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Lung Cancer

Edited by Anne-Marie C. Dingemans,

Martin Reck and Virginie Westeel

ERS monograph

Lung Cancer ER

S monograph 68

ERS monograph

Print ISSN: 2312-508XOnline ISSN: 2312-5098Print ISBN: 978-1-84984-061-3 Online ISBN: 978-1-84984-062-0

June 2015

€55.00

ISBN 978- 1- 84984- 061- 3

9 781849 840613

Lung cancer is the most common cause of death from cancer worldwide – it is estimated to cause nearly one in five cancer deaths. Most lung cancer patients are diagnosed late and for many of them, there are currently no curative therapy options available, meaning long-term survival is still low. Nevertheless, enormous progress has been made in the field during the last decade. This Monograph provides a comprehensive overview of the current knowledge of and advances in lung cancer, covering areas such as: screening; tobacco control; COPD; diagnosis; therapy; and treatment of early stage lung cancer from both a surgeon’s and radiation oncologist’s perspective. Very recent achievements in innovative fields, such as targeted therapies and immunotherapies, are also discussed.

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Lung Cancer Edited by

Anne-Marie C. Dingemans, Martin Reck and Virginie Westeel

Editor in Chief Tobias Welte

Th is book is one in a series of ERS Monographs. Each individual issue provides a comprehensive overview of one specifi c clinical area of respiratory health, communicating information about the most advanced techniques and systems required for its investigation. It provides factual and useful scientifi c detail, drawing on specifi c case studies and looking into the diagnosis and management of individual patients. Previously published titles in this series are listed at the back of this Monograph.

ERS Monographs are available online at www.erspublications.com and print copies are available from www.ersbookshop.com

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Editor in Chief elect: Robert Bals (Saarbrücken, Germany).

Editorial Board: Antonio Anzueto (San Antonio, TX, USA), Leif Bjermer (Lund, Sweden), John Hurst (London, UK) and Carlos Robalo Cordeiro (Coimbra, Portugal).

Managing Editor: Rachel WhiteEuropean Respiratory Society, 442 Glossop Road, Sheffield, S10 2PX, UKTel: 44 114 2672860 | E-mail: Monograph@ersj.org.uk

Published by European Respiratory Society ©2015June 2015Print ISBN: 978-1-84984-061-3 Online ISBN: 978-1-84984-062-0 Print ISSN: 2312-508XOnline ISSN: 2312-5098Printed by Charlesworth Press, Wakefield, UK

All material is copyright to European Respiratory Society. It may not be reproduced in any way including electronic means without the express permission of the company.

Statements in the volume reflect the views of the authors, and not necessarily those of the European Respiratory Society, editors or publishers.

C O P E C O M M I T T E E O N P U B L I C A T I O N E T H I C S

This journal is a member of and subscribes to the principles of the Committee on Publication Ethics.

Continuing medical education (CME) credits are available through many issues of the ERS Monograph. Following evaluation, successful Monographs are accredited by the European Board for Accreditation in Pneumology (EBAP) for 5 CME credits. To earn CME credits, read the book of your choice (it is clearly indicated on the online table of contents whether CME credits are available) then complete the CME question form that is available at www.ers-education.org/e-learning/cme-tests.aspx

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Preface vii

Guest Editors ix

Introduction xiii

List of abbreviations xiv

1. Epidemiology: development and perspectives 1

Georgia Hardavella and Tariq Sethi

2. Screening 12

John K. Field, Anand Devaraj, Stephen W. Duffy and David R. Baldwin

3. Tobacco control 24

Thierry Urban, Michel Underner, José Hureaux and Xavier Quantin

4. The association with COPD 38

Juan P. de-Torres and Javier J. Zulueta

5. Idiopathic pulmonary fibrosis 50

Carlos Robalo Cordeiro, Tiago M. Alfaro, Sara Freitas and Jessica Cemlyn-Jones

6. Histological diagnosis: recent developments 64

Gavin M. Laing, Andrea D. Chapman, Louise M. Smart and Keith M. Kerr

7. The current and future roles of genomics 79

Kwun M. Fong, Marissa Daniels, Felicia Goh, Ian A. Yang and Rayleen V. Bowman

8. Molecular pathology 95

Florian Laenger, Nicolas Dickgreber and Ulrich Lehmann

9. Adequate tissue for adequate diagnosis: what do we really need? 119

Guido M.J.M. Roemen, Axel zur Hausen and Ernst Jan M. Speel

10. Management of early stage lung cancer: a surgeon’s perspective 136

Pascal A. Thomas

11. Management of early stage lung cancer: a radiation oncologist’s 148

perspective Esther G.C. Troost, Krista C.J. Wink, Jaap D. Zindler and Dirk De Ruysscher

ERS monograph

ContentsLung Cancer Number 68

June 2015

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12. Mediastinal staging 159

Christophe Dooms, Herbert Decaluwe and Paul De Leyn

13. Approaches in patients with locally advanced NSCLC: a surgeon’s 167

perspective Paul E. Van Schil, Michèle De Waele, Jeroen M. Hendriks and Patrick R. Lauwers

14. Approaches in patients with locally advanced NSCLC: a radiation 178

oncologist’s perspective Dirk De Ruysscher, Stéphanie Peeters and Esther G.C. Troost

15. Chemotherapy 186

Adam Januszewski and Sanjay Popat

16. Systemic treatment of elderly patients 202

Charlotte Leduc and Elisabeth Quoix

17. Achievements in targeted therapies 215

Paolo Bironzo, Teresa Mele and Silvia Novello

18. Can we expect progress from targeted therapy of SCLC? 234

Nevin Murray and Krista L. Noonan

19. Immunotherapy 247

Niels Reinmuth and David F. Heigener

20. Perspective of a pulmonologist: what might we expect and what do 261

we need to know? Nicolas Guibert, Elise Noel-Savina and Julien Mazières

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ERS | monograph

Preface

Tobias Welte, Editor in Chief

The GLOBOCAN project (http://www.globocan.iarc.fr) is acomprehensive cancer surveillance database managed by theInternational Association of Cancer Registries (IACR) andsupported by the World Health Organization (WHO). Theproject aims to provide up-to-date estimates of the incidence,mortality and prevalence of major cancer types, at a nationallevel, for 184 countries. GLOBOCAN estimate that ∼14.1 millionnew cancer cases and 8.2 million deaths occurred in 2012worldwide [1]. There were estimated to be 1.8 million new lungcancer cases in 2012 (12.9% of the total), 57% (65% of cancerdeaths worldwide) of which occurred in the less developedregions, making lung cancer the most common cancer in theworld. In both more and less developed countries, lung cancer isthe leading cause of cancer death among males, with the highestestimated age-standardised incidence rates occurring in Centraland Eastern Europe (53.5 per 100000) and Eastern Asia (50.4 per100000). In more developed countries, lung cancer has surpassedbreast cancer as the leading cause of cancer death among females.The highest estimated rates in females are in northern America(33.8) and northern Europe (23.7), with a relatively high rate inEastern Asia (19.2) and the lowest rates in Western and MiddleAfrica (1.1 and 0.8 per 100 000, respectively) [1].

Lung cancer is the most common cause of death from cancerworldwide; it is estimated that it causes nearly one in five deaths(1.59 million deaths, 19.4% of the total). Its high fatality (it hasan overall the overall mortality to incidence ratio of 0.87) and therelative lack of variability in survival in different regions of theworld, mean that the geographical patterns of mortality closelyfollow those of incidence. Even so, most lung cancer patients arediagnosed late, with the majority of them at an advanced diseasestage. There are currently no curative therapy options availableand long-term survival amongst lung cancer patients is still low.

Nevertheless, enormous progress has been made during the lastdecade. Multimodal therapies have improved the prognosis as hasthe development of new surgical techniques, the optimisation of

Copyright ©ERS 2015. Print ISBN: 978-1-84984-061-3. Online ISBN: 978-1-84984-062-0. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

ERS Monogr 2015; 68: vii–viii DOI: 10.1183/2312508X.10003915 viiPurchased by , From: European Respiratory Society Publications (reader.ersjournals.com)

radiation therapy and the introduction of new chemotherapeuticagents. However, the decisive breakthrough has been thedevelopment of new immunopathological techniques, which allowfor the detection of special genetic mutations and initiateindividualised therapy according to this finding. The number ofpatients who benefit is still small; however, the quality of life andsurvival rates of those who respond to this treatment areimpressive. The pharmaceutical industry invests heavily in thedevelopment of new diagnostic tools and effective treatmentmodalities, so expectations for the future are great.

Smoking is still the most important risk factor worldwide. Theset-up of preventive measures to reduce the smoking rate istherefore of paramount importance. However, some measuresmust be viewed with a critical distance. The dissemination ofelectronic cigarettes all over the world is viewed critically byexperts and most of the lung societies [2]. The long-termconsequences of these devices must be carefully examined beforea final assessment is possible.

Thoracic oncology plays an increasingly important role inrespiratory medicine, as well as in the European Respiratory Society(ERS). Knowledge about oncology must make up a substantial partof a respiratory physician’s training, not only for those working ina hospital, but also for those in an outpatient setting.

This issue of the ERS Monograph provides a comprehensiveoverview of the current knowledge of lung cancer in clinicalpractice and research. The Guest Editors have done great job ofensuring that all aspects of this complex disease are represented,meaning this book will be of interest to a very broad readership.

References

1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin2015; 65: 87–108.

2. Brandon TH, Goniewicz ML, Hanna NH, et al. Electronic nicotine deliverysystems: a policy statement from the American Association for Cancer Researchand the American Society of Clinical Oncology. Clin Cancer Res 2015; 21: 514–525.

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ERS | monograph

Guest Editors

Anne-Marie C. Dingemans

Anne-Marie C. Dingemans has been associate professor ofpulmonology at the Maastricht University Medical Center(Maastricht, the Netherlands) since 2004, where she currently shecoordinates clinical lung cancer trials and is involved intranslational research on lung cancer.

Anne-Marie Dingemans received her medical degree atMaastricht University (Maastricht) in 1994 and subsequently herPhD at VU Medical Center (Amsterdam, the Netherlands) in2000 for laboratory research on resistance to chemotherapy inlung cancer. She performed her training as a pulmonologist atVU Medical Center and at Leiden University Medical Center(Leiden, the Netherlands).

Anne-Marie is a board member of the Netherlands RespiratorySociety (NRS) and the secretary of the NVALT studiesfoundation. She is also a member of the Lung and Other ThoracicTumours faculty of the European Society for Medical Oncology(ESMO), and of the Harmonised Education in RespiratoryMedicine for European Specialists (HERMES) Thoracic Oncologytask force. Anne-Marie is a member of the American Associationof Cancer Research (AACR), the American Society of ClinicalOncology (ASCO), the International Association for the Studyof Lung Cancer (IASLC) and the European Thoracic OncologyPlatform (ETOP). She has (co)-authored more than 80publications and book chapters.

Martin Reck

Martin Reck is head of the Department of Thoracic Oncologyand head of the Clinical Trial Department in the Department ofThoracic Oncology at the Lung Clinic Grosshansdorf(Grosshansdorf, Germany). He is also Principal Investigator atthe Airway Research Center North (ARCN) (Lung ClinicGrosshansdorf), which is a member of the German Centre forLung Research (DZL).

Copyright ©ERS 2015. Print ISBN: 978-1-84984-061-3. Online ISBN: 978-1-84984-062-0. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

ERS Monogr 2015; 68: ix–xi. DOI: 10.1183/2312508X.10004115 ixPurchased by , From: European Respiratory Society Publications (reader.ersjournals.com)

Martin Reck underwent medical training at the University ofHamburg (Hamburg, Germany) from 1986–1993. He completedhis doctorate at the General Hospital Wandsbek, Hamburg, in1995, and received post-graduate training at the HospitalGrosshansdorf. He was appointed as a specialist in internalmedicine in 2001 and as a specialist in pulmonology in 2002. In2008, he was awarded a post-doctoral lecturing qualification bythe University of Schleswig-Holstein (Kiel, Germany).

Martin Reck has acted as a Principal Investigator or Co-PrincipalInvestigator in various clinical trials since 1993. His maininterests are new medical treatments for thoracic malignanciesand translational research related to predictive markers. Aparticular focus of his work is the clinical development ofantiangiogenic compounds, such as bevacizumab, nintedanib andother compounds. Recently, he also has been deeply involved inseveral key trials with immunotherapies, including ipilimumab,programmed cell death protein-1 and programmed cell deathligand-1 antibodies and other agents.

In addition to the International Association for the Study ofLung Cancer (IASLC), Martin Reck is also a member of theEuropean Society for Medical Oncology (ESMO), the AmericanSociety of Clinical Oncology (ASCO), the German WorkingGroup for Lung Cancer, the German Cancer Society (DKG) andthe German Respiratory Society (DGP). He has published papersin numerous peer-reviewed journals and is member of theEditorial Boards of the Journal of Thoracic Oncology, Annals ofOncology and Lung Cancer.

Virginie Westeel

Virginie Westeel is professor of pulmonology at the University ofFranche-Comté (Besançon, France) and head of the ThoracicOncology unit at the University Hospital of Besançon (Besançon).

She is a graduate of the University of Franche-Comté. Herclinical and research activities are exclusively dedicated to lungcancer and her research interests include lung cancertherapeutics, follow-up and evidence-based medicine.

Virginie Westeel is currently the Principal Investigator of theonly large multicentre randomised trial that has been conductedto date on follow-up after lung cancer surgery. Her 93publications mostly include the results of clinical trials in bothearly stage and advanced lung cancer.

Virginie Westeel took on the role of Joint Coordinating Editor ofthe Cochrane Lung Cancer Review Group in 2013. She led the

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development of the French guidelines for lung cancer staging.She has been a member of the scientific committee of theFrench research group, the Intergroupe Francophone deCancérologie Thoracique (IFCT), from 2009 to 2013, and she iscurrently a member of the executive committee of IFCT.Virginie was also a member of the scientific committee ofIASLC between 2005 and 2009, and of the scientific committeeof several World Conference on Lung Cancer (WCLC). She is amember of the American Society of Clinical Oncology (ASCO)and the International Association for the Study of Lung Cancer(IASLC).

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ERS | monograph

IntroductionMartin Reck1, Anne-Marie C. Dingemans2 and Virginie Westeel3

Lung cancer still represents one of the most frequent solid tumours with the highesttumour-associated mortality and increasing global incidence rates.

Relevant changes have been seen in epidemiology and there have been substantialimprovements in all disciplines of lung cancer treatment. However, the picture of lungcancer treatment has become quite complex, and treatment strategies are moving more andmore from global treatment algorithms to individualised treatment.

Standardised and adequate histological, as well as molecular classification (as it is reflectedin the recommendations for ADC classification), have become crucial in order to give theindividual patient the chance of optimal treatment.

As well as relevant steps in surgery and radiotherapy, new impressive opportunities insystemic treatment have opened up through the identification of treatable oncogenic driveralterations and the appropriate targeted therapies. Furthermore, in 2015, after decades ofnegative trials, we are experiencing a fascinating phase of immunotherapy with a completelynew class of agents.

Of all the solid tumours, lung cancer has really demonstrated rapid and substantialprogress in treatment efficacy based on major progress in diagnostics. Therefore, it is ofparamount importance that the pulmonologist as key member of the interdisciplinary teamis familiar with the current state of the art in lung cancer care.

We hope that this issue will be of interest to all researchers, clinicians and surgeons in therespiratory field and that it will help to improve understanding about lung cancer,answering all the questions encountered in everyday practice.

Copyright ©ERS 2015. Print ISBN: 978-1-84984-061-3. Online ISBN: 978-1-84984-062-0. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

Correspondence: Dept of Thoracic Oncology, Lung Clinic, Airway Research Center North (ARCN), Woehrendamm 80, Grosshansdorf 22927,Germany. E-mail: m.reck@lungenclinic.de

1Dept of Thoracic Oncology, Lung Clinic, Airway Research Center North (ARCN), Grosshansdorf, Germany. 2Pulmonology, MaastrichtUniversity Medical Centre, Maastricht, The Netherlands. 3Service de Pneumologie, CHRU Hôpital Jean Minjoz, Besançon cedex, France.4Université de Franche-Comté, Besançon, France.

ERS Monogr 2015; 68: xiii DOI: 10.1183/2312508X.10003615 xiiiPurchased by , From: European Respiratory Society Publications (reader.ersjournals.com)

ADC Adenocarcinoma

ALK Anaplastic lymphoma kinase

COPD Chronic obstructive pulmonary disease

CT Computed tomography

CTLA4 Cytotoxic T-lymphocyte antigen 4

DLCO Diffusing capacity of the lung for carbon monoxide

EBUS Endobronchial ultrasound

EGF Epidermal growth factor

EGFR Epidermal growth factor receptor

EGFR-TKI Epidermal growth factor receptor tyrosine kinase inhibitor

EUS Endoscopic ultrasound

FEV1 Forced expiratory volume in 1 s

FGFR Fibroblast growth factor receptor

FISH Fluorescence in situ hybridisation

FVC Forced vital capacity

HER2 Human epidermal growth factor receptor 2

HGF Hepatocyte growth factor

IHC Immunohistochemistry

LCNEC Large cell neuroendocrine carcinoma

NGS Next-generation sequencing

NSCLC Nonsmall cell lung cancer

PET Positron emission tomography

PFS Progression-free survival

SCC Squamous cell carcinoma

SCLC Small cell lung cancer

TGF Transforming growth factor

TKI Tyrosine kinase inhibitor

VATS Video-assisted thoracoscopic surgery

VEGF Vascular endothelial growth factor

VEGFR Vascular endothelial growth factor receptor

List of abbreviations

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