 40. Skubitz KM. Phase II trial of pegylated-liposomal doxorubicin (Doxil) in mesothelioma. Cancer Invest 2002; 20:693–9. 41. Giaccone G, O’Brien MER, Byrne MJ et al. Phase II trial of ZD0473 as second-line therapy in mesothelioma. Eur J Cancer 2002; 38(Suppl 8): S19–24. 42. Baas P, Ardizzoni A, Grossi F et al. The activity of raltitrexed (Tomudex) in malignant pleural mesothelioma: an EORTC phase II study (08992). Eur J Cancer 2003; 39:353–7. 43. Scagliotti GV, Shin D, Kindler HL et al. Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol 2003; 21:1556–61. 44. Nowak AK, Byrne MJ, Ryan G et al. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer 2002; 87: 491–6. 45. Fizazi K, Doubre H, Le Chevalier T et al. Combination of raltitrexed and oxaliplatin is an active regimen in malignant mesothelioma: results of a phase II study. J Clin Oncol 2003; 21: 349–54. 46. Hughes A, Calvert P, Azzabi A et al. Phase I clinical and pharmacokinetic study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma. J Clin Oncol 2002; 20: 3533– 44. 47. Portalone L, Antilli A, Lombardi A et al. Epirubicin and gemcitabine (EG) as first-line treatment in malignant pleural mesothelioma (MPM): An A.I.P.O. multicenter phase II trial. Ann Oncol 2002; 13:Abst 549P. 48. Monneuse O, Beaujard AC, Guibert B et al. Long-term results of intrathoracic chemohyperthermia (ITCH) for the treatment of pleural malignancies. Br J Cancer 2003; 88:1839–43. 49. Vogelzang NJ, Rusthoven JJ, Symanowski J et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003; 21: 2636–44.

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50. Vogelzang N, Paoletti P, Symanowski J et al. Pemetrexed+cisplatin vs. cisplatin alone in chemonaive patients with malignant pleural mesothelioma: results of a phase III trial. Ann Oncol 2002; 13: Abst 474PD. 51. Rusch VW. Pemetrexed and cisplatin for malignant pleural mesothelioma: a new standard of care? J Clin Oncol 2003; 21:2699–30. 52. Qian W, Girling DJ, Muers MF. British Thoracic Society (BTS) randomized feasibility study of active symptom control with or without chemotherapy in malignant pleural mesothelioma. Br J Cancer 2002; 86(Suppl 1):S62.

9 Summary

A short summary of the management of small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and mesothelioma is given in this chapter, based on the evidence from randomized trials, even though it should be realized that patients included in clinical trials are not representative of the patient population as a whole. Additional information on the management of lung cancer can be found in a number of review articles and guidelines.1–10

SMALL CELL LUNG CANCER Limited disease Surgical resection, followed by postoperative chemotherapy, is the treatment of choice for the rare patient who presents with stage I disease. The results for SCLC are equivalent to the treatment of stage I and II NSCLC. For the more typical SCLC patient who presents with bulky limited disease, combination chemotherapy is the mainstay of treatment, in conjunction with radiotherapy. For chemotherapy, etoposide-cisplatin (EP) has become the most commonly recommended regimen. The combination of carboplatin and etoposide produces similar results to EP and has a more favorable toxicity profile. Based on meta-analyses, chest irradiation has shown superior results in patients receiving combination chemotherapy and radiotherapy compared with those receiving chemotherapy alone. The optimal timing and dosing of chest irradiation are still uncertain, but there is a tendency to initiate radiotherapy early during the first two courses at total doses of at least 50 Gy. Hyperfractionated radiotherapy given twice a day has yielded superior survival data in one randomized trial compared with conventional radiotherapy when combined with cisplatin and etoposide. Prophylactic cranial irradiation (PCI) has also been demonstrated to have a statistically significant impact on survival in patients with limited disease who achieve a complete remission, although no such data exist for patients with extensive disease achieving a complete remission. The optimal dose and timing of radiotherapy are again uncertain; most frequently, the total dose does not exceed 30 Gy given in fractions of 2.5 Gy daily.

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Extensive disease A combination of etoposide and cisplatin is the preferred standard treatment. The replacement of etoposide with irinotecan given together with cisplatin has resulted in significantly better median and 1-year survival in one randomized trial. Again, carboplatin can be substituted for cisplatin because of its similar activity and fewer sideeffects, even though myelosuppression is higher. Recent results have indicated that a four-drug combination of etoposide, cisplatin, epirubicin, and cyclophosphamide may be superior to etoposide and cisplatin alone. With regard to maintenance therapy, the hypothesis has been tested of adding either oral etoposide or topotecan to the treatment regimen in patients demonstrating a response to initial therapy. The results showed a slight improvement in median progression-free survival with etoposide, whereas topotecan did not show any significant difference. The impact of dose intensification remains uncertain. None of the phase III trials incorporating new agents has shown superior results compared with classical combinations such as cisplatin/carboplatin and etoposide. In patients presenting with poor prognostic factors, such as performance status 3–4, involvement of the liver and bone marrow, or severe comorbid diseases, the initial dose of chemotherapy should be reduced, and careful monitoring is recommended over the first weeks. Elderly patients with poor performance status and widespread disease have a substantially higher risk of incurring treatment-related complications and generally have a poor outcome. Supportive measures alone are often the best option for some of these patients. Recurrent disease The treatment options depend on the anatomic site of relapse, symptomatology, and previous treatment. Local relapse in patients without prior chest irradition is best treated with palliative radiotherapy. Late relapse in patients who initially responded to a platinum-containing regimen should be treated with the same regimen again. Otherwise, single-agent chemotherapy with, for example, topotecan or combination chemotherapy with cyclophosphamide, doxorubicin, and vincristine is the treatment of choice. Newer agents are being tested in this group of patients either as single agents or in combinations, but are yielding response rates of less than 20%.

NON-SMALL CELL LUNG CANCER A short summary of the management of NSCLC is given in this section. Chapter 7 provides detailed information on the current treatment options for patients with this disease.

Summary

119

Stages I, II, and resectable IIIA Stage I The standard therapy for stage I NSCLC continues to be complete surgical resection when possible. This should include lobectomy plus sampling of all mediastinal nodal stations or complete lymph node dissection. However, the surgical technique to perform a lobectomy and mediastinal exploration may change as experience with minimally invasive surgery grows. Recent data have revealed encouraging results with videoassisted thoracic surgery (VATS) lobectomy and mediastinal sampling or dissection. With minimal invasive surgery becoming popular, the efficacy of minimal resections such as segmentectomy and wedge resection is also being readdressed as smaller tumors (<1–2 cm) are being identified with spiral computed tomography (CT) scans. Another critical question is the relationship of tumor size to nodal metastasis. Data have been presented suggesting that histology and size may be beneficial in determining nodal risk. For patients who are medically inoperable, advances in radiotherapy such as threedimensional (3D) conformal and stereotactic radiosurgery are producing more durable results with decreased toxicity. Stage IB–IIIA The results of several large randomized trials of postoperative chemotherapy have been published, but with differing results (see Tables 7.1 and 7.2 in Chapter 7), and are thus also difficult to interpret. It appears that the weight of evidence suggests that postoperative cisplatin-based chemotherapy improves survival after surgery in patients with stage IB–IIA NSCLC, but the magnitude of this effect is small and variable. Similar results have been obtained by Japanese investigators using the oral drug combination of uracil and tegafur (UFT), both in individual trials and when meta-analysis of the results was performed. The results were most impressive in patients with adenocarcinomas. Alternatively, neoadjuvant therapies are being increasingly used. While large randomized trials investigating this important topic continue to enroll patients, we have now learned that neoadjuvant chemotherapy does not significantly increase surgical morbidity or mortality. Hopefully, these data demonstrating the feasibility of administering neoadjuvant chemotherapy will foster accrual to these large trials. For patients with operable stage III (N2) disease, the number of lymph nodes involved and the ability to eradicate tumor from the lymph nodes with neoadjuvant therapy have been found to be important prognostic factors. The pivotal question concerning the role of surgery in the treatment of stage IIIA (N2) disease is still open, awaiting the results from several ongoing trials. Furthermore, as multimodality therapy leads to improved survival for patients with operable NSCLC, an increased frequency of isolated brain metastases has been observed, which must be addressed.

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Inoperable stage III Current chemo/radiotherapy is the standard of care for patients with inoperable stage III NSCLC. However, numerous questions remain regarding the optimal means to combine these two modalities and whether there is a benefit of additional therapy before or after chemo/radiotherapy. Randomized phase II trials with newer cytotoxic agents given with concurrent radiation or trials incorporating an induction or consolidation chemotherapy approach have failed to show median survivals beyond the standard 17 months in most instances. Trials evaluating altered radiotherapy fractions have also not improved survival. Exciting areas of future research include the roles of 3D conformal radiotherapy, intensity-modulated radiotherapy (IMRT), and the addition of targeted agents, with several agents demonstrating radio-sensitization. Stage IV (and IIIB with pleural effusion) Doublet chemotherapy for stage IIIB with pleural effusion and stage IV NSCLC patients with adequate performance status has been shown in multiple randomized studies to improve survival and quality of life, and remains the standard of care. We have spent the last decade determining whether any new platinum-based regimen was superior. Numerous randomized trials clearly found all regimens to be equally efficacious, but to differ in toxicity and cost. Current trials have continued to support this finding. Furthermore, data from randomized trials that included a non-platinum regimen were equivalent in efficacy to platinum regimens, but with a more favorable toxicity profile. Controversy continues regarding the number of cycles of chemotherapy to be administered in the first-line setting. Several guidelines suggest a maximum of 6 cycles, but there is an accumulation of data indicating that 3–4 cycles are sufficient. While numerous phase II cytotoxic regimens have been evaluated, none has produced amazing results. Thus, enthusiasm for exploring traditional cytotoxic regimens has dampened, and the focus has switched to targeted therapies. A variety of targeted agents are currently being evaluated. At the forefront of the promising agents are the epidermal growth factor receptor inhibitors (gefitinib (Iressa), erlotinib (Tarceva), and cetuximab (Erbitux)), which have produced responses in heavily pretreated patients and are in large phase III trials. A host of targeted agents are in earlier stages of clinical evaluation, such as COX-2 inhibitors, the preapoptotic inhibitor exisulind, proteasome inhibitors, targretin, and vaccines. However, we must be cautiously optimistic about targeted therapy, because it brings with it a new set of problems to tackle. Determining clinical and biologic efficacy is a major barrier, and long-term toxicity is ill-defined for most of these agents. Improving upon the efficacy of second-line docetaxel, investigators have focused on the addition of a second cytotoxic agent. Several small studies showed a favorable survival improvement for doublet therapy, but further investigation is needed. Pemetrexed (Alimta), a novel multitargeted antifolate, has in a randomized trial resulted in similar response rates, median survival, and overall survival as docetaxel, but toxicity favored the pemetrexed arm, with significantly less neutropenia. The second-line setting is ideal for evaluating targeted therapies. These agents will undoubtedly be investigated

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alone or in combination with doxetaxel. Doublets have also been explored in the elderly population, but have not demonstrated value over a single agent.

MESOTHELIOMA Surgery should be considered when mesothelioma remains localized, usually as extrapleural pneumonectomy. Chemotherapy and/or radiotherapy have not yet proved to be effective in preventing local recurrence, nor has the use of photodynamic therapy (PDT) or intracavitary chemotherapy. With respect to chemotherapy, quantitative and qualitative overviews of the literature have suggested that cisplatin may play an important role in combination therapy. It is also emerging that response rates of 30–40% can be obtained when combining cisplatin with other agents, e.g. altitrexed and pemitrexed. A combination of cisplatin and pemetrexed has in one randomized trial been superior to cisplatin alone, resulting in superior response rate, duration of response, and quality of life. PDT, hyperthemia, and immunotherapy with Mycobacterium vaccae combined with chemotherapy have also been tested in phase II trials, but the relatively small numbers of patients in these trials preclude firm conclusions.

REFERENCES 1. Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med 2004; 350:379–92. 2. Hansen HH, Pappot, H. Primary malignant tumours of the lung and pleura. In: Textbook of Medical Oncology, 3rd edn. London: Taylor & Francis, 2004:163–81. 3. Diagnosis and management of lung cancer: ACCP evidence-based guidelines. Chest 2003; 123(Suppl):S1–332. 4. Laurie SA, Logan D, Markman BR et al. Practice guideline for the role of combination chemotherapy in the initial management of limited-stage small-cell lung cancer. Lung Cancer 2004, 43:223–40. 5. Simon GR, Wagner H. Small cell lung cancer. Chest 2003; 123:259S– 71S. 6. Depierre A, Lagrange JL, Theobald S et al. Summary report of the standards, options and recommendations for the management of patients with non-small-cell lung carcinoma (2000). Br J Cancer 2003; 89(Suppl 1):S35–49. 7. Van Houtte P. IASLC Workshop. Progress and guidelines in the management of non-small cell lung cancer. Lung Cancer 2003; 42(Suppl 1): S1–92. 8. Zielinski C, Krainer M, Hirsch FR (eds). European Consensus Conference on Medical Treatment of Non-Small Cell Lung Cancer. Lung Cancer 2002; 38(Suppl 3):S1–81 9. Pfister DG, Johnson DH, Assoli CG et al. American Society of Clinical Oncology Treatment of Unresectable Non-Small-Cell Lung Cancer Guideline: update 2003. J Clin Oncol 2004; 22:330– 53. 10. Dark G. Recent advances in mesothelioma. Clin Med 2003; 3:314–17.

Index

N.B. Combination drugs are shown with components in alphabetical order.

adenocarcinoma classification 18, 21 incidence 6–7, 19 survival 21 adenosquamous carcinoma 18 Adjuvant Lung Project of Italy (ALPI) trial 66 ADT see anethole dithiolethione affinitak+carboplatin+paclitaxel 111, 112 age lung cancer 6–7 SCLC radiotherapy 44 air pollution and lung cancer 6 alcohol consumption and lung cancer 6 Alimta 103 American Society of Clinical Oncology (ASCO) 1 amifostine 46 anethole dithiolethione (ADT) adverse effects 9 phase IIb trials 9–10 antibiotics, prophylactic 55 antibodies anti-BEC2 59 anti-cytokeratin (CK) 29 commercial 21 asbestos exposure 127 autofluorescence bronchoscopy (AFB) 10 basic fibroblast growth factor (bFGF) 35 BBR3464 103, 104 Bestatin see ubenimex Big Lung Trial 66 biomarkers 10 see also markers BMS-18447 104

Index

123

BMS-247550 104 brain metastases NSCLC 143 SCLC 47, 58 British Thoracic Society trial 137 bronchial epithelia, premalignant lesions of 9–10 bronchioalveolar carcinoma (BAC) 19 classification 21 FDG-PET 30 incidence 19 survival 21 targeted therapy 111 bronchoscopy 10 CALGB prognostic scoring system 132 trials 9730 97 phase II 100 Cancer and Leukemia Group B see CALGB capecitabine+docetaxel 108 carboplatin 68 +celecoxib+paclitaxel 70 +cetuximab +gemcitabine 113 +paclitaxel 113 +cisplatin+etoposide 56, 57 +docetaxel 73, 76, 87, 88, 107 +G-CSF+ifosfamide 93 +etoposide +G-CSF+ifosfamide 54 +ifosfamide 54 +paclitaxel (ICE-T) 54 +paclitaxel 50, 52 +vincristine 50, 52 +G-CSF+vinorelbine 56 +gemcitabine 68, 71, 72, 74, 75, 76, 77, 78, 79, 81, 84, 85, 87, 89 +paclitaxel 79, 82, 101 elderly patients 99 +ifosfamide+paclitaxel 49 +irinotecan 56, 57, 142 +paclitaxel 90 +mitomycin C+vinblastine 77 +paclitaxel 70, 71, 72, 73, 76, 77, 78, 79, 80, 81, 82, 86, 87, 88 +tirapazamine 78, 82 +vinorelbine+G-CSF+G-CSF 93, 95 elderly patients 97, 99 in phase II patients 100 poor-risk patients 101 +pemetrexed 86, 134, 136 +vinorelbine 58, 74, 90, 91

Index

124

elderly patients 97, 98 second-line therapy 103, 104 carcinoembryonic antigen (CEA) 22 mRNA in metastases detection 33 in NSCLC 70 carcinogen detoxification enzymes 9 carcinoids classification 17, 18 diagnostic criteria 19, 20 in relapsed SCLC 59 celecoxib 70 +docetaxel 102, 109, 110 in combined therapy see under carboplatin cetuximab 109 +cisplatin+vinorelbine 113 +docetaxel 110 in combined therapy see under carboplatin CEV see cyclophosphamide+epirubicin+vincristine chemohyperthermia 134 chemoprevention trials 9–10 chemotherapy cycle number 77 drug dose 97 elderly patients 95–6 intensity/duration of treatment 53–4 mesothelioma 134–7 toxicity prevention 55 see also specific agents and under specific diseases chest X-ray for lung cancer screening 13 chromogranin A 34 chromosomal analysis 19 chronic obstructive pulmonary disease (COPD) 13 CI-994+gemcitabine 109, 110 cisplatin 103, 134, 137 +cyclophosphamide+epirubicin+etoposide 142 +docetaxel 71, 72, 73, 76, 79, 87, 88 +gemcitabine 85, 90, 93, 95 +irinotecan 93 elderly patients 97, 98 +doxorubicin 134 +erlotinib +gemcitabine 111 +etoposide +gemcitabine 49 +irinotecan 51, 52–3 +paclitaxel (TEP) 52 +paclitaxel+topotecan 49 +topotecan 49 elderly patients 99 in NSCLC 66, 68, 79, 84 in SCLC 46, 50, 56, 57, 141, 142 +etoposide (EP) 48, 52

Index

125

+gefitinib+gemcitabine 111, 112 +gemcitabine 68, 73, 74, 75, 76, 77, 79, 80, 81, 83, 84, 87, 89 +ifosfamide 93 +paclitaxel 93 +vinorelbine 95 +vinorelbine 68, 78, 82, 83, 93 elderly patients 97, 99 in mesothelioma 134, 136 in phase II patients 100 poor-risk patients 101 +ifosfamide+mitomycin C 66, 68, 75, 77 +irinotecan +docetaxel 90, 92 +paclitaxel 92 +topotecan 56 in NSCLC 73, 76, 90, 92, 106 in SCLC 46, 142 second-line therapy 103 +mitomycin C +vinblastine 68, 75, 77, 137 +vindesine (MVP) 66, 67 +paclitaxel 79, 84, 85, 87 +pemetrexed 137, 145 +rhuG-CSF+vinorelbine 80 +topotecan 49, 57 +vinblastine 66, 68 +vindesine 66, 68, 73, 76 +vinorelbine elderly patients 97 in mesothelioma 113 in NSCLC 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 84, 85, 91 in SCLC 66, 68 in combined therapy see under carboplatin poor-risk patients 101 second-line therapy 106 coincidence imaging see FDG-CI combined modality therapy for SCLC 46, 54 compliance 70 computed tomography (CT) for mesothelioma 128, 132 radiotherapy planning 32 spiral follow-up studies 71 lung cancer screening 12–13 CT-2103 102 cyclooxygenase-2 expression 132 cyclophosphamide +doxorubicin +etoposide+G-CSF 53 +vincristine 46 +epirubicin+vincristine (CEV) 48, 50 in combined therapy see under cisplatin

Index

126

CYFRA 21–1 33, 34 diagnostic criteria carcinoids 19 neuroendocrine tumors 19 non-small cell lung cancer (NSCLC) 19 docetaxel 71, 72, 79, 135, 144–5 +epirubicin 108 +gemcitabine 78, 101, 108 +rhuG-CSF 80 +irinotecan 107 +paclitaxel 104 +vinorelbine 107 in combined therapy see under celecoxib; cetuximab; cisplatin second-line therapy 100, 103, 105, 109 and targeted therapies 109 toxicity 103 doxorubicin in combined therapy see under cisplatin; cyclophosphamide pegylated-liposomal 135 Eastern Cooperative Oncology Group (ECOG) 95, 96, 97, 100 Eindhoven Cancer Registry 6 elderly patients with NSCLC 95–100 with relapsed SCLC 56–7, 142 endoscopic ultrasound (EUS) 32 EORTC Lung Cancer Group prognostic scoring system 132 trial 52, 55 EP see cisplatin+etoposide epidemiology of lung cancer 5–8 epidermal growth factor receptor (EGFR) expression rate and lesion stage 11 mesothelioma treatment 133 in NSCLC 70 epidermal growth factor receptor (EGFR) inhibitors 109 epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors 111 epirubicin+gemcitabine 81, 134, 136 epirubicin in combined therapy see under cisplatin; cyclophosphamide; docetaxel epithelioid mesothelioma 129 epithilones 103 erlotinib 109, 113 in combined therapy see under cisplatin etoposide 48, 142 +topotecan 49

Index

127

in combined therapy see under carboplatin; cisplatin; cyclophosphamide EUROBASE database 6 European Lung Cancer Working Party trial 56 European Organization for Research and Treatment of Cancer see EORTC FDG-CI 132 FDG-PET evaluation 31 metastases, detection of 31 NSCLC staging 29, 30, 31 SCLC staging 33–4 febrile leukopenia prevention 55 fibrous pleuritis 129 fine needle aspiration (FNA) 32 [18F]fluorodeoxyglucose coincidence imaging see FDG-CI [18F]fluorodeoxyglucose positron emission tomography see FDG-PET Framework Convention on Tobacco Control 1 G-CSF see granulocyte colony-stimulating factor G3139 59 gefitinib (Iressa) 109, 113 in combined therapy see under cisplatin salvage therapy 110 gemcitabine 56, 57, 71, 72 +irinotecan 103, 106, 107, 108 +oxaliplatin 87, 89 +paclitaxel 77, 78, 80, 81 poor-risk patients 102 +vinorelbine elderly patients 99 in NSCLC 68, 77, 78, 79, 80, 82, 83, 84, 90, 108 poor-risk patients 102 in SCLC 56, 57 in combined therapy 48 see also under carboplatin; cisplatin; docetaxel; epirubicin drug dose trial 97, 98, 100 poor-risk patients 101, 102 salvage therapy 110 gender bronchioalveolar carcinoma 70 lung cancer 6–7 mesothelioma 127 neuroendocrine tumor classification 17 Gleevec see imatinib Glivec see imatinib

Index

128

glycoprotein 90K expression 132–3 granulocyte colony-stimulating factor (G-CSF) in combined therapy see under carboplatin; cyclophosphamide in SCLC combined therapy 53, 54, 55 Greek Lung Cancer Cooperative Group trial 52 Hellenic Cooperative Oncology Group 77 histochemistry 128 hyperthermia 134 ICE-T see carboplatin+etoposide+ifosfamide+paclitaxel IDEAL trials 109 ifosfamide +irinotecan 56, 57 +vinorelbine 68, 83 in combined therapy see under carboplatin imatinib (ST1571, Gleevec/Glivec) 35 immunohistochemistry of mesothelioma 128 INTACT trials 111 International Adjuvant Lung Trial (IALT) 66 International Association for the Study of Lung Cancer (IASLC) 1 lung cancer classification 17 International Mesothelioma Interest Group 128 TNM staging 130–1 International Staging System for Lung Cancer 25–8 Committee 25 international tobacco control treaty 1 Iressa see gefitinib irinotecan (CPT-11) 46, 103, 106 in combined therapy see under carboplatin; cisplatin; docetaxel; gemcitabine; ifosfamide vinorelbine 107 irradiation see prophylactic cranial irradiation; radiotherapy; thoracic radiotherapy karenitecin 103, 104 large cell carcinomas classification 18 survival 21 large cell neuroendocrine carcinomas (LCNEC) diagnostic criteria 20 prognosis 19 survival 21 large neuroendocrine carcinomas 17

Index

129

lenograstim see granulocyte colony-stimulating factor liver metastases 59 lung cancer age/gender 6–7 biology, advances in 2 classification 17, 18–19 early detection 10 epidemiology 5–8 histopathology 17–23 incidence 1, 6–7 mortality trends 7 rare tumors 22 risk factors 5–6 screening 12–13 socioeconomics 7 vs mesotheliomas of pleura 21 lung/pleural tumors, classification of 18–19 lymph nodes in mesothelioma 132 in NSCLC 143 size 28–9 in staging 25–8 marimastat 58 markers epithelioid mesothelioma 22 immunohistochemical 21 tumor 33 volatile organic compounds in breath 11 Mayo Lung Project trial 12 mediastinal lymph node disease 30 mediastinoscopy 30 for mesothelioma 128, 132 medical associations against tobacco 1 mesothelial hyperplasia 129 mesothelioma 127–40, 144–5 cervical mediastinoscopy for 128, 132 classification 128 computed tomography for 128, 132 gene expression ratios 133 immunohistochemistry 128, 129 immunotherapy 134, 145 incidence 127 increases 127 malignant 128 prognostic factors 132–3 radiologic manifestations 128 surgery 133 treatment 133–7 metalloproteinase inhibitor 58 metastases

Index

130

immunohistochemistry 129 lymph nodes NSCLC 65 see also specific sites micrometastases 29 mitomycin C in combined therapy see under carboplatin; cisplatin molecular diagnostics 10 mortality trends in lung cancer 7 neuroendocrine tumors classification 17, 19 diagnostic criteria 19, 20 in relapsed SCLC 59–60 nicotine dependence treatment 6 non-small cell lung cancer (NSCLC) 142 chemotherapy stage I–IIIA 65–71 follow-up 71 postoperative (adjuvant) 66, 68, 69–70 preoperative (neoadjuvant) 70 prognostic factors 70 stage IIIB–IV 71–95 combined modality therapy 68, 144 diagnostic criteria 19 elderly patients 95–100 metastases 29, 31 phase II trials 103 phase III trials 103 poor-risk patients 100, 101–2 postoperative follow-up 14 prognostic factors 33 randomized phase II trials 79, 84–7 second-line therapy 100, 101–9, 144–5 combination regimens 107–8 phase II studies 104 randomized trials 105–6 single agent therapy 103 stage I 143 stage IB–IIIA 143 stage III inoperable 144 stage IIIB–IV 144–5 irinotecan-platinum doublets 92 irinotecan-platinum doublets 90 non-platinum doublets 90 phase II triplet regimes 90, 93–4, 95 phase III non-platinum regimens 77–8, 80–1 triplets 82–3 phase III platinum-based regimens 80–1 doublets 71–7, 79 triplets 78–9

Index

131

taxane-platinum doublets 87, 88 vinorelbine-platinum doublets 91 vinorelbine-platinum doublets 90 staging procedures 29–33 surgery 143 survival rates, postsurgical 65 treatment 65–125 North-East Japan Study Group for Lung Cancer Surgery 69 NSCLC see non-small cell lung cancer Oltipraz 9 oxaliplatin +paclitaxel 88 +pemetrexed 86 +raltitrexed 136 in combined therapy see under gemcitabine paclitaxel 71, 72 +topotecan 46, 49 +vinorelbine 78, 81 in combined therapy 46, 48 see also under carboplatin; docetaxel; gemcitabine; oxaliplatin elderly patients 97 poor-risk patients 102 second-line therapy 103, 104 palliation mesothelioma 137 targeted therapy 109 pemetrexed 103, 105, 134, 135, 145 in combined therapy see under carboplatin; cisplatin; oxaliplatin PET see positron emission tomography photodynamic therapy (PDT) 133 pivanex 109, 110 platelet-derived growth factor receptor (PDGFR) 133 platinum doublets in NSCLS 71–7 pleural fluid cytology 128, 129 pleural tumor classification 18–19 pneumonic-type adenocarcinoma (P-ADC) 22 polymerase chain reaction (PCR) PCR-based TRAP assay 11 preproGRP-specific nested RT 34 poor-risk patients in NSCLC 100, 101–2 positron emission tomography (PET) FDG-PET 29, 30, 31 integrated with CT 30 NSCLC staging 29–31

Index

132

radiotherapy planning 32 SCLC staging 34 preprogastrin-releasing peptide (preproGRP) 34 prognosis in large cell neuroendocrine (LCNEC) 19 prognostic factors 28–9 mesothelioma 132 NSCLC 33, 70, 143 prophylactic cranial irradiation (PCI) 43–4, 141 and brain metastases 47 radiosurgery 143 radiotherapy mesothelioma 133–4 NSCLC 143 NSCLC combined modality therapy 68 see also prophylactic cranial irradiation raltitrexed 134, 135 in combined therapy see under oxaliplatin rebeccamycin 103, 104 relapse adenocarcinoma 19 bronchioalveolar carcinoma (BAC) 19 9-cis-retinoic acid 10 13-cis-retinoic acid 11 retinoic acid receptor β (RAR-β) 10 rhuG-CSF in combined therapy see under cisplatin; docetaxel risk factors of lung cancer 5–6 rock production and lung cancer 6 Roy Castle International Centre for Lung Cancer Research 10 salvage therapy targeted therapy 109–11 see also second-line therapy sarcoma 129 sarcomatoid mesothelioma 129 SCLC see small cell lung cancer screening for lung cancer 12–13 second-line therapy 100, 101–9 second primary lung cancer (SPLC) 14 sentinel lymph node mapping 32 slag wool production and lung cancer 6 small cell lung cancer (SCLC) chemotherapy 48–55 combination 48, 49 intensity/duration of treatment 53–4 postoperative (adjuvant) 141 randomized trials 48 advanced disease 50–1 classification 17, 18 diagnostic criteria 20

Index

133

carboplatin continued extensive disease 142 limited disease 141 metastases 47 brain 47, 58 liver 59 radiotherapy chest irradiation (thoracic radiotherapy) 45–7 in combined modality therapy 141 prophylactic cranial irradiation 47 unresolved issues 45 recurrent disease 142 relapsed 56–60 smoking cessation 6 staging 33–5 surgery 44, 141 after relapse 59 treatment 43–64 combined therapy 44, 45 long-term results of 43–4 reviews 43 smoking consumption 1 forces for/against 1 global approach to policy 2 and lung cancer 5–7 lung cancer screening 13 in SCLC trials 46–7 smoking cessation 5–6 and survival rates 65 vs abstinence 5 socioeconomics of lung cancer 7 South West Oncology Group 111 sputum cytology 10 lung cancer screening 12–13 squamous cell carcinoma classification 18 smoking cessation 6 ST1571 see imatinib staging 25–8 biological models 33 international system 25–8 mesothelioma 128 NSCLC 29–33 purpose 25 and survival 28 stem cell support 54 Surveillance, Epidemiology and End Results (SEER) database 43 survival bronchioalveolar carcinoma 21 large cell carcinomas 21 Systemized Nomenclature of Medicine (SNOMED) 17

Index

134

TALENT trial 111 tar yield-lung cancer relationship 5 targeted therapy advanced disease 109–13 non-small cell lung cancer (NSCLC) 144 TAX 326 95, 96, 97 TEC see carboplatin+etoposide+paclitaxel tegafur+uracil 69 telomerase activity 11 telomeric repeat amplification protocol (TRAP) assay 11 temozolomide 135 TEP see cisplatin+etoposide+paclitaxel thoracic radiotherapy (TRT) in combined modality therapy 46 optimum timing in SCLC 46 in SCLC combined therapy 54 tirapazamine in combined therapy see under carboplatin TNM staging evaluation in SCLC 28 mesothelioma 130–1 tobacco smoking see smoking α-tocopherol 11 topotecan 49, 51, 142 in combined therapy 48 see also under cisplatin; etoposide; paclitaxel transesophageal endoscopic ultrasound-guided fine needle aspiration 32 TRIBUTE trial 111 tumor markers 33 tumor size 28–9 tyrosine kinase receptor (c-Kit) 35 ubenimex (Bestatin) 69–70 UFT see tegafur,+uracil vaccines 59 vascular endothelial growth factor (VEGF) mesothelioma treatment 133 SCLC staging 34–5 vinblastine in combined therapy see under carboplatin; cisplatin vincristine in combined therapy see under carboplatin; cyclophosphamide vindesine in combined therapy see under cisplatin vinorelbine 137 in combined therapy see under carboplatin; cisplatin; docetaxel; gemcitabine;

Index

ifosfamide; paclitaxel elderly patients 97, 98 volatile organic compounds (VOCs) 11–12 white-light bronchoscopy (WLB) 10 whole-body hyperthermia 134 women and lung cancer 6, 7 World Conference on Lung Cancer 2 World Health Organization international tobacco control treaty 1 lung cancer classification 17 ZD0473 135

135