ESMO Essentials Clinicians Thoracic Tumours 2019 PDF

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Rolf A. Stahel · Solange Peters · Marina Garassino

edited by
Rolf A. Stahel
THORACIC TUMOURS THORACIC TUMOURS Solange Peters

Marina Garassino
SECOND EDITION
E S S E N T I A L S forC L I N I C I A N S SECOND EDITION
E S S E N T I A L S forC L I N I C I A N S
THORACIC TUMOURS
edited by
Rolf A. Stahel
Solange Peters
Marina Garassino
Thoracic Tumours: Essentials for Clinicians
is intended primarily to be read by young oncologists
(residents at the beginning of their career) and provides the reader
with the essential information or ‘What every oncologist
SECOND EDITION
should know’. In addition to more common cancers such as
non-small cell lung cancer, the title also discusses rarer tumour types,
such as extragonadal germ cell tumours. This second edition includes
new chapters on targeted therapy for oncogene-addicted tumours and
immunotherapy for advanced NSCLC. In addition
to the essentials, the book also introduces more advanced
knowledge for those who wish to explore the topic further.
As with all titles in the Essentials for Clinicians series,
the subject is presented in a very visual and didactic
format to enable the reader to easily assimilate the information
and includes revision questions to test the acquired knowledge.
ISBN 978-88-941795-8-3
Series Editor ESMO Press · ISBN 978-88-941795-8-3
Michele Ghielmini
ESMO Press
9 788894 179583
ESMO Press ESMO Press
Thoracic Tumours
Essentials for Clinicians
Second edition
Thoracic Tumours
Essentials for Clinicians
Second edition
Edited by
Rolf A. Stahel
Comprehensive Cancer Center Zürich
Department of Medical Oncology and Hematology
University Hospital Zürich, Zürich, Switzerland
Solange Peters
Department of Oncology, University of Lausanne
Lausanne, Switzerland
Marina Chiara Garassino

Medical Oncology Unit at
Fondazione IRCCS “Istituto Nazionale dei Tumori”, Milan, Italy
Series editor
Michele Ghielmini
Oncology Institute of Southern Switzerland, Ospedale San Giovanni
Bellinzona, Switzerland
ESMO Press
First published in 2014 by ESMO Press. Second edition published in 2019
© 2019 European Society for Medical Oncology
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Contents
Preface vi
Editors vii
Contributors viii
Abbreviations x
Acknowledgements xi
A. W
hat every oncologist should know
1. Epidemiology, pathogenesis and risk factors 1
E Capelletto & S Novello
2. Prevention and screening of lung cancer 7
G Veronesi
3. Diagnosing lung cancer 14
C Dooms
4. Histopathological and molecular characterisation of lung cancer 20
A Warth
5. Principles of surgery of non-small cell lung cancer 26
MA Hoda, T Klikovits & W Klepetko
6. Principles of radiotherapy of thoracic tumours 32
T Finazzi & S Senan
7. Adjuvant and neoadjuvant therapy 38
B Besse
8. Treatment of metastatic non-small cell lung cancer 44
N Reinmuth & M Reck
9. Treatment of small cell lung cancer: chemotherapy and radiotherapy 50
D De Ruysscher
10. Targeted therapy for oncogene-addicted metastatic non-small cell lung cancer 58
M-J Ahn & JF Gainor
11. Immunotherapy for thoracic malignancies: Part A - Non-small cell lung cancer 64
KHJ Lim, V Calvo, M Provencio & R Califano
B. More advanced knowledge

12. Malignant pleural mesothelioma 75
GL Ceresoli, L Gianoncelli & M Bonomi
13. Thymic malignancies 79
N Girard & C Merveilleux du Vignaux
14. Neuroendocrine tumours of lung origin 83
MC Garassino, D Femia & S Pusceddu
15. Immunotherapy for thoracic malignancies: Part B - Small cell lung cancer and mesothelioma 87
V Calvo, KHJ Lim, R Califano & M Provencio
16. Emerging targets and new agents in lung cancer 90
A Januszewski & SB Popat
Appendices
1. WHO Classification 98
2. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory
Society Classification of Lung Adenocarcinoma in Resection Specimens 100
3. Selected treatment schedules 101
Image sources 112

Declarations of interest 114
Index 116
v
Contents
Preface
We are witnessing big improvements in the diagnosis and therapy of thoracic malignancies. This second
edition of Thoracic Tumours: Essentials for Clinicians encompasses the whole spectrum of current
knowledge and provides clinicians with an easily accessible overview as well as a focus on key developments
in thoracic malignancies.
Under the editorial supervision of Solange Peters and Marina Garassino, all the chapters have been
contributed by experts in thoracic malignancies highly regarded in their field, including epidemiology,
pathology, pulmonology, surgery, radiotherapy and medical oncology.
The topics range from pathology to early diagnosis and screening to the current therapeutic options for
lung cancer. In addition, essential information on less common forms of thoracic malignancies such as
mesothelioma, thymic malignancies and neuroendocrine tumours is included. The short and to the point text
together with the many colour illustrations provide the reader with a pleasurable way to acquire information.
Professor Rolf Stahel

Zürich, Switzerland
vi
Preface
Editors
Rolf A. Stahel, MD
Comprehensive Cancer Center Zürich, Department of Medical Oncology and Hematology,
University Hospital Zürich, Zürich, Switzerland
Rolf A. Stahel, MD is Chair of the Comprehensive Cancer Center Zürich, Head of the Center for Lung and Thoracic
Oncology and Senior Staff Physician at the Department of Medical Oncology and Hematology, University Hospital of
Zürich as well as Titular Professor of Medicine at the University of Zürich, Switzerland.
He is a member of the International Association for the Study of Lung Cancer (IASLC), where he served as Chair of the
Fellowship Committee and was a member of the board of directors. In the European Society for Medical Oncology (ESMO)
he has chaired several committees, is a member of the ESMO Council and was ESMO President from 2014 to 2015.
Professor Stahel is President of the Foundation Council of the International Breast Cancer Study Group (IBCSG) and
President of the European Thoracic Oncology Platform (ETOP). He is Editor-in-Chief of Lung Cancer, Editor of Cancer
Treatment Reviews and Editor of the series Progress in Tumor Research.
Solange Peters, MD, PhD

Department of Oncology, University of Lausanne,
Lausanne, Switzerland
Solange Peters is Professor and Chair of Medical Oncology as well as the thoracic malignancies programme in the
Department of Oncology, University Hospital of Lausanne, Switzerland. Professor Peters’ main field of interest is new
biomarker discovery and validation in preclinical and clinical settings. She is also strongly involved and interested in
multimodality trial building for locally advanced non-small cell lung cancer (NSCLC), as well as cancer immunotherapy.
Professor Peters has authored numerous peer-reviewed manuscripts and book chapters and serves as deputy
editor of the Journal of Thoracic Oncology. Professor Peters is active in the educational programmes of the European
Society for Medical Oncology (ESMO) and the International Association for the Study of Lung Cancer (IASLC), notably
working as the current editor of the ESMO lung cancer Clinical Practice Guidelines. She is the Chair of the ESMO
Women for Oncology Committee and the youngest ESMO President-Elect ever, for a mandate in 2020-2021.
Marina Chiara Garassino, MD

Medical Oncology Unit at Fondazione IRCSS “Istituto Nazionale dei Tumori”,
Milan, Italy
Dr Marina Chiara Garassino is Head of the Thoracic Unit at the Medical Oncology Division of the National Cancer
Institute of Milan, Italy, where her main area of research is thoracic oncology.
She graduated in medicine from the University of Milan, and in 1999 she achieved her board specialisation in oncology
and trained in various European institutions. From 2005 to 2011, she held a clinical post at the Fatebenefratelli
Ophthalmic Hospital in Milan.
Dr Garassino is a member of the European Society for Medical Oncology (ESMO) Lung Cancer Faculty, the EU Policy
Committee and Chair of the National Societies Committee. Previously, she was a member of the Publishing Working
Group and ESMO National Representative in Italy. She is the President of Women for Oncology Italy. Dr Garassino has
published 130 articles in English.
vii
Editors
Contributors
M-J Ahn
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Korea
B Besse
Gustave Roussy Cancer Campus, Villejuif; Paris-Sud University, Orsay, France
M Bonomi
Thoracic and GU Oncology Unit, Medical Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy
R Califano
Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester; Department of Medical Oncology,
Manchester University Hospital NHS Foundation Trust, Manchester; Division of Cancer Sciences,
University of Manchester, Manchester, UK
V Calvo
Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
E Capelletto
Department of Oncology, University of Turin, Turin, Italy
GL Ceresoli
Thoracic and GU Oncology Unit, Medical Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy
D De Ruysscher
MAASTRO Clinic, GROW Research Institute, Maastricht University, Maastricht, Netherlands
C Dooms
Department of Respiratory Diseases, University Hospitals KU Leuven, Leuven, Belgium
D Femia
Medical Oncology Unit at Fondazione IRCCS “Istituto Nazionale dei Tumori”, Milan, Italy
T Finazzi
Department of Radiation Oncology, VU University Medical Center, Amsterdam, Netherlands
JF Gainor
Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School,
Boston, MA, USA
MC Garassino
L Gianoncelli
Thoracic and GU Oncology Unit, Medical Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy; Supported by
Fondazione Buzzi Unicem, Casale Monferrato (AL), Italy
N Girard
Thorax Institute Curie Montsouris, Curie Institute, Paris, France
MA Hoda
Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Centre Vienna,
Medical University of Vienna, Vienna, Austria
viii
Contributors
A Januszewski
Department of Medicine, Royal Marsden Hospital, London, UK
W Klepetko
T Klikovits
KHJ Lim
Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
C Merveilleux du Vignaux
Cancer Institute of the Hospices Civils de Lyon, Lyon, France
S Novello
Department of Oncology, University of Turin, Turin, Italy
SB Popat
Department of Medicine, Royal Marsden Hospital, London, UK
M Provencio
Department of Medical Oncology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain
S Pusceddu
M Reck
Department of Thoracic Oncology, LungenClinic Grosshansdorf GmbH, Grosshansdorf, Germany
N Reinmuth
Thoracic Oncology, Asklepios Clinics Munich-Gauting, Gauting, Germany
S Senan
Department of Radiation Oncology, VU University Medical Center, Amsterdam, Netherlands
G Veronesi
Robotic Thoracic Surgery, Humanitas Research Hospital, Milan, Italy
A Warth
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
ix
Contributors
Abbreviations
ABCP Atezolizumab/bevacizumab/carboplatin/paclitaxel LCNEC Large cell neuroendocrine carcinoma

AC Atypical carcinoid LDCT Low-dose computed tomography
ACP Atezolizumab/carboplatin/paclitaxel LINAC Linear accelerator
ACTH Adrenocorticotropic hormone LN Lymph node
ADC Adenocarcinoma mAb Monoclonal antibody
AE Adverse event MEN-1 Multiple endocrine neoplasia type 1
AIS Adenocarcinoma in situ MHC Major histocompatibility complex
AJCC American Joint Committee on Cancer MKI Multikinase inhibitor
ALK Anaplastic lymphoma kinase MPE Malignant pleural effusion
ALL Acute lymphoblastic leukaemia MPM Malignant pleural mesothelioma
APC Antigen-presenting cell MRI Magnetic resonance imaging
ASCO American Society of Clinical Oncology mTOR Mammalian target of rapamycin
ATP Adenosine triphosphate nAChR Nicotinic acetylcholine receptor
BCP Bevacizumab/carboplatin/paclitaxel NET Neuroendocrine tumour
BID Twice daily NGS Next generation sequencing
BSC Best supportive care NK Natural killer
CAR Chimeric antigen receptor NLST National Lung Screening Trial
ChT Chemotherapy NRT Nicotine replacement therapy
CI Confidence interval NSCLC Non-small cell lung cancer
CIS Carcinoma in situ NSE Neuron-specific enolase
CISH Chromogenic in situ hybridisation NSQ Nonsquamous
CNS Central nervous system NTRK Neurotrophic tyrosine receptor kinase
COPD Chronic obstructive pulmonary disease ORR Objective response rate / Overall response rate
CRP C-reactive protein OS Overall survival
CRS Cytokine release syndrome P/D Pleurectomy/decortication
CRT Chemoradiotherapy PAH Polycyclic aromatic hydrocarbon
CT Computed tomography PAS Periodic acid-Schiff
ctDNA Circulating tumour DNA PCI Prophylactic cranial irradiation
CTLA-4 Cytotoxic T-lymphocyte antigen 4 PCR Polymerase chain reaction
DC Dendritic cell PD-1/2 Programmed cell death protein 1/2
DCR Disease control rate PDGFR Platelet-derived growth factor receptor
DFS Disease-free survival PD-L1/2 Programmed death-ligand 1/2
DoR Duration of response PET Positron emission tomography
EBUS Endobronchial ultrsound PFS Progression-free survival
ECOG Eastern Cooperative Oncology Group PORT Postoperative radiotherapy
EGF Epidermal growth factor PS Performance status
EGFR Epidermal growth factor receptor QD Once a day
EMT Epithelial mesenchymal transition qPCR Quantitative polymerase chain reaction
EORTC European Organisation for Research and RATS Robotic-assisted thoracic surgery
Treatment of Cancer RCT Randomised clinical trial
EPP Extrapleural pneumonectomy RECIST Response Evaluation Criteria in Solid Tumours
ERCC1 Excision repair cross-complementation group 1 RR Response rate
ES Extensive stage RT Radiotherapy
ETOP European Thoracic Oncology Platform SABR Stereotactic ablative radiotherapy
EUS Endoscopic ultrasound SBM Solitary brain metastasis
EvG Elastica van Gieson SCC Squamous cell carcinoma
FDA Food & Drug Administration SCLC Small cell lung cancer
FDG Fluorodeoxyglucose SPN Solitary pulmonary nodule
FGFR Fibroblast growth factor receptor SQ Squamous
FISH Fluorescent in situ hybridisation SR Sleeve resection
FNA Fine needle aspiration SST Superior sulcus tumours
GGO Ground glass opacity TBNA Transbronchial needle aspiration
GSP General secretory pathway TC Typical carcinoid
HE Haematoxylin–eosin TCR T cell receptor
HER2 Human epidermal growth factor receptor 2 T-DM1 Ado-trastuzumab emtansine
HIAA Hydroxyindoleacetic acid Teff Effector T cell
HR Hazard ratio TIM-3 T cell immunoglobulin and mucin domain 3
IALT International Adjuvant Lung Cancer Trial TKI Tyrosine kinase inhibitor
IARC International Agency for Research on Cancer TMB Tumour mutation burden
IASLC International Association for the Study of Lung Cancer TMD Transmembrane domain
ICI Immune checkpoint inhibitor TNM Tumour, Node, Metastasis
IDO Indoleamine 2,3-dioxygenase TPC Tunnelled pleural catheter
IFN Interferon TRK Tropomyosin receptor kinase
Ig Immunoglobulin TTF1 Thyroid transcription factor 1
IHC Immunohistochemistry TTP Time to progression
IL Interleukin UFT Tegafur-uracil
IMRT Intensity modulated radiotherapy UICC Union for International Cancer Control
IPD Individual patient data VATS Video-assisted thoracoscopic surgery
ISH In situ hybridisation VDT Volume doubling time
ITT Intention to treat VEGF Vascular endothelial growth factor
LACE Lung Adjuvant Cisplatin Evaluation VEGFR Vascular endothelial growth factor receptor
LAG-3 Lymphocyte-activation gene 3 WBRT Whole brain radiotherapy
LAR Long-acting release WHO World Health Organization
x
Abbreviations
Acknowledgements
We thank all the contributors who have been patient in seeing their work coming to fruition and have
kindly updated their chapters with the most recent data. We also thank Jean-Yves Douillard, who did
a thorough review of many chapters, and Arsela Prelaj, for her work on providing the update to the
treatment schedules.
xi
Acknowledgements
A
What every oncologist should know

1 Epidemiology, pathogenesis and risk factors
USA Incidence and mortality
Lung cancer is the leading cause of cancer-related Estimated New Cases
death in both genders worldwide. In 2019, it is expected Prostate 174,650 20% Breast 268,600 30%
to account for 228 150 new cases and 142 670 deaths in Lung & bronchus 116,440 13% Lung & bronchus 111,710 13%
Colon & rectum 78,500 9% Colon & rectum 67,100 8%
the USA. Urinary bladder 61,700 7% Uterine corpus 61,880 7%
Melanoma of the skin 57,220 7% Melanoma of the skin 39,260 4%
Kidney & renal pelvis 44,120 5% Thyroid 37,810 4%
It is the second most common solid tumour type in both Non-Hodgkin lymphoma
Oral cavity & pharynx
41,090
38,140
5%
4%
Non-Hodgkin lymphoma
Kidney & renal pelvis
33,110
29,700
4%
3%
genders, after prostate cancer in men and breast cancer Leukemia

Pancreas
35,920
29,940
4%
3%
Pancreas
Leukemia
26,830
25,860
3%
3%
in women. All Sites 870,970 100% All Sites 891,480 100%
Estimated Deaths
Lung cancer is the cause of 24% and 23% of all male and
female cancer-related deaths, respectively, exceeding Lung & bronchus
Prostate
76,650
31,620
24%
10%
Lung & bronchus
Breast
66,020
41,760
23%
15%
prostate and breast cancer mortality. Colon & rectum

Pancreas
27,640
23,800
9%
7%
Colon & rectum
Pancreas
23,380
21,950
8%
8%
Liver & intrahepatic bile duct 21,600 7% Ovary 13,980 5%
Leukemia 13,150 4% Uterine corpus 12,160 4%
Esophagus 13,020 4% Liver & intrahepatic bile duct 10,180 4%
Urinary bladder 12,870 4% Leukemia 9,690 3%
Non-Hodgkin lymphoma 11,510 4% Non-Hodgkin lymphoma 8,460 3%
Brain & other nervous system 9,910 3% Brain & other nervous system 7,850 3%
All Sites 321,670 100% All Sites 285,210 100%
Fig. 1.1
In both genders, USA lung cancer incidence rates

increased from the 1970s, until the mid 1980s in men and
the late 1990s in women.
Incidence is now beginning to decline, possibly due

to the reduction in smoking prevalence. Differences
in lung cancer incidence patterns between men and
women reflect mainly historical disparities in smoking
habits.
Cigarette smoking prevalence peaked about 20 years

later in women than in men.
Fig. 1.2
The USA lung cancer death rate rose for most of the
20th century, peaking at the beginning of the 1990s for
men, and almost two decades later for women.
Lung cancer death rates have followed the same trend as

smoking prevalence and incidence rates, demonstrating
the strong correlation between the major risk factor and
the disease and the poor prognosis of this malignancy,
respectively.
Recently, a steady decline in lung cancer death rates has
been observed in both sexes, as a result of combined
improvements in primary prevention, control of associated
risk factors, and treatment.
Fig. 1.3
REVISION QUESTIONS
1. What is the lung cancer incidence trend in the USA over the last 20 years?
2. Is there a difference in lung cancer mortality rates between men and women?
3. What is the percentage of deaths due to lung cancer among all cancer-related deaths?
1
Capelletto & Novello
European scenario
European predictions for the year 2018 in men and 60

60
EU
EU male
male EUEUfemale
female
women, estimated 267 000 and 121 000 lung cancer-

related deaths, respectively, corresponding to about 50
50
20
20
20% of total cancer deaths in both sexes combined.
population
population
40
40
population
population
15
15
Lung cancer is the primary cause of cancer-related deaths

Lung
Lung
Breast
Breast
100 000
100 000
Lung
Lung
in men in Europe and is second only to breast cancer
per 100,000
per 100,000
30
30
in women, with a very slight difference in the number of 10

10
Deathsper
Deathsper
Colorectum
Colorectum
Deaths
Deaths
expected deaths. 20
20
Colorectum
Colorectum
Pancreas
Pancreas
55
European mortality for lung cancer peaked in the late 10
10 Prostate
Prostate
Pancreas
Pancreas
Uterus
Uterus
Stomach
Stomach
1980s in men and began declining later, while in women, Stomach

Stomach
Leukemias
Leukemias
Leukemias
Leukemias
in contrast to the USA scenario, mortality continues to 00 00
increase with 26.4 cases/100 000 in 2018. An opposite 1970 1980 1990 2000 2010 2020 1970 1980 1990 2000 2010 2020
1970 1980 1990 2000 2010 2020 1970 1980 1990 2000 2010 2020
Calendar year
Calendar year Calendar
Calendaryear
year
trend has been observed in breast cancer. Fig. 1.4
An evaluation performed in 2018 revealed that the lung

Men Women cancer incidence rate for men was highest in Central
Europe 65.2 26.4
and Eastern European countries and lowest in
EU-28 63.5 32.2
Northern Europe.
Western Europe
Belgium 78.1 39.7

France (metropolitan) 74.2 31.8
Germany 60.9 39.2
Netherlands 52.0 47.1
Luxembourg
Austria
Switzerland
60.9
48.4
40.0
26.6
33.0
28.3
On the contrary, with the exception of Hungary, the
Serbia
Greece
100.9
99.0 23.5
42.8 incidence rate for women was highest in Northern
Montenegro
European countries and lowest in Eastern Europe.
89.5 26.8
Southern Europe
Bosnia Herzegovina 89.4 19.3

FYR Macedonia 79.0 20.0
Slovenia 68.5 29.7
Croatia 75.6 25.8
Spain 62.3 19.7
Italy
Considering both sexes combined, the highest incidence
52.7 23.3
Cyprus 61.3 12.4
Albania 56.2 10.5
Portugal
rates were seen in Hungary (incidence rate 111.6 cases/
55.2 13.8
Malta 43.7 17.1
Denmark
100 000 for men and 58.7 cases/100 000 for women).
56.4 53.8
Ireland 59.4 43.9
Northern Europe
United Kingdom 55.0 45.6

Norway 47.0 43.3
Iceland 41.0 48.1
Estonia 76.3 21.9
Lithuania 77.0 13.5
Latvia 77.6 14.0
Finland 37.8 21.8
Sweden 25.6 26.4
Central & Eastern Europe
Hungary 111.6 58.7

Poland 78.5 35.4
Slovakia 79.7 19.1
Romania 72.8 18.1
Bulgaria 71.1 15.8
Czech Republic 57.7 26.5
Moldova 71.3 14.9
Belarus 78.2 8.2
Russian Federation 69.6 11.7
Ukraine 59.7 9.2
120 100 80 60 40 20 0 20 40 60
Age-standardised incidence (E) per 100,000
Fig. 1.5
Lung cancer rates in underdeveloped countries are lower

than in developed ones, although incidence and mortality
are slowly increasing.
The World Health Organization estimates that lung cancer
deaths worldwide will continue to rise, largely as a result
of an increase in global tobacco consumption (over one
billion smokers worldwide).
Worldwide, every year, as many people die from

lung cancer as the cumulative number resulting from
prostate, breast and colon cancers. Fig. 1.6
REVISION QUESTIONS
1. Are there differences in the lung cancer mortality rates between the USA and Europe?
2. Is lung cancer incidence homogeneous throughout Europe?
3. What is the mortality rate due to lung cancer compared with other ‘big killers’?
2
Epidemiology, pathogenesis and risk factors
Clinical features and survival expectancy
Around only 15% of all lung cancer cases are diagnosed n All Races n White n Black
at an early stage, with a 5-year survival rate >50%.
In a large percentage of cases, lung cancer is diagnosed

at an advanced stage with distant metastases and a 57 57
61
Percent
Percent
56 56 52
5-year survival rate of about 5%.
30 30 27
The 5-year survival rate for all lung cancer stages 16 17 13
22 22 22
19 19 16
combined is about 18%. 5 5 5
Stage at Diagnosis Stage at Diagnosis

Fig. 1.7
Stage distribution 5-year relative

by race, United States, survival rates by race and stage
2008-2014 at diagnosis, United States,
2008-2014
Lung cancer in both sexes is predominantly diagnosed

in the elderly population (median age at diagnosis is
71 years).
Compared with men, women are less likely to have a

smoking history, are generally younger at the time of
diagnosis, and have a better survival expectancy at any
stage, independent of the therapeutic approach.
Lung adenocarcinoma is the most common histological
subtype among women.
Fig. 1.8
Adenocarcinoma accounts for 38.5% of all lung cancer

cases, while squamous cell carcinoma and large cell
carcinoma account for 20.0% and 2.9%, respectively.
Over the past decades, adenocarcinoma incidence
has progressively increased, and it has now replaced
squamous cell carcinoma as the most prevalent
non-small cell lung cancer histotype.
Lung adenocarcinoma is also the most represented

histotype among never-smokers.
Fig. 1.9
REVISION QUESTIONS
1. What is the proportion of patients with lung cancer diagnosed at early stage of disease?
2. Is there a correlation between a clinical characteristic (such as female gender or smoking attitude) and one specific histotype?
3. Is the subtype histology prevalence the same compared with 30 years ago?
3
Pathogenesis of lung cancer
The major function of the lungs is respiratory exchange. Central compartment Large bronchus
Ciliated cell
Inhaled air and potentially dangerous substances are Mucous cell
conducted to the alveoli through a network of bronchi

and bronchioles. Primary
Neuro-endocrine
bronchus
cell
Basal cell Basement membrane
The putative stem cells of the bronchus are basal cells,
Secondary
bronchus
Tertiary Peripheral compartment
which are believed to give rise to the differentiation of bronchus

Respiratory bronchiole
ciliated, mucous and neuroendocrine cells. Bronchiole
Terminal
Lung cancer may arise from all these differentiated bronchiole
Alveoli
and undifferentiated cells, from either the central (small
Alveolus
cell lung cancer and squamous cell carcinoma) or the Respiratory bronchiole
Clara cell
peripheral (adenocarcinoma) airway compartment. Respiratory

bronchiole Alveolar
Ciliated cell duct
Basement
membrane Alveolus
Interstitium Alveolus
Type I
pneumocyte
Type II
pneumocyte
Alveolus
Fig. 1.10
The interaction between inhaled carcinogens and the

epithelium of upper and lower airways leads to the
formation of DNA adducts: pieces of DNA covalently
bound to a cancer-causing chemical.
Repair processes may remove the DNA adducts and

restore normal DNA, or alternatively cells with damaged
DNA may undergo apoptosis.
If DNA adducts persist or are misrepaired, they result in a

mutation and can cause genomic alterations. These are
key events in lung cancer pathogenesis, especially if they
Fig. 1.11
occur in critical oncogenes and tumour suppressor genes.
Lung cancer pathogenesis is also affected by a genetic Carrier Healthy

component: it relates to the host susceptibility to lung
cancer, with or without exposure to carcinogens.
Normal gene
Studies on familial aggregation have supported the
Mutated gene
hypothesis that a multifactorial hereditary component Cancer susceptibility
is possible, even if a clear mechanism of familial
transmission is still not described.
The addition of smoking to this genetic inheritance is

associated with a three-fold increased lung cancer risk.
Carrier Carrier Healthy Healthy Fig. 1.12
REVISION QUESTIONS
1. Is there a unique and specific component of airway epithelium from which lung cancer can arise?
2. What are the consequences of the action of inhaled carcinogens on the airways’ epithelium?
3. Does the hereditary component have a role in lung cancer pathogenesis?
4
Risk factors
Smoking is considered the principal risk factor in lung

Common risk factors for lung cancer
cancer patients, causing more than 80% of all cases.
Non-smoking-related risk factors include occupational

exposure to asbestos, chromium, arsenic, cadmium, Occupation
(miners,
silica and nickel, as well as second-hand smoke, heavy metal Smoking/ Second-hand Dietary
workers) tobacco smoke Family history factors
outdoor air pollutants, previous lung diseases, radon
exposure and dietary factors.
The main modifiable risk factors for cancer pathogenesis

are smoking habit, alcohol consumption, overweight Other illnesses
(such as COPD, Exposure to
and obesity, and the correct intake of meat, fruit and Radon gas Ageing tuberculosis, etc) Pollution radiation
vegetables in the diet.

Fig. 1.13
COPD, Chronic obstructive pulmonary disease
Acetone
(solvent) Cyanhydric acid
(was used in the gas chambers) The International Agency for Research on Cancer (IARC)
*Naphthylamine has identified at least 50 carcinogens in tobacco smoke,
Ammoniac
(detergent)
Methanol targeting both central and peripheral airways.
(used as rocket fuel)
*Pyrene *Urethane
The most potent carcinogens in cigarette smoke are
Naphthalene Toluene the polycyclic aromatic hydrocarbons (PAHs) and the
(moth-repellent) (industrial solvent)
aromatic amines, N-nitrosamines. It also contains
Nicotine Arsenic
(used as a herbicide and insecticide) (lethal poison) benzene, vinyl chloride, arsenic, chromium, radon, and
its decay products, bismuth and polonium.
*Cadmium *Dibenzacridine
(used in batteries)
*Polonium 210
Carbon monoxide (a radioactive element) In the absence of such risk factors, the genetic
(found in exhaust fumes) DDT susceptibility to lung cancer remains the only other
(insecticide)
Vinyl chloride parameter predisposing to the onset of the disease.
(used in plastic materials) *Known carcinogenic substances
Fig. 1.14
An estimated 10%–25% of lung cancers worldwide

occur in never-smokers, defined as individuals who have 5
smoked less than 100 cigarettes in their lifetime. All 10 Europe (n = 22,742)
22 US (n = 15,181)
Cancers arising in never-smokers predominantly target 23
East Asia (n = 20,206)
the distal airways, favouring adenocarcinoma histology 2
South Asia (n = 1,166)
and female gender. One of the most relevant risk factors Male 6
11
is environmental tobacco smoke exposure. 15
21
Lung cancer prevalence in never-smokers is higher in Female 15
Asian countries, especially in women, probably due 61
83
to the inhalation of cooking oil vapours and particles
0 20 40 60 80 100
emitted by domestic use of coal for cooking and heating. Proportion of lung cancer cases in never-smokers (%)
Fig. 1.15
REVISION QUESTIONS
1. What is the definition of ‘never-smokers’?
2. Is there a different distribution of lung cancer in never-smokers across the world?
3. Which are the most potent carcinogens of cigarette smoke?
5
Summary: Epidemiology, pathogenesis, and risk factors
• Lung cancer is the leading cause of cancer-related death worldwide in both genders
• USA incidence rates in both genders increased until the 1990s and began to decline later, similar to the trend in mortality
• In Europe, lung cancer-related deaths in women are secondary only to breast cancer and, in contrast to the USA
scenario, the mortality rate continues to increase
• Worldwide, every year, as many people die from lung cancer as from the other ‘big killers’ (prostate, breast, and colon
cancer) combined
• Only 15% of all lung cancer cases are diagnosed at an early stage, while the majority present with distant metastases
at diagnosis and a 5-year survival rate of about 5%
• Median age at diagnosis is 71 years and adenocarcinoma is now the most prevalent histotype
• Lung cancer may arise from all the differentiated and undifferentiated cells of the upper and lower airways. The
formation of DNA adducts as a consequence of the inhalation of carcinogens plays a central role in lung cancer
pathogenesis
• Lung cancer pathogenesis is also affected by a genetic multifactorial susceptibility, which may be further influenced by
exposure to certain carcinogens
• Smoking is the principal risk factor for lung cancer, causing more than 80% of all cases
• Non-smoking-related risk factors include occupational exposure to carcinogens, second-hand smoke, pollution,
dietary factors, radon exposure and genetic susceptibility
Further Reading
Boffetta P. Classic epidemiology of lung cancer. Chapter 3 in: Multidisciplinary Approach to Thoracic Oncology. Aurora, Colorado:
IASLC Press, 2014.
Couraud S, Zalcman G, Milleron B, et al. Lung cancer in never smokers – a review. Eur J Cancer 2012; 48:1299–1311.
Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med 2011; 32:605–644.
Didkowska J, Wojciechowska U, Mańczuk M, Lobaszewski J. Lung cancer epidemiology: contemporary and future challenges
worldwide. Ann Transl Med 2016; 4:150.
Ferlay J, Colombet M, Soerjomataram I, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 European countries
and 25 major cancers in 2018. Eur J Cancer 2018; 103:356–387.
Gazdar AF, Zhou C. Lung cancer in never smokers: a different disease. Chapter 4 in: Multidisciplinary Approach to Thoracic Oncology.
Aurora, Colorado: IASLC Press, 2014.
Hashim D, Boffetta P, La Vecchia C, et al. The global decrease in cancer mortality: trends and disparities. Ann Oncol 2016; 27:926–933.
Malhotra J, Malvezzi M, Negri E, et al. Risk factors for lung cancer worldwide. Eur Respir J 2016; 48:889–902.
Nielsen LS, Bælum J, Rasmussen J, et al. Occupational asbestos exposure and lung cancer – a systematic review of the literature.
Arch Environ Occup Health 2014, 69:191–206.
Novello S, Stabile LP, Siegfried JM. Gender-related differences in lung cancer. Chapter 5 in: Multidisciplinary Approach to Thoracic
Oncology. Aurora, Colorado: IASLC Press, 2014.
Pallis GA, Syrigos KN. Lung cancer in never smokers: disease characteristics and risk factors. Crit Rev Oncol Hematol 2013;
88:494–503.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69:7–34.
Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers – a different disease. Nat Rev Cancer 2007; 7:778–790.
Torres-Durán M, Barros-Dios JM, Fernández-Villar A, Ruano-Ravina A. Residential radon and lung cancer in never smokers.
A systematic review. Cancer Lett 2014; 345:21–26.
6
2 Prevention and screening of lung cancer
Smoking cessation
Nicotine dependence – also called tobacco dependence

– is an addiction to tobacco products caused by nicotine
products present in tobacco.
Nicotine binds nicotinic acetylcholine receptors

(nAChRs), increasing levels of several neurotransmitters
which contribute to inducing strong dependence.
Proven treatments fall into two major categories:

psychosocial counselling (also called behavioural support)
and pharmacotherapy. Combining the two enhances the
success rate.
Fig. 2.1
GABA, Gamma-aminobutyric acid.
Three first-line treatment categories are approved in the USA

Tailored online support and many other countries: nicotine replacement therapy
(NRT), bupropion (atypical antidepressant), and varenicline
One-to-one support
or cytisine (selective nicotine receptor partial agonists).
Group support
Varenicline, the newest product to market, is effective, but
Telephone support enthusiasm has been tempered by post-marketing concerns
NRT alone
about psychiatric side effects and possible increased risk
of cardiovascular events. A similar compound is available at
NRT/bupropion +
support lower cost and comparable in efficacy (cytisine).
Varenicline + support
The figure shows percentage increases in the success
0 5 10 15 20 rate for smoking cessation at 6 months compared with
Fig. 2.2 unaided attempts for each type of cessation support.
NRT, Nicotine replacement therapy.
Smoking cessation is associated with anger, anxiety, Within 20 min, blood pressure and heart rate decrease
depression, impaired concentration, impatience, insomnia Within 12 hours, carbon monoxide levels in the blood decrease to normal
and restlessness. These symptoms peak within the first
Within 48 hours, nerve endings and sense of smell and taste start recovering
week and last 2–4 weeks.
Within 3 months, circulation and lung function improve
The table summarises the immediate and late benefits
Within 9 months, coughing and shortness of breath decrease
of smoking cessation.
Within 1 year, the risk of coronary heart disease is cut by half
The risk of cardiovascular events reduces rapidly after Within 5 years, the risk of stroke falls to that of a non-smoker, and the risks of
cessation, while oncological risks remain higher than developing several cancers (mouth, throat, oesophagus, bladder, uterine cervix)
fall significantly
those of never smokers for ~15 years.
Within 10 years, the risk of dying from lung cancer is cut by half, and the risks of
laryngeal and pancreatic cancers also decrease considerably
Within 15 years, the risk of coronary heart disease falls to that of a non-smoker;
the risk of developing chronic obstructive pulmonary disease (COPD) also falls
considerably Fig. 2.3
REVISION QUESTIONS
1. What are the two main treatment categories for nicotine dependence?
2. What are the main symptoms that can occur after stopping smoking?
3. What are the early and late benefits of smoking cessation?
7
Veronesi
Chemoprevention of lung cancer
The figure illustrates the steps in the development of

squamous cell lung cancer. Bronchial epithelial cells
pass through several altered stages in the progression to
carcinoma in situ (CIS).
Adenocarcinoma, on the other hand, seems to be preceded

by a premalignant lesion (atypical adenomatous hyperplasia)
and preinvasive adenocarcinoma in situ (AIS, formerly known as
bronchoalveolar carcinoma) which progresses to invasive cancer.
Chemopreventive agents are expected to promote tissue/cell
repair and block progression, by suppressing inflammation,
interfering with growth stimulation, restoring epithelial
differentiation and/or improving immune surveillance.
CIS, Carcinoma in situ. Fig. 2.4

Intervention Endpoint n Outcome
13-cis-retinoic acid Metaplasia, dysplasia 100 Negative
Fenretinide Metaplasia 82 Negative
Phase III lung cancer prevention trials have tested
Etretinate Sputum atypia 150 Negative aspirin, retinyl palmitate, 13-cis-retinoic acid,
Beta-carotene Sputum atypia 1067 Negative vitamin E, multivitamin supplement,
Vitamin B12/folate Sputum atypia 73 Negative mineral supplement, selenium and beta-
Negative for primary endpoint;
Budesonide Dysplasia 112 fewer nodules in treatment group carotene. All were ineffective. Beta-carotene
Budesonide Nodule size 202 Negative was harmful to current smokers.
Fluticasone Nodule size and number 201 Negative
Negative for primary endpoint; rate of Phase II cancer prevention trials rely on
Anethole dithiolethione New dysplastic lesions 101 worsening lower in treatment group intermediate biological endpoints as surrogates
Positive in former smokers only
Iloprost Dysplasia 152 (improved endobronchial histology) of cancer incidence and mortality.
Positive (decreased Ki-67 labelling
Ki-67 204 index in former smokers) The table shows the main published phase II
Celecoxib Ki-67 101 Positive (decreased Ki-67 labelling
index in former smokers) trials, types of agent used, number of cases and
Promising: a phase I trial with results. No trial has shown a clear benefit for a
Myo-inositol Dysplasia 26 historical control Fig. 2.5
chemopreventive agent compared to placebo.
While in the past most studies had precursors of squamous
cell carcinoma as potential pathological target lesions, after
the introduction of lung cancer screening, more recent studies
have focused on precursors of adenocarcinoma (sub-solid
peripheral lesions). Control Aspirin
5
Results of meta-analysis on the effect of daily aspirin on long-
term risk of cancer death led to aspirin being considered as 4
Risk of cancer death (%)
one of the most promising investigational cancer prevention

3
agents. Aspirin was associated with reduced mortality risk for
adenocarcinoma affecting several distinct organs (-40% for 2
lung cancer adenocarcinoma).
1
Recent data from a large randomised, placebo-controlled
study on canakinumab, an interleukin-1 beta inhibitor given 0
0 5 10 15 20
for cardiovascular prevention in CRP (C-reactive protein)-
Year to death
positive patients, showed a significant reduction in lung cancer Fig. 2.6
incidence and mortality.
REVISION QUESTIONS
1. By what mechanisms do chemopreventive agents promote cell repair and block tumour progression?
2. Have chemopreventive agents against lung cancer proven effective when tested in phase III trials?
3. What are the main endpoints of phase II trials on lung cancer prevention?
8
Prevention and screening of lung cancer
Chest X-ray and low-dose computed tomography
The aim of screening is to detect lung cancer at a stage

when it is not causing symptoms and when treatment is
most successful.
Screening should: (a) improve outcomes; (b) be

scientifically validated in terms of sensitivity and
specificity; and (c) be low risk, reproducible, accessible
and cost effective.
In the 1970s chest X-ray and sputum screening trials
showed no mortality reduction in the screening arm
compared with the no-screening arm. The results of the
Mayo Lung Project, from over 10 000 high-risk men, are
shown in the figure. Fig. 2.7
The introduction of spiral multi-detector computed

100 Resected clinical stage I cancer, 92% (95% CI, 88–95)
tomography (CT) of the chest has made it possible to
80 All lung cancers, 80% (95% CI, 74–85) reduce the radiation dose to 10%–20% of that of standard
CT, maintaining high sensitivity for small nodules.
Survival (%)
60
40
The single arm I-ELCAP study used low-dose CT
20 (LDCT) screening to detect 484 lung cancer cases
0 among 31 000 participants. Overall cancer-specific
0 12 24 36 48 60 72 84 96 108 120
Months
survival was very high at 80% in a publication from 2006.
No. at Risk
All participants
Participants
484
302
433
280
356
242
280
191
183
120
90
59
50
34
28
18
16
12
9
7
2
1
Other single-arm studies have shown similarly high
undergoing survival, as well as favourable stage distribution and small
resection
Fig. 2.8 mean size of diagnosed cancers.
CI, Confidence interval.
Lung nodules detected at CT are divided into: solid, partially

solid and non-solid. Volume doubling time (VDT) has been
introduced to distinguish malignant from benign nodules
and define the aggressiveness of malignant nodules.
No-contrast LDCT has limited resolution in centrally

located cancers. The figures show a right lower lobe
cancer diagnosed only at the 4th scan in one year.
LDCT has much higher resolution in peripheral nodules.
In fact, most cancers diagnosed by LDCT screening
are peripheral stage I adenocarcinomas.
LCDT screening also gives useful information on collateral

smoking-related diseases such as cardiovascular risk
(with calcium score) and emphysema.
Fig. 2.9
REVISION QUESTIONS
1. Did trials on chest X-ray screening show reduced lung cancer mortality in the screened arm?
2. What was the main result of the I-ELCAP study on LDCT screening for lung cancer?
3. What is the most common type of lung cancer diagnosed by LDCT screening?
9
Veronesi
LDCT screening for lung cancer:
results of randomised studies and guidelines
Over-diagnosis and lead-time bias may contribute to

improved survival and stage shift found for screening- LDCT - RANDOMISED STUDIES
detected lung cancers compared with historical controls.
To overcome these biases and determine mortality

reduction in LDCT-screened populations compared
with controls, a number of randomised trials were
started in Europe and the USA.
The USA National Lung Screening Trial (NLST) was a

prospective, randomised lung cancer screening trial
comparing annual LDCT scan with annual chest X-ray
for 3 years.
Fig. 2.10
DLCT, Danish Lung Cancer Screening Trial; LDCT, low-dose computed tomography; LSS, Lung
Screening Study; NLST, USA National Lung Screening Trial.
The NLST enrolled 53 454 high-risk participants aged

Death from Lung Cancer
55–74 years who had at least a 30-pack-year
500 smoking history.
Cumulative No. of Lung-Cancer Deaths
Chest radiography
400
The NLST found a 20% reduction in lung cancer-
Low-dose CT
specific mortality and a 7% reduction in all-cause
300
mortality in the screened arm after 5 years.
200
100
Most published European studies did not find a
significant reduction in mortality; however, recent data
0 from the NELSON study showed a significant reduction
0 1 2 3 4 5 6 7 8
Years since Randomisation
in lung cancer mortality in the CT arm compared with the
Fig. 2.11 control (hazard ratio [HR] 0.84 in men, 0.58 in women).
CT, Computed tomography.
As a consequence of the NLST and NELSON findings,

NELSON study
most scientific organisations have recommended LDCT lung
cancer screening implementation in high-risk individuals.
High-risk populations are defined according to the NLST
(age >55 years, at least 30 pack-years). Those enrolled in
LDCT screening should also adhere to smoking cessation
programmes.
Most authorities agree that LDCT screening should

take place only within a programme run by a centre
with experience in CT screening, a dedicated
multidisciplinary team to manage findings, and with
Fig. 2.12
quality and effectiveness control procedures in place.
REVISION QUESTIONS
1. What are the potential biases of single-arm screening studies with LDCT?
2. Was the NLST able to demonstrate a reduction in lung cancer mortality in the screened arm?
3. What are the recommendations of several scientific societies to heavy smokers regarding the possibility to be screened?
10
Performance of LDCT screening and risk modelling
The figure shows the distribution according to VDT of

lung cancers diagnosed over 5 years in a screening
study; 10% of cases had VDT ≥600 days and were
considered indolent or ‘over-diagnosed’.
Another risk of screening is that invasive procedures are often

performed for what is benign disease: 0%–25% of ‘positive’
nodules are diagnosed as benign in published studies.
Eight to nine percent of screening-detected lung cancers
are estimated as diagnosed with delay, due to central
position or fast-growing disease. Fig. 2.13
PET, Positron emission tomography.
To reduce the proportion of false-positives and false-

negatives, diagnostic protocols have been developed
to manage the high number of indeterminate nodules
detected by CT screening.
A ‘further investigation’ threshold of 5 mm was recently

amended to 6 mm; smaller nodules are investigated at
the next annual scan. Positron emission tomography
(PET) can be useful in reducing invasive investigations
for differential diagnosis. PET-CT can reduce the use of
more invasive procedures to diagnose benign disease.
Fig. 2.14
The NELSON study introduced software-calculated VDT
into the nodule management algorithm.
Lung Model prediction

Author, Variables included in lung cancer risk
Models have been developed to estimate Country cancer accuracy: area under
publication year prediction model
cases the ROC curve
the risk of individuals developing lung Bach et al, 2003 USA 1070 Age, sex, asbestos exposure history, smoking history 0.72
cancer: to reduce both costs and the Spitz et al, 2008 USA 725
Smoking history, emphysema, dust exposure,
family history of cancer, asbestos exposure history,
Former smokers: 0.70
Current smokers: 0.73
number of potentially harmful screening hayfever, DNA repair capacity, bleomycin treatment
Smoking history, pneumonia, asbestos exposure
CT scans. PLCO12 has been validated in Cassidy et al, 2008 UK 579 history, previous cancer, family history of cancer 0.70
large screening cohorts. Young et al, 2009 New Zealand 239 Panel of 20 single nucleotide polymorphisms, age, 0.77
family history of lung cancer
Calabro et al, 2010 Italy 57 FEV1%pred 0.70
The table summarises efficacy (area Smoking history, pneumonia, asbestos exposure
Raji et al, 2010 UK 200 history, previous cancer, family history of cancer 0.75
under ROC curve) of published + SEZ6L genotype
risk models. Most models use Maisonneuve et al,
Model 1: Age, sex, asbestos exposure history, Model 1: 0.62
Italy 55 and smoking history
epidemiological variables to estimate 2011
Model 2: As model 1 + CT findings Model 2: 0.76
risk; some combine epidemiological Tammemagi et al, Multinational Age, education, body mass index, family history of Model 1: 0.78
1040 lung cancer, COPD, recent chest X-ray, smoking
risk factors with DNA repair assays. 2011 10 sites Model 2: 0.84
history
Former smokers: 0.83
Hoggart et al, 2012 Multinational 1250 Smoking history Current smokers: 0.82
The COSMOS risk model incorporated Europe
Ever smokers: 0.84
epidemiological variables with first Lin et al, 2012 China 633 Sex, lung disease history, occupational exposure, 0.71
family history, smoking history
screening CT findings. Validation is Smoking status + genetic score based on 5 single
ongoing. Low-risk individuals identified Li et al, 2012 China 2283 nucleotide polymorphisms (rs2736100, rs402710,
rs1051730, rs4083914, rs4488809)
0.64
by this model may benefit from an Park et al, 2013 Korea 10 007 Smoking history, body mass index, physical activity, 0.87
fasting glucose levels
increased interval between screenings. Fig. 2.15
COPD, Chronic pulmonary obstructive disease; CT, computed tomography; FEV1%pred, forced expiratory volume in 1 second % predicted.
REVISION QUESTIONS
1. What is the estimated rate of indolent cancers (potentially over-diagnosed cases) in LDCT screening?
2. Are the risks of false-positive cases and useless interventions limitations of LDCT screening as currently practised?
3. What are the objectives of risk modelling in the screening context?
11
Veronesi
Future perspectives in diagnosis and treatment
Lung cancer biomarkers could gain a potential role

in risk stratification and early-stage disease detection.
A simple blood test providing a reliable risk estimate might
encourage widespread implementation and uptake of
screening and refine its specificity.
Potential biomarkers for lung cancer screening include:

serum autoantibodies, DNA hyper-methylation in
sputum, volatile compounds in breath, proteomic
methods and serum-micro RNAs.
More recently, mutation panel tests of cell-free circulating

tumour DNA have emerged as promising potential
screening markers.
Fig. 2.16
AC, Adenocarcinoma; SCC, squamous cell carcinoma.
Screening detects more cancers at an earlier stage,

where less invasive surgery is justified – this is associated
with less postoperative pain and fewer complications
when compared with traditional open thoracotomy.
A meta-analysis found that the video-thoracoscopic
approach seems to be associated with improved
oncological outcomes, compared with open thoracotomy.
Robotic surgery is a fast-growing development of

the video-thoracoscopic approach to lung cancer
resection. Advantages are: high-definition 3D view,
7 degrees of movement, hand tremor filtration, and
better ergonomics; although costs are higher.
Fig. 2.17
Less extensive lung resections might also be justified

in selected patients. Large retrospective studies show
that oncological outcomes after sublobar resection
in patients with cT1N0M0 non-small cell lung cancer
(NSCLC) of 2 cm or smaller are equivalent to those for
standard lobectomy. Randomised trials are ongoing.
Also for small (<1 cm) or PET-negative nodules, hilar and

mediastinal lymph node dissection may not be essential
as risk of nodal involvement is limited.
Pilot studies indicate that stereotactic ablative
radiotherapy (SABR) is a promising alternative to surgical
resection of very early cancers, as shown mainly in
inoperable patients to date. Fig. 2.18
REVISION QUESTIONS
1. Why are molecular markers likely to become important in the early detection of lung cancer?
2. What reduced-invasiveness surgical treatments are currently being used and tested for early-stage lung cancers?
3. Is minimally invasive surgery indicated for screening-detected lung cancers?
12
Summary: Prevention and screening of lung cancer
• Smoking is a chronic disease-promoting condition due to nicotine addiction
• Treatment with varenicline, cytisine, nicotine replacement therapy or bupropion is more effective than counselling alone
in inducing people to stop smoking
• None of the chemopreventive agents tested in large phase III lung trials demonstrated a protective effect against lung
cancer
• Recent phase II trials of chemopreventive agents adopted intermediate endpoints (adenocarcinoma precursors)
as surrogates for cancer incidence and mortality
• Screening with chest X-ray is not effective in reducing lung cancer mortality, as demonstrated by several trials
conducted in the 1970s
• Studies show that LDCT is highly sensitive for very early cancers. The results of the I-ELCAP study indicate that
screening can diagnose lung cancer at an early stage and improve survival
• The USA NLST and the European NELSON study showed that LDCT screening significantly reduces lung cancer
mortality in a defined high-risk population
• Most scientific societies recommend annual LDCT screening in smokers (>30 pack-years) over 55 years of age but
risk models are emerging as new tools to select target population
• Diagnostic algorithms should be used to manage indeterminate nodules and reduce false positives
• Assessment of calcium score to prevent cardiovascular events is considered a collateral benefit of LDCT screening
• Persons undergoing LDCT screening should be actively encouraged to stop smoking
Further Reading
Bianchi F, Nicassio F, Marzi M, et al. A serum circulating miRNA diagnostic test to identify asymptomatic high-risk individuals with early
stage lung cancer. EMBO Mol Med 2011; 3:495–503.
International Early Lung Cancer Action Program Investigators, Henschke CI, Yankelevitz DF, Libby DM, et al. Survival of patients with
stage I lung cancer detected on CT screening. N Engl J Med 2006; 355:1763–1771.
De Koning H, Van Der Aalst C, Ten Haaf K, et al. Effects of volume CT lung cancer screening: Mortality results of the NELSON
randomized-controlled population based trial. 2018 World Conference on Lung Cancer. Abstract PL02.05.
Keith RL, Miller YE. Lung cancer chemoprevention: current status and future prospects. Nat Rev Clin Oncol 2013; 10:334–343.
Lemmens V, Oenema A, Knut IK, Brug J. Effectiveness of smoking cessation interventions among adults: a systematic review of
reviews. Eur J Cancer Prev 2008; 17:535–544.
Maisonneuve P, Bagnardi V, Bellomi M, et al. Lung cancer risk prediction to select smokers for screening CT—a model based on the
Italian COSMOS trial. Cancer Prev Res (Phila) 2011; 4:1778–1789.
National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose
computed tomographic screening. N Engl J Med 2011; 365:395–409.
Ridker PM, MacFadyen JG, Thuren T, et al; CANTOS Trial Group. Effect of interleukin-1β inhibition with canakinumab on incident lung
cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 2017;
390:1833–1842.
Rothwell PM, Fowkes FG, Belch JF, et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient
data from randomised trials. Lancet 2011; 377:31–41.
van Klaveren RJ, Oudkerk M, Prokop M, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med 2009;
361:2221–2229.
Veronesi G, Maisonneuve P, Bellomi M, et al. Estimating overdiagnosis in low-dose computed tomography screening for lung cancer:
a cohort study. Ann Intern Med 2012; 157:776–784.
Wender R, Fontham ET, Barrera E Jr, et al. American Cancer Society lung cancer screening guidelines. CA Cancer J Clin 2013;
63:107–117.
13
Veronesi
Diagnosing lung cancer 3
Clinical presentation
Lung cancer may be found

incidentally on chest imaging, within
a screening programme, or may
present with symptoms.
Symptoms as a result of the location

of the primary tumour: cough,
haemoptysis, dyspnoea, wheezing.
Fig. 3.1
Cough with Screen-detected

haemoptysis nodule
Symptoms as a result of local

invasion or compression of adjacent
structures: chest pain (pleural, chest
wall or mediastinal invasion), stridor,
hoarseness (left recurrent laryngeal
nerve), dysphagia, diaphragmatic
paralysis (phrenic nerve), superior
vena cava syndrome, Pancoast
syndrome (shoulder pain, Horner
upper extremity muscle wasting).
Fig. 3.2
Symptoms as a result of distant metastasis: brain, bone, SIADH/hyponatraemia; PTH/hypercalcaemia; ACTH/Cushing;

liver, adrenal gland; constitutional symptoms (loss of Endocrine b-hCG/gynaecomastia; insulin-like factor/hypoglycaemia;
growth hormone/acromegaly; TSH/hyperthyroidism;
appetite, weight loss, fatigue, malaise). prolactin/galactorrhoea
Symptoms of paraneoplastic syndrome in 10% of Hypertrophic osteoarthropathy; clubbing; polymyositis;

Musculoskeletal dermatomyositis; myopathy
lung cancer patients.
Lambert-Eaton myasthenia; cerebellar degeneration;
Neurological peripheral, encephalitis, or autonomic neuropathy
Haematological (anaemia, thrombocytosis, leucocytosis,

Other non-bacterial thrombotic endocarditis); skin (pruritus,
erythema multiforme, acanthosis nigricans) Fig. 3.3
ACTH, Adrenocorticotropic hormone; β-hCG, human chorionic gonadotropin; PTH, parathyroid
hormone; SIADH, syndrome of inappropriate antidiuretic hormone; TSH, thyroid stimulating hormone.
REVISION QUESTIONS
1. How may a patient with lung cancer present?
2. What are the typical symptoms of locoregional lung cancer invasion?
3. What are the paraneoplastic syndromes seen in lung cancer?
14
Diagnosing lung cancer
Clinical presentation (continued)
An asymptomatic pulmonary lesion found

incidentally on chest imaging is often a
non-calcified solitary pulmonary nodule (SPN),
which is defined as a solitary radiographic opacity
≤3 cm in diameter on a computed tomography
(CT) scan with at least two thirds of its margins
surrounded by normal lung parenchyma and not
associated with intrathoracic lymph nodes (LNs)
or a pleural effusion. Fig. 3.4
<5 mm No follow-up
Clinical evaluation of an SPN is dependent on:
1. Appearance and size on thin-section
≥5 mm Follow-up thin-section CT scan CT scan
2. Calculation of pretest probability of
<5 mm No follow-up
malignancy: consider the Brock model,
5-7 mm Follow-up thin-section CT scan <5%: follow-up
the Mayo model, the Herder model.
≥8 mm Pre-test probability calculation 5-70%: PET
>70%: tissue
Fig. 3.5
CT, Computed tomography; PET, positron emission tomography.
Staging of lung cancer Stage group T N M Stage group T N M

0ccult Ca Tx N0 M0 IIIA T1a N2 M0
T1b N2 M0
O Tis N0 M0 T1c N2 M0
Tumour, Node, Metastasis (TNM) staging is a T2a N2 M0
IA1 T1a(mi) N0 M0 T2b N2 M0
multidisciplinary process involving physical examination T1a N0 M0 T3 N1 M0
and endoscopic, imaging and surgical techniques to IA2 T1b N0 M0 T4 N0 M0
T4 N1 M0
establish the TNM category and stage group. IA3 T1c N0 M0
IIIB T1a N3 M0
IB T2a N0 M0 T1b N3 M0
The TNM 8th edition paradigm is based solely on anatomy. T1c N3 M0
IIA T2b N0 M0 T2a N3 M0
Different types of TNM categories are used dependent on T2b N3 M0
IIB T1a N1 M0 T3 N2 M0
the time point of evaluation: c, clinical before any therapy; T1b N1 M0 T4 N2 M0
y, restaging after systemic therapy; p, pathological after T1c N1 M0
T2a N1 M0 IIIC T3 N3 M0
surgical resection; r, at disease relapse. T2b N1 M0 T4 N3 M0
T3 N0 M0
The disease stage is the most important prognostic factor IVB Any T Any N M1c
IVA Any T Any N M1a
in lung cancer to date. Any T Any N M1b Fig. 3.6
Ca, Carcinoma; M, metastasis; N, node; T, tumour.
REVISION QUESTIONS
1. What is the definition of an SPN?
2. How is an SPN clinically evaluated?
3. What is clinical TNM staging?
15
Dooms
Staging of lung cancer (continued)
Standard white light video bronchoscopy and

autofluorescence bronchoscopy: in addition to pathological
confirmation, it also permits endobronchial staging, i.e. Right upper lobe bronchus
detection of synchronous radio-occult endobronchial tumour ≤3 cm not extending into
main bronchus
lesions or extension of the primary tumour.
T-descriptor:
• eT1: tumour ≤3 cm not extending into main bronchus
(see Fig. 3.7)
• eT2: tumour involving main bronchus distal to main carina
• eT4: tumour involving main carina and/or distal trachea
Fig. 3.7
Resectable by bilobectomy CT scan of chest and upper abdomen are done in all
superior (fissure) with sleeve
of pulmonary artery patients to detect nodal and extranodal disease. Cranial
magnetic resonance imaging (MRI) is required for patients
with stage IB-III lung cancer.
Modern spiral contrast-enhanced multi-detector CT

with multiplanar reconstruction offers great anatomical
detail and is the standard to assess resectability, type
of resection, and T-descriptor (e.g. relation to fissures,
mediastinum or chest wall).
Fig. 3.8
Lung adenocarcinoma
Positron emission tomography (PET) has a cT2aN1M1b (solitary right
complementary role to CT for two reasons: scapula)
• Detection of unexpected LN involvement or distant
metastatic organ spread in 4%–12% of stage I-III lung
cancer. The overall evidence points to significantly
more accurate TNM staging with PET-CT.
• Determination of the nature of some equivocal lesions
on conventional CT imaging.
Randomised trials demonstrated the utility of integrated

PET-CT to significantly reduce futile thoracotomy rate or
futile (chemo)radiotherapy rate.
Fig. 3.9
REVISION QUESTIONS
1. How does bronchoscopy impact on the T-stage?
2. What is the value of a multi-detector CT scan of the chest?
3. What is the clinical impact of PET-CT?
16
Staging of lung cancer (continued)
For the N-descriptor, contrast-

enhanced CT is accurate in azygos vein
delineating LN enlargement (defined station 4L LN
station 10R LN station 4L LN
as ≥10 mm short axis) and helps to
allocate the nodal stations as defined station 11Rs azygos vein
station 7
in the International Association for the station 12L station 12L
Study of Lung Cancer (IASLC) lymph station 11Ri
node map (Rusch 2009).
Fig. 3.10
LN, Lymph node.
For the N-descriptor, integrated PET-CT has a pooled

weighted sensitivity of 0.76 (95% confidence interval [CI]
0.65–0.84) and specificity of 0.88 (95% CI 0.82–0.92).
False-negative PET findings in mediastinal LN staging

occur in presence of:
• a central tumour
• N1 nodes
• tumour >3 cm
• enlarged LNs on CT
False-positive PET findings in mediastinal LNs are due
Fig. 3.11
to the fact that fluorodeoxyglucose (FDG) uptake is not
tumour specific.
Invasive mediastinal nodal staging

starting with endosonography
(endobronchial ultrasound [EBUS] and LN
endoscopic ultrasound [EUS]) and
– if negative – surgical staging has
been proven to detect significantly
more mediastinal nodal disease aorta
compared with mediastinoscopy alone.
The negative likelihood ratio of

Fig. 3.12
endosonography alone is 0.13–0.15.
LN, Lymph node.
Therefore, in routine practice a preoperative surgical staging procedure (videomediastinoscopy
or video-assisted thoracic surgery [VATS]) is indicated in case of a negative endosonography.
The implementation of endosonography for baseline mediastinal nodal staging clearly reduces
the need for surgical mediastinoscopy.
REVISION QUESTIONS
1. What is the value of a chest CT scan for N-staging?
2. Which situations make mediastinal nodal staging by FDG-PET unreliable?
3. Discuss the post-test probability of combined endosonography.
17
Dooms
Techniques for achieving histological diagnosis
Clinicians must obtain tissue from an appropriate tumour

site in sufficient quantity and of appropriate quality for
accurate pathological testing.
Factors to be considered in choosing the optimal technique:
• anticipated diagnostic yield and diagnostic accuracy
• invasiveness and risk of a procedure
• efficiency: accessible site, also relevant for staging
Fig. 3.13
• local expertise available
Endoscopic biopsy:
• endobronchial biopsy (forceps biopsy or cryobiopsy)
• transbronchial lung biopsy: guidance by radial EBUS miniprobe
• EBUS-controlled transbronchial needle aspiration (EBUS-TBNA)
• EUS-guided fine needle aspiration (EUS-FNA)
• thoracocentesis or medical pleuroscopy
Image-guided percutaneous core

needle biopsy:
= CT-guided biopsy or ultrasound-
guided biopsy of
• supraclavicular LN
• pulmonary lesion: parenchymal
or pleural node/mass
Fig. 3.14 • liver or adrenal metastasis
Surgical biopsy:
• VATS for diagnostic
wedge resection
• VATS for sampling of

nodal station 5/6 LNs
• cervical mediastinoscopy
• parasternotomy
• (solitary) bone, adrenal, Fig. 3.15
or skin lesion
REVISION QUESTIONS
1. Which factors determine the invasive test chosen?
2. Discuss the different types of endoscopic biopsy techniques.
3. How can mediastinal nodal stations 5 and 6 be staged?
18
Summary: Diagnosing lung cancer
• Clinical presentation: incidentally – symptoms – screening programme
• Multidisciplinary tumour board evaluation: thoracic surgeon, radiotherapist, oncologist, thoracic radiologist and nuclear
clinician, pulmonologist
• Staging of (suspected) lung cancer:
• TNM 8 is the staging system currently used
• Imaging required: contrast-enhanced CT of chest and upper abdomen in all patients; integrated PET-CT in stage I-III;
brain MRI in stage IB-III
• Pathological mediastinal LN evaluation in stage I-III patients, except for a peripherally located stage IA lung cancer
• Additional investigations required for specific situations (e.g. solitary metastasis)
• Disease stage based on TNM group is currently the best prognostic factor
• Techniques for achieving histological diagnosis: thoracic endoscopy, imaging-guided percutaneous core needle
biopsy, or surgical biopsy
Further Reading
Annema JT, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy versus endosonography for mediastinal nodal staging of lung cancer:
a randomized trial. JAMA 2010; 304:2245–2252.
Callister ME, Baldwin DR, Akram AR, et al. British Thoracic Society guidelines for the investigation and management of pulmonary
nodules. Thorax 2015; 70:(Suppl 2) ii1–ii54.
Dooms C, Muylle I, Yserbyt J, Ninane V. Endobronchial ultrasound in the management of non-small cell lung cancer. Eur Respir Rev
2013; 22:169–177.
Fischer B, Lassen U, Mortensen J, et al. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med 2009; 361:32–39.
Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage
groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol 2016; 11:39–51.
MacMahon H, Austin JH, Gamsu G, et al. Guidelines for management of small pulmonary nodules detected on CT scans:
A statement from the Fleischner society. Radiology 2005; 237:395–400.
Naidich D, Bankier A, MacMahon H, et al. Recommendations for the management of subsolid pulmonary nodules detected at CT:
A statement from the Fleischner Society. Radiology 2013; 266:304–317.
Ost DE, Gould MK. Decision making in patients with pulmonary nodules. Am J Respir Crit Care Med 2012; 185:363–372.
Patel V, Naik SK, Naidich DP, et al. A practical algorithmic approach to the diagnosis and management of solitary pulmonary nodules:
part 1: radiologic characteristics and imaging modalities. Chest 2013; 143:825–839.
Planchard D, Popat S, Kerr K, et al. Metastatic non-small Cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment
and follow-up. Ann Oncol 2018; 29(suppl 4):iv192–iv237.
Postmus PE, Kerr KM, Oudkerk M, et al. Early-stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO Clinical
Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28(suppl 4):iv1–iv21.
Rusch VW, Asamura H, Watanabe H, et al. The IASLC Lung Cancer Staging Project: a proposal for a new international lymph node map
in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2009; 4:568–577.
Thunnissen E, Kerr KM, Herth FJ, et al. The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach
of a working group. Lung Cancer 2012; 76:1–18.
Yeung SC, Habra MA, Thosani SN. Lung cancer-induced paraneoplastic syndromes. Curr Opin Pulm Med 2011; 17:260–268.
19
Dooms
Histopathological and molecular
characterisation of lung cancer 4
Introduction – cytology and histology Tissue processing Cutting of paraffin-
for intraoperative embedded tissue specimens
cryosections with a microtome
Pathology (derived from logos, ‘study’, and pathos,
‘suffering’) is a discipline devoted to studying
histomorphological and molecular changes associated
with disease in cells, tissues and organs.
When lung cancer diagnosis is suspected, the material
obtained is examined macroscopically, microscopically,
and with the aid of immunophenotypic and genetic
studies (diagnostic and predictive biomarkers).
Cryosections are required for intraoperative diagnosis,

while most specimens are paraffin-embedded,
sectioned in 2–5 µm slides, and stained with
haematoxylin–eosin (HE) or other useful stains (e.g.
periodic acid-Schiff [PAS], Elastica van Gieson [EvG]).
EvG, Elastica van Gieson; Fig. 4.1
HE, haematoxylin-eosin
After HE and EvG
deparaffinisation the slides (green label) stained slides
are stained with HE of a lobectomy specimen
Lung cancer is usually diagnosed in advanced stages.

Thus, in the majority of cases, only cytology or
small biopsy material are available for both precise
morphological and immunohistochemical subtyping,
and predictive molecular analyses.
Therefore, rational tissue processing is essential. In

order not to waste sparse tumour tissue, frequent
re-cutting of the paraffin blocks must be avoided.
Fig. 4.2
FFPE, Formalin-fixed, paraffin-embedded; HE, haematoxylin-eosin; PAS, periodic acid-Schiff.
The amount of tumour material available is influenced by

the biopsy or resection strategy.
About 200 tumour cells are sufficient for diagnosis and
predictive biomarker analyses. For cytological specimens,
the preparation of cell blocks is recommended.
Cryobiopsies and transthoracic needle core biopsies Cell block Forceps biopsy
are usually superior to forceps biopsies with respect to
tumour quantity.
Needle core biopsy Resection specimen

Fig. 4.3
REVISION QUESTIONS
1. How is pathology defined?
2. How are lung cancer specimens processed?
3. How are diagnostic and predictive analyses influenced by different sampling methods?
20
Histopathological and molecular characterisation of lung cancer
Histopathology of lung cancer
Historically, and based on therapeutic options, lung

cancer is classified as small cell lung cancer (SCLC;
approx. 15%) and non-small cell lung cancer (NSCLC).
NSCLC (~85%)
Furthermore, carcinoids, salivary gland tumours and other
rare entities need to be considered. SCLC
NSCLC is further categorised into adenocarcinomas
(ADCs), squamous cell carcinomas (SCCs),
adenosquamous carcinomas, large cell carcinomas and Adenocarcinoma Squamous cell
carcinoma
Adeno-squamous
carcinoma
Large cell
carcinoma
Sarcomatoid
carcinoma
sarcomatoid carcinomas. Lung tumours can show a
combination of different histotypes.
Surgical resection (only early stages) Chemotherapy
NSCLC, Non-small cell lung cancer; SCLC, small cell lung cancer. Fig. 4.4
A: Squamous cell carcinoma B: Small cell carcinoma
A B ADCs seem to have different precursors. Centrally

located ADCs are thought to arise from the surface
or glandular epithelium of bronchi, in contrast to the
terminal respiratory unit ADCs, for which the stem
cells are likely to be exocrine bronchiolar cells and
type II pneumocytes.
C
SCCs occur after squamous metaplasia of the respiratory
epithelium with subsequent dysplasia, usually as a
consequence of chronic, smoking-related inflammation of
the airways.
In smokers, the occurrence of multiple synchronous
NSCLC is common due to an effect designated as field
cancerisation.
Fig. 4.5
C: Combined large cell neuroendocrine (left) and adenocarcinoma (right)
ADCs are characterised by various histomorphological

Lymph node metastasis based on predominant pattern
growth patterns. Semi-quantitative assessment of pulmonary adenocarcinomas
(subtyping) of these patterns provides relevant clues for
optimised treatment decisions. Lepidic: 7%
The predominant ADC growth pattern is associated with Acinar: 46%
the patient’s prognosis and has been demonstrated to be
a stage-independent predictor of survival. Papillary: 43%
Specific ADC growth patterns are associated with a Solid: 51%

distinct tumour biological behaviour, prevalence of
predictive biomarkers and lymph node metastasis. Micropapillary: 76%
Fig. 4.6
REVISION QUESTIONS
1. How is lung cancer classified? What is the rationale behind this classification?
2. How do SCCs arise in the respiratory epithelium?
3. What is the clinical impact of morphological ADC subtyping?
21
Warth
Histochemistry and immunohistochemistry
Histochemistry is the aspect of histology concerned

with the identification of chemical components in cells
and tissues. Besides HE, additional histochemical
stains are used to improve the diagnostic accuracy of
histomorphological diagnoses.
PAS staining is essential for the diagnosis of solid ADC

Fig. 4.7
(PAS-positive intracytoplasmic mucin droplets).
Haematoxylin-eosin staining (left) and Elastica van Gieson staining (right) of a
EvG staining is used to identify elastic fibres (dark black) pulmonary adenocarcinoma. The elastic layers of the pleura are delineated in
black and thus allow optimised tumour staging.
and is recommended to specifically assess tumour
infiltration of the visceral and parietal pleura.
Immunohistochemistry (IHC) refers to the process of

detecting antigens in cells. By exploiting the principle of
antibodies binding specifically to antigens, IHC represents
the most important method for immunophenotyping of
Secondary antibody labelled morphologically unclear cancers.
with chromogens (purple) IHC allows the visualisation of an antigen by means
Primary antibody of primary monoclonal or polyclonal antibodies and a
detection system.
Antigen A primary (direct method) or secondary antibody

(indirect method; more sensitive) is therefore labelled
Tumour cell with a chromogen. Counterstains are used to provide
contrast that helps the primary stain stand out.
Fig. 4.8
For reliable tumour diagnoses, lineage-specific

Step 1: unclear clear
antibodies are required. Thyroid transcription factor Morphology (HE, PAS)

morphology
(NSCLC NOS)
morphology
(ADC, SCC)
1 (TTF1) and napsin A are frequently used to confirm

pulmonary ADC; p63 (p40) and cytokeratin 5/6 are Step 2:
used as markers for SCC. Immunohistochemistry unclear clear
- squamous: CK5/6, p40, p63 immunophenotype immunophenotype
- non-squamous: CK7, TTF1, Napsin (NSCLC NOS) (ADC, SCC)
A neuroendocrine differentiation is confirmed with
antibodies against chromogranin A, synaptophysin, Step 3:
or CD56. Immunohistochemistry
- FISH, CISH Predictive Biomarker
IHC staining requires a careful correlation with - IHC Analysis
- PCR (Sequencing)
the morphological findings to define lineage and
Fig. 4.9
immunophenotype of the neoplastic cells. ADC, Adenocarcinoma; CISH, Chromogenic in situ hybridisation; FISH, fluorescent in situ
hybridisation; HE, haematoxylin-eosin; IHC, immunohistochemistry; NOS, not otherwise specified;
NSCLC, non-small cell lung cancer; PAS, periodic acid-Schiff; PCR, polymerase chain reaction;
SCC, squamous cell carcinoma; TTF1, thyroid transcription factor 1.
REVISION QUESTIONS
1. Which stains are commonly used in cytology and histology?
2. What is the difference between histochemical and immunohistochemical stains?
3. Which markers are used to separate SCC and ADC?
22
Molecular diagnostics – polymerase chain reaction (PCR) and sequencing
PCR is a very sensitive method to detect mutations but

also DNA or RNA of bacteria or viruses. It can also be used
to detect specific chromosomal rearrangements.
For DNA extraction, tumour areas with high tumour cell

content are identified by a pathologist.
Subsequent microdissection is essential in order

to minimise the amount of contaminating Fig. 4.10
non-neoplastic cells. Identification of areas with high tumour cell content after haematoxylin-eosin
staining (left) and the same slide after microdissection (right)
Frequent alterations in adenocarcinomas In NSCLC, especially in ADC, a still-increasing number

Unknown of potentially druggable mutations and amplifications
have been identified.
KRAS
EGFR For each biomarker, reliable diagnostic methods (e.g. IHC,

NRAS PCR-based mutation analysis, in situ hybridisation [ISH])
and respective cutoff values for clinical decisions need to
HER2
be established.
BRAF
Various methods for PCR-based mutation analyses are
PIK3CA available. Targeted detection PCR, Sanger sequencing,
AKT1 pyrosequencing, or next generation sequencing
ROS1
approaches are used in pathological institutions.
RET
Fig. 4.11
EGFR, Epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2.
c.2573T>G (p.L858R) c.2369C>T (p.T790M)

Sanger sequencing is based on the selective
incorporation of modified, labelled chain-terminating
dideoxynucleotides by DNA polymerase during in vitro
DNA replication, resulting in interruption of DNA
extension. After electrophoretic separation, the DNA
sequence of the analysed amplicon can be read.
c.2237_56delinsTT (p.E746_S752delinsV)
For reliable Sanger sequencing a tumour cell
concentration of 30% is required to detect all types of
mutations.
Pyrosequencing and next generation sequencing have Upper left: Common point mutation of epidermal growth factor receptor (EGFR)
(arrow). Upper right: Point mutation in EGFR resulting in tyrosine kinase inhibitor
a higher sensitivity when only sparse tumour material is resistance. The lower sequence demonstrates a complex EGFR deletion/
available. insertion mutation. Note the sequence shift of the mutated allele
compared to the wild-type allele Fig. 4.12
REVISION QUESTIONS
1. Why is PCR used in pathological tissues?
2. Which molecular methods are used to analyse predictive biomarkers?
3. What is a major limitation of Sanger sequencing?
23
Warth
Molecular diagnostics – in situ hybridisation
ISH uses labelled probes (complementary DNA or RNA

strands) which are hybridised to specific DNA or RNA
sequences in interphase nuclei of tissue or cytology
specimens.
The probes for specific gene loci are labelled with

different colours. In case of a fusion strategy,
juxtaposed probes indicate a reciprocal translocation.
In break-apart (or split-signal) probes, split signals Fig. 4.13
(single red and green signals) indicate a translocation. Fluorescent (FISH; left) and chromogenic in situ hybridisation (CISH; right)
demonstrating a translocation of the ALK (anaplastic lymphoma kinase) gene
locus with juxtaposed probes of the normal chromosome (yellow in FISH, brown
ISH analyses require high tissue quality and tailored in CISH) and rearranged probes (single red or green signals)
handling procedures. Interpretation of the results should
be performed by specifically trained personnel.
ISH with break-apart strategy is used to detect

rearrangements of the investigated gene, without
Normal chromosome with juxtaposed knowing the partner involved in the translocation.
red and green probes flanking ALK
For ISH fusion strategies, the fusion partners must be

known.
Since even clinically relevant chromosomal
rearrangements in NSCLC (for example, translocations
of anaplastic lymphoma kinase [ALK] or ROS1) involve
Inversion of the ALK gene and fusion multiple fusion partners, break-apart probes are more
with EML4 (split of red and green signal) commonly used in daily practice.
Fig. 4.14
ALK, Anaplastic lymphoma kinase.
Amplification of a specific gene is another relevant finding

to be analysed by ISH. For example, in 20%–25% of
SCCs, fibroblast growth factor receptor 1 (FGFR1) has
been found amplified, which is currently exploited by
usage of FGFR1 inhibitors in clinical trials.
For amplification analyses, the ISH probe for the gene

of interest is labelled with one colour and for internal
reference a centromere probe is labelled with a
different colour.
By counting the signals per cell, the amplification of the

relevant gene is determined.
Fig. 4.15
Amplification of the FGFR1 gene locus (green) in relation to the centromere

probe (red) in a SCC
FGFR1, Fibroblast growth factor receptor 1; SCC, squamous cell carcinoma.
REVISION QUESTIONS
1. What is the difference between CISH and FISH?
2. What are the different ISH strategies to test for chromosomal rearrangements?
3. How is an amplification determined by ISH?
24
Summary: Histopathological and molecular characterisation
of lung cancer
• Pathology is a discipline devoted to studying histomorphological and molecular changes associated with disease in
cells, tissues and organs
• Historically, lung cancer is classified as NSCLC or SCLC based on cytological and histomorphological criteria
• NSCLC is further categorised into ADCs, SCCs, adenosquamous carcinomas, large cell carcinomas and sarcomatoid
carcinomas
• Whereas cryosections are required for intraoperative diagnosis, most biopsy and resection specimens are formalin-
fixed, embedded in paraffin, and subsequently stained histochemically and/or immunohistochemically
• Histochemical and immunohistochemical stains are important for subtyping of NSCLC, especially in small biopsy or
cytology specimens
• The amount of available tumour material is critical to facilitate all required diagnostic and predictive analyses. The
tumour cell concentration is significantly influenced by the biopsy or resection strategy
• After microdissection and DNA extraction from tumour-containing samples, PCR and sequencing are used to detect
specific mutations relevant for targeted antitumour therapies
• FISH and CISH allow visualisation of chromosomal translocations or amplifications important for targeted antitumour
therapies
Further Reading
Cagle P, Allen TC, Beasley MB, et al (Eds). Molecular Pathology of Lung Cancer. New York: Springer, 2012.
Fletcher CDM (Ed). Diagnostic Histopathology of Tumors. Third edition. Philadelphia: Elsevier Health Sciences, 2007.
Hasleton P, Flieder DB (Eds). Spencer’s Pathology of the Lung. Sixth edition. Cambridge: Cambridge University Press, 2013.
Kumar V, Abbas AK, Fausto N, et al (Eds). Robbins and Cotran Pathologic Basis of Disease. Eighth edition. Philadelphia: Elsevier, 2009.
Rosai J (Ed). Rosai and Ackerman’s Surgical Pathology. Tenth edition. E-Book. Philadelphia: Elsevier Health Sciences, 2011.
Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European
Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011; 6:244–285.
Warth A, Muley T, Meister M, et al. The novel histologic International Association for the Study of Lung Cancer/American Thoracic
Society/European Respiratory Society classification system of lung adenocarcinoma is a stage-independent predictor of survival. J Clin
Oncol 2012; 30:1438–1446.
25
Warth
Principles of surgery of non-small cell lung cancer 5
Stage I and II non-small cell lung cancer (NSCLC)
Principles of surgery in stage I and II disease without

mediastinal lymph node involvement: complete radical
resection of the primary tumour.
In order to obtain full surgical staging, a systematic

mediastinal lymphadenectomy should be performed in
every case.
Depending on functional status of the patient, radical
resection can be achieved by: sublobar resection
(anatomical segmentectomy, wedge resection),
lobectomy, bilobectomy or pneumonectomy.
Fig. 5.1
Apical
Upper lobe A muscle-sparing anterolateral thoracotomy is the
most common approach for open surgery. However, a
Posterior Anterior posterolateral or muscle-sparing posterior thoracotomy
is also commonly used.
The role of sublobar resection (anatomical

segmentectomy, or wide-wedge resection) is being
Lower lobe Middle lobe reconsidered for very early lung cancer (cT1N0) presenting
as ground glass opacities (GGOs). Evidence exists from
retrospective studies and this approach is being evaluated
in prospective clinical trials.
Well-selected use of sublobar resection, especially
for pure adenocarcinoma in situ (AIS) of <2 cm, yields
comparable survival and recurrence rates to lobectomy.
Fig. 5.2
Lobectomy with mediastinal lymph node dissection

Right Upper Lobectomy
is considered the standard surgical treatment for all Normal
Lymph Nodes
tumours >2 cm and tumours <2 cm that have a solid
appearance on chest computed tomography (CT). Cancer
Lobe
Removed
In experienced hands, mediastinal lymph node dissection
does not increase morbidity, while intraoperative staging
becomes more precise.
Morbidity rates after lobectomy vary from 3% to 6%. Right Upper Lobe
Typical complications are prolonged air leak, bleeding, Containing Tumour and
Lymph Nodes
chylothorax and recurrent nerve palsy.
Right Lung Left Lung
Fig. 5.3
REVISION QUESTIONS
1. What is the most common surgical approach?
2. What is the standard surgical treatment for tumours <2 cm that have a solid appearance on chest CT?
3. Is there a role for sublobar resection?
26
Principles of surgery of non-small cell lung cancer
Minimal invasive thoracic surgery and parenchyma-sparing resections
The current evidence indicates that lobectomy

performed with minimal invasive thoracic surgery
techniques like video-assisted thoracic surgery (VATS)
and robotic-assisted thoracic surgery (RATS) for early-
stage NSCLC is associated with fewer postoperative
complications than open lobectomy.
Current data also strongly suggest oncological

equivalence of minimal invasive versus open lobectomy
for patients with early-stage NSCLC.
Minimal invasive lobectomy should be performed at
experienced centres. Patients should undergo an accurate
preoperative work-up to exclude locally advanced disease.
Fig. 5.4
In recent reports, the 5-year survival for minimal

invasive lobectomy in stage IA NSCLC is close to 80%,
similar to that for open lobectomy.
Minimal invasive lobectomy for early-stage NSCLC might

be associated with less negative biological impact than
open lobectomy.
Postoperative pain and length of hospital stay might be
decreased. Patients can be mobilised earlier and may be
more compliant to receive adjuvant therapies compared
with patients undergoing open procedures.
Fig. 5.5
CI, Confidence interval; VATS, video-assisted thoracoscopic surgery.
In case of a centrally located tumour, a parenchyma-

sparing sleeve resection (SR) can be performed in
order to avoid a pneumonectomy.
Sleeve lobectomy can be performed with low morbidity

and mortality and a favourable oncological outcome
comparable to standard lobectomy or pneumonectomy.
Evidence in the literature indicates that parenchyma-
sparing SR can even be safely performed after induction
treatment.
Fig. 5.6
REVISION QUESTIONS
1. Is minimal invasive lobectomy associated with fewer postoperative complications?
2. Is the long-term outcome of minimal invasive lobectomy comparable to standard lobectomy?
3. In centrally located tumours, what is the alternative to pneumonectomy?
27
Hoda et al
Stage III non-small cell lung cancer
Stage III NSCLC is a heterogeneous CT FDG-PET CT

disease, which can be subclassified
into locally advanced primary tumours
(T3N1, T4N0-1) and N2-positive NSCLC.
In case of locally advanced lung cancer

(T3N1, T4N0-1), radical resection can be
achieved with or without neoadjuvant
treatment.
CT, Computed tomography; FDG-PET, fluorodeoxyglucose positron emission tomography
Patients with limited mediastinal lymph
node involvement undergoing neoadjuvant Fig. 5.7
treatment can be eligible for radical

resection after down-staging.
100 ChT/RT/S Patients with N2 disease undergoing surgery

ChT/RT
after neoadjuvant treatment had a significantly longer
HR 0·77 (95% CI 0·62–0·96); p=0·017
progression-free survival compared with those
receiving chemoradiotherapy (CRT) alone.
Patients alive without progression (%)
75
Patients undergoing induction CRT and lobectomy had

50 an improved overall survival compared with patients with
CRT alone.
This result could not be confirmed for patients undergoing
25
pneumonectomy due to unusually high mortality.
0
Number at risk
ChT/RT/S 202 102 63 51 40 32
ChT/RT 194 88 43 31 21 13
Fig. 5.8
ChT, Chemotherapy; CI, Confidence interval; HR, hazard ratio; RT, radiotherapy; S, surgery.
However, pneumonectomy after induction CRT can

100 ChT/RT/S
ChT/RT
obtain favourable outcomes when performed at

experienced centres. 75
Patients must be selected very carefully with regard to

Patients alive (%)
their performance status and must be staged accurately 50
in order to exclude more advanced disease. Current

published evidence suggests that there is no difference
in outcomes in the choice of neoadjuvant treatment 25
protocols (chemotherapy vs CRT).

However, clear evidence-based treatment protocols for 0
Number at risk
patients with N2-positive NSCLC cannot be defined on ChT/RT/S 90 73 56 40 28 21
ChT/RT 90 60 39 24 17 10
the basis of the current literature. Fig. 5.9
ChT, Chemotherapy; RT, radiotherapy; S, surgery.
REVISION QUESTIONS
1. Does surgery play a role in patients with proven N2 disease?
2. Does every patient with T4N0 NSCLC need to undergo neoadjuvant treatment?
3. Should pneumonectomy be avoided in N2-positive patients even after neoadjuvant treatment?
28
Pancoast tumours
Pancoast or superior pulmonary sulcus tumours Pancoast’s Syndrome

(SSTs) are a rare subset of NSCLC, occurring with an Brachial plexus Vertebral body
(arm and
incidence of less than 5% of all lung cancers. shoulder pain) Vagus nerve
Sympathetic trunk Recurrent nerve
(Horner’s
The clinical picture consists of typical symptoms (pain syndrome)
(vocal cord paralysis)
Subclavian
down the arm, Horner’s syndrome) and radiographic artery
evidence of first rib and/or vertebral body destruction. and vein
Neoadjuvant CRT followed by surgical resection

(multimodality approach) has become the treatment of
choice for Pancoast tumour patients.
Originally described by
the radiologist Henry Pancoast
in 1932 as tumours located Fig. 5.10
in the superior sulcus
Surgery requires expertise and should

Vascular, neural and
be performed only in specialised centres
vertebral body involvement by an experienced team, including also a
can be managed with advanced neurosurgeon or orthopaedic surgeon.
surgical techniques and
interdisciplinary
approaches The distinct anatomical location of SSTs
has necessitated the development of
special surgical approaches for adequate
resection of the tumour and involved
adherent structures.
Differentiation into anterior (infiltration

of great vessels and ribs) and posterior
(infiltration of vertebral body and plexus)
SST type is important for planning
adequate surgery.
Fig. 5.11
Data pooled from
different publications reporting
long-term survival rates after
different therapeutic
Combined treatment schedules have led to 5-year survival
modalities
90
improvements in completeness of resection and clinical
80
and pathological response rates, resulting in improved 70
5-year survival (%)
long-term survival. 60
50
The three most important prognostic factors for tumour 40
recurrence are completeness of resection, T status, and 30
N status of the tumour. 20
10
For SSTs, the expected incidence of brain metastasis as 0
a first site of recurrence has been described as high as n=18 n=23 n=10
24%, but occurrence of brain metastasis did not impact RT RT+Surgery ChT+RT+
Surgery
on survival. Fig. 5.12
ChT, Chemotherapy; RT, radiotherapy.
REVISION QUESTIONS
1. Which therapy modality has become the modern treatment standard for SSTs?
2. Is infiltration in the adjacent anatomical structures a contraindication for surgical treatment?
3. Which factors are the most important prognosticators in the treatment of Pancoast tumours?
29
Hoda et al
Surgery in the palliative setting and stage IV NSCLC
Carefully selected patients with oligometastatic disease

may benefit from resection of both the primary and
metastatic sites in a multimodality treatment approach.
Isolated adrenal and solitary brain metastasis (SBM):

if the primary is resectable, adrenalectomy or resection
of SBM can be considered in combination with
chemotherapy in selected patients.
Fig. 5.13
Good survival results can be expected in those patients
in whom a complete resection of the primary tumour and
radical control of the distant disease are accomplished.
A B Salvage resections can be indicated in patients with

intratumoural cavitation and superinfection, for whom
no other treatment modality is appropriate.
Salvage resection can also be performed for recurrent

lung cancer following definitive CRT, with acceptable
morbidity and mortality rates.
C
For both patient groups, careful selection and
preoperative assessment as well as postoperative care
can result in overall survival up to 30 months.
Fig. 5.14
Talc pleurodesis
performed by minimal
invasive thoracic surgery
in a patient with
right-sided MPE, white
powder = talc
In NSCLC, malignant pleural effusion (MPE) is a terminal
condition diminishing quality of life and requiring
multiple hospital admissions and interventions. Suggested Placement Procedure
MPE can be treated surgically with talc pleurodesis

or tunnelled pleural catheters (TPCs). TPCs became
popular as a less invasive, outpatient modality in MPE
management in NSCLC.
TPCs are particularly preferred for patients with trapped Tunneled
First Incision:
Guidewire
lung or those who are not considered candidates for portion of
catheter
insertion site
Second
pleurodesis because of short life-expectancy. Incision:
Catheter
External portion exit site
of catheter
Fig. 5.15
MPE, Malignant pleural effusion.
REVISION QUESTIONS
1. Are all lung cancer patients with metastasis eligible for curative resection within multimodality protocols?
2. Which is the treatment of choice for superinfected tumour cavitation after CRT?
3. Do NSCLC patients need any surgical intervention for recurrent MPE?
30
Summary: Principles of surgery of non-small cell lung cancer
• Stage I and II NSCLC: primary resection and systematic mediastinal lymph node dissection
• Anterolateral thoracotomy is the most common approach
• Minimal invasive lobectomy may be oncologically equivalent to open lobectomy
• Parenchyma-sparing sleeve lobectomies are considered a safe alternative to pneumonectomy in centrally
located tumours
• Stage III NSCLC is a heterogeneous disease with different surgical/multimodal treatment concepts
• N2-positive NSCLC: patients can benefit from radical resection after responding to neoadjuvant treatment
• Pancoast tumours: induction CRT followed by surgery is the treatment of choice
• Patients with isolated adrenal and/or brain metastasis can benefit from resection with a multimodality protocol
• Salvage resections are indicated for infected cavitated tumours or patients with recurrence after definitive CRT
• Talc pleurodesis and tunnelled pleural catheters are an effective palliative surgical treatment for recurrent
pleural effusions
Further Reading
Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell
lung cancer: a phase III randomised controlled trial. Lancet 2009; 374:379–386.
Bauman JE, Mulligan MS, Martins RG, et al. Salvage lung resection after definitive radiation (>59 Gy) for non-small cell lung cancer:
surgical and oncologic outcomes. Ann Thorac Surg 2008; 86:1632–1638.
Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer
Study Group. Ann Thorac Surg 1995; 60:615–622.
Pfannschmidt J, Dienemann H. Surgical treatment of oligometastatic non-small cell lung cancer. Lung Cancer 2010; 69:251–258.
Predina JD, Kunkala M, Aliperti LA, et al. Sleeve lobectomy: current indications and future directions. Ann Thorac Cardiovasc Surg 2010;
16:310–318.
Rueth NM, Andrade RS. Is VATS lobectomy better: perioperatively, biologically and oncologically? Ann Thorac Surg 2010;
89:S2107–S2111.
Suzuki K, Servais EL, Rizk NP, et al. Palliation and pleurodesis in malignant pleural effusion: the role for tunneled pleural catheters.
J Thorac Oncol 2011; 6:762–767.
Tamura M, Hoda MA, Klepetko W. Current treatment paradigms of superior sulcus tumours. Eur J Cardiothorac Surg 2009; 36:747–753.
Van Schil PE, Asamura H, Rusch VW, et al. Surgical implications of the new IASLC/ATS/ERS adenocarcinoma classification. Eur Respir J
2012; 39:478–486.
Yanagawa J, Rusch VW. Current surgical therapy for stage IIIA (N2) non-small cell lung cancer. Semin Thorac Cardiovasc Surg 2011;
23:291–296.
31
Hoda et al
Principles of radiotherapy of thoracic tumours 6
Background
External beam radiotherapy (RT) is a key modality in both

the curative and palliative treatment of lung cancer.
Radiation is usually delivered using a linear accelerator

(LINAC), a device used to generate high-energy X-rays
that destroy tumour cells.
Patients are positioned on a moveable treatment couch,

where imaging using X-rays and computed tomography
(CT) scan allows for more accurate delivery.
LINAC
Fig. 6.1
Example of 3D imaging (A) and 4D imaging (B) for the same tumour. LINAC – yellow simulates the radiation beam, while green simulates the X-rays
used for imaging patient anatomy
(A) Position of tumour in right upper lobe in a single conventional scan; however,
(B) shows all positions occupied by tumour during respiratory cycle,
illustrated in a maximum intensity projection image
A planning CT scan is performed before high-dose RT,
A B to generate a treatment plan.
Treatment plans are optimised to ensure dose coverage
of the ‘target volume’, while limiting doses to surrounding
organs.
A 4-dimensional (or respiration-correlated) CT scan is the

preferred technique for planning curative radiation, as it
Fig. 6.2 allows for motion to be visualised for tailored delivery.
Target coverage can be improved by performing Any changes in tumour position can be accounted
on-table cone-beam CT scans with the patient on the for by ‘adapting’ the initial plan in order to ensure
LINAC couch. dose coverage.
Repeated imaging during treatment delivery is a
component of modern image-guided RT.
Planning CT (A) and cone-beam CT (B) for a stage III non-small cell lung cancer
A B
Fig. 6.3
REVISION QUESTIONS
1. Can radiation cure patients with lung cancer?
2. How is RT delivered to patients?
3. What is image-guided RT?
32
Principles of radiotherapy of thoracic tumours
Dose-fractionation schemes
Palliative RT for vertebral metastases, using either simple 2D field (left) or CT planning (right)
The radiation dose delivered at each
session is measured in units called
Grays (Gy).
Palliation involves the use of doses

ranging from 4 Gy to 8 Gy, delivered in
1–5 fractions. High response rates are
seen for painful lesions and bleeding.
If required, palliative RT can be

repeated.
Fig. 6.4
CT, Computed tomography; RT, radiotherapy.
Pre- and post-treatment imaging of a cystic brain metastasis (arrow)

Stereotactic ablative radiotherapy (SABR) is a form of
high-dose, high-precision delivery, resulting in high local
control rates.
In patients with 1–3 brain metastases, superior local

control is obtained using single doses of stereotactic
RT rather than conventional whole-brain RT.
Stereotactic RT is an established treatment of early-stage

non-small cell lung cancer (NSCLC). Local control rates
of 90% are reported following delivery in a total of 1-8
fractions.
Pre-treatment Post-treatment Fig. 6.5 Large radiation field for a locally advanced lung cancer
In locally advanced NSCLC, 30 once-daily fractions

of 2 Gy are typically delivered concurrently with
chemotherapy (ChT).
For limited-stage small cell lung cancer (SCLC), ChT with

concurrent thoracic RT (30 twice-daily fractions of 1.5 Gy,
or 30-33 once-daily fractions of 2 Gy) is the standard of care.
If RT follows ChT, e.g. in less fit patients, higher daily
doses (e.g. 2.6–3 Gy) are used to shorten treatment
times and improve survival.
Fig. 6.6
REVISION QUESTIONS
1. How many treatment fractions are used to deliver palliative RT?
2. What are the features of SABR?
3. How frequently are patients irradiated for locally advanced lung tumours?
33
Finazzi & Senan
Locally advanced non-small cell lung cancer (NSCLC)
In fit patients, platinum-based Durvalumab, a PD-L1 inhibitor, improved PFS (left) and OS (right) when administered for up to 12 months
concurrent chemoradiotherapy in patients who completed CRT
No. of Events/ Median 12-Mo 24-Mo
(CRT) is the standard of care, No. of Events/

Total No.
of Patients
Median PFS
(95% CI)
12-Mo PFS
(95% CI)
18-Mo PFS
(95% CI)
Total No.
of Patients
Overall Survival Overall Survival Rate Overall Survival Rate
(95% CI) (95% CI) (95% CI)
mo % %
followed by consolidative treatment

1.0 mo % %
Durvalumab 214/476 16.8 (13. 0–18.1) 55.9 (51. 0–60.4) 44.2 (37. 7–50.5) Durvalumab 183/476 NR (34. 7–NR) 83.1 (79. 4–86.2) 66.3 (61. 7–70.4)
Probability of Progression-free Survival

0.9 Placebo 157/237 5.6 (4.6–7.8) 35.3 (29. 0–41.7) 27.0 (19. 9–34.5) Placebo 116/237 28.7 (22. 9–NR) 75.3 (69. 2–80.4) 55.6 (48. 9–61.8)
1.0
with the immune checkpoint

Stratified hazard ratio for death, 0.68 (99.73% CI, 0.4 7–0.997)
0.8 Two-sided P=0.0025
0.9
Probability of Overall Survival

0.7
inhibitor durvalumab.
0.8
0.6 0.7
0.5 0.6 Durvalumab

Durvalumab
0.5
0.4
The ChT schemes recommended for 0.3

Placebo
0.4
0.3
Placebo
concurrent CRT include cisplatin or

0.2
Stratified hazard ratio for disease progression 0.2
0.1 or death, 0.52 (95% CI, 0.4 2–0.65)
0.1
Two-sided P<0.001
carboplatin doublets with etoposide, 0.0

0 3 6 9 12 15 18 21 24 27
0.0
0 1 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Months since Randomization Months since Randomization
vinorelbine, pemetrexed and paclitaxel. No. at Risk

Durvalumab 476 377 301 264 159 86 44 21 4 1
No. at Risk
Durvalumab 476 464 431 415 385 364 343 319 274 210 115 57 23 2 0 0
Placebo 237 163 106 87 52 28 15 4 3 0 Placebo 237 220 198 178 170 155 141 130 117 78 42 21 9 3 1 0
The recommended RT dose is 60 Gy,

CI, Confidence interval; CRT, chemoradiotherapy; NR, not reached; OS, overall survival; PD-L1, programmed death-ligand 1; Fig. 6.7
delivered in once-daily doses of 2 Gy. PFS, progression-free survival.
Radiation plan showing large fields. High-dose regions in mediastinum and left lung
Treatment toxicities include pain with swallowing
(oesophagitis), haematological toxicity and radiation
pneumonitis.
Dietary advice and painkillers can mitigate symptoms

of oesophagitis, but severe reactions occur in up to
20% of cases, and a feeding tube may be required.
Severe radiation pneumonitis rates are below 5%–10%

in trials, in which RT is focused on areas with proven or
suspected disease.
Pre- and post-treatment images showing radiation fibrosis
Fig. 6.8
Post-treatment response evaluation can be difficult due

to fibrosis, but up to 30% of patients may develop a
local recurrence vs 50% with distant failures.
The routine addition of surgery has not improved overall Pre-treatment

survival vs use of CRT only.
All patients should undergo long-term follow-up to identify
and treat any complications, co-existing disease such
as chronic obstructive pulmonary disease (COPD) and
second tumours.
6 months post-treatment Fig. 6.9
REVISION QUESTIONS
1. What is the common ChT of choice with concurrent RT?
2. Name two common toxicities of concurrent thoracic RT.
3. What proportion of patients develop distant disease failures after CRT?
34
Stereotactic ablative radiotherapy (SABR)
SABR is the non-surgical treatment of choice for USA population changes in types of RT use for inoperable early-stage NSCLC
early-stage NSCLC and local control rates in excess 100%
of 90% are obtained. 90%

SABR
80%
So-called ‘risk-adapted’ dosing schemes are used to 70%
Percent utilisation
deliver a biologically equivalent tumour dose of ≥100 Gy, 60%
in 1–8 fractions. 50%
SABR is associated with low toxicity in patients with 40%
COPD and the elderly, and improves population-based 30%
survival in elderly patients. 20%

Conventional
10%
CFRT SBRT
0%
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Year of diagnosis
Fig. 6.10
CFRT, Conventionally fractionated radiotherapy; NSCLC, non-small cell lung cancer; SABR,
stereotactic ablative radiotherapy; SBRT, stereotactic body radiotherapy; RT, radiotherapy.
On-table cone-beam CT of a patient undergoing SABR for a right-sided lung tumour

Patients are treated on LINACs in an outpatient setting,
and each session can take as little as 20 minutes in total.
A variety of different treatment machines are in use.
Pre-treatment, on-table image guidance utilises

cone-beam CT scans on the treatment table and, less
commonly, tracking of implanted fiducial markers.
SABR is an effective treatment for metastases. Use of

SABR in so called oligometastatic disease (patients with
up to five lesions) can improve progression-free and
overall survival.
CT, Computed tomography; SABR, stereotactic ablative radiotherapy. Fig. 6.11
Post-SABR fibrosis
Radiological follow-up is required after SABR in order

to distinguish benign fibrosis, which is common, from
local tumour recurrence.
Most recurrences after SABR for early-stage NSCLC are

distant or regional metastases.
Long-term follow-up can identify both locoregional failures
and new primary tumours, both of which are suitable for
curative therapies.
Fig. 6.12
SABR, Stereotactic ablative radiotherapy.
REVISION QUESTIONS
1. What is the local control rate after SABR for early-stage lung tumours?
2. What is the predominant pattern of disease recurrence after SABR?
3. What is the aim of follow-up after treatment of early-stage lung cancer?
35
Finazzi & Senan
Small cell lung cancer (SCLC)
Both ChT and RT are essential in the treatment of both

Comparable survival in patients with limited-stage SCLC after CRT with
early-stage and advanced SCLC. twice-daily (3 weeks) and once-daily (6.5 weeks) RT
In fit patients with limited-stage SCLC, the standard
treatment is CRT to the thorax using a platinum-based
scheme, and prophylactic cranial irradiation (PCI).
Thoracic RT is delivered twice-daily over 3 weeks, or

once daily over 6–6½ weeks. Results are comparable,
with 5-year survival of up to ~30% in recent trials.
Fig. 6.13
CI, Confidence interval; CRT, chemoradiotherapy; HR, hazard ratio; RT, radiotherapy;
SCLC, small cell lung cancer.
Administration of PCI in limited-disease SCLC improved overall survival

and reduced the risk for brain relapses
PCI reduces the risk of brain metastases,
and increases absolute survival rates by 5%
in limited-stage SCLC.
PCI is delivered in 10 fractions of 2.5 Gy, and

is associated with alopecia and a short-term
decrease in quality of life.
Concurrent CRT to the thorax is associated
with oesophagitis, bone-marrow depression
and a risk of radiation pneumonitis.
PCI, Prophylactic cranial irradiation; SCLC, small cell lung cancer. Fig. 6.14
Immobilisation mask and simulation radiograph for delivery of conventional brain irradiation
In extensive-disease SCLC, ChT is the
mainstay of treatment. RT is used for
palliation, and PCI can improve survival in
patients who respond to ChT.
In patients with extensive-disease SCLC

who do not undergo PCI, periodic brain MRI
(magnetic resonance imaging) during follow-up
can be considered as an alternative.
Long-term survivors of limited-stage SCLC are
at risk for a second lung cancer, and should be
Fig. 6.15
counselled on smoking cessation.
REVISION QUESTIONS
1. Can use of prophylactic brain RT improve survival in SCLC?
2. What are common side effects of PCI?
3. Are survivors of SCLC at risk of developing other lung tumours?
36
Summary: Principles of radiotherapy of thoracic tumours
• RT is used in both the curative and palliative treatment of thoracic tumours
• In patients with early-stage NSCLC who are unfit or unwilling to undergo surgery, SABR is a curative treatment option
• In both limited-stage SCLC and locally advanced NSCLC, concurrent CRT offers the best chance of cure
• Prophylactic brain irradiation improves the survival of patients with SCLC whose disease does not progress
following ChT
• Precise targeting of tumours using image-guided RT can minimise the risk of normal tissue damage
Further Reading
Aupérin A, Le Péchoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced
non-small-cell lung cancer. J Clin Oncol 2010; 28:2181–2190.
Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation
carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a
randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015; 16:187–199.
De Ruysscher D, Faivre-Finn C, Moeller D, et al; European Organisation for Research and Treatment of Cancer recommendations for
planning and delivery of high-dose, high-precision radiotherapy for lung cancer. Radiother Oncol 2017; 124:1–10.
Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage
small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol 2017; 18:1116–1125.
Guckenberger M, Andratschke N, Dieckmann K, et al; ESTRO ACROP consensus guideline on implementation and practice of
stereotactic body radiotherapy for peripherally located early stage non-small cell lung cancer. Radiother Oncol 2017; 124:11–17.
Palma D, Visser O, Lagerwaard FJ, et al. Impact of introducing stereotactic lung radiotherapy for elderly patients with stage I
non-small-cell lung cancer: a population-based time-trend analysis. J Clin Oncol 2010; 28:5153–5159.
Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice
Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28(Suppl_4):iv1–iv21.
Ronden MI, Palma D, Slotman BJ, et al. Brief report on radiological changes following stereotactic ablative radiotherapy (SABR) for early-
stage lung tumors: a pictorial essay. J Thorac Oncol 2018; 13:855–862.
Slotman B, Faivre-Finn C, Kramer G, et al; EORTC Radiation Oncology Group and Lung Cancer Group. Prophylactic cranial irradiation
in extensive small-cell lung cancer. N Engl J Med 2007; 357:664–672.
Takahashi T, Yamanaka T, Seto T, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell
lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2017; 18:663–671.
37
Finazzi & Senan
Adjuvant and neoadjuvant therapy 7
Perioperative therapy
Five-year survival rates for resected non-small cell lung First positive study
First positive study
in breast cancer
cancer (NSCLC) range between 73% for pathological stage in NSCLC
IA and 25% for pathological stage IIIA (American Joint
Cisplatin-based ChT CMF ADJUVANT
Committee on Cancer/Union for International Cancer Control NSCLC Breast Cancer
[AJCC/UICC] TNM [Tumour, Node, Metastasis] 7th edition). 100 + 4% at 5 yrs 1.0
0.9

The International Adjuvant Lung Cancer Trial (IALT) was the 80 Chemotherapy (469 deaths) 0.8
Overall Survival (%)

0.7
first randomised study to show a benefit for a cisplatin- 60 0.6

0.5
CMF
based chemotherapy (ChT) regimen after complete 40 Control (504 deaths)
0.4
0.3
surgical resection in patients with stage I to III NSCLC. 20 P<0.03 0.2 P – 0.03 (adjusted) Control
0.1
0 0.0
0 1 2 3 4 5 5 10 15 20
Years Years after Mastectomy
The 5-year survival rate was 45% in the ChT arm vs No. at Risk
Chemotherapy 932 775 624 450 308 181
5 yrs
40% in the control arm (hazard ratio [HR] 0.86, 95% Control 935 774 602 432 286 164
Fig. 7.1
confidence interval [CI] 0.76–0.98; p < 0.03).
ChT, Chemotherapy; CMF, cyclophosphamide/methotrexate/fluorouracil;
NSCLC, non-small cell lung cancer.
The Lung Adjuvant Cisplatin Evaluation (LACE) pooled

Absolute OS benefit analysis included 4584 patients accrued in five large
at 5 years cisplatin-based adjuvant trials. Adjuvant ChT showed
5.3% ± 1.6% a 5.3% improvement in overall survival (OS) and 5.2%
improvement in disease-free survival (DFS) at 5 years.
Toxic death
0.8 to 2%
The treatment should ideally begin within 2 months
after surgery in Eastern Cooperative Oncology Group
Performance Status (ECOG PS) 0-1 patients without
postoperative complications and who are <75 years of age.
Three to four cycles of ChT should be offered, although
the duration of ChT is still challenging.
Fig. 7.2
CI, Confidence interval; HR, hazard ratio; OS, overall survival.
Chemotherapy (No. of cycles, dose of No. of

Inclusion
Vinorelbine is the most frequently used compound Trial name
criteria
cisplatin by cycle, daily dose × No. of Radiotherapy Inclusion period patients
doses for other drugs) included
in combination with cisplatin in the adjuvant setting.
JBR.10 pT2pN0 or 4 cycles, cisplatin (50 × 2) mg/m2 No radiotherapy 1994–2001 482
Other third-generation cytotoxics have not been pT1-2pN1 Vinorelbine 25 mg/m2 × 16
formally compared with vinorelbine-containing Adjuvant Lung Stage I, 3 cycles, cisplatin 100 mg/m 2
Optional after 1994–1999 1088
Cancer Project II, IIIA Mitomycin 8 mg/m2 × 3, vindesine chemotherapy
regimens but can be used based on LACE. Italy 3 mg/m2 × 6
Adjuvant Stage I, 4 cycles, cisplatin 100 mg/m2 Optional for 1994–2000 840
Navelbine II, IIIA Vinorelbine 30 mg/m2 × 16 pN+ after
Three out of five studies included in LACE International chemotherapy
Trialist
offered 4 cycles of high-dose cisplatin Association 01
(100 mg/m² every 4 weeks) and vinorelbine International Stage I, 3 cycles, cisplatin 100 or 120 mg/m2 or Optional 1995–2001 1867
Adjuvant Lung II, III 4 cycles, cisplatin 80 or 100 mg/m2 according
(25–30 mg/m² every week, up to 16 weeks) in Trial Vindesine 3 mg/m2 × 6-8, or to pN after
Vinblastine 4 mg/m2 × 6-8, or chemotherapy
the experimental arm. Vinorelbine 30 mg/m2 weekly × 13, or
Etoposide 100 mg/m2 × 9-12
However, in the metastatic setting the high dose Big Lung Trial Stage I,
II, III
3 cycles, cisplatin 80 mg/m2 (bitherapies)
or 50 mg/m2 (tritherapies)
Optional after
chemotherapy
1995–2001 307
is similar to an alternative lower dose regimen: Vindesine 3 mg/m2 × 6, or

Vinorelbine 30 mg/m2 × 6, or
75–80 mg/m², which is more frequently prescribed Mitomycin 6 mg/m2 × 3 and ifosfamide
3 g/m2 × 3, or
in the adjuvant setting although it has not been Mitomycin 6 mg/m2 × 3 and vinblastine
6 g/m2 × 3
prospectively evaluated. Fig. 7.3
pN, Pathological node; pN+, pathological node positive.
REVISION QUESTIONS
1. What is the 5-year benefit of adjuvant ChT?
2. What are the characteristics of patients eligible for adjuvant ChT?
3. How many cycles should be given in the adjuvant setting?
38
Adjuvant and neoadjuvant therapy
Perioperative therapy (continued)
In LACE, histology is not a predictive factor for the benefit

of adjuvant ChT.
Stage II and III NSCLC patients are candidates for

adjuvant ChT: the risk reduction is 17%.
There was a negative effect of adjuvant ChT for stage IA.

The risk reduction was 8% for stage IB, in which adjuvant
ChT is still debated.
Most adjuvant studies used the 6th TNM classification,
where stage IB was defined as tumours ≥3 cm. Five-year
survival benefit rates cannot be applied to the 8th TNM
classification but specific trial criteria can be used for Fig. 7.4
treatment decisions.
The CALGB study, which was terminated prematurely,

CALGB STAGE IB TRIAL
compared 4 cycles of paclitaxel/carboplatin in patients
with resected stage IB NSCLC. There was a significant
Paclitaxel 200 mg/m² and carboplatin
benefit for tumours ≥4 cm.
AUC 6 q3w
4 cycles
In the JBR.10 study, patients with tumours ≥4 cm derived
clinically meaningful benefit from ChT (HR 0.66, 95% CI
0.39–1.14; p = 0.13) as opposed to those with tumours
<4 cm (HR 1.73, 95% CI 0.98–3.04; p = 0.06).
Most of the ongoing adjuvant trials include patients with
≥4cm <4cm stage IB ≥4 cm, stage II and stage III NSCLC. According
to the 8th TNM definition, pathological stage II and stage
III are eligible for adjuvant ChT.
Fig. 7.5
AUC, Area under the curve; CI; confidence interval; HR, hazard ratio; q3W, every 3 weeks.
Three large adjuvant ChT trials have been updated. The

CALGB 9633 was initially reported as a positive trial for
OS and DFS after 2.8 years of median follow-up and as
a negative trial after 4.5 and 6.1 years of follow-up.
In both IALT and JBR.10 updated results, a smaller benefit

was seen than in first reports.
Late effects of cisplatin-containing ChT regimens,
particularly for vascular disease, could explain this
fading effect.
Fig. 7.6
CI, Confidence interval; HR, hazard ratio; IALT, International Adjuvant Lung Cancer Trial;
LACE, Lung Adjuvant Cisplatin Evaluation; N, number.
REVISION QUESTIONS
1. When can adjuvant ChT be offered after resection of stage IB NSCLC?
2. Is carboplatin a standard treatment in the adjuvant setting?
3. Is the long-term toxicity of ChT a concern?
39
Besse
A 2-year adjuvant treatment with tegafur-uracil (UFT) vs

surgery alone, showed benefit in Japanese patients with
stage I disease.
A meta-analysis of 2003 eligible patients showed an

increase in survival rates at 5 and 7 years in favour of
UFT plus surgery vs surgery alone (81.5% and 76.5%,
respectively) in T1 and T2 tumours.
The use of adjuvant UFT is restricted to stage I NSCLC in

the Asian population.
Fig. 7.7
OS, Overall survival; UFT, tegafur/uracil.
Events Totals
1.0 S alone 1729 4142
S+ChT 1594 4305
0.9
0.8
0.7
+ 4% at 5 years
0.6
Survival
0.5 The individual patient data (IPD) meta-analysis

0.4 (8447 patients) showed an absolute benefit in OS at
0.3 N=8447 5 years of 4% in all stages of adjuvant treatment.
0.2
0.1
Platinum-based ChT was used in 18 trials. In stage I
0
0 1 2 3 4 5 6 7 8 patients, representing 65% of the cohort, the meta-
Years
Number at risk
S alone 4142 3648 3102 2584 2083 1601 841 407 148
analysis is not conclusive for stage IA.
S+ChT 4305 3809 3261 2746 2278 1785 936 473 165
HR 0.87, 95% CI 0.81–0.93; p < 0.000001

Fig. 7.8
ChT, Chemotherapy; CI, confidence interval; HR, hazard ratio; S, surgery.
Events Totals
1.0 No preoperative chemotherapy 745 1207
The IPD meta-analysis of 15 trials (2385 patients) 0.9 Preoperative chemotherapy 682 1178
showed that preoperative ChT significantly increased 0.8
survival (HR 0.87, 95% CI 0.78–0.96; p = 0.007). 0.7 + 5% at 5 years

0.6
Survival
No subgroup of patients was identified who derived more 0.5

0.4
benefit from preoperative ChT based on age, PS, sex,
0.3
histology and stage. 0.2
N=2385
When preoperative ChT induces a response, there is a 0.1
0
trend for greater benefit when adjuvant ChT is given 0 1 2 3 4 5 6 7 8
Number at risk Time from randomisation (years)
(HR 0.78, 95% CI 0.64–0.95; p = 0.02). No preoperative 1207 893 674 527 409 300 209 147 102
chemotherapy
Preoperative 1178 928 712 570 442 346 253 172 123
chemotherapy
HR 0.87, 95% CI 0.78–0.96; p = 0.007 Fig. 7.9
CI, Confidence interval; HR, hazard ratio.
REVISION QUESTIONS
1. Which patients are eligible for adjuvant UFT?
2. W
hat are the HRs between surgery and surgery + neoadjuvant or postoperative surgery in the two meta-analyses based on
individual patient data?
3. Is there a group of patients who would derive more benefit from adjuvant ChT compared with preoperative ChT?
40
Adjuvant and neoadjuvant therapy (continued)
Two phase III trials have compared preoperative or Preoperative chemotherapy v Surgery alone:
HR = 0.96 (95% CI, 0.84 to 1.1); P = .56
adjuvant ChT with surgery alone, without pointing out a Phase III
1.0 Adjuvant chemotherapy v Surgery alone:
HR = 0.99 (95% CI, 0.75 to 1.3); P = .93
better setting based on DFS. 0.8
Events: Preoperative chemotherapy 99 (49.7%)
Adjuvant chemotherapy 102 (48.6%)
Disease-Free Survival
624 patients Surgery 109 (51.9%)
IA (>2 cm),
(probability)
0.6
Compliance is improved with preoperative ChT. In the IB, II, T3N1
IFCT-0002 study, 90.4% of patients received 4 cycles of 0.4
Arm 1 : surgery
preoperative ChT in one arm compared with 75.2% in the Arm 2 : 3XPC then surgery 0.2 Preoperative chemotherapy
other arm (2 cycles before and 2 cycles after surgery). Arm 3 : surgery then 3XPC Adjuvant chemotherapy
Surgery alone

0 1 2 3 4 5 6
Preoperative ChT does not promote lung-sparing Time (years)
surgery, meaning that it does not decrease the rate of No. at risk
165 131 99 71 45 31
Preoperative
pneumonectomy vs lobectomy. Adjuvant 161 121 90 65 40 29
Surgery 168 131 105 72 40 27
PC = paclitaxel 200 mg/m² + carboplatin AUC 6 q3w

Fig. 7.10
AUC, Area under the curve; CI, confidence interval; HR, hazard ratio; q3W, every 3 weeks.
Postoperative radiotherapy (PORT) remains controversial

PORT Improves Overall Survival
in completely resected NSCLC patients with pathologically
involved mediastinal lymph nodes (N2); it is not a standard
for stage I and II.
Recent data provide evidence of the possible benefit of

PORT in patients with mediastinal nodal involvement.
A large multi-institutional randomised trial evaluating

PORT in this patient population is under way.
In the National Cancer Data Base, PORT (n=1850) was compared to no PORT (2633) in
patients with completely resected N2 NSCLC
OS was increased by 4.5% at 5 years Fig. 7.11
NSCLC, Non-small cell lung cancer; OS, overall survival; PORT, postoperative radiotherapy;
Tx, treatment.
No biomarker has been fully validated as able to identify 100

subgroups of patients for whom adjuvant treatment would
80
be of particular benefit.
Overall survival (%)
60
Despite great efforts, no validated biological tools beyond
This high-risk group
tumour staging are available for identifying resistance to 40
might benefit from adjuvant
ChT (i.e. the excision repair cross-complementation 20
chemotherapy
group 1 [ERCC1] enzyme). p trend=0.0016
0
0 12 24 36 48 60
The figure shows an example of a 14-gene expression Number at risk
Low risk 78 74
Months
71 64 60 56
assay that uses quantitative polymerase chain Intermediate risk 104
High risk 151
101
140
92
121
80
99
67
86
59
71
reaction (qPCR) to identify patients with early-stage

Overall survival for 330 patients with American Joint Commission on Cancer stage IA and
non-squamous NSCLC at high risk for mortality after IB disease considered to be low risk as per conventional pathological criteria (National
surgical resection. Comprehensive Cancer Network); median survival was 113 months in the low-risk group,
88 months in the intermediate-risk group, and 70 months in the high-risk group
Fig. 7.12
REVISION QUESTIONS
1. How can you increase perioperative ChT compliance?
2. Are pneumonectomies a contraindication to perioperative ChT?
3. Is mediastinal radiotherapy a standard treatment for resected N2 NSCLC patients?
41
Besse
Adjuvant and neoadjuvant therapy (continued)
The RADIANT study explored the activity of 2-year Disease-free Survival: EGFR M+
treatment with erlotinib (150 mg/day) in patients with
immunohistochemically or fluorescent in situ hybridisation
(FISH)-evaluated epidermal growth factor receptor
(EGFR)-positive tumours.
There was no difference in DFS (HR 0.90, 95%

CI 0.74–1.10; p = 0.0324) or OS in the overall
population (HR 1.13, 95% CI 0.08–1.44; p = 0.324).
Overall Survival: EGFR M+
In EGFR-mutated NSCLC patients, DFS was not
significantly increased (HR 0.61, 95% CI 0.38–0.98;
p = 0.039) and OS was similar (HR 1.09, 95% CI 0.5–2.1;
p = 0.81). The use of EGFR tyrosine kinase inhibitors
(TKIs) in this setting is not validated.
Fig. 7.13
A
CI, Confidence interval; EGFR M+, epidermal growth factor receptor, mutation positive;
100 Group A (chemotherapy)
HR, hazard ratio.
Group B (chemotherapy plus bevacizumab)
HR 0·99 (95% CI 0·82–1·19); p=0·90
80
60
The use of the anti-vascular endothelial growth factor
40 (VEGF) antibody bevacizumab (15 mg/kg every 3 weeks
for 1 year) did not improve OS.
20
0 Other non-ChT approaches include the MAGE-A3

0 12 24 36 48 60 72 84
Number at risk antigen-specific vaccine, which has not shown any
(number censored)
Group A (chemotherapy) 749 (0)
Group B (chemotherapy 752 (0)
671 (33)
651 (56)
540 (79) 393 (177) 278 (266) 152 (373)
537 (105) 387 (202) 250 (300) 143 (394)
84 (432)
67 (459)
17 (491)
17 (504)
advantage in two of the three co-primary endpoints
plus bevacizumab) after accrual of >2000 patients.
B Fig. 7.14
CI, Confidence interval;100HR, hazard ratio. HR 1·00 (95% CI 0·82–1·22); p=0·97
80
Percentage of Pathological Regression, According to Subgroup

Immune checkpoint
60 inhibitors (such as anti-programmed Current/ex-smoker Never smoked ADC SCC
cell death protein 1 [PD-1] or programmed death-ligand Other PR SD LN+ LN–
40
1 [PD-L1] antibodies) are currently evaluated in the Smoking Status
Histologic Subtype
RECIST Response
peri-operative 20setting. The first induction study with two LN Metastases
injections of nivolumab
0
showed impressive activity. 0
0 12 24 36 48 60 72 84
Time since registration (months) –20
A major(numberpathological
Number at risk
response, defined as a tumour
Regression (%)
censored)
Group A (chemotherapy) 628 (0) 562 (30) 449 (68) 323 (152) 233 (218) 131 (304) 73 (356) 14 (408)
with no
Group B more than 10% 451viable
(chemotherapy
plus bevacizumab)
639 (0) 553 (49) tumour
(95) 318 (180) cells,
201 (263) 115 occurred
(339) 51 (394) 9 (431) –40
in 9 out of 20 resected tumours (45%). –60 PD-L1+

PD-L1–
Unknown
Many ongoing randomised studies are exploring the –80
role of induction or adjuvant immunotherapy, alone or in –100

combination with ChT. Fig. 7.15
ADC, Adenocarcinoma; LN, lymph node; PD-L1, programmed death-ligand 1; PR, partial response;
RECIST, Response Evaluation Criteria in Solid Tumours; SCC, squamous cell carcinoma; SD, stable disease.
REVISION QUESTIONS
1. Which biomarker is mandatory for the adjuvant ChT indication?
2. Is cisplatin-based ChT indicated for a resected stage II NSCLC with EGFR mutation?
3. What is the role of immunotherapy in the perioperative setting?
42
Summary: Adjuvant and neoadjuvant therapy
• Perioperative ChT improves survival in resected NSCLC patients
• Meta-analysis of preoperative ChT and adjuvant ChT demonstrated a benefit that is in the same range in both settings
• Standard: cisplatin-based ChT
• Standard: stage II-IIIA
• Option: IB (>4 cm recommended)
• Option: carboplatin
• Criteria: <75 years / <2 months after surgery / PS 0-1 / no postoperative complications
• No biomarker is validated to select a subgroup of patients who might derive more benefit from perioperative ChT
• Never use targeted therapy (i.e. TKIs of activating mutations such as EGFR, anaplastic lymphoma kinase [ALK]
or antiangiogenic agents)
Further Reading
Arriagada R, Bergman B, Dunant A, et al; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant
chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350:351–360.
Booth CM, Shepherd FA, Peng Y, et al. Adoption of adjuvant chemotherapy for non-small-cell lung cancer: a population-based
outcomes study. J Clin Oncol 2010; 28:3472–3478.
Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med 2018; 378:1976–1986.
Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage
groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007; 2:706–714.
Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the
NCIC CTG BR19 study. J Clin Oncol 2013; 31:3320–3326.
Kato H, Ichinose Y, Ohta M, et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung.
N Engl J Med 2004; 350:1713–1721.
Kelly K, Altorki NK, Eberhardt WE, et al. Adjuvant erlotinib versus placebo in patients with stage IB-IIA non-small-cell lung cancer
(RADIANT): A randomized, double-blind, Phase III trial. J Clin Oncol 2015; 33:4007–4014.
Kratz JR, He J, Van Den Eeden SK, et al. A practical molecular assay to predict survival in resected non-squamous, non-small-cell
lung cancer: development and international validation studies. Lancet 2012; 379:823–832.
Le Péchoux C. Role of postoperative radiotherapy in resected non-small cell lung cancer: a reassessment based on new data.
Oncologist 2011; 16: 672–681.
NSCLC Meta-analyses Collaborative Group, Arriagada R, Auperin A, Burdett S, et al. Adjuvant chemotherapy, with or without
postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010;
375:1267–1277.
NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and
meta-analysis of individual participant data. Lancet 2014; 383:1561–1571.
Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group.
J Clin Oncol 2008; 26:3552–3559.
Strauss GM, Herndon JE 2nd, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB
non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group,
and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008; 26:5043–5051.
Wakelee HA, Dahlberg SE, Keller SM, et al. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-
cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol 2017; 18:1610–1623.
Westeel V, Quoix E, Puyraveau M, et al. A randomised trial comparing preoperative to perioperative chemotherapy in early-stage
non-small-cell lung cancer (IFCT 0002 trial). Eur J Cancer 2013; 49:2654–2664.
43
Besse
Treatment of metastatic non-small cell lung cancer 8
First-line chemotherapy
Chemotherapy (ChT) in metastatic non-small cell lung

cancer (NSCLC) has reached a plateau. 100 Cisplatin and paclitaxel
Cisplatin and gemcitabine
A total of 1207 patients were randomly assigned to 80 Cisplatin and docetaxel
cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/ Carboplatin and paclitaxel
Survival (%)
docetaxel, or carboplatin/paclitaxel. 60
The overall survival (OS) of all regimens was 40

7.4–8.1 months. There was no significant difference
20
between the four treatment regimens.
0
0 10 20 30 40
Fig. 8.1
Planned subgroup analysis In 1725 ChT-naïve patients with stage IIIB or IV

Median; 95% CI
NSCLC, cisplatin/pemetrexed provided similar efficacy
1.0
0.9 CP 11.8; 10.4, 13.2
compared with cisplatin/gemcitabine.
Survival Probability
0.8 CG 10.4; 9.6, 11.2

0.7 CP v CG Adjusted HR; 95% CI In the intent-to-treat population, OS for cisplatin/
0.6 0.81; 0.70, 0.94 pemetrexed was non-inferior to cisplatin/gemcitabine
0.5 (median survival, 10.3 vs 10.3 months, respectively,
0.4 hazard ratio [HR] 0.94, 95% confidence interval [CI]
0.3
0.84–1.05).
0.2
0.1 In a prespecified subgroup analysis, cisplatin/pemetrexed-
treated patients with non-squamous histology had a
0 6 12 18 24 30
Fig. 8.2
significantly better survival than cisplatin/gemcitabine-
CG, Cisplatin/gemcitabine; CP, cisplatin/pemetrexed; CI, confidence interval; HR, hazard ratio.
treated patients.
Meta-analysis included 13 randomised Study (Year Extended Standard Hazard ratio (fixed) Weight Hazard ratio (fixed)
published) duration duration 95% CI % 95% CI
clinical trials (RCTs) and 3027
Zarogoulidis (1995) 36 38 3 0.71 (0.45 to 1.12)
patients receiving first-line (largely Buccheri (1989) 38 36 2 0.73 (0.46 to 1.17)
Barata (2007) 110 110 7 0.77 (0.59 to 1.01)
platinum-based) ChT for 3–4 cycles vs Ciuleanu (2008) 441 222 10 0.79 (0.63 to 1.01)
Fidias (2007) 153 154 9 0.84 (0.65 to 1.08)
continuation of the same ChT for Brodowicz (2006) 138 68 2 0.84 (0.52 to 1.38)
Smith (2001) 153 155 15 0.88 (0.72 to 1.07)
6 cycles or until disease progression. Socinski (2002) 116 114 23 0.96 (0.82 to 1.12)
Belani (2003) 65 65 3 1.02 (0.66 to 1.57)
von Plessen (2006) 147 150 10 1.04 (0.82 to 1.32)
Extending ChT improved progression-free Westeel (2005)
Park (2007)
91
158
90
156
6
6
1.08 (0.79 to 1.48)
1.11 (0.82 to 1.48)
survival (PFS) substantially (HR 0.75, 95% Tourani (1990) 12 11 4 1.26 (0.85 to 1.86)
CI 0.69–0.81; p < 0.00001) and showed Total (95% CI) 1,658 1,369
Test for heterogeneity: χ2 = 12.68, df = 12 (P = .39), I 2 = 5%
100 0.92 (0.85 to 0.99)
no significant improvement in OS (HR Test for overall effect: z = 2.18, P = .03
0.94, 95% CI 0.86–1.01; p = 0.10). 0.5 0.7 1 1.5 2

Extended better Standard better
Extending ChT was associated with CI, Confidence interval. Fig. 8.3
higher toxicity and impaired quality of life.
Overall survival analysis:
extending chemotherapy
beyond a standard
duration
REVISION QUESTIONS
1. What is the best ChT regimen for first-line therapy?
2. What is the optimal duration of first-line ChT?
3. Is the histological subgroup important?
44
Treatment of metastatic non-small cell lung cancer
First-line chemotherapy in combination with antibodies
878 NSCLC patients (stage IIIB or IV) were treated with

paclitaxel/carboplatin with or without bevacizumab. After 100
Hazard ratio, 0.79
6 cycles, bevacizumab was administered every 3 weeks P=0.003
80
until disease progression. BPC group

(305 events in
417 patients)
60
The median survival was superior for the bevacizumab-
containing regimen (12.3 vs 10.3 months, HR 0.79; 40
p = 0.003). Similarly, PFS was improved (6.2 vs 4.5
PC group
months, HR 0.66; p < 0.001) with corresponding 20 (344 events in
433 patients)
response rates of 35% and 15% (p < 0.001). In this study,
rates of clinically significant bleeding were 4.4% and 0
0 6 12 18 24 30 36 42
0.7%, respectively (p < 0.001).
Month
Patients with squamous cell tumours, tumour infiltration of Fig. 8.4
large central vessels and clinically significant haemoptysis BPC, Paclitaxel/carboplatin plus bevacizumab; PC, paclitaxel/carboplatin.
should not receive bevacizumab.
In a three-arm phase III study, 1043 patients received

cisplatin/gemcitabine with or without low-dose
1.0 Placebo + CG (n = 347)
(7.5 mg/kg) or high-dose bevacizumab (15 mg/kg).
Survival (probability)
The rates of ≥grade 3 hypertension, bleeding and

Progression-Free
Bevacizumab 15 mg/kg + CG (n = 351)

0.8 HR (95% CI) = 0.82 (0.68 to 0.98)
P = .03
proteinuria were modestly higher in the bevacizumab
0.6 arms than in the placebo arm.
0.4
PFS was significantly prolonged (low-dose group: median
0.2 PFS 6.7 vs 6.1 months, HR 0.75; p = 0.003; high-dose
group: median PFS 6.5 vs 6.1 months, HR 0.82; p = 0.03).
0 3 6 9 12 15 18
Time (months) Median OS was >13 months in all treatment groups;

No. of patients at risk
Placebo + CG 347 228 122 36 12 3 0 OS was not significantly increased with the addition of
Bev 15 mg/kg + CG 351 238 148 46 16 5 0
Fig. 8.5
bevacizumab. Most patients (62%) received multiple lines
CG, Cisplatin/gemcitabine; CI, confidence interval; HR, hazard ratio.
of post-study treatment.
Most squamous NSCLC tumours express epidermal Sub-group of

growth factor receptor (EGFR) protein. Two phase III trials EGFR-expressing
NSCLC
(FLEX and SQUIRE) demonstrated an OS benefit by the 100
addition of the EGFR antibody cetuximab (HR 0.80) or HR (95% CI): 0.79 (0.69, 0.92); P=0.002
necitumumab (HR 0.84) to first-line cisplatin-based ChT. 80

Median OS, months:
Necitumumab+gemcitabine-cisplatin: 11.7
Gemcitabine-cisplatin: 10.0
In the SQUIRE trial, there were more grade 3 or worse 60
adverse events (72% vs 62%). The rate of grade 3/4 febrile

neutropaenia was similar (in contrast to the FLEX study). 40
20
In the exploratory subgroup of EGFR-expressing
Necitumumab+gemcitabine-cisplatin
tumours (95%), the survival benefit in the necitumumab 0
Gemcitabine-cisplatin
group was more pronounced (median 11.7 vs 10.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Time since randomisation (months)
months, HR 0.79, 95% CI 0.69-0.92; p = 0.002). Fig. 8.6
CI, Confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio;
NSCLC, non-small cell lung cancer; OS; overall survival.
REVISION QUESTIONS
1. What are the options for systemic first-line therapy?
2. What is the optimal duration of first-line ChT?
3. Is the histological subgroup important?
4. What is the benefit of adding antibody therapies to ChT in defined NSCLC subgroups?
45
Reinmuth & Reck
Maintenance therapy
To test the hypothesis of switch maintenance, 663 patients

with stage IIIB or IV NSCLC who had not progressed on 1·0
Pemetrexed
Placebo
4 cycles of platinum-based ChT received pemetrexed 0·9
0·8
(n=441) or placebo (n=222) until disease progression. 0·7
PFS probability
0·6 HR 0·50 (95% CI 0·42–0·61); p<0·0001
0·5
Pemetrexed significantly improved PFS (4.3 vs 2.6 months, 0·4
HR 0.50, 95% CI 0.42–0.61; p < 0.0001) and OS (13.4 vs 0·3
0·2
10.6 months, HR 0.79, 95% CI 0.65–0.95; p = 0.012). 0·1
0
0 6 12 18 24
Maintenance therapy with pemetrexed was generally well Number at risk
tolerated. For patients with squamous histology, PFS was Pemetrexed 441
Placebo 222
122
19
33
3
9
1
1
0
not significantly different (p = 0.896).
Fig. 8.7
CI, Confidence interval; HR, hazard ratio; PFS, progression-free survival.
Subgroup of EGFR
1.0
wild-type patients NSCLC patients without disease progression after
first-line therapy received erlotinib (n=438) or placebo
Progression-free survival
0.8
(n=451) until progression or unacceptable toxicity.
0.6
0.4 Overall, median PFS was significantly longer with

0.2
erlotinib than with placebo (12.3 vs 11.1 weeks, HR 0.71,
HR=0.78 (0.63-0.96); p=0.0185 95% CI 0.62–0.82; p < 0.0001).
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88
Time (weeks)
Number at risk However, in the phase III IUNO trial, OS with maintenance
Erlotinib
165
158
91 79 57
43 37 29 17 15 11 8 7 7 5 5 5 4 2 2 1 0 0
Placebo 163
158
82 55 37
26 22 17 11 10 9 8 7 7 6 5 3 3 1 1 1 1 1 erlotinib was not superior to second-line treatment
Fig. 8.8 in patients without activating EGFR mutations.
EGFR, Epidermal growth factor receptor; HR, hazard ratio. Consequently, erlotinib is not approved for maintenance
therapy of EGFR wild-type patients.
In contrast to switch maintenance where a third agent is 100 Pemetrexed+BSC
initiated after 4 cycles of platinum-based double-agent Placebo+BSC

Median PFS (95% CI)
ChT, continuous maintenance uses an agent that was 80 Pemetrexed 4·1 (3·2–4·6)
Progression-free survival (%)
Placebo 2·8 (2·6–3·1)

already part of the first-line treatment. 60
Log-rank p<0·0001
HR=0·62 (95% CI 0·49–0·79)
Wald p<0·0001
After 4 cycles of pemetrexed plus cisplatin, 539 stage

40
IIIB/IV NSCLC patients received continuation maintenance
with pemetrexed (n=359) or placebo (n=180). 20
Patients in the pemetrexed arm had superior PFS 0

0 3 6 9 12 15 18
Number at risk
(4.1 vs 2.8 months; p < 0.0001) and OS (16.9 vs Pemetrexed+BSC 359 132 57 21 4 0
Placebo+BSC 180 52 15 5 0 0
14 months; p = 0.0191).
Fig. 8.9
BSC, Best supportive care; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.
REVISION QUESTIONS
1. What is the difference between continuous and switch maintenance?
2. Which patients should receive maintenance therapy?
3. If a patient does not undergo maintenance therapy, what are the optimal follow-up intervals?
46
Second-line therapy
Patients with stage IIIB/IV NSCLC and progression after 1.0

DOCETAXEL 75 mg/m2 (n=55)
platinum-based ChT were randomised to treatment 0.9 BSC75 (n=49)
with docetaxel 100 mg/m² (49 patients) or 75 mg/m²
0.8
(55 patients) or best supportive care (BSC).
0.7
CUMULATIVE PROBABILITY
Log-rank test, p=0.010
Time to progression was longer for docetaxel patients 0.6
overall than for BSC patients (10.6 vs 6.7 weeks, 0.5

respectively; p < 0.001), as was median survival 0.4
(7.0 vs 4.6 months; log-rank test, p = 0.047).
0.3
No benefit in survival was seen for patients treated with 0.2
docetaxel 100 mg/m². Conclusively, the benefits of 0.1
docetaxel therapy at a dose of 75 mg/m² outweigh 0.0

the risks.
0 3 6 9 12 15 18 21
SURVIVAL TIME (MONTHS) Fig. 8.10
BSC, Best supportive care.
571 NSCLC patients with one prior ChT regimen were

treated with pemetrexed 500 mg/m² or docetaxel 75 mg/m².
Treatment with pemetrexed resulted in equivalent PFS

(2.9 months for each arm) and median survival time (8.3
vs 7.9 months for pemetrexed and docetaxel, p = 0.99).
Pemetrexed therapy was associated with significantly
fewer side effects compared with docetaxel.
In a retrospective subgroup analysis, PFS under

pemetrexed was superior for non-squamous patients
(median 3.4 vs 3.0 months) while it was inferior for
patients with squamous NSCLC (2.3 vs 2.7 months).
Fig. 8.11
CI, Confidence interval; MST, median survival time; OS, overall survival.
100 P < 0.001 by stratified log-rank test

Hazard ratio, 0.70 (95% CI, 0.58–0.85)
After progression on one or two prior ChT regimens,
80
731 patients not eligible for additional ChT were randomly
assigned in a 2:1 ratio to receive oral erlotinib or placebo.
Patients (%)
60
For erlotinib and placebo, PFS was 2.2 months and 40

1.8 months, respectively (HR 0.61; p < 0.001) and OS
was 6.7 months and 4.7 months (HR 0.70; p < 0.001). 20 Placebo Erlotinib
In a retrospective analysis of 204 tumours, 34 (17%) had 0

0 6 12 18 24 30
EGFR exon 19 deletion or exon 21 L858R mutations. After
Months
erlotinib therapy, response rates were higher in EGFR
No. at Risk
mutant tumours (27% vs 7%; p = 0.03) but no significant Placebo 243 107 50 9 0 0
Erlotinib 488 255 145 23 4 0
OS benefit was seen (wild-type EGFR HR 0.74; p = 0.09;
Overall survival
mutant EGFR HR 0.55; p = 0.12). Fig. 8.12
REVISION QUESTIONS
1. What are the treatment options for progressing NSCLC tumours after first-line therapy with ChT?
2. Is histology important for treatment selection of second-line therapy?
3. Is ChT the first choice for second-line therapy?
47
Reinmuth & Reck
Second-line therapy (continued)
795 patients with stage IIIB or IV squamous NSCLC

and progression after at least 4 cycles of platinum-
based ChT were treated with afatinib (40 mg per day)
or erlotinib (150 mg per day) until disease progression.
Treatment with afatinib was associated with significantly

longer PFS (median 2.4 vs 1.9 months; HR 0.82;
95% CI 0.68–1.00; p = 0.0427) and OS (median 7.9 vs
6.8 months; HR 0.81, 95% CI 0.69–0.95; p = 0.0077).
Fig. 8.13
1314 patients with histologically or cytologically confirmed

Nintedanib+ Placebo+
stage IIIB/IV or recurrent NSCLC were randomised to
docetaxel docetaxel HR (95% CI) p value
therapy with docetaxel with or without nintedanib. All NSCLC
PFS, months histologies were included. PFS and OS data are displayed.
All patients 3.4 2.7 0.79 (0.68–0.92) 0.0019
Adenocarcinoma 4.0 2.8 0.77 (0.62–0.96) 0.0153 Nintedanib is a multi-tyrosine kinase inhibitor (TKI)
SCC 2.2 2.6 0.77 (0.62–0.96) 0.0200 inhibiting vascular endothelial growth factor receptor
(VEGFR), platelet-derived growth factor receptor
OS, months
(PDGFR) and fibroblast growth factor receptor (FGFR).
All patients 10.1 9.1 0.94 (0.83–1.05) 0.2720
Both OS and PFS were significantly prolonged only in
Adenocarcinoma 12.6 10.3 0.83 (0.70–0.99) 0.0359 the subgroup of patients with adenocarcinoma as part
SCC 8.6 8.7 1.01 (0.85–1.21) 0.8907 of pre-planned histological subgroup analyses.
Fig. 8.14
CI, Confidence interval; HR, hazard ratio; OS, overall survival; PFS progression-free
survival; SCC, squamous cell carcinoma.
Interestingly, particularly patients with disease
progression as best response in first-line therapy or
disease progression within 9 months of initiation of first-
line ChT benefitted from the addition of nintedanib. So
far, there is no biomarker for antiangiogenic treatment.
The phase III REVEL trial treated 1253 NSCLC patients

after platinum-based therapy with docetaxel with or
without the anti-VEGFR2 antibody ramucirumab. The
primary endpoint was OS.
The numerical survival benefit was seen in both non-
squamous (HR 0.83; p = 0.02) and squamous (HR 0.883;
p = 0.19) NSCLC subgroups.
Median OS was 10.5 months (vs 9.1 months) for patients

allocated to ramucirumab plus docetaxel (HR 0.86,
95% CI 0.75−0.98; p = 0.023). Median PFS was 4.5 vs
3.0 months (HR 0.76, 95% CI 0.68–0.86; p < 0.0001). Fig. 8.15
REVISION QUESTIONS
1. How can experiences from first-line treatment be used for selection of second-line therapy?
2. Does treatment with TKIs in unselected patients lead to improved survival?
48
Summary: Treatment of metastatic non-small cell lung cancer
• Histology: Defining the histological subgroup has an impact on selection of molecular screening and therapy options
• At least non-squamous NSCLC should be screened for activating EGFR and BRAF-V600 mutations as well as
activated ALK (anaplastic lymphoma kinase) and ROS1
• ChT: New cytotoxic agents display improved efficacy in defined patient subgroups
• Antiangiogenic agents improve PFS and may lead to prolonged OS
• Maintenance therapy should be considered for selected patients with good performance status after first-line therapy
• Second-line therapy does lead to survival benefit
• TKIs can be a treatment option in unselected NSCLC patients
• Systemic ChT with or without antiangiogenic agents remains a major treatment option in NSCLC
Further Reading
Cicènas S, Geater SL, Petrov P, et al. Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-
cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study). Lung Cancer 2016; 102:30–37.
Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage
IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised
phase 3 trial. Lancet 2014; 384:665–673.
Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell
lung cancer previously treated with chemotherapy. J Clin Oncol 2004; 22:1589–1597.
Malvezzi M, Bertuccio P, Rosso T, et al. European cancer mortality predictions for the year 2015: does lung cancer have the highest
death rate in EU women? Ann Oncol 2015; 26:779–786.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;
361:947–957.
Ratcliffe MJ, Sharpe A, Midha A, et al. Agreement between programmed cell death ligand-1 diagnostic assays across multiple protein
expression cutoffs in non-small cell lung cancer. Clin Cancer Res 2017; 23:3585–3591.
Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line
therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009; 27:1227–1234.
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;
355:2542–2550.
Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in
chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008; 26:3543–3551.
Schiller JH, Harrington D, Belani CP, et al; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for
advanced non-small-cell lung cancer. N Engl J Med 2002; 346:92–98.
Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with
non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000; 18:2095–2103.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously
treated non-small-cell lung cancer. N Engl J Med 2005; 353:123–132.
Soria JC, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of
the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 2015; 16:897–907.
Stinchcombe TE, Socinski MA. Maintenance therapy in advanced non-small cell lung cancer: current status and future implications.
J Thorac Oncol 2011; 6:174–182.
Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line
therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial.
Lancet Oncol 2015; 16:763–774.
49
Reinmuth & Reck
Treatment of small cell lung cancer:
chemotherapy and radiotherapy 9
General principles
80% of patients with small cell lung cancer (SCLC)

SCLC pT1 M0
present with metastatic (stage IV) disease. 100% Median
Deaths / N in Months
20% have stage I–III SCLC, which overlaps with the N0
N1
37 / 68
22 / 37
78
29
80%
former so-called ‘limited stage’. N2 15 / 20 18
60%
Very rarely, SCLC presents as a solitary nodule, stage I.
40%
20%
0%
0 2 4 6 8 10
Survival, Years Fig. 9.1
SCLC, Small cell lung cancer.
Survival of patients with small cell lung cancer treated Early attempts to treat SCLC with surgery failed.
primarily by methods other than operation
Survival, year/s In early trials, radiotherapy (RT) was better than
Treatment No. pt. <1 1-2 2-3 7+
surgery, but still palliative when used alone.
Radiation only 80 72 7 1 …
Radiation & radioisotopes 2 2 … … …
The survival improvement was observed when patients
Chemotherapy only 30 28 2 … …
were treated with cyclophosphamide.
Chemotherapy & radiation 95 82 6 6 1
Fig. 9.2
Review: Platinum versus non-platinum chemotherapy regimens for small cell lung cancer
Comparison: 1 Treatment Regimens
Outcome: 3 24-month survival Non-
Platinum
Study or subgroup Platinum regime regime Weight
Risk Ratio Risk Ratio
M-H, M-H,
n/N n/N Random, 95% CI Random, 95% CI
1 Undifferentiated
Farris 1993 8/56 6/57 3.7 % 1.36 [ 0.50, 3.66 ]
Fukuoka 1991 14/97 12/97 5.5 % 1.17 [ 0.57, 2.39 ]
Postmus 1992 4/60 5/63 2.6 % 0.84 [ 0.24, 2.98 ]
Sculier 1990 9/95 12/106 4.7 % 0.84 [ 0.37, 1.90 ]
Sculier 1993 11/107 9/108 4.6 % 1.23 [ 0.53, 2.86 ]
Smith 1991 6/47 4/48 2.8 % 1.53 [ 0.46, 5.08 ]
Souhami 1997 0/80 4/75 0.6 % 0.10 [ 0.01, 1.90 ]
Urban 1999b 11/229 11/228 4.7 % 1.00 [ 0.44, 2.25 ]
Veronesi 1994 5/70 11/66 3.6 % 0.43 [ 0.16, 1.17 ]
White 2001 2/60 2/59 1.3 % 0.98 [ 0.14, 6.75 ]
Subtotal (95% CI) 901 907 34.1% 0.97 [0.71,1.33]
Total events: 70 (Platinum regime), 76 (Non-Platinum regime)
Heterogeneity: Tau2 = 0.0; Chi2 = 6.62, df = 9 (P = 0.68); I2 =0.0%
Test for overall effect: Z = 0.18 (P = 0.86)
2 Limited Disease
Systemic treatment has improved survival in Eagan 1981

Fukuoka 1986
10/31
1/10
9/31
2/11
5.2
1.0
%
%
1.11
0.55
[
[
0.52,
0.06,
2.35
5.18
]
]
Goodman 1990 62/194 52/194 9.7 % 1.19 [ 0.87, 1.63 ]
all SCLC stages and is the cornerstone Havemann 1987
Jones 1993
7/51
0/17
6/53
5/15
3.5
0.6
%
%
1.21
0.08
[
[
0.44,
0.00,
3.36
1.35
]
]
of the treatment. Sundstrom 2002

Urban 1999a
26/105
8/81
9/109
20/88
5.5
5.1
%
%
3.00
0.43
[
[
1.48,
0.20,
6.09
0.93
]
]
Wolf 1987 6/27 3/27 2.5 % 2.00 [ 0.56, 7.19 ]
Subtotal (95% CI) 516 528 33.2% 1.11 [0.67,1.82]
Non-platinum combinations Total events: 120 (Platinum regime), 106 (Non-Platinum regime)
Heterogeneity: Tau2 = 0.26; Chi2 = 17.90, df = 7 (P = 0.01); I2 =61%
(e.g. cyclophosphamide, doxorubicin,

3 Extensive Disease
etoposide) are efficacious but less used Chahinian 1989
Fukuoka 1986
2/105
3/25
4/103
2/23
1.6
1.6
%
%
0.49 [ 0.09, 2.62
1.38 [ 0.25, 7.53
]
]
than cisplatin/etoposide.
Gatzemeier 1994 24/171 24/173 7.3 % 1.01 [ 0.60, 1.71 ]
Greco 2005 5/60 9/60 3.5 % 0.56 [ 0.20, 1.56 ]
Havemann 1987 6/99 3/99 2.3 % 2.00 [ 0.51, 7.77 ]
Jones 1993 0/37 1/35 0.5 % 0.32 [ 0.01, 7.50 ]
Kanitz 1992 0/59 14/52 0.6 % 0.03 [ 0.00, 0.50 ]
Lyss 2002 0/12 2/13 0.6 % 0.22 [ 0.01, 4.08 ]
In stage I–III SCLC, cisplatin/etoposide is Postmus 1996
Roth 1992
5/70
12/148
5/73
6/146
2.8
3.9
%
%
1.04 [ 0.32, 3.45
1.97 [ 0.76, 5.12
]
]
combined with concurrent chest RT. Sundstrom 2002

Urban 1999a
5/113
4/110
4/109
0/115
2.5
0.6
%
%
1.21 [ 0.33, 4.37
9.41 [ 0.51, 172.68
]
]
Wampler 1991 13/85 3/85 2.7 % 4.33 [ 1.28, 14.66 ]
Wolf 1987 3/46 4/41 2.1 % 0.67 [ 0.16, 2.81 ]
Subtotal (95% CI) 1140 1127 32.7% 1.08 [0.68,1.71]
Heterogeneity:2 Tau = 0.25; Chi2 = 20.83, df = 13 (P = 0.08); I2 =38%
Total (95% CI) 2557 2562 100.0% 1.06 [0.84,1.33]
Heterogeneity: Tau2 = 0.12; Chi2 = 46.27, df = 31 (P = 0.04); I2 =33%
0.1 0.2 0.5 1 2 5 10

CI, Confidence interval. Favours Non-Platinum Favours Platinum Fig. 9.3
REVISION QUESTIONS
1. What proportion of patients with newly diagnosed SCLC already have disseminated disease?
2. Does surgery have a major role to play in the management of non-disseminated SCLC?
3. What is the cornerstone of treatment of SCLC?
50
Treatment of small cell lung cancer: chemotherapy and radiotherapy
Disseminated disease: first-line treatment
SCLC is, in first line, a very chemosensitive disease. Rapid

1.0
tumour responses are observed in over 80% of patients.
0.9
Chemotherapy (ChT) is also useful in patients with a poor
performance status, but at the cost of more toxicity. 0.8
0.7
Probability of survival
The first-choice treatment is 4–6 cycles of etoposide 0.6
and a platinum derivative (cisplatin or carboplatin).
0.5
Combinations other than platinum/etoposide may 0.4

have similar activity, but this has not been consistently 0.3 EP
demonstrated. Cisplatin can probably safely be replaced 0.2
CEV
by carboplatin in order to decrease toxicity and to 0.1
facilitate the delivery. 0.0
0 12 24 36 48 60
Time (months)
Fig. 9.4
CEV, Cyclophosphamide/epirubicin/vincristine; EP, etoposide/cisplatin.
The combination of cisplatin/irinotecan was superior

for survival to cisplatin and etoposide, but only in Asian
populations.
Studies in Europe and the USA did not demonstrate

a beneficial effect of cisplatin/irinotecan over cisplatin/
etoposide, the latter remaining first choice.
European and USA patients experienced more toxicity
with irinotecan than Asians, possibly due to genetic
differences in topoisomerase I enzymes.
Fig. 9.5
CBP, Carboplatin; CI, confidence interval; DDP, cisplatin; HR, hazard ratio.
Overall Survival
100 Rate of Overall Survival at 12 Mo

90 Atezolizumab 51.7% (95% CI, 44. 4–59.0)
Placebo 38.2% (95% CI, 31. 2–45.3)
Patients Who Survived (%)
80
The concurrent administration of the programmed death-
Stratified hazard ratio for death, 0.70 (95% CI, 0.5 4–0.91)
70 P=0.007
ligand 1 (PD-L1) inhibitor atezolizumab with carboplatin/ 60

50
etoposide ChT followed by atezolizumab maintenance, 40
improved the median overall survival from 10.3 months to 30

Atezolizumab
12.3 months. 20
10 Median in the placebo group, Median in the atezolizumab group, Placebo
10.3 mo (95% CI, 9. 3–11.3) 12.3 mo (95% CI, 10.8–15.9)
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Months
Fig. 9.6
REVISION QUESTIONS
1. Is combination therapy acceptable in patients with a poor performance status?
2. Can cisplatin be substituted by carboplatin?
3. What is the impact of immune treatment in first-line for disseminated SCLC?
51
De Ruysscher
Disseminated disease: first-line treatment (continued)
Immediate whole-brain radiotherapy (WBRT) is indicated Time to progression inside the brain
in patients with brain metastases and intracranial %
hypertension or neurological emergencies. 100

90
Asymptomatic brain metastases can be treated with 80 N 0
60 55 ChT
systemic therapy and WBRT deferred to symptomatic 70 60 51 ChT + WBRT
60
relapse. 50 Logrank P = 0.005
40
Directly after WBRT, systemic therapy can be given. 30
20
10
(months)
0 2 4 6 8 10
Number of patients at risk:
60 24 11 3 2 ChT
60 33 19 15 12 ChT + WBRT
Fig. 9.7
ChT, Chemotherapy; WBRT, whole-brain radiotherapy.
Because of the fast response to systemic treatment,

a superior vena cava syndrome can be treated with
ChT alone.
Alternating non-cross-resistant drugs and increased total
dose, dose intensity, number of courses or number of
drugs have been unsuccessful.
The median survival is 8–13 months and the 5-year

survival 5%.
Fig. 9.8
100
PE, Cisplatin/etoposide; TP, topotecan/cisplatin. A
90
80
Symptomatic brain metastases occur in nearly 50% 70

60
of patients, even in those without detectable brain 50
metastases at diagnosis. 40
30
P=0.003
20 Control
Prophylactic cranial irradiation (PCI) given after ChT to 10
Irradiation
patients showing any response and with a reasonable 0

0 3 6 9 12 15 18 21 24
performance status decreases the incidence of No. at Risk Months
Control 143 115 58 36 15 3 2 1
symptomatic brain metastases. Irradiation 143 119 67 44 26 17 11 6
B
PCI also increases survival in these cases. The addition
of chest RT did not lead to an increased survival, but
may be offered in selected patients (A).
In patients with a brain MRI negative for brain

metastases, PCI with 3-monthly MRI surveillance did
not offer a survival advantage over MRI surveillance
Fig. 9.9
and subsequent treatment of brain metastases (B).
REVISION QUESTIONS
1. Should asymptomatic brain metastases at diagnosis be treated with WBRT?
2. What is the treatment of brain metastases with important neurological symptoms?
3. When is PCI given?
4. Should all patients that achieve remission after ChT receive chest RT?
52
Disseminated disease: second-line treatment
Virtually all patients with disseminated disease will Progression free survival
100 Eligible patients who started treatment
relapse even after having achieved a remission with 90
first-line ChT or chemo-immunotherapy. 80 Median in Months (95% 2-sided CI)
70 Amrub: 5.2 (3.0, 7.5)
Amrub + Cisp: 6.9 (6.0, 7.5)
Patients are classified as having a sensitive relapse when 60 Cisp + Etop: 5.8 (5.3, 7.8)
the recurrence is seen 90 days or more after the end of 50
first-line treatment. 40
30
A resistant relapse is defined as a recurrence within 20
90 days after the end of first-line ChT. 10

0 (months)

0 3 6 9 12 15 18 21 24 27
O
N Number of patients at risk: Treatment
27 17
28 12 4 3 2 1 0 0 Amrub
28 24
30 18 5 1 1 1 1 1 Amrub + Cisp
28 23
30 14 3 1 0 0 0 0 Cisp + Etop
Amrub, Amrubicin; Cisp, cisplatin; CI, confidence interval; Etop, etoposide. Fig. 9.10
1.0
≥Median
<Median
Survival Probability
0.8
HR = 0.52 If disease progresses during initial ChT, the SCLC is called
P = 0.025
0.6 refractory.
0.4 Second-line treatment is useful only in those patients in a

good general condition and with adequate organ function.
0.2
In case of a sensitive relapse, the same ChT as initially
0.0
given can be considered.
0 3 6 9 12 15
Time (Months)
≥Median (n) 47 31 17 7 1 0
<Median (n) 42 19 11 2 1 0
Fig. 9.11
HR, Hazard ratio.
1.0
In case of a resistant relapse, second-line therapy results 0.8

Topotecan (n = 71)
Cumulative Proportion Alive
in less than 10% remissions, with a few months of life Best supportive care (n = 70)
prolongation.
0.6
Topotecan is the only approved drug for resistant

0.4
relapse in second line.
After platinum and etoposide, besides topotecan, 0.2
cyclophosphamide, doxorubicin and vincristine are

often given. 0 24 48 72 96 120 144 168 192
Time (weeks)
Fig. 9.12
REVISION QUESTIONS
1. When is the same ChT as in first line indicated at relapse?
2. What is a resistant relapse?
3. Which drug is approved for resistant relapse?
53
De Ruysscher
Localised disease
A rare subgroup of patients with very early stage SCLC,

Pathological TNM Stage
i.e. T1-2N0M0, may be considered for primary surgery. 100% Median
Deaths / N in Months
IA 37 / 68 78
Even after complete resection, adjuvant ChT is standard, 80% IB
IIA
55 / 91
22 / 37
31
29
as well as PCI. IIB

IIIA
26 / 34
67 / 76
33
14
60% IIIB 27 / 33 17
IV 9 / 10 13
In most patients, RT is the standard local treatment.
40%
20%
0%
0 2 4 6 8 10
Survival, Years
Fig. 9.13
TNM, Tumour, Node, Metastasis.
Old meta-analyses showed that the addition of thoracic

RT to ChT improved survival over ChT alone.
ChT delivered concurrently with chest RT is the first choice.

In frail patients, sequential ChT and chest RT may be
considered.
Fig. 9.14
Overall survival
The best results were achieved by combining 4 cycles of 100
1-sided P = .90
cisplatin/etoposide with chest RT. HR = 1.43 (80% CI, 1.00 to 2.05)
Vandetanib
80
Placebo
New drug combinations have not improved survival.
Probability (%)
60
There is no role for maintenance therapy after cisplatin/

40
etoposide and thoracic RT. As an example, the addition
of vandetanib did not improve the OS. 20
0 6 12 18 24
Time (months)
No. at risk
Placebo 54 42 15 8 1
Vandetanib 53 30 14 7 2
Fig. 9.15
REVISION QUESTIONS
1. What is the role of surgery in SCLC?
2. What is the best drug combination for localised SCLC?
3. How should thoracic RT be combined with ChT?
54
Localised disease (continued)
Delivering chest RT in a short overall treatment time 40
leads to a better survival than giving the same dose

35
over a longer time. After a phase III trial comparing
45 Gy BID versus 66 Gy QD, the BID schedule remains 30
5-Year Survival (%)

standard of care.
25
Beginning chest RT as soon as possible after the start of 20

ChT is associated with higher long-term survival.
15
Because of radiation-induced radiological changes, the
remission status cannot be assessed adequately, except 10
in the case of frank disease progression. 0 20 40 60 80 100 120 140 160 180
SER (days)
Fig. 9.16
SER, End of radiotherapy.
Even in patients with negative findings on brain imaging

at diagnosis, 50% will subsequently develop brain
metastases.
Patients with brain metastases have a median survival of
3 months. Prevention is thus essential.
PCI reduces the incidence of brain metastases by 50%

and increases long-term survival.
Fig. 9.17
PCI, Prophylactic cranial irradiation.
LS–Memory
LENT-SOMA: Memory
PCI may lead to slight neurocognitive impairment, p=0.17

which may also be present at diagnosis and due to ChT. 60% 36-Gy group
40%
PCI is standard in all patients who show no disease
20% 25-Gy group
progression after ChT and thoracic RT and who are in a
reasonable general condition. 0% 60%
PCI should be given within 4 weeks after the last 40%

administration of ChT. 20%
0%
0 12 24 36
Fig. 9.18
LENT-SOMA, Late Effects Normal Tissue Task

Force-Subjective, Objective, Management scale. Proportion of patients
in the four classes of
unfavourable status [grade 1
REVISION QUESTIONS (left), grade 2, grade 3 and
grade 4 (right)] in
1. How and when should thoracic irradiation be delivered? each arm
2. Which patients should receive PCI?
3. When should PCI be given?
55
De Ruysscher
Localised disease: radiotherapy details
Two Phase III studies (USA and European Organisation for Frequency and location of recurrences as assessed by CT
Research and Treatment of Cancer [EORTC]) compared
the current standard RT schedule (45 Gy/30 twice-daily Recurrence Patients (n)
fractions of 1.5 Gy) with 66–70 Gy in 2 Gy per day, 5 days None 21 (35)
per week schedules. The EORTC (CONVERT) study, with Local 9 (15)
a non-inferiority design, could not demonstrate that the In field 3 (5.0)
Out of field 4 (6.7)
experimental arm (66 Gy) was beneficial and the 45 Gy Both in field and out of field 2 (3.3)
BID arm was numerically better for survival. Isolated local 2 (3.3)
Local and distant/nodal 7 (11.7)
In both arms of these studies, thoracic RT began at Nodal 20 (33.3)
day 1 of the second cycle of ChT. In field 8 (13.3)
Out of field 7 (11.7)
Both in field and out of field 5 (8.0)
Elective nodal irradiation could be omitted provided Isolated nodal 2 (3.3)
the RT volumes were defined by fluorodeoxyglucose- Nodal and distant/nodal 18 (30.0)
Distant 34 (56.7)
positron emission tomography/computed tomography Isolated distant 19 (31.7)
(FDG-PET/CT) scans. Distant and local/nodal 15 (25.0)
Isolated brain 9 (15.0)
CT, Computed tomography. Fig. 9.19
Acute oesophagitis grade 3 occurred in 20% of patients Oesophagitis healed within 3–6 weeks after the end of RT.
treated with accelerated RT when elective nodal irradiation
was omitted, which is similar to the incidence with 66 Gy There is not a higher risk of radiation pneumonitis for
in 33 QD fractions. accelerated RT compared with conventional RT.
Effect of modified radiotherapy compared with conventional radiotherapy on toxicity events

Availability Result
No. of No. of Toxicity Rate in Toxicity Rate in
OR 95% CI P Efficacy I2 (%) P Heterogeneity
Severe Toxicity Trials Patients Control Arm (%) Experimental Arm (%)
Small cell lung cancer
Acute oesophageal 2 667 12 25 2.41 1.62 to 3.59 < .001 0 .99
Acute pulmonary 2 675 5 6 1.32 0.69 to 2.51 .40 0 .33
Acute cardiac 2 670 1 3 2.96 1.13 to 7.73 .03 0 .76
Haematological 2 674 83 86 1.22 0.81 to 1.86 .34 0 .36
Neutrophils 2 643 84 87 1.31 0.84 to 2.04 .23 0 .70
Platelets 2 666 38 30 0.70 0.50 to 0.98 .04 36 .21
Haemoglobin 2 673 18 19 1.06 0.71 to 1.59 .76 0 .35 Fig. 9.20
CI, Confidence interval; OR, odds ratio.
A higher dose of PCI was shown not to be beneficial. 100
The standard PCI dose remains 25 Gy in 10 daily 80
fractions.
60 Standard dose
Avoidance of the hippocampus to preserve
neurocognition is being evaluated in clinical studies. 40
Higher dose
20
0
0 1 2 3 4
Years
Number at risk
Standard dose 25 Gy 3 60 266 117 65 41
Higher dose 36 Gy 360 238 109 60 36
Fig. 9.21
Gy, Gray.
REVISION QUESTIONS
1. Which is the standard dose of chest RT?
2. What are the differences in late side effects of RT comparing accelerated RT with conventional fractionation?
3. What is the standard schedule of PCI?
56
Summary: Treatment of small cell lung cancer:
chemotherapy and radiotherapy
• Standard of care is 4–6 cycles of etoposide and a platinum derivative (cisplatin or carboplatin), if available concurrently
with atezolizumab (with carboplatin)
• Directly after palliative WBRT, systemic treatment can be administered
• PCI improves survival in all stages, but in stage IV disease MRI surveillance is an alternative
• Second-line treatment is useful in patients in a good general condition and with good organ function
• Topotecan is the only approved drug for resistant relapse in second line
• In limited disease early thoracic RT is standard of care, in extensive disease it should be considered as consolidation
• Delivering chest RT in a short overall treatment time leads to a better long-term survival than giving the same RT dose
over a longer time
Further Reading
Amarasena IU, Walters JA, Wood-Baker R, et al. Platinum versus non-platinum chemotherapy regimens for small cell lung cancer.
Cochrane Database Syst Rev 2008; (4):CD006849.
De Ruysscher D, Lueza B, Le Péchoux C, et al. RTT-SCLC Collaborative Group. Impact of thoracic radiotherapy timing in limited-stage
small-cell lung cancer: usefulness of the individual patient data meta-analysis. Ann Oncol 2017; 27:1818–1828.
De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time between the first day of chemotherapy and the last day of chest
radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 2006; 24:1057–1063.
Faivre-Finn C, Snee M, Ashcroft L, et al. CONVERT Study Team. Concurrent once-daily versus twice-daily chemoradiotherapy in
patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol 2017;
18:1116–1125.
Früh M, De Ruysscher D, Popat S, et al; ESMO Guidelines Working Group. Small-cell lung cancer (SCLC): ESMO Clinical Practice
Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(Suppl 6):vi99–105.
Horn L, Mansfield AS, Szczęsna A, et al; IMpower133 Study Group. First-line atezolizumab plus chemotherapy in extensive-stage
small-cell lung cancer. N Engl J Med 2018; 379:2220–2229.
Le Péchoux C, Dunant A, Senan S, et al; Prophylactic Cranial Irradiation (PCI) Collaborative Group. Standard-dose versus higher-dose
prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and
thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol 2009;
10:467–474.
O’Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in
patients with relapsed small-cell lung cancer. J Clin Oncol 2006; 24:5441–5447.
Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992;
327:1618–1624.
Slotman B, Faivre-Finn C, Kramer G, et al; EORTC Radiation Oncology Group and Lung Cancer Group. Prophylactic cranial irradiation in
extensive small-cell lung cancer. N Engl J Med 2007; 357:664–672.
Takahashi T, Yamanaka T, Seto T, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell
lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017; 18:663–671.
van Loon J, De Ruysscher D, Wanders R, et al. Selective nodal irradiation on basis of 18FDG-PET scans in limited-disease small-cell lung
cancer: a prospective study. Int J Radiat Oncol Biol Phys 2010; 77:329–336.
57
De Ruysscher
Targeted therapy for oncogene-addicted
metastatic non-small cell lung cancer 10
Epidermal growth factor receptor mutations and targeted therapy
Frequency of molecular aberrations in various driver oncogenes in lung

Histologically defined non-small cell lung cancers adenocarcinomas and currently available drugs against oncogenic proteins
(NSCLCs) are heterogeneous and consist of numerous
molecular subsets.
Somatic mutations in the epidermal growth factor

receptor (EGFR) gene are detected in 30%–40% of
NSCLCs in Asian patients and in 10%–15% of NSCLCs in
Caucasian patients.
Among the various types of EGFR mutations, deletion
in exon 19 and L858R in exon 21 are the most common
sensitising mutations, accounting for 90% of activating
EGFR mutations.
ALK, Anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; Fig. 10.1
HER2, human epidermal growth factor receptor 2.
Randomised phase III trials comparing EGFR TKIs with platinum doublets
in EGFR-mutant NSCLC First-generation EGFR tyrosine kinase inhibitors
EGFR Response (TKIs) (gefitinib, erlotinib) and second-generation TKIs
Trial EGFR TKI n mutation rate (%) PFS (months) OS (months)
(afatinib) are associated with a high response rate and
NEJ002 Gefitinib 224 224 74 vs 31 10.8 vs 5.4 30.5 vs 23.6
p <0.001 HR=0.30 (0.22-0.41) prolonged progression-free survival (PFS) compared
WJTOG-3405 Gefitinib 172 172 62 vs 32
p <0.0001
9.6 vs 6.6
HR=0.52 (0.38-0.72)
35.5 vs 38.8
HR=1.185 (0.76-1.83)
with a platinum doublet as first-line therapy.
OPTIMAL Erlotinib 154 154 83 vs 36 13.7 vs 4.6 22.7 vs 28.9
p <0.0001 HR=0.16 (0.10-0.26) HR=1.04 (0.69-1.58) Afatinib only demonstrated improvement in overall survival
EURTAC Erlotinib 173 173 58 vs 15 9.7 vs 5.2 19.3 vs 19.5
HR=0.37 (0.25-0.54) HR=1.04 (0.65-1.68) (OS) compared with platinum doublets in EGFR-mutant
ENSURE Erlotinib 217 217 68.2 vs 39.3 11.0 vs 5.6 NA NSCLC. Dacomitinib improved PFS and OS compared
p <0.0001
to gefitinib.
LUX-Lung 3 Afatinib 345 345 56 vs 23 11.1 vs 6.0 28.2 vs 28.2
p <0.001 HR=0.58 (0.43-0.78) HR=0.88
LUX-Lung 6 Afatinib 364 364 67 vs 23 11.0 vs 5.6 23.1 vs 23.5
Head-to-head comparison of second-generation EGFR
p <0.0001 HR=0.28 (0.20-0.39) HR=0.93 TKIs, afatinib or dacomitinib, showed a higher response
ARCHER Dacomitinib 452 452 76 vs 70
p=0.2541
14.7 vs 9.2 34.1 vs 26.8
HR=0.59 (0.47-0.74) HR=0.76
rate and longer PFS compared with gefitinib, but only
EGFR, Epidermal growth factor receptor; HR, hazard ratio; NA, not applicable; Fig. 10.2 dacomitinib showed significant improvement in OS (hazard
NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; ratio [HR], 0.76; 95% confidence interval [CI], 0.582-0.993).
TKI, tyrosine kinase inhibitor.
Mechanisms of EGFR-mutant NSCLC resistant to erlotinib and gefitinib

Almost all patients ultimately develop resistance, with an
AR mechanism
average 9–14 months PFS. EMT ~1–2% ~15–20%
~8–13%
Repeat biopsy revealed various different mechanisms Bypass BRAF ~1% T790M
of EGFR TKI resistance. Among them, T790m accounts tracks
~20%
alone
~40–55%
for 50%–60% of acquired resistance mechanisms. PIK3CA ~1–2%
T790M EGFR
SCLC alone ~6% target
with EGFR
alteration
Other resistance mechanisms include c-met amplification, SCLC with PI3K ~4%
~10% ~60%
human epidermal growth factor receptor 2 (HER2) Other EGFR

point mutations
amplification, small cell lung cancer transformation or 1–2%
epithelial mesenchymal transition (EMT). Fig. 10.3
AR, Acquired resistance; EGFR, epidermal growth factor receptor; EMT, epithelial mesenchymal
transition; HER2, human epidermal growth factor receptor 2; NSCLC, non-small cell lung cancer;
REVISION QUESTIONS
1. Is molecular profiling using next generation sequencing (NGS) essential to guide treatment in NSCLC?
2. How do you choose between first-generation EGFR TKIs, gefitinib or erlotinib, and second-generation TKIs, afatinib or dacomitinib?
3. Is repeat biopsy essential in patients who develop resistance to EGFR TKIs?
58
Targeted therapy for oncogene-addicted metastatic non-small cell lung cancer
EGFR mutations: third-generation EGFR TKIs, cfDNA and resistance
Third-generation EGFR TKIs target both activating EGFR Kaplan-Meier estimates of the duration of progression-free survival
mutations and T790M but spare wild-type EGFR. as assessed by investigators in the intention to treat population
A
Median
1.0
Probability of Progression-free
No. of Progression-free
The third-generation EGFR TKI osimertinib produced 0.8
Patients Survival
mo (95% CI)
significant improvements in objective response rate (ORR) Osimertinib Osimertinib 279 10.1 (8. 3–12.3)
Survival
0.6 Platinum–pemetrexed 140 4.4 (4. 2–5.6)
and PFS compared with platinum/pemetrexed in EGFR 0.4 Hazard ratio for disease progression
T790M-positive NSCLC (A). Osimertinib also showed

or death, 0.30 (95% CI, 0.2 3–0.41)
P<0.001
0.2
significant improvement in ORR and PFS compared with

Platinum–pemetrexed
0.0
first-generation EGFR TKI as first-line therapy (B). No. at Risk

0 3 6 9
Month
12 15 18
Osimertinib 279 240 162 88 50 13 0

Platinum– 140 93 44 17 7 1 0
Osimertinib can penetrate the blood–brain barrier and

pemetrexed
B
has demonstrated activity in central nervous system Median Progression-free
Probability of Progression-free
1.0 No. of Survival
(CNS) metastases. 0.8 Osimertinib
Patients (95% CI)
mo
Osimertinib 279 18.9 (15. 2–21.4)
Standard EGFR-TKI 277 10.2 (9. 6–11.1)
Survival
0.6
Hazard ratio for disease progression or death,
0.46 (95% CI, 0.3 7–0.57)
0.4 P<0.001
Kaplan-Meier curves of PFS in T790M-positive (T790M+) and T790M-negative 0.2 Standard EGFR-TKI
(T790M-) subpopulations treated with osimertinib. (A) Patients with T790M+ 0.0
tumours have a dramatically longer PFS than patients with T790M- tumours. 0 3 6 9 12 15 18 21 24 27
(B) Plasma genotyping for T790M fails to identify two subgroups with different PFS No. at Risk
Month
Osimertinib 279 262 233 210 178 139 71 26 4 0
Standard 277 239 197 152 107 78 37 10 2 0 Fig. 10.4
EGFR-TKI
A Tumour T790M+ (n = 179)
B Plasma T790M+ (n = 169)
100 Median PFS, 9.7 months 100 Median PFS, 9.7 months (95% CI, 8.3 to 11.1)
CI, Confidence interval; EGFR TKI, epidermal growth factor receptor tyrosine kinase inhibitor.
Probability of PFS
Probability of PFS
(95% CI, 8.3 to 12.5) Plasma T790M– (n = 104)

80 Tumour T790M– (n = 58) 80 Median PFS, 8.2 months (95% CI, 5.3 to 10.9)
Median PFS, 3.4 months
Log-rank test P = .188
(95% CI, 2.1 to 4.3)
60 60
Log-rank test P < .001
40 40
20 20 Repeat biopsies can identify patients who may benefit from
0 0 third-generation EGFR TKIs; however, repeat biopsies are
0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24
Time From First Dose (months) invasive and
Time From First Dosenot always possible due to tumour location,
(months)
pattern of tumour or poor performance status.
No. at risk No. at risk
Tumour T790M+ 179 131 107 75 56 36 5 Plasma T790M+ 167 130 102 79 53 31 9 2
Tumour T790M – 58 29 16 13 9 6 2 Plasma T790M– 104 69 54 42 34 25 6
B
Plasma genotyping is used as a screening test for
Tumour T790M+ (n = 179) Plasma T790M+ (n = 169)
Median PFS, 9.7 months 100 Median PFS, 9.7 months (95% CI, 8.3 to 11.1)
Probability of PFS
(95% CI, 8.3 to 12.5) Plasma T790M– (n = 104)

Tumour T790M– (n = 58)
Median PFS, 3.4 months
80 Median PFS, 8.2 months (95% CI, 5.3 to 10.9)
Log-rank test P = .188
T790M prior to performing an EGFR-resistance biopsy.
(95% CI, 2.1 to 4.3)
60
Log-rank test P < .001
40
20
The sensitivity and specificity of plasma genotyping
0 for EGFR-sensitising mutation and T790M mutation is
12 15 18 21 24 0 3 6 9 12 15 18 21 24
First Dose (months) Time From First Dose (months)
70%–85%.
No. at risk
56 36 5 Plasma T790M+ 167 130 102 79 53 31 9 2
9 6 2 Plasma T790M– 104 69 54 42 34 25 6
Fig. 10.5
CI, Confidence interval; PFS, progression-free survival.
Results: Candidate acquired resistance mechanisms with

Patients treated with third-generation EGFR TKIs also osimertinib (n=91)*
develop resistance within 8–11 months. • No evidence of acquired EGFR T790M
Resistance mechanisms include EGFR C797S mutation,

loss of T790M, EGFR gene amplification, c-met
amplification small cell lung cancer transformation or
MAPK activation.
Evolution of resistance mechanisms is inevitable

for survival of cancer cells, commonly leading to Fig. 10.6
heterogeneity. ALK, Anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; HER2, human
epidermal growth factor receptor 2; mTOR; mammalian target of rapamycin.
REVISION QUESTIONS
1. Is repeat biopsy essential for detection of T790M?
2. Can plasma genotyping replace tissue genotyping?
3. What would be the treatment options for patients who failed third-generation EGFR TKIs?
59
Ahn & Gainor
Anaplastic lymphoma kinase (ALK) rearrangements – crizotinib
ALK rearrangements are present in 3%–5% of NSCLCs (A) ALK fluorescent in situ hybridisation (FISH). Splitting of the red and
green signals (white arrows) in ≥15% of cells is diagnostic of an ALK
and define a distinct molecular subtype of the disease. rearrangement. (B) ALK immunohistochemistry staining.
Diagnostic assays for ALK rearrangements A B

include fluorescent in situ hybridisation (FISH),
immunohistochemistry and next-generation
sequencing (NGS).
ALK rearrangements are associated with a younger age,

lack of smoking history and adenocarcinoma histology.
Fig. 10.7
Kaplan-Meier estimates of progression-free survival in PROFILE 1014

Progression-free Survival (%)
100 Hazard ratio for progression Crizotinib, a first-generation ALK inhibitor, provided the
or death in the crizotinib group,
80 0.45 (95% CI, 0.35–0.60) first evidence that ALK-positive (ALK+) lung cancers are
P<0.001 (two-sided stratified log-rank test)
targetable alterations.
60
In PROFILE 1014, crizotinib produced significant

40
Crizotinib improvements in ORR and PFS compared with first-line
20 platinum/pemetrexed in ALK+ patients.
Chemotherapy
0
0 5 10 15 20 25 30 35
Despite the significant activity of crizotinib, patients
Months almost invariably develop resistance – typically within
No. at Risk 7.7–10.9 months.
Crizotinib 172 120 65 38 19 7 1 0
Chemotherapy 171 105 36 12 2 1 0 0
Fig. 10.8
The central nervous system (CNS) is the most common Brain magnetic resonance imaging (MRI) scans of an ALK+ patient following
disease progression on crizotinib (left) and after treatment with the
site of relapse among patients receiving crizotinib due to second-generation ALK inhibitor brigatinib (right)
insufficient penetration across the blood-brain barrier.
To combat crizotinib resistance, second-generation

ALK inhibitors (ceritinib, alectinib, brigatinib) and third-
generation ALK inhibitors have been developed. These
agents are more potent and selective for ALK.
Second-generation ALK TKIs have demonstrated

significant systemic and intracranial activity in crizotinib-
resistant, ALK+ patients.
Fig. 10.9
ALK+, Anaplastic lymphoma kinase positive.
REVISION QUESTIONS
1. What is the preferred diagnostic test for detection of ALK rearrangements?
2. What is the role of crizotinib in the setting of newer second-generation ALK inhibitors?
3. What is the preferred approach for patients progressing in the CNS on crizotinib?
60
ALK rearrangements – second- and third-generation ALK inhibitors
In phase III studies, alectinib (ALEX, J-ALEX) and Kaplan-Meier estimates of progression-free survival in the Global ALEX study
brigatinib (ALTA-1L) produced significant improvements 100 Hazard ratio for disease progression or death,
0.47 (95% CI, 0.3 4–0.65)
in PFS compared with crizotinib in ALK inhibitor-naïve 90 P<0.001 by log-rank test
Progression-free Survival
patients. 80
70
(% of patients)
Alectinib
60
Alectinib also produced a significant improvement in
50
the cumulative incidence of CNS progression (HR 0.16; 40
P <0.001). 30
20
Second-generation ALK inhibitors are now standard 10 Crizotinib
therapies for newly diagnosed ALK+ patients. Each second- 0
generation ALK inhibitor has a different toxicity profile. Day 3 6 9 12 15 18 21 24 27 30
1
Month
No. at Risk
Alectinib 152 135 113 109 97 81 67 35 15 3
Crizotinib 151 132 104 84 65 46 35 16 5
Fig. 10.10
Breakdown of specific ALK resistance mutations among
ALK+ patients progressing on each ALK inhibitor CI, Confidence interval.
1151Tins
C1156Y
I1171T/N/S
F1174L/S
Each ALK inhibitor is associated with a distinct spectrum
ALK resistance mutation
of ALK resistance mutations upon progression.

V1180L
L1196M ALK resistance mutations, particularly ALK G1202R, are

G1202R more common after treatment with second-generation
D1203N
ALK inhibitors.
S1206Y/C Repeat biopsies and circulating tumour DNA (ctDNA)
E1210K
assays are being studied as tools to guide treatment after
progression on second-generation ALK TKIs.
G1269A
0 20 40 60
Frequency of mutation (%)
Crizotinib Ceritinib Alectinib Brigatinib Fig. 10.11
Lorlatinib is a CNS-penetrant, third-generation ALK Best percentage change in tumour size from baseline with lorlatinib in ALK+
inhibitor designed to overcome ALK resistance mutations, patients previously treated with two or more ALK inhibitors
including ALK G1202R. 80 Best overall response
Change in tumour size from baseline (%)
70 Complete response Objective progression

60
50 Partial response Indeterminate
*
Lorlatinib was associated with an ORR of 38.7% in 40
*
Stable disease/no response * Off treatment or PD occurred
30
ALK+ patients treated with two or more prior ALK 20
10
* **
* ****
inhibitors. 0
–10
***
** * *
–20
**** * ** *
** ** ****
–30 * *** ***
** *
The most common adverse events on lorlatinib are –40
–50
****
**
****
hypercholesterolaemia, hypertriglyceridaemia, oedema –60
–70
**
* ** *
* **
–80
and peripheral neuropathy. Cognitive effects are seen in –90
*
*
–100
18% of patients. ** *
*Indicates patients off treatment or progressive disease occurred. Fig. 10.12

ALK+, Anaplastic lymphoma kinase positive.
REVISION QUESTIONS
1. What is the preferred first-line agent for newly diagnosed ALK+ NSCLC?
2. Should ALK+ patients routinely undergo repeat biopsies or ctDNA analysis upon progression on second-generation ALK inhibitors?
3. What is the most common ALK resistance mutation after treatment with second-generation ALK inhibitors?
61
Ahn & Gainor
Additional oncogene-addicted targets: ROS1, BRAF and RET
ROS1 rearrangements define a distinct molecular subset Positron emission tomography (PET) of a ROS1-rearranged patient
of NSCLCs, identified in 1%–2% of patients. prior to and after treatment with crizotinib
ROS1 rearrangements confer sensitivity to treatment

with the ALK/ROS1/MET inhibitor crizotinib.
In the PROFILE 1001 study, crizotinib was associated with

an ORR of 72% and median PFS of 19.2 months among
ROS1-positive (ROS1+) NSCLC patients.
Baseline After 7 weeks Fig. 10.13
Maximum tumour response to dabrafenib and trametinib in

BRAF V600E-mutant NSCLC BRAF mutations are found in approximately 3%–4%
40
of lung adenocarcinomas, but only half are V600E
mutations.
Maximum reduction from baseline (%)
20
0
The BRAF inhibitors dabrafenib and vemurafenib have
-20
been associated with single-agent response rates of 33%
-40
and 42%, respectively.
-60
-80 Best confirmed response
Complete response
Partial response
The combination of dabrafenib and trametinib (MEK
-100 Stable disease
Progressive disease
Not evaluable
inhibitor) achieved an ORR of 63.2% and median PFS
-120
Patient
Fig. 10.14
of 9.7 months.
NSCLC, Non-small cell lung cancer.
RET rearrangements are present in 1%–2% of NSCLCs Multitargeted kinase inhibitors with anti-RET activity evaluated to date
and are generally mutually exclusive to other oncogenic
drivers (e.g. EGFR, ALK). Agent Other molecular targets Trial ID N ORR
Cabozantinib VEGFR, MET, TIE2, AXL, FLT3, KIT NCT01639508 25 28%
Multikinase inhibitors (MKIs), such as cabozantinib and Vandetanib VEGFR, HER, EGFR NCT01823068 17 18%
vandetanib, are associated with ORRs of 28% and UMIN000010095 17 53%
18%-53%, respectively. Lenvatinib VEGFR1-3, FGFR1-4, PDGFR, KIT NCT1877083 25 16%
Sunitinib FR1-2, PDGFRβ, FLT3, KIT NCT01829217 35 NR
Recently, two selective RET inhibitors, BLU-667
Ponatinib ABL, FLT3, KIT, FGFR, VEGFR, NCT01813734 20 NR
and LOXO-292, have been developed. Each has PDFGR NCT01935336 110 NR
demonstrated promising anti-tumour activity in RET- Apatinib VEGFR2 NCT02540824 40 NR
positive (RET+) NSCLC. EGFR, Epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; Fig. 10.15
HER, human epidermal growth factor receptor; NR, not reached; ORR, objective response rate;
PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor.
REVISION QUESTIONS
1. What is the preferred therapy for ROS1+ lung cancer?
2. Should BRAF-mutant NSCLC patients be treated with a single-agent BRAF inhibitor?
3. What are the limitations of trials evaluating RET inhibitors to date?
62
Summary: Targeted therapy for oncogene-addicted non-small cell
lung cancer
• Histologically defined NSCLCs are heterogeneous and consist of numerous small molecular subsets according to
genomic alterations
• The discovery of EGFR mutations and the development of EGFR TKIs have revolutionised the clinical management
of NSCLC
• The development of resistance to EGFR TKIs remains challenging
• ALK rearrangements define a distinct molecular subset of NSCLC that confer sensitivity to treatment with crizotinib
• As with the experience of EGFR inhibitors in EGFR-mutant NSCLC, ALK+ patients invariably develop resistance to
crizotinib. To combat this problem, second- and third-generation ALK inhibitors have been developed
• Second-generation ALK inhibitors are now standard therapy for newly diagnosed, ALK+ NSCLC
• Based upon the success of targeted therapies in NSCLC patients harbouring EGFR mutations and ALK
rearrangements, efforts are underway to identify additional therapeutic targets
• BRAF V600E mutations, ROS1 rearrangements and RET rearrangements represent important new therapeutic targets
in NSCLC
Further Reading
Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK-positive non-small cell lung cancer. N Engl J Med 2018;
379:2027–2039.
Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol 2014;
11:473–481.
Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 2013; 18:865–875.
Jänne PA, Engelman JA, Johnson BE. Epidermal growth factor receptor mutations in non-small-cell lung cancer: implications for
treatment and tumor biology. J Clin Oncol 2005; 23:3227–3234.
Lin JJ, Riely GJ, Shaw AT. Targeting ALK: Precision medicine takes on drug resistance. Cancer Discov 2017; 7:137–155.
Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017;
376:629–640.
Oxnard GR, Thress KS, Alden RS, et al. Association between plasma genotyping and outcomes of treatment with osimertinib
(AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol 2016; 34:3375–3382.
Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small cell lung cancer. N Engl J Med
2017; 377:829–838.
Piotrowska Z, Sequist LV. Treatment of EGFR-mutant lung cancers after progression in patients receiving first-line EGFR tyrosine
kinase inhibitors: A review. JAMA Oncol 2016; 2:948–954.
Planchard D, Besse B, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant
metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 2016; 17:984–993.
Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 2014; 371:1963–1971.
Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;
371:2167–2177.
Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small cell lung cancer. N Engl J Med
2018; 378:113–125.
63
Ahn & Gainor
Immunotherapy for thoracic malignancies:
Part A – Non-small cell lung cancer 11
Lung cancer and the immune system
The immune system plays a key role in cancer through an

intricately regulated process of immunosurveillance and
immunoediting.
The immune system is now increasingly recognised as

an important ‘hallmark of cancer’.
Cancer cells can develop mechanisms of evading the

immune system in order to proliferate and metastasise.
Fig. 11.1
Lung cancer is characterised by a strongly

immunosuppressive microenvironment.
However, recent observation of the high somatic

mutational burden in non-small cell lung cancer
(NSCLC) (squamous [SQ] and adenocarcinoma), second
only to that of melanoma, suggests the existence of
neoantigens and its potential immunogenicity.
Based on these data, several treatment strategies have

been evaluated with immune checkpoint inhibitors in
ALL, Acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; Fig. 11.2
CLL, chronic lymphocytic leukaemia. thoracic malignancies.
The advent of novel immunotherapy targeting immune

checkpoints has revolutionised the landscape of
management of solid malignancies in recent times,
including advanced NSCLC.
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) and

programmed cell death protein 1/programmed death-
ligand 1 (PD-1/PD-L1) pathways in particular have
been identified to be druggable immune checkpoints
allowing for immune-mediated self-destruction of
cancer cells. Monoclonal antibodies (mAbs) blocking
these checkpoints have been studied in recent trials.
APC, Antigen-presenting cell; CAR T cell, chimeric antigen receptor-modified T cell; Fig. 11.3
CTLA-4, cytotoxic T-lymphocyte antigen 4; DC, dendritic cell; IL-10, interleukin-10; LAG
3, lymphocyte activation gene 3; MHC I/II, major histocompatibility complex I/II; PD-1/2;
programmed cell death protein 1/2; PD-L1/2, programmed death-ligand 1/2; TCR, T cell receptor;
TGFβ, transforming growth factor beta; TIL, tumour-infiltrating lymphocyte.
REVISION QUESTIONS
1. What are the ‘hallmarks of cancer’?
2. Describe how cancer cells avoid immune destruction.
3. How does the mutational burden in NSCLC compare to other solid malignancies?
64
Immunotherapy for thoracic malignancies: Part A – Non-small cell lung cancer
The role of immune checkpoints: CTLA-4 and PD-1/PD-L1
Tumour-associated antigens are recognised and

phagocytosed by dendritic cells (DCs) or antigen-
presenting cells (APCs) and are presented on the major
histocompatibility complex (MHC).
Following presentation to the T cell receptor (TCR),
a second co-stimulatory signal is required for T cell
activation. CD28 receptor on the T cell surface binds to
CD80 (B7-1) or CD86 (B7-2), resulting in interleukin-2 (IL-2)
and/or interferon (IFN) release and proliferation of T cells.
CTLA-4 present on regulatory T cells has a higher

affinity to B7 ligand and often competitively binds to the
B7 ligand, deactivating the immune system by arresting
IL-2 secretion resulting in T cell anergy. Fig. 11.4
CTLA-4, Cytotoxic T-lymphocyte antigen 4; DC, dendritic cell; MHC, major histocompatibility
complex; TCR, T cell receptor.
PD-1 receptors on the T cell surface interact with

PD-L1, expressed upon IFN-γ or IFN type I stimulation
and programmed death-ligand 2 (PD-L2) found on the
membrane of cancer cells.
Following successful activation, as a CD8+ cytotoxic

T cell approaches a cancer cell, the PD-L1 or PD-L2
ligand expressed on the cancer cell binds to the PD-1
receptor on the T cell resulting in T cell anergy, and
thus facilitating immune escape.
Under normal physiological circumstances, the binding

of immune checkpoints
PrimingPriming
phase phase to their receptors can
Effector phasehelp
Effector phase to
maintain immune self-tolerance and protect tissues during
Fig. 11.5 the immune response T cell T cell
to a pathogen.T cell T cell
DendriticDendritic
cell cell Cancer cell
Cancer cell
PD-1, Programmed cell death protein 1; PD-L1/2, programmed death-ligand 1/2.
Lymph Lymph Peripheral

Peripheral
node node tissue tissue
Currently used immunotherapy agents for thoracic Priming phase Effector phase
malignancies include mAbs against: MHC MHC TCR TCR
TCR TCR MHC MHC
•C
TLA-4: Ipilimumab (Immunoglobulin [Ig] G1) and
Activation
Activation
signals signals
tremelimumab (IgG2) B7 B7 CD28 CD28
NegativeNegative
regulation
regulation
• PD-1: Nivolumab and pembrolizumab (both IgG4) PD-1 PD-1
PD-L1 PD-L1
Inhibitory
Inhibitory
signals signals
•P
D-L1: Atezolizumab, durvalumab and avelumab
(all IgG1) B7 B7
AntibodyAntibody CTLA-4 CTLA-4
AntibodyAntibody AntibodyAntibody
CTLA-4, Cytotoxic T-lymphocyte antigen 4; MHC, major histocompatibility complex; PD-1, Fig. 11.6
programmed cell death protein 1; PD-L1, programmed death-ligand 1; TCR, T cell receptor.
REVISION QUESTIONS
1. What is the role of CTLA-4 in the immune response in cancer?
2. What is the effect of PD-1/PD-L1 interaction in advanced NSCLC?
3. List all the immune checkpoint inhibitors which have been approved for clinical use.
65
Lim et al
Immune checkpoint blockade for treatment-naïve advanced NSCLC
The phase III KEYNOTE-024 randomised 305 treatment-

naïve advanced NSCLC (SQ and non-squamous [NSQ]) 100
patients (pts) with high PD-L1 expression (≥50%) to 90 0.50 (95% CI, 0.37–0.68)
P<0.001 PFS 10.3
Progression-free Survival (%)

pembrolizumab 200 mg Q3W or physician’s choice of 80
vs 6.0 months
in favour of
platinum-containing doublet chemotherapy (ChT). 70
pembrolizumab
60
Pts in the pembrolizumab arm had longer progression- 50
free survival (PFS) and higher overall response rate 40 Pembrolizumab
(ORR) (44.8% vs 27.8%). At last follow-up, median overall 30
survival (mOS) was 30.0 months with pembrolizumab vs 20
14.2 months with ChT (hazard ratio [HR] 0.63, p = 0.002). 10 Chemotherapy
0
0 3 6 9 12 15 18
Grade 3-5 adverse events (AEs) occurred in 31.2% and Month
53.3% of pts in the pembrolizumab and ChT groups, No. at Risk
Pembrolizumab 154 104 89 44 22 3 1
respectively. Quality of life was also improved in the Chemotherapy 151 99 70 18 9 1 0
Fig. 11.7
pembrolizumab arm. CI, Confidence interval; PFS, progression-free survival.
Primary Endpoint (PFS per IRRC in ≥5% PD-L1+) The first-line CheckMate 026 phase III study randomised
CheckMate 026: Nivolumab vs Chemotherapy in First-line NSCLC 541 pts with PD–L1 positive (≥1%) tumours (SQ and NSQ) to
100 receive nivolumab 3 mg/kg Q2W (until disease progression
80
Nivolumab
n = 211
Chemotherapy
n = 212 or intolerable toxicity) or platinum-based ChT (up to 6 cycles).
Median PFS, months 4.2 5.9
(95% CI) (3.0, 5.6) (5.4, 6.9)
60
The primary endpoint was not met: median PFS (mPFS)
PFS (%)
1- year PFS rate, % 23.6 23.2
40
HR = 1.15 (95% CI: 0.91, 1.45), P = 0.2511
in pts with PD-L1 ≥5% was 4.2 and 5.9 months with
20 Nivolumab nivolumab and ChT, respectively. ORR was 26% vs
Chemotherapy 33% and mOS was 14.4 vs 13.2 months (HR 1.02, 95%
0
0 3 6 9 12 15 18 21 24 27 confidence interval [CI] 0.80-1.30) for the nivolumab and
Months
No. of patients at risk:
Nivolumab 211 104 71 49 35 24 6 3 1 0 ChT arms, respectively.
Chemotherapy 212 144 74 47 28 21 8 1 0 0
All randomised patients (≥1% PD-L1+): HR = 1.17 (95% CI: 0.95, 1.43)
Fig. 11.8
Among all treated pts, grade 3-4 treatment-related AEs were
CI, Confidence interval; HR, hazard ratio; IRRC, independent radiology review committee; NSCLC,
non-small cell lung cancer; PD-L1, programmed death-ligand 1; PFS, progression-free survival. 18% with nivolumab compared with 51% with doublet ChT.
The phase III KEYNOTE-189 study randomised (2:1) 616 Overall Survival
treatment-naïve advanced NSQ NSCLC pts to receive 100
platinum/pemetrexed ChT + pembrolizumab 200 mg

90
80
Q3W or placebo followed by maintenance pemetrexed + 70 Pembrolizumab combination
pembrolizumab or placebo (up to 35 cycles). 60
50
ORR was higher in the pembrolizumab-combination 40 Placebo combination

30
arm (47.6% vs 18.9%, p < 0.001). mPFS and reported 20
12-month OS were significantly longer in the combination 10 Hazard ratio for death, 0.49 (95% CI, 0.38–0.64)
P<0.001
arm: 8.8 vs 4.9 months (HR 0.52, p < 0.001) and not 0
0 3 6 9 12 15 18 21
reached vs 11.3 months, respectively. Response was Months

No. at Risk
observed across all PD-L1 strata, magnitude correlated to Pembrolizumab combination
Placebo combination
410
206
377
183
347
149
278
104
163
59
71
25
18
8
0
0
PD-L1, and best in PD-L1 ≥50% (ORR 61.4% vs 22.9%).

Fig. 11.9

There was a similar incidence of grade 3-5 AEs between
the two arms (67.2% vs 65.8%).
REVISION QUESTIONS
1. How does immunotherapy compare to standard platinum-doublet ChT in treatment-naïve advanced NSCLC?
2. What is the cut-off for PD-L1 positivity in KEYNOTE-024?
3. How do the endpoints of CheckMate 026 compare with KEYNOTE-024?
66
(continued)
The phase III IMpower150 randomised 1202 advanced 100
NSQ NSCLC pts (1:1:1) to atezolizumab/carboplatin/ 90

At 12 mo
Rate of Overall Survival
At 24 mo
paclitaxel (ACP), bevacizumab/carboplatin/paclitaxel 80 ABCP

BCP
67.3% (95% CI, 62.4–72.2)
60.6% (95% CI, 55. 3–65.9)
43.4% (95% CI, 36.9–49.9)
33.7% (95% CI, 27. 4–40.0)
(BCP), or atezolizumab/BCP (ABCP) Q3W, followed

70 Stratified hazard ratio, 0.78 (95% CI, 0.6 4–0.96)

P=0.02
60
by maintenance atezolizumab, bevacizumab, or both. 50
The ABCP and BCP groups were compared (statistical 40

ABCP
hierarchical analysis). 30
BCP
20
10 Median in the BCP group, Median in the ABCP group,

mPFS and mOS with ABCP vs BCP were 8.3 vs 0
14.7 mo (95% CI, 13. 3–16.9) 19.2 mo (95% CI, 17. 0–23.8)
6.8 months (HR 0.62, p < 0.001) and 19.2 vs 14.7 months
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
Months
(HR 0.78, p = 0.02), respectively. PFS benefit was more No. at Risk
ABCP 359 339 328 323 314 310 296 284 273 264 256 250 235 218 188 167 147 133 119 103 84 66 57 41 34 28 16 9 2 2 2
marked in the effector T cell (Teff)-high subpopulation

BCP 337 326 315 308 287 280 268 255 247 233 216 203 196 174 152 129 115 101 87 77 66 56 40 32 29 22 13 6 3 1 1 1 1
and correlated to PD-L1 expression. Fig. 11.10
CI, Confidence interval; BCP. bevacizumab/carboplatin/paclitaxel; ABCP, atezolizumab/BCP.

Grade 3-5 toxicities were slightly higher in ABCP vs BCP,
58.5% vs 50.0%.
In the phase III IMpower132, 578 advanced NSQ

NSCLC pts were randomised 1:1 to receive cisplatin
(or carboplatin) + pemetrexed followed by maintenance
pemetrexed with or without atezolizumab 1200 mg Q3W,
until disease progression.
Addition of atezolizumab improved mPFS (7.6 vs

5.2 months, HR 0.60, p < 0.0001) but did not show
statistically significant OS benefit (18.1 vs 13.6 months).
The rate of grade 3-4 AEs was higher with the addition
of atezolizumab, 53.6% vs 39.1% than with ChT alone.
Fig. 11.11
Similarly in the phase III IMpower130, ACP was superior to
C, Carboplatin (or cisplatin); CI, confidence interval; HR, hazard ratio; NE, not estimable; P, pemetrexed.
ChT alone (OS 18.6 vs 13.9 months, HR 0.79, p = 0.033).
The phase III KEYNOTE-407 study randomised (1:1) Overall Survival
559 advanced SQ NSCLC pts to first-line carboplatin/ 100

90
paclitaxel (or nab-paclitaxel)/pembrolizumab 200 mg
80
Q3W or placebo up to 35 cycles. 70

60 Pembrolizumab combination
50
Irrespective of PD-L1 expression, but with a proportional 40
magnitude of activity, the addition of pembrolizumab 30
Placebo combination
prolonged both mPFS and mOS: 6.4 vs 4.8 months 20

Hazard ratio for death, 0.64 (95% CI, 0.49–0.85)
10 P<0.001
(HR 0.56, p < 0.001) and 15.9 vs 11.3 months (HR 0.64, 0
p < 0.001), respectively. 0 3 6 9

Months
12 15 18 21
No. at Risk
Adding pembrolizumab did not increase grade 3-5 Pembrolizumab combination 278
Placebo combination 281
256
246
188
175
124
93
62
45
17
16
2
4
0
0
toxicities (69.8% vs 68.2%) but led to a higher treatment Fig. 11.12

discontinuation rate (13.3% vs 6.4%). CI, Confidence interval.
67
Lim et al
(continued)
In the phase III IMpower131 study 1021 pts with advanced
Arm B: Arm C:
SQ NSCLC were randomised (1:1:1) to carboplatin/nab- Atezo + CnP CnP
paclitaxel plus atezolizumab 1200 mg Q3W or carboplatin/ Median PFS 6.3 5.6
Progression-Free Survival (%)

(95% CI), mo (5.7, 7.1) (5.5, 5.7)
nab-paclitaxel or carboplatin/paclitaxel. HRa (95% CI) 0.71 (0.60, 0.85)
P value 0.0001
The addition of atezolizumab led to a modest Minimum follow-up, 9.8 mo

12-month PFS
improvement in mPFS, 6.3 vs 5.6 months (HR 0.71, 24.7%
Median follow-up, 17.1 mo
p = 0.0001) with carboplatin/nab-paclitaxel with no gain

in OS at interim analysis. Results from the carboplatin/ 12.0%
paclitaxel arm are still awaited.

Time (months)
No. at risk
Grade 3-4 toxicity rates were higher with the addition of Fig. 11.13
atezolizumab, 20% vs 10% with carboplatin/nab-paclitaxel. Atezo, Atezolizumab; CnP, carboplatin/nab-paclitaxel; CI, confidence interval; HR, hazard ratio;
PFS, progression free survival.
REVISION QUESTIONS
1. Is it safe to use immunotherapy and ChT concurrently in advanced NSCLC?
2. What is the current evidence for the use of anti-PD-L1 agents in treatment-naïve NSCLC?
3. Is there a role for maintenance immunotherapy after first-line treatment in advanced NSCLC?
Second-line therapy
100 Pembrolizumab 2 mg/kg

The phase III study KEYNOTE-010 randomised 1034 PD-L1
90
Pembrolizumab 10 mg/kg
Docetaxel
positive (≥1%) pts to receive pembrolizumab 2 mg/kg or
pembrolizumab 10 mg/kg, or docetaxel 75 mg/m2.
Progression-free survival (%)
80
70
60
50
PFS was significantly longer in both pembrolizumab
40 arms compared with docetaxel: 2 mg/kg subgroup –
30
5.0 vs 4.1 months, HR 0.59, p = 0.0001; and 10 mg/kg
20
10
subgroup – 5.2 vs 4.1 months, HR 0.59, p < 0.0001.
0
Number at risk
0 5 10 15 20 25
OS was also longer in the pembrolizumab arms: 2 mg/kg
Pembrolizumab 2 mg/kg 139
Pembrolizumab 10 mg/kg 151
66
72
29
36
6
12
0
0
0
0 – 14.9 vs 8.2 months, HR 0.54, p = 0.0002; and 10 mg/kg
Docetaxel 152 45 17 5 0 0
– 17.3 vs 8.2 months, HR 0.50, p < 0.0001. Subgroup
Fig. 11.14
analysis for pts with PD-L1 ≥50% showed even higher
PFS and OS benefit. Pembrolizumab is approved for
pre-treated pts with PD-L1 expression ≥1%.
In the phase III study CheckMate 017, 272 pts with

advanced SQ NSCLC (unselected for PD-L1 expression) 100 Median Overall Survival 1-Yr Overall Survival No. of
mo (95% CI) % of patients (95% CI) Deaths
were randomised to receive nivolumab 3 mg/kg Q2W 90
Nivolumab ( N= 135) 9.2 (7 .3–13.3) 42 (34–50) 86
Overall Survival (% of patients)
80 Docetaxel (N= 137) 6.0 (5 .1–7.3) 24 (17–31) 113

or docetaxel 75 mg/m2 as second-line treatment. The 70
primary endpoint was OS. 60

Hazard ratio for death, 0.59 (0.4 4–0.79)
50 P<0.001
42
Pts in the nivolumab arm had longer OS (9.2 vs 6.0

40
Nivolumab
30
24
months, HR 0.59, p < 0.001), longer PFS (3.5 vs 2.8 20
months, HR 0.62, p < 0.001) and higher ORR (20% vs 10

Docetaxel
0
9%, p = 0.008). 0 3 6 9 12 15 18 21 24
Months
No. at Risk
Nivolumab was also better tolerated than docetaxel with Nivolumab

Docetaxel
135
137
113
103
86
68
69
45
52
30
31
14
15
7
7
2
0
0
significantly lower incidence of grade 3-4 AEs (7% vs 55%). Fig. 11.15
68
Second-line therapy (continued)
Similarly, CheckMate 057 randomised 290 pre-treated NSQ Overall Survival

pts to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2. 100
Overall Survival (% of patients)

90
80
Pts treated with nivolumab had longer OS (12.2 vs 9.5 70
60
months, HR 0.75, p = 0.002) and higher ORR (19% vs 50
51
12%, p = 0.02) but no difference in PFS. 40

39 Nivolumab
30
20
Docetaxel
A subgroup analysis showed no difference in OS for PD-L1 10
0
<1% and increased benefit on OS with higher PD-L1 0 3 6 9 12 15 18 21 24 27
Months
expression. Nivolumab is approved as second-line treatment No. at Risk
in both histologies, regardless of PD-L1 expression. Nivolumab
Docetaxel
292
290
232
244
194
194
169
150
146
111
123
88
62
34
32
10
9
5
0
0
Fig. 11.16
Overall Survival, ITT (N = 850) Following the positive phase II POPLAR study, in the
HR, 0.73a phase III OAK study, 850 pts were randomised to either
(95% CI, 0.62, 0.87)
P = 0.0003 anti-PD-L1 atezolizumab 1200 mg Q3W or docetaxel
Minimum follow up = 19 months

75 mg/m2 as second- or third-line treatment.
Atezolizumab
In the intention-to-treat (ITT) cohort, pts receiving
Docetaxel
atezolizumab had longer OS (13.8 vs 9.6 months) and
Median 9.6 mo Median 13.8 mo
(95% CI, 8.6, 11.2) (95% CI, 11.8, 15.7)
duration of response (16.3 vs 6.2 months).
Months The survival benefit was observed irrespective of PD-L1

a
Stratified HR.
expression and grade 3-4 AEs were less frequent with
Fig. 11.17
atezolizumab (15% vs 43%).
CI, Confidence interval; HR, hazard ratio; ITT, intention to treat.
REVISION QUESTIONS
1. What is the role for immunotherapy in pre-treated advanced NSCLC?
2. How does the AE profile compare with that for standard second-line ChT with docetaxel?
3. Is there an OS advantage in using immunotherapy?
Immunotherapy for locally advanced NSCLC

The phase III PACIFIC study randomised 713 pts (2:1), No. of Events/
Total No.
Median
Overall Survival
12-Mo
Overall Survival Rate
24-Mo
Overall Survival Rate
with unresectable stage III NSCLC after concurrent of Patients (95% CI)
mo
(95% CI)
%
(95% CI)
%
chemoradiotherapy (CRT), to durvalumab 10 mg/kg Q2W

Durvalumab 183/476 NR (34. 7–NR) 83.1 (79. 4–86.2) 66.3 (61. 7–70.4)
Placebo 116/237 28.7 (22. 9–NR) 75.3 (69. 2–80.4) 55.6 (48. 9–61.8)
1.0
Stratified hazard ratio for death, 0.68 (99.73% CI, 0.4 7–0.997)
or placebo up to 12 months. 0.9 Two-sided P=0.0025

0.8
0.7
0.6 Durvalumab
At 24 months, mPFS was 17.2 vs 5.6 months (HR 0.51, 0.5
0.4 Placebo
p < 0.01) and OS 66.3% vs 55.6% (HR 0.68, p = 0.0025). 0.3
0.2
0.1
The incidence of grade 3-4 AEs and discontinuation rate

0.0
0 1 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Months since Randomization
were similar – durvalumab vs placebo arms: 30.5% vs 26.1% No. at Risk

Durvalumab
Placebo
476 464
237 220
431
198
415
178
385
170
364
155
343
141
319
130
274
117
210
78
115
42
57
21
23
9
2
3
0
1
0
0
(pneumonitis 4.8% vs 2.6%) and 15.4% vs 9.8%, respectively.

CI, Confidence interval; NR, not reached. Fig. 11.18
REVISION QUESTIONS
1. Is there an OS advantage in using immunotherapy in locally advanced NSCLC?
2. How does the AE profile compare with current standard of care in locally advanced NSCLC?
3. Is there a significant rate of pneumonitis using immunotherapy following concurrent CRT?
69
Lim et al
PD-L1 expression as a biomarker
High levels of expression of PD-L1 in tumours suggests

Nivolumab Pembrolizumab Atezolizumab Durvalumab
the mechanisms of immune avoidance are active and
Primary antibody 28-8 (Dako) 22C3 (Dako) SP142 (Ventana) SP263 (Ventana)
therefore a target for this therapeutic approach. clone used in the
assay system
The vast majority of published studies have shown Interpretative Tumour cell Tumour cell Tumour cell Tumour cell
scoring membrane membrane membrane membrane
consistently higher ORR and longer OS in pts with higher
Infiltrating
expression of PD-L1 by immunohistochemistry (IHC). immune cells
Instrument EnVision EnVision Flex Optiview Optiview
PD-L1 expression is heterogeneous and the biopsy and detection Flex on on Autostainer Detection and Detection on
systems required Autostainer Link 48 Amplification Benchmark
sample may not reflect the overall disease burden. Link 48 on Benchmark ULTRA
Furthermore, PD-L1 protein expression is a continuous ULTRA
variable from zero to high levels. Fig. 11.19
Assay comparison: overall percentage agreement in patient classification Different trials with different drugs have defined their own
when staining assay is ‘mismatched’ with the clinical cut-off threshold for PD-L1 ‘positivity’, which varies from over 1%,
Assay Scoring algorithm 25% or 50% of tumour cells.
clone
used There are currently at least five anti-PD-1/PD-L1 agents
for slide with their own specifically developed PD-L1 IHC assay
staining 22C3 1% TPS 28-8 1% TPS SP142 TC1/IC1 SP263 25% TPS
validated in their respective clinical trials.
22C3 38/38 (100%) 36/38 (94.7%) 33/38 (86.8%) 34/38 (89.5%)
28-8 36/38 (94.7%) 38/38 (100%) 31/38 (81.6%) 33/38 (86.8%)

The Blueprint PD-L1 IHC Assay Comparison Project
aimed to provide information on the analytical and
SP142 24/38 (63.2%) 24/38 (63.2%) 38/38 (100%) 25/38 (65.8%) clinical comparability of 4 PD-L1 IHC assays used in
clinical trials. It revealed that 3 out of the 4 assays were
SP263 34/38 (89.5%) 34/38 (89.5%) 22/38 (86.8%) 38/38 (100%)
closely aligned on tumour cell staining, while the 4th
IC, Immune cell; TC, tumour cell; TPS, tumour proportion score. Fig. 11.20 showed consistently fewer tumour cells stained.
REVISION QUESTIONS
1. Is PD-L1 a strict predictive biomarker in NSCLC?
2. Define what is considered positive PD-L1 expression.
3. What are the current issues with the use of PD-L1 as a biomarker?
CTLA-4 blockade and combination strategies for NSCLC

The phase III CA184-041 study investigated a phased Chemotherapy + Ipilimumab Chemotherapy + Placebo
combination of ipilimumab 10 mg/kg plus paclitaxel/ 100

No. of events/No. of patients 281/388 272/361
carboplatin as first-line therapy compared with ChT alone

Median OS, months (95% CI)* 13.4 (11.8 to 14.8) 12.4 (11.6 to 13.6)
80 HR (95% CI)† 0.91 (0.77 to 1.07)
in advanced SQ NSCLC. Log-rank P ‡ .25

OS (%)
60
1-year OS rate = 54%
1-year OS rate = 53%
40
The addition of ipilimumab did not significantly improve
OS (13.4 vs 12.4 months, HR 0.91, p = 0.25). 20
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
The safety profile of ipilimumab in lung cancer was Time (months)

No. at risk:
consistent with previous studies with this drug. Chemotherapy + ipilimumab 388 385 347 302 265 234 198 173 138 104
Chemotherapy + placebo 361 361 344 310 275 216 177 141 100 74
83
57
60
43
42
30
34
19
28
14
20
10
12
7
9
5
5
4
4
2
1
1
0
1
0
0
Fig. 11.21
CI, Confidence interval; HR, hazard ratio; OS, overall survival.
70
CTLA-4 blockade and combination strategies for NSCLC (continued)
CheckMate 227 Part 1 Study Designa

The multipart phase III CheckMate 227 study evaluated
nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q6W
vs histology-based ChT in treatment-naïve advanced
NSCLC pts.
Pts were stratified according to PD-L1 ≥1% or <1%, and then

randomised in a ratio of 1:1:1 to treatment arms as shown.
Primary endpoint was PFS in high tumour mutational
burden (TMB) (≥10 mutations per megabase [mut/Mb]).
In the ITT population (irrespective of PD-L1 expression),
mPFS was 4.9 months with nivolumab/ipilimumab vs Database lock: January 24, 2018; minimum follow-up: 11.2 months.
5.5 months with ChT. a
NCT02477826; bNSQ: pemetrexed + cisplatin or carboplatin, Q3W for ≤4 cycles, with optional pemetrexed
maintenance following chemotherapy or nivolumab + pemetrexed maintenance following nivolumab + chemotherapy;
SQ: gemcitabine + carboplatin, Q3W for ≤4 cycles; cthe TMB co-primary analysis was conducted in the subset
of patients randomised to nivolumab or chemotherapy who had evaluable TMB ≥10 mut/Mb. Fig. 11.22
ALK, Anaplastic lymphoma kinase; ECOG PS, Eastern Cooperative Oncology Group Performance
Status; EGFR, epidermal growth factor receptor; mut/MB, mutations per megabase; NSCLC, non-
small cell lung cancer; NSQ, non-squamous; PD-L1, programmed death-ligand 1; SQ, squamous;
TMB, tumour mutational burden; R, randomised.
Progression-free Survival
0.58 (97.5% CI, 0.4 1–0.81)
Patients with Progression-free
100 P<0.001
90 The combination of nivolumab and ipilimumab confers
80
70 better PFS in pts with high TMB compared with ChT;
Survival (%)
60
Nivolumab+ mPFS 7.2 vs 5.5 months (HR 0.58, p < 0.001).
50 43 ipilimumab
40
30 There was also a higher ORR in this cohort (45.3% vs
20 13 Chemotherapy 26.9%), with median duration of response not reached at
10
0 last follow-up, compared with 5.4 months with ChT.
0 3 6 9 12 15 18 21 24
Months Both combination immunotherapy and ChT had similar
No. at Risk rates of grade 3-4 AEs, 31.2% vs 36.1%, respectively.
Nivolumab + 139 85 66 55 36 24 11 3 0
ipilimumab
Chemotherapy 160 103 51 17 7 6 4 0 0
Fig. 11.23

OS: bTMB Subgroups (Exploratory Analysis)
bTMB ≥16 mut/Mb population
Following the phase Ib study (NCT02000947) in pts with

advanced NSCLC, durvalumab 20 mg/kg + tremelimumab
1 mg/kg dose was selected for further studies.
Although the phase III MYSTIC (first line) did not meet
its primary PFS or OS endpoints, pts with high TMB
(≥16 mut/Mb) had longer OS with the combination
immunotherapy compared with ChT (16.5 vs 10.5
months, HR 0.62).
Similarly, the phase III ARCTIC study (at least two prior
systemic treatments) did not meet its primary endpoints
of PFS or OS benefit. bTMB, Blood tumour mutational burden; CI, confidence interval; ChT, chemotherapy; Fig. 11.24
HR, hazard ratio; mut/Mb, mutation per megabase; OS, overall survival.
REVISION QUESTIONS
1. Is there a role for CTLA-4 blockade in advanced NSCLC?
2. Is the combination of immunotherapy with ChT safe in the treatment of NSCLC?
3. Is the combination of dual checkpoint inhibitors more effective in advanced NSCLC?
71
Lim et al
Summary: Immunotherapy for thoracic malignancies:
Part A – Non-small cell lung cancer
• The high somatic mutational burden in NSCLC suggests its potential immunogenicity
• Immunotherapy targeting PD-1 and PD-L1 has been demonstrated to be efficacious in patients with advanced NSCLC,
and superior to standard-of-care ChT in both ChT-naïve and pre-treated patients
• So far, patients with EGFR-mutated NSCLC have been shown to present with a lower activity of immunotherapy,
albeit numbers are still small and randomised trials are awaited. Very few anaplastic lymphoma kinase
(ALK)-rearranged NSCLC patients have been treated and reported so far
• High neoantigen burden and molecular smoking signatures are associated with increased objective response and
prolonged PFS with immunotherapy
• Immunotherapy results in durable clinical benefit in a subset of patients, yet to be characterised
• Patient selection may maximise the benefits from immunotherapy and remains a key area for research
• Currently PD-L1 remains the main biomarker in selecting patients for immunotherapy, despite obvious limitations and
a need for homogenisation and certification of testing. Better biomarkers will be needed
• Ongoing clinical trials are investigating the safety and efficacy of immunotherapy drugs when used in combination with
each other (targeting CTLA-4 and PD-1 or PD-L1) or in addition to ChT +/- targeted therapy
Further Reading
Alexandrov LB, Nik-Zainal S, Wedge S, et al. Signatures of mutational processes in human cancer. Nature 2013; 500:415–421.
Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung
cancer: a multicentre, phase 1b study. Lancet Oncol 2016; 17:299–308.
Antonia S, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018;
379:2342–2350.
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med
2015; 373:1627–1639.
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Eng J
Med 2015; 373:123–135.
Gandhi L, Rodriguez-Abreu D, Gadgeel S et al. Pembrolizumab plus chemotherapy in metastatic non-small cell lung cancer. N Engl J
Med 2018; 378:2078–2092.
Haanen JBAG, Lugowska I, Garassino MC, Califano R. ESMO Handbook of Immuno-Oncology. Lugano, ESMO Press, 2018.
Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high mutational burden. N Engl J Med 2018;
378:2093–2104.
Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung
cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387:1540–1550.
Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
N Engl J Med 2016; 375:1823–1833.
Rivzi NA, Hellman MD, Snyder A, et al. Cancer Immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small
cell lung cancer. Science 2015; 348:124–128.
72
B
More advanced knowledge

12 Malignant pleural mesothelioma
Clinical presentation and pathology
Malignant pleural mesothelioma (MPM) incidence is 100

Male deaths
increasing worldwide due to extensive exposure to Female deaths
asbestos. The latency to disease onset often exceeds All mesothelioma deaths
40 years. Therefore MPM is mostly diagnosed in the
Age-adjusted mortality rate

(per million population)
elderly (at least in Europe and the USA).
10
The typical onset of symptoms of MPM includes
progressive dyspnoea (mainly due to pleural effusion),
cough and thoracic pain.
1
1994 1996 1998 2000 2002 2004 2006 2008
Year
Fig. 12.1
MPM staging follows the revised 8th edition of the TNM

(Tumour, Node, Metastasis) classification. Diagnostic
and staging procedures include chest and abdominal
computed tomography (CT) scan and video-assisted
thoracoscopic surgery (VATS).
Response assessment uses the modified Response

Evaluation Criteria in Solid Tumours (RECIST) method,
which is based on unidimensional measurements of
tumour thickness perpendicular to the chest wall or
mediastinum on CT scan.
Fig. 12.2
The diagnosis should be established by an experienced

pathologist.
Three histological subtypes are reported: epithelioid,

biphasic (or mixed) and sarcomatoid. MPM is defined
as biphasic when each component occupies at least
10% of a sample.
Epithelioid type Calretinin
Histology is a major prognostic factor in MPM, with
epithelioid tumours carrying the best prognosis, while
biphasic and sarcomatoid MPMs have the worst
outcomes.
Approximately 60%–80% of MPMs are epithelioid, 10%–
15% biphasic, and <10% sarcomatoid. The epithelioid
pleomorphic subtype is associated with a poor prognosis,
Sarcomatoid type Biphasic type
similar to that of sarcomatoid malignant mesothelioma.
Fig. 12.3
REVISION QUESTIONS
1. What are the most frequent symptoms of MPM?
2. What is the most frequent histological subtype of MPM?
3. What are the suggested staging procedures?
75
Ceresoli et al
Surgery and multimodality treatment
Only a minority of MPM patients are amenable to surgical

resection. The role of surgery is debated. The two
proposed interventions are extrapleural pneumonectomy
(EPP) and pleurectomy/decortication (P/D).
EPP is an aggressive procedure entailing en bloc

resection of the parietal and visceral pleura with the
enclosed lung, pericardium, ipsilateral diaphragm
and mediastinal nodes. Postoperative morbidity is
100
high (up to 50%), but mortality is <5%. In the only EPP
No EPP

available randomised trial (the MARS trial), EPP within 75
multimodality treatment offered no survival benefit 50
compared with chemotherapy (ChT) alone. 25
0
0 6 12 18
Number of events/ Time from randomisation (months)
at risk
EPP 0/24 8/16 3/12 3/8
No EPP 0/26 3/24 4/20 5/11
EPP, Extrapleural pneumonectomy. Fig. 12.4
P/D allows the removal of the visceral, parietal and

pericardial pleura; morbidity and mortality are lower,
but cytoreduction is less effective than with EPP.
However, no intervention has shown significant
curative/long-term success.
In a randomised trial (the MesoVATS trial), P/D was

compared to talc pleurodesis. Better effusion control
but no survival benefit was achieved with P/D.
VATs, Video-assisted thoracoscopic surgery. Fig. 12.5
Intensity-modulated radiotherapy (IMRT) improves tumour

coverage and normal tissue sparing; however, lung
toxicity is a major concern, mainly after P/D.
When postoperative radiotherapy (PORT) is applied, strict

constraints must be adhered to. In a randomised trial, use
of hemithoracic IMRT after neoadjuvant ChT and EPP did
not improve survival or loco-regional control.
Recent randomised trials (SMART and PIT) have shown that

prophylactic radiotherapy (RT) should not be routinely used
to prevent procedure-tract metastases in mesothelioma.
Fig. 12.6
REVISION QUESTIONS
1. What is the role of surgery in MPM?
2. What are the proposed surgical interventions?
3. Is RT with IMRT a standard procedure?
76
Malignant pleural mesothelioma
Systemic treatment: state of the art and future outlook
The combination of cisplatin and pemetrexed is the A 1.00 B 1.00
standard first-line treatment, with a median time to

MS TTP
Pemetrexed/Cisplatin 12.1 months Pemetrexed/Cisplatin 5.7 months
Cisplatin 9.3 months Cisplatin 3.9 months
Log rank p value 0.020 Log rank p value 0.001
progression (TTP) of 5.7 months and a median overall 0.75 0.75
Proportion progressed
Proportion alive
survival (OS) of 12.1 months. 0.50 0.50
Schedules with carboplatin have shown similar outcomes 0.25 0.25
with a more favourable toxicity profile; 4–6 cycles are

usually administered. 0.00
0 5 10 15 20 25 30
0.00
0 5 10 15 20 25 30
Survival time (months) Time to PD (months)
Nearly all MPM patients progress during or after first-line Pts at risk
Pem/Cis
Cis
226
222
185
173
111
91
50
32
19
19
7
3
0
0
Pts at risk
Pem/Cis
Cis
226
222
124
84
42
29
18
8
3
4
1
0
0
0
treatment. The role of second-line treatment in MPM

MS, Median survival; PD, progressive disease; TTP, time to progression. Fig. 12.7
is not established. Several phase II and III trials have
exploited different chemotherapeutic (e.g. gemcitabine,
vinorelbine) and targeted agents, but activity has been
shown to be generally modest.
Angiogenesis: In the randomised phase II-III MAPS

study of 448 patients, the addition of bevacizumab
PFS by investigator assessment
to pemetrexed/cisplatin was associated with an
improvement in PFS and OS. In the LUME-Meso study,
no benefit in response rate, PFS and OS was observed
with the addition of nintedanib to cisplatin/pemetrexed
in the first-line setting.
Mesothelin is highly expressed in mesothelioma, mainly

in the epithelioid subtype. Several strategies targeting
this pathway have been exploited, unfortunately with
CI, Confidence interval; HR, hazard ratio; PFS, progression-free survival. Fig. 12.8 discouraging results. A randomised phase II trial
comparing anetumab ravtansine (an antibody–drug
conjugate) to vinorelbine failed to improve PFS.
Immune checkpoint inhibitors (ICIs): Response rates (RRs)

of 9%-29% and disease control rates (DCRs) of 38%- 1 Median PFS, 95%CI: 4.0 [2.8-5.7], events = 53, censored = 10 1 Median PFS, 95%CI: 5.6 [3.2-8.4], events = 48, censored = 14
72% were reported in phase II trials with pembrolizumab,

0.9 0.9
4.0 months 5.6 months
0.8 0.8
nivolumab and avelumab in pretreated patients. 0.7 0.7

Combinations with nivolumab/ipilimumab (the MAPS2 0.6
0.5
0.6
0.5
study) showed RR of 28% and 12-week DCR of 52% in 0.4 0.4
the same setting. Ongoing trials are exploring ChT plus 0.3 0.3
programmed cell death protein 1/programmed death-

0.2 0.2
0.1 0.1
NIVO arm (n=63) NIVO+IPI arm (n=62)
ligand 1 (PD-1/PD-L1) inhibitors as first-line treatment 0
0 2 4 6 8 10 12 14 16
0
0 2 4 6 8 10 12 14 16
in unresectable MPM. The low mutational burden and Time (months) Time (months)
the highly immune-suppressive microenvironment of CI, Confidence interval; IPI, ipilimumab; NIVO, nivolumab; PFS, progression-free survival. Fig. 12.9
MPM limit the activity of ICIs targeting PD-1/PD-L1 in
mesothelioma. A deeper knowledge of tumour biology,
including evaluation of other immune checkpoints, could
help to fully exploit the immune axis as a valid target.
REVISION QUESTIONS
1. What is the standard first-line treatment in MPM?
2. What are the options for second-line treatment?
3. What is the role of ICIs in the treatment of MPM?
77
Ceresoli et al
Summary: Malignant pleural mesothelioma
• The incidence of MPM is increasing worldwide due to asbestos exposure
• There are three main histological subtypes of MPM (epithelioid, sarcomatoid and biphasic), with different outcomes
• The role of surgery and IMRT in this disease is still undefined
• The combination of pemetrexed with cisplatin is the standard first-line treatment in patients with unresectable MPM;
carboplatin plus pemetrexed is a valid option, especially in elderly patients
• In patients progressing after a pemetrexed-based regimen, there is no standard second-line therapy, and this remains
an ideal field in which to test new agents
• Inhibition of angiogenesis, targeting of mesothelin and immunotherapy with ICIs are the main pathways explored in
clinical trials
• The association of anti-angiogenic agents (bevacizumab, nintedanib) to standard ChT in the first-line setting has
provided inconclusive data and is not going to modify the standard of care
• Mesothelin-targeting agents have failed to improve survival, so far
• ICIs as single agents or in combination show limited benefit, likely due to the low mutational burden and the highly
immune-suppressive microenvironment of MPM
• A deeper knowledge of the complex biology of MPM is needed to exploit new agents and combinations able to
improve its poor outcome
Further Reading
Alley EW, Lopez J, Santoro A, et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma
(KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol 2017; 18:623–630.
Bueno R, Opitz I, on behalf of the IASLC Mesothelioma Taskforce. Surgery in malignant pleural mesothelioma. J Thorac Oncol 2018;
13:1638–1654.
Ceresoli GL, Mantovani A. Immune checkpoint inhibitors in malignant pleural mesothelioma. Lancet Oncol 2017; 18:559–561.
Hassan R, Thomas A, Alewine C, et al. Mesothelin immunotherapy for cancer: ready for prime time? J Clin Oncol 2016; 34:4171–4179.
Hmeljak J, Sanchez-Vega F, Hoadley KA, et al. Integrative molecular characterization of malignant pleural mesothelioma. Cancer Discov
2018; 8:1548–1565.
Husain AN, Colby T, Ordonez N, et al; International Mesothelioma Interest Group. Guidelines for pathologic diagnosis of malignant
mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med
2013; 137:647–667.
Rimner A, Zauderer MG, Gomez DR, et al. Phase II study of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT)
as part of lung-sparing multimodality therapy in patients with malignant pleural mesothelioma. J Clin Oncol 2016; 34:2761–2768.
Scherpereel A, Mazieres J, Greillier L, et al. Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural
mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial. Lancet Oncol 2019;
20:239–253.
Stahel RA, Riesterer O, Xyrafas A, et al. Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural
mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial.
Lancet Oncol 2015; 16:1651–1658.
Treasure T, Lang-Lazdunski L, Waller D, et al; MARS trialists. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for
patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility
study. Lancet Oncol 2011; 12:763–772.
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; 21:2636–2644.
Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin
Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 2016; 387:1405–1414.
78
Malignant pleural mesothelioma
13 Thymic malignancies
Pathology, staging and prognostic factors
Thymic malignancies are rare epithelial tumours arising in

A AB B1
the anterior mediastinum. The current histopathological
classification distinguishes thymomas from thymic
carcinomas. Neuroendocrine tumours – carcinoids, large
and small cell – may also occur.
Thymomas are further subdivided into different types

(so-called A, AB, B1, B2, and B3) based upon the atypia B2 B3 Car
of tumour cells, the relative proportion of the associated
non-tumoural lymphocytic component, and resemblance
to the normal thymic architecture. Thymic carcinomas are
similar to their extrathymic counterpart, the most frequent
subtype being squamous cell carcinoma. Fig. 13.1
The histopathological diagnosis is mostly based on morphology; recommended antibodies for immunohistochemistry
include: pancytokeratin (AE1/3); CD5 (T cells, epithelial cells of carcinomas); CD117 (epithelial cells of carcinomas);
TdT (immature T cells), and desmin (myoid cells in the medulla).
TNM Staging The Tumour, Node, Metastasis (TNM) 8th edition

T – Primary Tumour staging system is replacing the historical Masaoka–
T1 Tumour encapsulated or extending into the mediastinal fat, may involve the Koga staging.
mediastinal pleura.
T1a No mediastinal pleural involvement
T1b Direct invasion of the mediastinal pleura In this system, Masaoka–Koga stage I (encapsulated
T2 Tumour with direct involvement of the pericardium (partial or full thickness) tumours), stage II (IIa with a microscopic invasion of the
T3 Tumour with direct invasion into any of the following; lung, brachiocephalic
vein, superior vena cava, phrenic nerve, chest wall, or extrapericardial capsule; IIb with an invasion of the capsule or surrounding
pulmonary artery or vein fatty tissue, or adherent to the mediastinal pleura or the
T4 Tumour with direct invasion into any of the following; aorta (ascending, arch
or descending), arch vessels, intrapericardial pulmonary artery, myocardium,
mediastinum), and some stage III are grouped together
trachea, or oesophagus into the TNM stage I cluster.
N – Regional Lymph Nodes
NX Regional lymph nodes cannot be assessed Stage III is further subdivided into TNM stage IIIA and IIIB
N0 No regional lymph node metastasis based on the resectability of the invaded structures.
N1 Metastasis in anterior (perithymic) lymph nodes
N2 Metastasis in deep intrathoracic or cervical lymph nodes Besides complete resection, tumour stage at baseline
M – Distant Metastasis represents the most significant prognostic factor for
M0 No pleural, pericardial or distant metastasis
M1 Distant metastasis survival.
M1a Separate pleural or pericardial nodule(s)
M1b Distant metastasis beyond the pleura or pericardium The World Health Organization (WHO) classification
is correlated with stage at diagnosis, as 80%–90% of
Stage I T1 N0 M0
type A to B1 thymomas present as stage I–II tumours,
Stage II T2 N0 M0
whereas 50%–60% of type B2 and 60%–80% of type
Stage IIIA T3 N0 M0 B3 thymomas and carcinomas present with stage III–IV
Stage IIIB T4 N0 M0 extent. Thus histology was also reported as a prognostic
Stage IVA Any T N1 M0 factor in thymic epithelial tumours.
Any T N0, N1 M1a
Stage IVB Any T N2 M0, M1a
Any T Any N M1b
TNM, Tumour, Node, Metastasis. Fig. 13.2
REVISION QUESTIONS
1. Are thymomas epithelial or lymphoid malignancies?
2. What is the standard staging system for thymic tumours?
3. What is the most significant prognostic factor in thymic tumours?
79
Girard & Merveilleux du Vignaux
Clinical features, diagnosis and surgery
One third of patients are asymptomatic. Another third of

patients present with local symptoms such as cough,
dyspnoea or chest pain. The remaining third present
with autoimmune disorders, most commonly
myasthenia gravis.
Myasthenia gravis is found in 30% of patients with
thymoma, and is caused by circulating antibodies
that block acetylcholine receptors at the postsynaptic
neuromuscular junction.
Systematic immunological check-up is recommended
when a diagnosis of thymoma is suspected, including
complete blood cell count with reticulocytes, serum
protein electrophoresis, as well as anti-acetylcholine
receptor and antinuclear antibody tests.
Most frequent differential diagnoses of anterior
mediastinal masses include thymic hyperplasia,
lymphoma and benign or malignant germ cell neoplasms; Fig. 13.3
surgical biopsy is frequently required.
The treatment strategy for thymic epithelial tumours is primarily based on whether the tumour may be resected
upfront or not. If complete resection is deemed to be achievable, upfront surgery represents the first step in
the treatment; if not, primary chemotherapy (ChT) is administered, part of a curative-intent sequential strategy
integrating subsequent surgery or radiotherapy (RT).
Surgical principles are as follows:

• Median sternotomy as the standard approach
n
minimally invasive surgery is possible
• Complete exploration of the pleural cavities
• Complete thymectomy, including the tumour,
normal thymus and mediastinal fat
• En bloc resection of involved structures: lung,
vessels, pleural implants, phrenic nerves
• Marking of areas of uncertain margins with clips
• Nodal resection and sampling for invasive tumours
• Frozen section not recommended for margin
assessment
Fig. 13.4 Surgical pathology diagnosis requires communication

between surgeons and pathologists. Orientation of
the specimen and designation of involved structures,
organs, or areas of concern may be done using a
mediastinal board.
REVISION QUESTIONS
1. What is the most frequent autoimmune disorder observed in patients with thymoma?
2. What is the first step in the treatment strategy for thymic tumours?
3. What are the surgical principles for thymic tumour resection?
80
Thymic malignancies
Radiotherapy and chemotherapy; prognostic factors
Postoperative RT aims at decreasing the risk of Masaoka– Postoperative radiotherapy (RT ) / chemotherapy (ChT)
mediastinal recurrence. Proposed indications, based Koga
stage
on expert opinion, are summarised in the table.
Stage I Complete resection: - Thymoma: no postoperative RT
- Thymic carcinoma: consider postoperative RT
The principles of RT include: the use of conformal Incomplete resection: Postoperative RT
techniques; a clinical target volume including the whole Stage IIa Complete resection: - Type A-B2 thymoma: no postoperative RT
thymic space, the tumour and its extensions, and the - T ype B3 thymoma–thymic carcinoma:
anterior, superior, and middle mediastinum; a total dose consider postoperative RT
Incomplete resection: Postoperative RT
ranging from 40 to 60 Gy. Thymic carcinoma: Consider postoperative ChT
Definitive RT may be delivered for advanced non- Stage IIb Complete resection: - Type A-B1 thymoma: no postoperative RT
- T ype B2-B3 thymoma–thymic carcinoma:
resectable thymic tumours, after induction ChT. consider postoperative RT
Concurrent chemoradiotherapy (CRT) may be an Incomplete resection: Postoperative RT
Thymic carcinoma: Consider postoperative ChT
option in thymic carcinomas.
Stage III-IVa Postoperative RT, with boost on areas of concern
Thymic carcinoma: Consider postoperative ChT
Fig. 13.5
Regimen Agents Doses Primary ChT refers to ChT delivered as the first part
of the multimodal curative-intent treatment of locally
ADOC Doxorubicin 40 mg/m2 / 3 w
Cisplatin 50 mg/m2 / 3 w advanced non-resectable thymic tumours, and is
Vincristine 0.6 mg/m2 / 3 w subsequently combined with surgery or RT. Major
Cyclophosphamide 700 mg/m2 / 3 w regimens are presented in the table. There is currently
CAP Cisplatin 50 mg/m2 / 3 w
Doxorubicin 50 mg/m2 / 3 w
no rationale to support the use of postoperative ChT in
Cyclophosphamide 500 mg/m2 / 3 w thymomas; this may be discussed in thymic carcinoma.
PE Cisplatin 60 mg/m2 / 3 w
Etoposide 120 mg/m2/ × 3 / 3 w ChT may be administered as the sole treatment modality for
VIP Etoposide 75 mg/m2 × 4d / 3 w metastatic, unresectable, recurrent disease not eligible for
Ifosfamide 1.2 g/m2 × 4d / 3 w
Cisplatin 20 mg/m2 × 4d / 3 w RT. Regimens are similar to those for primary ChT (table).
Carbo-Px Carboplatin AUC 5 / 3 w Paclitaxel may be preferred for first-line for carcinomas.
Paclitaxel 225 mg/m2 / 3 w Single agents represent options for subsequent lines.
AUC, Area under the curve. Fig. 13.6
The treatment of recurrences relies, besides surgery and

RT if feasible, on systemic treatment. ChT but also anti-
angiogenic multikinase inhibitors such as sunitinib and
targeted agents including octreotide and everolimus.
Immunotherapy is currently assessed in ongoing clinical
trials in thymic carcinomas. Frequent and severe immune-
related adverse events may occur, including myocarditis,
myositis and Lyell’s syndrome.
When interpreting prognostic data, one must take into

consideration that only 50% of patients overall actually Fig. 13.7
die from tumour progression; causes of death include
autoimmune diseases and non-related disorders
(each accounting for 25%).
REVISION QUESTIONS
1. Is postoperative RT delivered after complete resection of stage I thymoma?
2. What are the two major ChT drugs delivered in thymic tumours?
3. Which targeted therapies may be used in advanced disease?
81
Girard & Merveilleux du Vignaux
Summary: Thymic malignancies
• Thymic tumours are rare epithelial malignancies; the pathological classification distinguishes thymomas and thymic
carcinomas
• Thymomas may be associated with autoimmune disorders, such as myasthenia gravis
• Tumour stage is assessed using the TNM 8th edition
• Surgery is the mainstay of the treatment of thymic tumours. Upfront resection is the standard strategy for resectable
tumours
• Postoperative RT may be delivered, depending on the completeness of surgical resection, tumour stage and histology
• For unresectable locally advanced tumours, primary ChT is the standard, aiming at allowing subsequent R0 surgical
resection or, alternatively, sequential definitive RT
• The main ChT regimens include doxorubicin- and cisplatin-based protocols
• Major prognostic factors include tumour stage, completeness of surgical resection and histology
Further Reading
Brierley JD, Gospodarowicz MK, Wittekind C (eds). Thymic Tumours in TNM Classification of Malignant Tumours, 8th Edition.
Oxford: Wiley Blackwell, 2016.
Detterbeck F, Youssef S, Ruffini E, Okumura M. A review of prognostic factors in thymic malignancies. J Thorac Oncol 2011;
6(7 Suppl 3):S1698–S1704.
Detterbeck FC, Moran C, Huang J, et al. Which way is up? Policies and procedures for surgeons and pathologists regarding
resection specimens of thymic malignancy. J Thoracic Oncol 2011; 6(7 Suppl 3):S1730–S1738.
Detterbeck FC, Nicholson AG, Kondo K, et al. The Masaoka-Koga stage classification for thymic malignancies: clarification and
definition of terms. J Thoracic Oncol 2011; 6(7 Suppl 3):S1710–S1716.
Forquer JA, Rong N, Fakiris AJ, et al. Postoperative radiotherapy after surgical resection of thymoma: differing roles in localized and
regional disease. Int J Radiat Oncol Biol Phys 2010; 76:440–445.
Girard N, Mornex F, Van Houtte P, et al. Thymoma: a focus on current therapeutic management. J Thorac Oncol 2009; 4:119–126.
Girard N. Chemotherapy and targeted agents for thymic malignancies. Expert Rev Anticancer Ther 2012; 12:685–695.
Huang J, Detterbeck FC, Wang Z, Loehrer Sr PJ. Standard outcome measures for thymic malignancies. J Thorac Oncol 2011;
6(7 Suppl 3):S1691–S1697.
Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 2003;
76:878–884.
Marchevsky A, Marx A, Ströbel P, et al. Policies and reporting guidelines for small biopsy specimens of mediastinal masses. J Thorac
Oncol 2011; 6(7 Suppl 3):S1724-S1729.
Ruffini E, Van Raemdonck D, Detterbeck F, et al; European Society of Thoracic Surgeons Thymic Questionnaire Working Group.
Management of thymic tumors: a survey of current practice among members of the European Society of Thoracic Surgeons.
J Thorac Oncol 2011; 6:614–623.
82
Thymic malignancies
14 Neuroendocrine tumours of lung origin
Clinical presentation and pathology
Total atelectasis dx as
result of central bronchial
obstruction
Lung neuroendocrine tumours (NETs) account for fewer
than 1% of all pulmonary neoplasms; the incidence of these
neoplasms has risen dramatically over the past 30 years.
The tumours may be associated with multiple endocrine
neoplasia type 1 (MEN-1) in 4%–8% of cases.
Typical symptoms of lung NETs include obstructive

pneumonia, atelectasis and wheezing as a result of
central airway obstruction due to tumour mass. Fig. 14.1
Although NETs of the lung arise from cells capable of

producing serotonin and adrenocorticotrophin hormones,
hypersecretion of bioactive amines is rare.
TC with low mitotic count <2/10 HPF
AC
and absence of necrosis
They include a wide range of tumours, from well-
differentiated to poorly differentiated small cell lung cancer
(SCLC) and large cell neuroendocrine carcinoma (LCNEC).
The 2015 World Health Organization (WHO) classification

combines architectural growth patterns, mitotic index
and the presence of necrosis. It separates this group
LCNEC SCLC
of tumours into 4 major categories, including typical
carcinoid (TC), atypical carcinoid (AC), small cell
carcinoma (or SCLC) and LCNEC.
Histological type Necrosis Mitotic count

TC Absent <2/10 HPF
Fig. 14.2
AC Present focal 2–10/10 HPF
AC, Atypical carcinoid; HPF, high-power field; LCNEC, large cell neuroendocrine carcinoma;
SCLC, small cell lung cancer; TC, typical carcinoid. LCNEC Present (extensive) >10 HPF, usually >30 HPF
SCLC Present (extensive) >10 HPF, usually >60 HPF
AC, Atypical carcinoid; HPF, high-power field; LCNEC, large cell neuroendocrine carcinoma;
SCLC, small cell lung cancer; TC, typical carcinoid.
Histological subtype is the most important prognostic p<0.0001

factor, the survival of TC being higher than AC, while (95% CI 0.410-0.774)
LCNEC and SCLC have the worst outcome.
100
Nodal status is another important prognostic factor. Up TC
80
to 60% of patients with AC have lymph node metastases
Cum. Survival %
AC
and a 5-year survival of 61% to 88%. 60
Lymph node metastases are present in more than 40 LCNEC

15% of cases of TC lung NETs, and 5-year survival
SCLC
exceeds 90%. 20
0

0 25 50 75 100 125 150 175 200
Months Fig. 14.3
AC, Atypical carcinoid; CI, confidence interval; LCNEC, large cell neuroendocrine carcinoma;
SCLC, small cell lung cancer; TC, typical carcinoid.
REVISION QUESTIONS
1. How frequent are NETs among lung malignancies?
2. What are the four types of lung NETs?
3. What are the most important prognostic factors for lung NETs?
83
Garassino et al
Staging and local treatment
Staging with FDG-PET is
recommended only for LCNEC and
Biochemical evaluations: chromogranin A and SCLC. Its role is not well defined for
carcinoids (high rate of false negatives)
plasma neuron-specific enolase (NSE) for well- due to low grade, low mitotic count,
differentiated lung NETs; 5-hydroxyindoleacetic and often small lesion
acid (HIAA) in patients with carcinoid syndrome;
adrenocorticotropic hormone (ACTH) and urinary-free
cortisol in patients with Cushing syndrome.
Computed tomography (CT) of the chest may indicate
a diagnosis of lung NETs. Bronchoscopy is the best
procedure to detect central bronchial NETs.
68
Gallium positron emission tomography (PET) and
somatostatin receptor scintigraphy when somatostatin
receptors are expressed can be informative.
Fig. 14.4
Macroscopic
FDG-PET, Fluorodeoxyglucose positron emission tomography; LCNEC, large cell neuroendocrine
appearance of bronchial carcinoma; SCLC, small cell carcinoma.
carcinoid after surgical
resection
For more aggressive bronchial NETs such as LCNEC and
SCLC, a fluorodeoxyglucose (FDG)-PET scan would be
more informative.
The surgical approach depends upon the size, location

and tissue type. The cornerstone of therapy for TC and
AC is resection, considered even in resectable advanced
disease. The surgical approach for SCLC is restricted to
very limited disease and to stage I-IIIA for LCNEC.
The surgical techniques of choice are lobectomy or sleeve

resection. Pneumonectomy should be avoided except in
Fig. 14.5 selected cases.
Systemic nodal dissection should be performed since

lymphonodal metastases may be present in up to 15%
of cases in TC and >60% in AC.
Bronchoscopic laser excision of intraluminal typical

bronchial NETs should be considered as a suboptimal
treatment and reserved for inoperable patients.
The 5-year survival rate is 87%–90% in TC, 44%–78%
in AC, 15%–57% in LCNEC, and 15%–57% in SCLC.
Around 10% of
patients will have multifocal
lesions of bronchopulmonary
(BP) carcinoids
Fig. 14.6
REVISION QUESTIONS
1. What is the best diagnostic procedure to detect central bronchial NETs?
2. What is the main therapy for bronchial NETs?
3. Which NET subtype has the best 5-year survival rate?
84
Neuroendocrine tumours of lung origin
No randomised trial
evidence is available for
Systemic treatment chemotherapy, and its role for
bronchopulmonary carcinoids
continues to be debated
Cytotoxic treatment combined with surgical resection, Study/year n: primaries ORR m duration
when indicated, has been the standard for metastatic Moerdel/1991 27: GI lung well- 7% 4–6 months
lung NETs. CDDP+VP16 differentiated NET
Mitry/1999 12: well-differentiated Only 1, pt 8 months
CDDP+VP16 lung/mid gut 1/12 (9%)
Available chemotherapy regimens for TC and
Fjallskog/2001 32: lung/thymus, 34% 9 months
AC include a combination of streptozotocin plus CDDP+VP16 pancreas/ileum
5-fluorouracil/doxorubicin. Bajetta/2007 27: well-differentiated 3 pts PR (60%) 20 months
XELOX GEP, 5 pts lung 1 pt SD (20%)
Temozolomide alone, or in combination with 1 pt PD (20%)
Ekeblad/2007 36: well-differentiated Lung NETs 7 months
capecitabine and sometimes bevacizumab, TEMOZOLOMIDE NETs, 13 bronchial PR (31%)
has demonstrated clinical benefit. NETs (10 TCs and 3 ACs), SD (31%)
7 thymic
Spada/2016 70: GEP, 13% 8 months
CAPOX, FOLFOX-6, 15 bronchial
In the RADIANT-4 trial, 31% GEMOX
of patients in the experimental group Walter/2016 32 bronchial NETS PR (20%) 15 months
and 28% in the control group were FOLFOX, GEMOX (8 TCs and 24 ACs) SD (64%) Fig. 14.7
diagnosed with lung NETs
AC, Atypical carcinoid; CDDP, cisplatin; CAPOX (or XELOX), capecitabine/oxaliplatin; FOLFOX,
5-fluorouracil/leucovorin/oxaliplatin; GEMOX, gemcitabine/oxaliplatin; GEP, gastroenteropancreatic;
GI, gastrointestinal; NET, neuroendocrine tumour; ORR, overall response rate; PD, progressive
disease; PR, partial response; pt, patient; SD, stable disease; TC, typical carcinoid.
RADIANT-4 Study Design
For low proliferating tumours, treatment with somatostatin

R
A analogues might be an option in functional tumours with
N
D
O
clinical symptoms.
M
I
S
E
The PROMID trial showed antitumour efficacy of octreotide
long-acting release (LAR) in small intestinal NETs and it is
now widely accepted for non-functioning tumours.
Lung NETs are typically under-represented in clinical

trials of NET treatments. RADIANT-4 has reported
*Based on prognostic level, grouped as: Stratum A (better prognosis) – appendix, caecum, jejunum,
ileum, duodenum and NET of unknown primary. Stratum B (worse prognosis) – lung, stomach, results specific to lung NETs.
rectum and colon except caecum.
Fig. 14.8
AE, Adverse event; CgA, chromogranin; DCR, disease control rate; FACT-G, functional
assessment of cancer - general; GI, gastrointestinal; HRQoL, health-related quality of life;
NET, neuroendocrine tumour; NSE, neuron-specific enolase; ORR; overall response rate; OS,
overall survival; PD, progressive disease; PFS, progression-free survival; PK, pharmacokinetics; Radiant-4 PFS HR by primary tumour origin –
SSA, somatostatin analogue; WHO PS, World Health Organization performance status. Retrospective analysis, central review
Subgroups* No. Hazard ratio (95% CI)
RADIANT-4 evaluated the impact of the oral mammalian
target of rapamycin (mTOR)-inhibitor everolimus vs placebo. Lung 90 0.50 (0.28-0.88)
Treatment with everolimus in lung NETs was associated

with longer progression-free survival (PFS) – 9.2 months GI† 175 0.56 (0.37-0.84)
compared with 3.6 months in the placebo group.

NET of unknown
primary 36 0.60 (0.24-1.51)
Everolimus improved PFS by 6 months and reduced

0.1 0.4 1 10
tumour progression risk by 50% in patients with
advanced, progressive, non-functional lung NETs Everolimus better Placebo better
compared with placebo (hazard ratio [HR]= 0.50; 95% *One patent with thymus as primary tumour was not included.
†
Stomach, colon, rectum, appendix, caecum, ileum, duodenum and jejunum are grouped under GI.
confidence interval [CI], 0.28-0.88). Hazard ratio obtained from unstratified Cox model.
Fig. 14.9
CI, Confidence interval; GI, gastrointestinal; HR, hazard ratio; NET, neuroendocrine tumour;
PFS, progression-free survival.
REVISION QUESTIONS
1. Which drug has demonstrated clinical benefit?
2. Which drug would you prescribe for functional tumours?
3. Which result has been shown by the RADIANT-4 trial?
85
Garassino et al
Summary: Neuroendocrine tumours of lung origin
• NETs of the lung are rare (1% of all lung malignancies)
• Diagnosis is challenging and requires a specialised pathologist
• Proper distinction should be made between well- or moderately differentiated forms
• TCs and ACs or poorly differentiated forms (LCNEC and SCLC) have very different prognoses
• Nodal involvement is an important prognostic factor
• Imaging techniques: radiolabelled peptide scintigraphy is useful in well-differentiated forms
• In addition to CT scan, somatostatin receptor scintigraphy or 68Ga-PET/CT is preferred for well-differentiated forms
• For LCNEC and SCLC, a PET scan is more informative
• The main therapy is surgical resection and systemic nodal dissection
• The role of chemotherapy for bronchopulmonary carcinoids continues to be debated. Temozolomide, alone or in
combination with capecitabine and sometimes bevacizumab, has demonstrated clinical benefit
• In the RADIANT-4 trial, everolimus improved PFS by 6 months and reduced tumour progression risk by 50% in patients
with advanced, progressive, non-functional lung NETs compared with placebo (HR= 0.50; 95% CI, 0.28-0.88)
Further Reading
Bertino EM, Confer PD, Colonna JE, et al. Pulmonary neuroendocrine/carcinoid tumors: a review article. Cancer 2009; 115:4434–4441.
Daddi N, Ferolla P, Urbani M, et al. Surgical treatment of neuroendocrine tumors of the lung. Eur J Cardiothorac Surg 2004; 26:813–817.
Ekeblad S, Sundin A, Janson ET, et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine
tumors. Clin Cancer Res 2007; 13:2986–2991.
Fazio N, Granberg D, Grossman A, et al. Everolimus plus octreotide long-acting repeatable in patients with advanced lung
neuroendocrine tumors: analysis of the phase 3, randomized, placebo-controlled RADIANT-2 study. Chest 2013; 143:955–962.
Fazio N, Buzzoni R, Delle Fave G, et al. Efficacy and safety of everolimus in advanced; progressive, non functional neuroendocrine
tumours (NET) of the lung: a subgroup analysis of the phase 3 RADIANT-4 study. Abs 1437 presented at ENETS 2016 Annual Congress.
https://www.enets.org/efficacy-and-safety-of-everolimus-in-advanced-progressive-nonfunctional-neuroendocrine-tumors-net-of-the-
lung-a-subgroup-analysis-of-the-phase-3-radiant-4-study.html (22 February 2018, date last accessed).
Righi L, Volante M, Rapa I, et al. Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung.
Endocr Relat Cancer 2010; 17:977–987.
Righi L, Volante M, Tavaglione V, et al. Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and
immunohistochemical study of 218 “clinically aggressive” cases. Ann Oncol 2010; 21:548–555.
Travis W, Brambila E, Burke AP, et al. WHO classification of tumours of the lung, pleura, thymus and heart. 4th edition. Lyon (France):
IARC Press; 2015.
Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine
tumors in 35,825 cases in the United States. J Clin Oncol 2008; 26:3063-3072.
Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or
gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016; 387:968–977.
Zatelli MC, Minoia M, Martini C, et al. Everolimus as a new potential antiproliferative agent in aggressive human bronchial carcinoids.
Endocr Relat Cancer 2010; 17:719–729.
86
Neuroendocrine tumours of lung origin
15 Immunotherapy for thoracic malignancies:
Part B – Small cell lung cancer and mesothelioma
Immune checkpoint blockade in small cell lung cancer
In the phase III study CA184-156, 1132 patients were Phase III study CA184-156
randomised to receive chemotherapy (ChT) with
platinum/etoposide plus ipilimumab 10 mg/kg or placebo.
Ipilimumab 10 mg/kg IV Q3W +
platinum/etoposide
Patients without disease progression received
R 1:1
maintenance ipilimumab at 10 mg/kg or placebo every
12 weeks, until disease progression or unacceptable Placebo Q3W +
toxicity for a maximum of 3 years. platinum/etoposide
The investigational arm did not prolong overall survival

(OS) (11.0 vs 10.9 months, p = 0.3775) or progression-free Primary outcome measure: OS
Secondary outcome measure: PFS
survival (PFS) (4.6 vs 4.4 months, p = 0.0161). Fig. 15.1
CNS, Central nervous system; ECOG PS, Eastern Cooperative Oncology Group Performance
Status; IV, intravenously; OS, overall survival; PFS, progression-free survival; R, randomised;
IMpower133: Global Phase I/III randomised, placebo-controlled trial IMpower133 is a double-blind, placebo-controlled,
evaluated atezolizumab + carboplatin + etoposide in 1L ES-SCLC phase III trial to evaluate atezolizumab plus carboplatin/
etoposide in patients (pts) with extensive-stage (ES)
small cell lung cancer (SCLC) who had not previously
received treatment.
The addition of atezolizumab to ChT resulted in

significantly longer OS and PFS than ChT alone.
At a median follow-up of 13.9 months:
The median OS was 12.3 months in the atezolizumab
Fig. 15.2
group and 10.3 months in the placebo group (hazard
AUC, Area under the curve; ECOG PS, Eastern Cooperative Oncology Group Performance Status;
ES-SCLC, extensive-stage small cell lung cancer; IV, intravenous; PCI, prophylactic cranial ratio [HR] for death, 0.70; 95% confidence interval [CI],
irradiation; PD, progressive disease; PFS, progression-free survival; R, randomised; RECIST,
Response Evaluation Criteria in Solid Tumours. 0.54–0.91; p = 0.007).
The median PFS was 5.2 months and 4.3 months,
respectively (HR for disease progression or death, 0.77;
95% CI, 0.62–0.96; p = 0.02).
The phase I/II study CheckMate 032 evaluated the Tumour response
safety and efficacy of nivolumab either alone or in Nivolumab Nivolumab Nivolumab
combination with ipilimumab in pts with pretreated 3 mg/kg 1 mg/kg plus 3 mg/kg plus
(n=98) Ipilimumab 3 mg/kg Ipilimumab 1 mg/kg
SCLC unselected for programmed death-ligand 1 (n=61) (n=54)
(PD-L1) expression. Durable responses and clinical Objective response; 10 (10%; 5-18) 14 (23%; 13-36) 10 (19%; 9-31)
95% CI
activity were found in both the nivolumab monotherapy
and the combination therapy arms. Best overall response
Complete response 0 1 (2%) 0
Partial response 10 (10%) 13 (21%) 10 (19%)
The safety profiles for both treatment strategies were Stable disease 22 (22%) 13 (21%) 9 (17%)
Progressive disease 52 (53%) 23 (38%) 29 (54%)
manageable and consistent with these agents in other Unable to determine 12 (12%) 8 (13%) 6 (11%)
tumour histologies. Not reported 2 (2%) 3 (5%) 0
Time to objective 2.0 (1.3-2.8) 2.1 (1.4-2.8) 1.4 (1.3-2.7)
The combination of nivolumab and ipilimumab induced response (IQR), months
an overall response rate (ORR) of 46% in patients with Data are n (%) unless otherwise stated. All patients were enrolled at least 90 days prior to database lock.
recurrent SCLC with high tumour mutation burden (TMB), CI, Confidence interval; IQR, interquartile range. Fig. 15.3
according to an exploratory analysis from the phase I/II
CheckMate 032 study.
The phase III trial, CheckMate 331, evaluated nivolumab
vs the current standard of care, topotecan or amrubicin
(where approved), in pts with SCLC who relapsed
following platinum-based ChT. The study did not meet
its primary endpoint of OS.
87
Calvo et al
Immune checkpoint blockade in small cell lung cancer (continued)
The phase Ib multicohort study KEYNOTE-028 KEYNOTE-028 (NCT02054806): Phase Ib Multicohort Study of
evaluated the safety and efficacy of pembrolizumab in Pembrolizumab for PD-L1+ Advanced Solid Tumours
pts with SCLC who failed platinum-based ChT.
Patients
• Small cell lung cancer
All pts enrolled were PD-L1 positive (>1%) as evaluated • Failure of or inability
to receive standard
by immunohistochemistry (IHC) using the Merck 22C3 therapy Pembrolizumab
• ECOG PS 0 or 1 10 mg/kg IV
antibody. • ≥1 measurable lesion Q2W
• PD-L1 positivity
• No autoimmune
Pembrolizumab demonstrated a promising response disease or interstitial
lung disease Response
rate of 33% with median duration of response (DoR) assessment*
of 19.4 months and 1-year survival of 37.7%. *Response assessment: Every 8 weeks for the first 6 months; every 12 weeks thereafter
Primary endpoints: ORR per RECISTv1.1 and safety
Secondary endpoints: PFS, OS, duration of response
Sixty-seven percent of pts had an adverse event with Fig. 15.4
the most common being fatigue, rash, diarrhoea and ECOG PS, Eastern Cooperative Oncology Group Performance Status; IV, intravenously;
OS, overall survival; ORR, overall response rate; PD-L1+, programmed death-ligand 1-positive;
arthralgia. PFS, progression-free survival; RECIST, Response Evaluation in Solid Tumours.
Immune checkpoint blockade in mesothelioma

Single-arm phase II trials of tremelimumab (MESOT-
100 Tremelimumab
90 Placebo TREM-2008; MESOT-TREM-2012) achieved a partial
HR 0.92 (95% CI 0.76-1.12; p=0.41)
80 response (6.9% and 13.8%, respectively) and durable
70
60 disease control (31% and 52%, respectively).
50
40
30
The DETERMINE study evaluated tremelimumab or
20 placebo as second-/third-line treatment for pts with
10 unresectable pleural or peritoneal mesothelioma.
0
0 3 6 9 12 15 18 21 24 27 30 Tremelimumab did not demonstrate superiority to
Number at risk Time since randomisation (months)
(number censored) placebo for the primary endpoint of OS. Preliminary
Tremelimumab 382 (0) 300 (6) 232 (11) 163 (13) 116 (13) 69 (29) 36 (48) 16 (63) 3 (72) 1 (74) 0 (75)
Placebo 189 (0) 147 (3) 103 (6) 70 (9) 48 (10) 32 (14) 17 (26) 8 (29) 2 (34) 0 (35) 0 (35) safety data are consistent with the known safety profile
Fig. 15.5
of tremelimumab.
The single-arm, phase II DREAM trial combined

N=54
durvalumab, cisplatin and pemetrexed as first-line
therapy in malignant pleural mesothelioma. 57% of pts Durvalumab
Key Eligibility Criteria 1125 mg Q3W
achieved PFS for at least 6 months, while median PFS • Histologically or +
cytologically confirmed
was 6.9 months and median DoR, 6.5 months. MPM
Cisplatin
75 mg/m2 Q3W
• Not amenable to curative
surgery +
In the NIBIT-MESO-1 open label phase II trial evaluating • Measurable disease Pemetrexed
500 mg/m2 Q3W
• ECOG PS 0-1
durvalumab and tremelimumab as first- or second-line for 6 cycles
treatment for pleural or peritoneal mesothelioma, the ORR

Primary outcome: PFS at 6 months
was 25% and DoR 16.1 months. Secondary outcomes: ORR, toxicity, PFS, OS
The MAPS2 trial randomised pts to either nivolumab or Fig. 15.6
nivolumab and ipilimumab. Response rates were 17.5% vs ECOG PS, Eastern Cooperative Oncology Group Performance Status; MPM, malignant pleural
mesothelioma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS,
24.2% and grade ≥3 toxicities 9.5% vs 21.3%, respectively. progression-free survival.
REVISION QUESTIONS
1. In SCLC, when using anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and anti-PD-L1 or anti-PD-1 in combination, does the response
rate correlate with PD-L1 expression?
2. In SCLC, was ChT with platinum/etoposide plus ipilimumab 10 mg/kg vs placebo superior in OS?
3. D id tremelimumab demonstrate superiority to placebo for OS as second/third-line treatment for patients with unresectable pleural
or peritoneal malignant mesothelioma?
88
Immunotherapy for thoracic malignancies: Part B – Small cell lung cancer and mesothelioma
Summary: Immunotherapy for thoracic malignancies
Part B – Small cell lung cancer and mesothelioma
• Although combination ChTs continue to be the standard of care for SCLC, high rates of recurrence and limited
long-term response are common
• Durable response in first-line cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade and ChT combination strategies,
as well as second-line PD-1 and CTLA-4 blockade combination strategies, support the idea of bringing either dual-
targeted immunotherapies or other targeted therapy combinations to first-line treatment strategies in SCLC
• Optimal patient selection for immune checkpoint-directed therapies remains a challenge
• Further research on immune checkpoint pathways and associated therapeutic antibodies will be necessary to improve
outcomes for patients with SCLC
• Early-phase studies with immune checkpoint inhibitors in pre-treated malignant mesothelioma patients have shown
promising results. Results from ongoing trials are eagerly awaited
Further Reading
Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer
(CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016; 17:883–895.
Avelumab in metastatic or locally advanced solid tumors (JAVELIN Solid Tumor). Available from: https://clinicaltrials.gov/ct2/show/
NCT01772004 (27 February 2019, date last accessed).
Calabró L, Morra A, Fonsatti E, et al. Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant
malignant mesothelioma: an open-label, single-arm, phase 2 study. Lancet Respir Med 2015; 3:301–309.
Calabró L, Morra A, Fonsatti E, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an
open-label, single-arm, phase 2 trial. Lancet Oncol 2013; 14:1104–1111.
Hassan R, Thomas A, Patel MR, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma
from the JAVELIN solid tumor phase Ib trial: Safety, clinical activity, and PD-L1 expression. J Clin Oncol 2016; 34:(Suppl) abstract 8503.
Horn L, Mansfield AS, Szczesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J
Med 2018; 379:2220–2229.
Kindler HL, Scherpereel A, Calabró L, et al. Tremelimumab as second- or third-line treatment of unresectable malignant mesothelioma
(MM): Results from the global, double-blind, placebo-controlled DETERMINE study. J Clin Oncol 2016; 34:(Suppl) abstract 8502.
Ott PA, Fernandez MEE, Hiret S, et al. Pembrolizumab (MK-3475) in patients with extensive-stage small cell lung cancer: preliminary
safety and efficacy results from KEYNOTE-028. J Clin Oncol 2015; 33:(Suppl) abstract 7502.
Randomized, double-blind study comparing tremelimumab to placebo in subjects with unresectable malignant mesothelioma. Available
from: https://clinicaltrials.gov/ct2/show/nct01843374 (27 February 2019, date last accessed).
Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-
small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol 2013; 24:75–83.
Reck M, Luft A, Szczesna A, et al. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide
and platinum in extensive-stage small-cell lung cancer. J Clin Oncol 2016; 34:3740–3748.
89
Calvo et al
Emerging targets and new agents in lung cancer 16
Human epidermal growth factor receptor 2 (HER2) exon 20 mutations
HER2 is a receptor tyrosine kinase of the ERBB family Spectrum of HER2 exon 20 mutations
with no known identified ligand, functioning as a preferred
dimerisation partner. A775_G776insYVMA (83%, 20/24)
G776>VC (8%, 2/24)
V777_G778insCG (4%, 1/24)
Activating HER2 mutations in non-small cell lung cancer 770

P780_Y781insGSP (4%, 1/24)
831
(NSCLC) were identified in 2004, occurring in up to HER2 -E--A--Y--V--M--A--G--V--G--S--P--Y--V--S--R--L--L--G--I--C--L--T-=//=-A—K-
EGFR -E--A--Y--V--M--A--S--V--D--N--P--H--V--C--R--L--L--G--I--C--L--T-=//=-A—K-
2%–4% of cases, mutually exclusive to other oncogenic 762
A763_Y764insFHEA
823
V774_C775insHV
drivers, predominantly observed in adenocarcinomas.

H773_V774insNPH
A767_S768insTLA
H773_V774insH
V769_D770insASV H773_V774insPH
V769_D770insGE H773_V774insAH
Mutations usually map to exon 20, are in-frame P772_H773insNPH

P772_H773insNP
insertional and are homologous to epidermal growth N771_P772insH

D770_N771insSVD
factor receptor (EGFR) exon 20 insertions. Over 80% D770_N771insGT

D770_N771insGF
of cases harbour the A775_G776insYVMA insertion/ D770_N771insY

D770>GY
duplication. Fig. 16.1
EGFR, Epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2.
Afatinib and dacomitinib are pan-HER irreversible

tyrosine kinase inhibitors (TKIs). TKI activity is poor in
most patients with 1/13 responders to afatinib from the
European Thoracic Oncology Platform (ETOP) NICHE
trial and 3/26 responding in a phase II trial of dacomitinib.
Some patients may retain TKI sensitivity (e.g. dacomitinib

responders are noted to harbour a general secretory
pathway [GSP] insertion, an afatinib responder
V777_G778ins GSP and in vitro data identifying
sensitive mutations containing Gly700).
Several cases responding to weekly pulsed dosing of
afatinib (280 mg weekly) have been reported.
Fig. 16.2
WT, Wild type.
HER2-mutant lung cancer responses

Ado-trastuzumab emtansine (T-DM1) was trialled in a 100 Confirmed partial response
Stable disease
phase II study presented at the 2017 ASCO (American
Best Response per RECIST
75 Progressive disease
Society of Clinical Oncology) annual meeting, 50
identifying responses in 8/18 cases and a median 25
v1.1 (%)
progression-free survival (PFS) of 4 months. 0
–25
All responders had 0-2+ HER2 expression and no –30%
–50
amplification. Patients responding to chemotherapy
–75
(ChT)/trastuzumab combinations have been reported.
–100
The mutation-specific irreversible TKI AP32788 is in Patients
Fig. 16.3
development for NSCLCs with HER2 mutations.
HER2, Human epidermal growth factor receptor 2; RECIST, Response Evaluation Criteria In Solid Tumours.
REVISION QUESTIONS
1. Are all somatic HER2 mutations in exon 20?
2. What is the most common HER2 exon 20 genotype?
3. Which drugs have demonstrated potential sensitivity in HER2 exon 20 mutations?
90
Emerging targets and new agents in lung cancer
HER2 trans-membrane domain mutations
Table 1. Clinicopathologic Features of HER2 TMD Mutations in NSCLC

Smoking TMD Protein Concurrent HER2 TMB Response to
Case Age Sex Stage Status Alteration Codon Change Nucleotide Change Amplification MAF (mutations/Mb) HER2 TKI a
1 62 F 4 Never-smoker V659E GTT / GAA 1976_1977TT >AA N 0.42 7.19 First-line afatinib, PR, 5 mo
2 54 M 4 Never-smoker V659E GTTG GC / GAACGC 1976_1977TT >AA N 0.16 3.99 Second-line afatinib, PR,
G660R 1978G> C 18 mo, ongoing
3 73 M 4 Never-smoker V659E GTT / GAG 1976_1977TT >AG N 0.09 3.99 Third-line afatinib, 5 mo
of symptomatic improvement
and metabolic response
4 53 M 4 Positive history G660D GGC / GAC 1979G> A N 0.14 3.19 Second-line afatinib, PD,
10 weeks
5 52 F NR Light smoker V659E GTT / GAA 1976_1977TT >AA N 0.70 10.81 Second-line afatinib, not yet
evaluable
6 59 F 4 Minimal remote V659D GT T / GAT 1976T >A N 0.13 6.60 NA
smoking
history
7 69 M 4 NR V659D GT T / GAT 1976T >A Y (30 copies) 0.94 6.60 NA
8 47 F 4 Never-smoker V659D GT T / GAT 1976T >A N 0.14 5.50 NA
9 51 F NR NR V659E GTT / GAG 1976_1977TT >AG Y (14 copies) 0.45 2.20 NA
10 59 F 2 NR V659E GTT / GAG 1976_1977TT >AG N 0.11 1.10 NA
11 74 F NR NR V659E GTT / GAG 1976_1977TT >AG N 0.27 7.19 NA
12 48 F NR NR V659E GTT / GAA 1976_1977TT >AA N 0.46 7.99 NA
13 47 F 4 Minimal remote V659E GTT / GAA 1976_1977TT >AA N 0.08 2.70 NA
smoking
history
14 33 F NR NR V659_660VE G T G / GGGTTGAAG 1976_1979TG > GGTTGAAG N 0.2 2.20 NA
15 66 F NR Never-smoker G660D GGC / GAC 1979G> A N 0.12 3.30 NA
S310F TCT / TT T 929C> T
Note: Bold text indicates nucleotide changes.
a
Follow-up cutoff was October 1, 2016. Fig. 16.4
HER2, erb-b2 receptor tyrosine kinase 2 gene; TMD, transmembrane domain; MAF, mutant allele frequency; TMB, tumor mutational burden; TKI, tyrosine kinase inhibitor; F, female;
N, no; PR, partial response; M, male; PD, progressive disease; NR, not reported; NA, not applicable; Y, yes.
HER2 mutations usually map to the kinase domain. HER2 trans-membrane domains (TMDs) are important for receptor
activation and can affect downstream activity independent of kinase domain mutations.
The G660D mutation in exon 17 was identified in the germline from a Japanese kindred and subsequent screening of
HER TMDs identified the HER2 TMD mutation V659E (analogous to the V664E driver mutation in rats).
A single case of HER2 V659E with Li-Fraumeni responded to combination lapatinib/paclitaxel, with in vitro sensitivity
to lapatinib.
Several other TMD mutations have been identified (V664F,

V665M, I675M).
Treatment with afatinib identified responses in patients

with V659E and the compound V659E/G660R mutation.
In additional screening of 8551 genotyped adenocarcinomas

by Foundation Medicine, 2% were identified to harbour
HER2 659/660 variants (V659E, V659D, G660D,
V659_660VE, V659E/G660R compound).
Fig. 16.5
REVISION QUESTIONS
1. How do HER2 TMDs transform cells?
2. What are the most common HER2 TMD genotypes?
3. Which drug has induced durable responses in some patients with HER2 TMDs?
91
Januszewski & Popat
EGFR exon 20 insertions & MET copy number gain
Exon 20 insertions in the EGFR gene account for Exon 20 insertions Exon 20
around 5% of all EGFR mutations in NSCLC, usually 762

C-helix
823
between residues Glu762 and Cys775, and typically (753–766)
occur in never/light-smokers.
C-helix
Exon 20 insertions are usually resistant to erlotinib or gefitinib

761 762 763 764 765 766 767 768 769 770 771 772 773 774 775
with poor activity in vitro and in case reports/series, although
some genotypes (e.g. A763_Y764insFQEA) are sensitive.
Asp761–Glu762 InsX (1·6%)
Ala763–Tyr764 InsX (0·8%)
Tyr764–Tyr765 InsX (0·8%)
Met766–Ala767 InsX (0·8%)
Ala767–Val768 InsX (2·5%)
Ser768–Val769 InsX (5·7%)
Val769–Asp770 InsX (20·5%)
Asp770–Asn771 InsX (28·7%)
Asn771–Pro772 InsX (4·1%)
Pro772–His773 InsX (17·2%)
His773–Val774 InsX (14·0%)
Val774–Cys775 InsX (3·3%)

The pan-HER irreversible second-generation TKI afatinib
has demonstrated minimal activity against exon 20
insertions (8.7% responses, median PFS 2.7 months)
from analysis of the LUX-Lung 2, 3 and 6 trials, although Loop following C-helix
genotypes with distal insertions (e.g. a common Gly770) Fig. 16.6
may retain sensitivity.

Encouraging in vitro data suggest potential sensitivity to osimertinib. AP32788 is an EGFR wild-type sparing, irreversible
EGFR/HER2 inhibitor in development against EGFR and HER2 exon 20 mutations (NCT02716116).
Dysregulation of the MET pathway in lung cancer occurs

through a variety of mechanisms, including gene mutation,
amplification, rearrangement and protein overexpression.
MET/CEP7 ratio and classification of MET amplification
MET/CEP7 ratio MET amplification classification Percentage of total MET copy number gains arise from polysomy or
<1.8 Negative 92.6 amplification. The appropriate numbers of MET copies
≥1.8 to ≤2.2 Low 3.6 and relationship to centromere copy number status to
>2.2 to >5.0 Intermediate 3.0 best predict response from MET-directed therapy are
≥5.0 High 0.8
poorly understood and continue to be evaluated.
Total – 100.0 Fig. 16.7
CEP7, Centromeric portion of chromosome 7; MET, mesenchymal epithelial transition receptor.

To date, the highest level of MET amplification (MET/CEP7
ratio ≥5) has been associated with response to crizotinib.
De novo MET amplification occurs in 1%–5% of NSCLCs

and overlap exists between MET exon 14 genotype status.
In contrast, up to 30% of patients with EGFR mutation
progressing on osimertinib have MET amplification as a
potential resistance mechanism.
Several agents are in development against dysregulated

MET including: multi-kinase MET TKIs (crizotinib,
cabozantinib, MGCD265, AMG208, altiratinib, golvatinib),
selective MET TKIs (capmatinib, tepotinib, tivantinib),
anti-MET antibodies (onartuzumab, emibetuzumab) and
anti-HGF antibodies (ficlatuzumab, rilotumumab).
Fig. 16.8
HGF, Hepatocyte growth factor; mAb, monoclonal antibody; PSI, plexin semaphoring integrin
domain; TK, tyrosine kinase; TKI, tyrosine kinase inhibitor.
REVISION QUESTIONS
1. How frequent are EGFR exon 20 insertions?
2. Are EGFR exon 20 insertions usually associated with sensitivity to erlotinib/gefitinib?
3. Which assays can be used to detect increased MET copy number?
92
Neurotrophic tyrosine receptor kinase (NTRK) & NRG1 fusions
Gene fusions in NTRK1, NTRK2, NTRK3 are rare Schematic view of TRK receptor signalling
oncogenic drivers in NSCLC. Fusion partners include the
genes CD74, MPRIP, BCAN and ETV6.
The NTRK1-3 genes encode the TRKA-C proteins and
play roles in neuronal development, cell survival and
cellular proliferation.
Activated fusions signal through RAS-RAF-MEK-ERK,

PI3K-AKT-mTOR (mammalian target of rapamycin) and
PLCγ-PKC pathways, driving and propagating malignancy.
Tropomyosin receptor kinase (TRK) fusions occur in a
number of solid tumours including NSCLC, colonic, head
and neck, sarcomas and primary brain tumours.
Fig. 16.9
TRK, Tropomyosin receptor kinase.
A number of pan-TRK inhibitors are in development,

including entrectinib (RXDX-101), an adenosine
triphosphate (ATP)-competitive TKI with sub-nanomolar
enzymatic efficacy against TRKA, TRKB, TRKC, ROS1
and ALK, designed to cross the blood–brain barrier.
Other TRK inhibitors include LOXO-101, MGCD516,

TSR-011, PLX7486, DS-6051b and DCC-2701, as well as
cabozantinib.
Fig. 16.10 Waterfall plot of

entrectinib in treatment
ALK, Anaplastic lymphoma kinase; NTRK, neurotrophic tyrosine receptor kinase.
naïve solid tumours with Schematic of
differing fusions NRG1-CD74 fusion protein
and interactions with
ERBB signalling
CD74-NRG fusions are rare, occurring in around 0.5%

CD74
CD74 NRG1
NRG1
of NSCLCs. All cases identified from a larger cohort
were identified as invasive mucinous adenocarcinomas. 5q32
5q32 8q12
8q12
CD74-NRG fusions lead to extracellular expression of the

epidermal growth factor (EGF)-like domain of NRG1 III β3,
providing the ligand for HER2-HER3 complexes.
Fig. 16.11
Two patients with CD75-NRG fusions in invasive
mucinous adenocarcinomas with durable responses to
irreversible pan-HER TKI afatinib have been reported.
REVISION QUESTIONS
1. Which proteins do NTRK genes usually encode?
2. Which drugs targeted against NTRK fusions are in development?
3. Which drug has demonstrated sensitivity against NSCLC with NRG fusions?
93
Januszewski & Popat
Indoleamine 2,3-dioxygenase (IDO)
IDO is an intracellular enzyme responsible for IDO catabolism along the kynurenine pathway
the first (and rate-limiting) step in tryptophan Protein L-Tryptophan Serotonin
O2
degradation in the kynurenine pathway.
TDO IDO
Tryptophan is an essential amino acid and N-Formylkynurenine

Kynurenine formamidase
IDO overexpression reduces the availability of Formic acid
Kynurenine
tryptophan. This induces immune tolerance aminotransferase
Kynurenic acid L-Kynurenine
through promoting inflammation in the tumour Kynurenine-3-monooxygenase
microenvironment and suppressing T and
Anthranilic acid 3-Hydroxykynurenine
natural killer (NK) cell activity.
Kynureninase
IDO inhibition is designed to overcome 3-Hydroxyanthranilic acid
immune tolerance. 3-Hydroxyanthranilate dioxygenase
Aminocarboxymuconic semialdehyde
α-Amino-α-carboxymuconate–
Spontaneous reaction
ε-semialdehyde decarboxylase
Quinolinic acid Aminomuconic semialdehyde
Spontaneous reaction
Nicotinic acid ribonucleotide Glutaryl CoA Picolinic acid
Nicotinic acid adenine dinucleotide CO 2 + ATP
NAD +
Fig. 16.12
ATP, Adenosine triphosphate; IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase.

Modulation of immune response by IDO-expressing cells
a IDO + tumour cell NK cell

• Downregulation of
activating NK receptors
Tryptophan • Apoptosis
IDO1
Kynurenines • Cell cycle arrest
• Decreased activation
Cytotoxic T ce ll • Apoptosis
There are several IDO inhibitors in early phase

b Cytotoxic T ce ll • Cell cycle arrest
• Downregulation of TCR development.
ζ-chain expression
• Apoptosis
• Areactivity
Epacadostat (Incyte) is the most advanced in
IDO + DC
• Cell cycle arrest
these trials with phase I/II trials in both mono and
Tryptophan •
•
Apoptosis
Areactivity
combination therapy.
IDO1 • Conversion into T Reg cell
Kynurenines Naive CD4 + Epacadostat is a small molecule inhibitor of IDO1

T cell
and has been combined with pembrolizumab for
• Decreased production of IFN γ
• Increased production of IL -4 patients with NSCLC. Encouraging response rates
• Increased production of IL-13
(overall response rate [ORR] 35%) and tolerable
Invariant
NK cell toxicities have led to an ongoing phase III study
• Decreased antibody
in NSCLC.
Bystander production
suppression • Apoptosis
IDO – DC Lymphocyte Plasma cell
DC, Dendritic cell; IDO, indoleamine 2,3-dioxygenase; IFN, interferon; IL, interleukin; Fig. 16.13
NK, natural killer; TCR, T cell receptor.
REVISION QUESTIONS
1. What is the function of IDO and in which pathway does it lie?
2. What impact does overexpression of IDO in tumour cells have on the immune response?
3. Which agent has been combined with pembrolizumab in NSCLC clinical trials?
94
4-1BB & Lymphocyte-activation gene 3 (LAG-3)
T cell activation requires antigen presentation Antigen presenting cell

CD40 CD40L
T cell
and a balance between co-stimulatory signalling TL1A TNFRSF25

(e.g. CD80, CD86, CD40, OX40 and 4-1BB) to provoke GITR ligand GITR
T cell activation and inhibitory signalling (e.g. cytotoxic 4-1BB ligand 4-1BB
T-lymphocyte antigen 4 [CTLA-4], programmed cell OX40 ligand OX40
CD70 CD27
death protein 1 [PD-1], LAG-3, T cell immunoglobulin
HHLA2 TMIGD2 Activation
and mucin domain 3 [TIM-3], Tigit and Vista) to limit ICOS ligand ICOS
overstimulation. CD86
CD28
CD80
4-1BB (CD137) is a co-stimulatory member of the tumour MHC class II TCR Signal 1
necrosis factor receptor superfamily. T cell activation

upregulates 4-1BB and its ligation by 4-1BB ligand (CD137L).
LAG3
CD86 CTLA4
Early phase trials with anti-4-1BB monoclonal antibody CD80 PDL1
(mAb) urelumab caused liver toxicity, potentially with one PDL1 PD1
PDL2
case of fatal hepatitis. This led to the early termination of
CD80
VISTA ?
a number of 4-1BB studies. Trials have since restarted BTNL2 ?
Inhibition
as these toxicities seem mitigated through dose reduction B7-H3 ?
Fig. 16.14
(<1 mg/kg). Utomilumab (PF-05082566) is also an B7-H4 ?
CTLA-4, Cytotoxic T-lymphocyte antigen 4; LAG-3, lymphocyte-activation gene 3; MHC, major
anti-4-1BB mAb in early phase trials. histocompatibility complex;
Butyrophilin PD-1/2, programmed cell death protein 1/2;? PD-L1/2, programmed
family
death ligand-1/2; TCR, T cell receptor.
CD48 CD244
Galectin 9
Phosphatidylserine TIM3
BTLA
HVEM CD160
LAG-3 is a negative
Siglec family
co-stimulatory receptor and is
LIGHT
upregulated on tumour infiltrating lymphocytes. Activation
Blockade of LAG-3 results in increased T cell proliferation
and enhanced anti-tumour T cell responses. It is
frequently co-expressed with PD-1 on activated T cells.
Conversely, an alternatively spliced soluble form of

LAG-3 (sLAG-3) acts as an immune adjuvant on other
immune cells – enhancing their anti-tumoural effect.
A number of LAG-3-directed therapies are in

development. These trials are in combination with
anti-PD-1 agents (LAG525, BMS-986016) in solid organ
cancers (including lung cancer).
Fig. 16.15 Initial reports of LAG525 in combination with nivolumab
LAG-3, Lymphocyte-activation gene 3; MHC, major histocompatibility complex. in heavily pre-treated patients (including progression on
prior immunotherapy) with malignant melanoma suggest
a 16% ORR.
The LAG-3Ig fusion protein IMP321 is being tested in
phase II trials in breast cancer in combination with ChT
as an immune adjuvant.
REVISION QUESTIONS
1. Which cells in the immune system are affected by 4-1BB signalling?
2. What strategies are being utilised to manipulate the 4-1BB pathway therapeutically?
3. What is the physiological function of membrane-bound LAG-3 in the T cell?
4. What effect does antagonism of LAG-3 have in T cells in an activated T cell?
95
Januszewski & Popat
Chimeric antigen receptor (CAR) T cell therapy
CAR T cell therapy utilises patients’ (or allogenic

donors’) T cells, which are activated and
genetically modified ex vivo to recognise
tumoural antigens.
Extracellular antigen-recognition domains

are linked to intracellular signalling domains
by genetic modification. The CAR T cells are
then infused to induce an anti-tumoural effect.
Second- and third-generation CAR T cells are

now in development where co-stimulatory
domains like 4-1BB or CD28 enhance CAR T
cell efficacy.
Some are engineered to include a ‘suicide-
gene’ as a safety mechanism, activated in
the event of severe toxicity or unresponsive
to treatment. Serious adverse events include
cytokine release syndrome (CRS).
Fig. 16.16
CAR, Chimeric antigen receptor; CTLA-4, cytotoxic T-lymphocyte antigen 4; IL-12, interleukin 12;
mAb, monoclonal antibody; NK, natural killer; scFv, single chain fragment of variable region;
VEGFR, vascular endothelial growth factor receptor.
CAR targets for the treatment of solid malignancies In 2017, the first CAR T cell therapy tisagenlecleucel
Target CAR structure Malignancy Institution Reference received USA Food & Drug Administration (FDA)
approval targeting the CD19 antigen in patients with
Mesothelin CD3 and 4-1BB Malignant pleural UPenn NCT01355965
mesothelioma acute lymphoblastic leukaemia (ALL). CAR T challenges
Pancreatic cancer UPenn NCT02465983 in solid organ cancers include identifying tumoural
Metastatic UPenn NCT02159716 antigens that are specific.
pancreatic (ductal)
adenocarcinoma,
epithelial ovarian CAR T cells directed at mesothelin, an antigen found on
cancer and malignant pleural mesothelioma and some lung cancers,
malignant pleural
mesothelioma have been developed and are in early phase studies
CD3ζ and CD28 Mesothelioma and MSKCC NCT02414269 including third-generation CAR T cells (CD28/4-1BB).
malignant pleural
disease
CD3ζ, CD28 and Mesothelioma, NCI NCT01583686 Clinical trials with
4-1BB pancreatic and CAR T cells in lung cancer
ovarian cancer directed at mesothelin
FAP CD3ζ and CD28 Mesothelioma University of Zurich NCT01722149 and FAP
CAR, Chimeric antigen receptor; FAP, fibroblast activation protein; Fig. 16.17
MSKCC, Memorial Sloan Kettering Cancer Center; NCI, National Cancer Institute;
UPenn, University of Pennsylvania.
REVISION QUESTIONS
1. In what way are T cells manipulated to generate a CAR T cell?
2. What antigens are being targeted in mesothelioma in CAR T cell clinical trials?
3. What is a ‘suicide gene’?
96
Summary: Emerging targets and new agents in lung cancer
• Several new molecular drivers are being evaluated as drug targets in NSCLC
• Established molecular drivers previously deemed drug resistant are being evaluated to identify sensitive mutant genotypes
• HER2 and EGFR exon 20 insertions may be sensitive to afatinib, contingent on specific genotype
• A number of different HER2-directed approaches for HER2 exon 20 insertions or TMDs are being developed
(e.g. the use of ado-trastuzumab emtansine and genotype-specific afatinib)
• A number of different EGFR-directed approaches for exon 20 insertions are being developed (e.g. genotype-specific
afatinib and AP32788)
• MET aberrations remain a viable drug target. Efforts are ongoing to characterise MET amplification and genotypes that
result in exon 14 skipping to predict sensitivity to MET inhibitors
• A number of rare fusions in NSCLC are being further developed as drug targets including NRTK and NRG fusions
• Manipulation of the immune system has become the focus of many new therapies
• Physiological overexpression of IDO in tumour cells induces immune anergy and its inhibition aims to overcome tolerance
• Therapies targeted at the immune checkpoint designed to either reduce co-stimulatory negative signalling (e.g. LAG-3)
or enhance activating pathways (e.g. 4-1BB) are in trials in combination with established immunotherapies
• CAR T cell therapy demonstrates good response rates in ALL and, despite its expense and toxicity profile, the quest to
identify specific antigen targets in solid cancers with effective CAR T cell design is underway
Further Reading
Arcila ME, Chaft JE, Nafa K, et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase
mutations in lung adenocarcinomas. Clin Cancer Res 2012; 18:4910–4918.
Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open
2016; 1:e000023.
Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol 2018; 15:31–46.
Chester C, Ambulkar S, Kohrt HE. 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer Immunol Immunother
2016; 65:1243–1248.
Drilon A, Cappuzzo F, Ou SI, Camidge DR. Targeting MET in lung cancer: will expectations finally be MET? J Thorac Oncol 2017; 12:15–26.
Gay ND, Wang Y, Beadling C, et al. Durable response to afatinib in lung adenocarcinoma harboring NRG1 gene fusions. J Thorac Oncol
2017; 12:e107–e110.
Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward. Nat Rev Clin Oncol 2016; 13:370–383.
Kosaka T, Tanizaki J, Paranal RM, et al. Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2
inhibitors. Cancer Res 2017; 77:2712–2721.
Löb S, Königsrainer A, Rammensee HG, et al. Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for
the trees? Nat Rev Cancer 2009; 9:445–452.
Mazières J, Barlesi F, Filleron T, et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs:
results from the European EUHER2 cohort. Ann Oncol 2016; 27:281–286.
Nirschl CJ, Drake CG. Molecular pathways: coexpression of immune checkpoint molecules: signaling pathways and implications for
cancer immunotherapy. Clin Cancer Res 2013; 19:4917–4924.
Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3 – potential mechanisms of action. Nat Rev Immunol 2015; 15:45–56.
Ou SI, Schrock AB, Bocharov EV, et al. HER2 transmembrane domain (TMD) mutations (V659/G660) that stabilize homo- and
heterodimerization are rare oncogenic drivers in lung adenocarcinoma that respond to afatinib. J Thorac Oncol 2017; 12:446–457.
Vinay DS, Kwon BS. Immunotherapy of cancer with 4-1BB. Mol Cancer Ther 2012; 11:1062–1070.
Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical
implications. Lancet Oncol 2012; 13:e23–e31.
97
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Appendix 1: WHO 2015 Classification
Tumours of the lung

Adenocarcinoma Papillomas
Lepidic adenocarcinoma Squamous cell papilloma
Acinar adenocarcinoma Glandular papilloma
Papillary adenocarcinoma Mixed squamous cell and glandular papilloma
Micropapillary adenocarcinoma Adenomas
Solid adenocarcinoma Sclerosing pneumocytoma
Invasive mucinous adenocarcinoma Alveolar adenoma
Mixed invasive mucinous and non-mucinous adenocarcinoma Papillary adenoma
Colloid adenocarcinoma Mucinous cystadenoma
Fetal adenocarcinoma Mucous gland adenoma
Enteric adenocarcinoma Mesenchymal tumours
Minimally invasive adenocarcinoma Pulmonary hamartoma
Preinvasive lesions Chondroma
Atypical adenomatous hyperplasia PEComatous tumours
Adenocarcinoma in situ Congenital peribronchial myofibroblastic tumour
Squamous cell carcinoma Diffuse pulmonary lymphangiomatosis
Keratinizing Inflammatory myofibroblastic tumour
Non-keratinizing Epithelioid haemangioendothelioma
Basaloid squamous cell carcinoma Pleuropulmonary blastoma
Preinvasive lesion Synovial sarcoma
Squamous cell carcinoma in situ Pulmonary artery intimal sarcoma
Neuroendocrine tumours Pulmonary myxoid sarcoma with EWSR1-CREB1 translocation
Small cell carcinoma Myoepithelial tumours / myoepithelial carcinoma
Large cell neuroendocrine carcinoma Other mesenchymal tumours
Carcinoid tumour Lymphohistiocytic tumours
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia Extranodal marginal zone lymphoma of mucosa associated lymphoid
Large cell carcinoma tissue (MALT lymphoma)
Adenosquamous carcinoma Diffuse large B-cell lymphoma
Sarcomatoid carcinoma Lymphomatoid granulomatosis
Pleomorphic, spindle cell, and giant cell carcinoma Intravascular large B-cell lymphoma
Carcinosarcoma Pulmonary Langerhans cell histiocytosis
Pulmonary blastoma Erdheim-Chester disease
Other and unclassified carcinomas Tumours of ectopic origin
Lymphoepithelioma-like carcinoma Germ cell tumours
NUT carcinoma Intrapulmonary thymoma
Salivary gland-type tumours Melanoma
Mucoepidermoid carcinoma Meningioma
Adenoid cystic carcinoma Metastases to the lung
Epithelial-myoepithelial carcinoma
Pleomorphic adenoma
Tumours of the pleura

Mesothelial tumours Mesenchymal tumours
Diffuse malignant mesothelioma Epithelioid haemangioendothelioma
Epithelioid mesothelioma Angiosarcoma
Sarcomatoid, desmoplastic, and biphasic mesothelioma Synovial sarcoma
Localized malignant mesothelioma Solitary fibrous tumour
Well-differentiated papillary mesothelioma Desmoid-type fibromatosis
Adenomatoid tumour Calcifying fibrous tumour
Lymphoproliferative disorders Desmoplastic round cell tumour
Primary effusion lymphoma
Diffuse large B-cell lymphoma associated with chronic inflammation
98
Tumours of the thymus
Thymomas Lymphomas of the mediastinum
Type A thymoma, including atypical variant Primary mediastinal large B-cell lymphoma
Type AB thymoma Extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT
Type B1 thymoma lymphoma)
Type B2 thymoma Other mature B cell lymphomas
Type B3 thymoma T lymphoblastic leukaemia / lymphoma
Micronodular thymoma with lymphoid stroma Anaplastic large cell lymphoma and other rare mature T- and NK-cell lymphomas
Metaplastic thymoma Hodgkin lymphoma
Other rare thymomas B-cell lymphoma, unclassifiable, with features intermediate between diffuse
Microscopic thymoma large B-cell lymphoma and classical Hodgkin lymphoma
Sclerosing thymoma Histiocytic and dendritic cell neoplasms of the mediastinum
Lipofibroadenoma Langerhans cell lesions
Thymic carcinomas Histiocytic sarcoma
Squamous cell carcinoma Follicular dendritic cell sarcoma
Basaloid carcinoma Interdigitating dendritic cell sarcoma
Mucoepidermoid carcinoma Fibroblastic reticular cell tumour
Lymphoepithelioma-like carcinoma Other dendritic cell tumours
Clear cell carcinoma Myeloid sarcoma and extramedullary acute myeloid leukaemia
Sarcomatoid carcinoma Soft tissue tumours of the mediastinum
Adenocarcinomas Thymolipoma
NUT carcinoma Lipoma
Undifferentiated carcinoma Liposarcoma
Other rare thymic carcinomas Solitary fibrous tumour
Thymic neuroendocrine tumours Synovial sarcoma
Typical and atypical carcinoids Vascular neoplasms
Typical carcinoid Neurogenic tumours
Atypical carcinoid Ganglioneuroma, ganglioneuroblastoma, and neuroblastoma
Large cell neuroendocrine carcinoma Other rare mesenchymal tumours
Small cell carcinoma Ectopic tumours of the thymus
Combined thymic carcinomas Ectopic thyroid tumours
Germ cell tumours of the mediastinum Ectopic parathyroid tumours
Seminoma Other rare ectopic tumours
Embryonal carcinoma Metastasis to the thymus or mediastinum
Yolk sac tumour
Choriocarcinoma
Mature and immature teratoma
Mixed germ cell tumours
Germ cell tumours with somatic-type solid malignancy
Germ cell tumours with associated haematological malignancy
Tumours of the heart

Benign tumours and tumour-like lesions Malignant tumours
Rhabdomyoma Angiosarcoma
Histiocytoid cardiomyopathy Undifferentiated pleomorphic sarcoma
Hamartoma of mature cardiac myocytes Osteosarcoma
Adult cellular rhabdomyoma Myxofibrosarcoma
Cardiac myxoma Leiomyosarcoma
Papillary fibroelastoma Rhabdomyosarcoma
Haemangioma Synovial sarcoma
Cardiac fibroma Miscellaneous sarcomas
Lipoma Cardiac lymphomas
Cystic tumour of the atrioventricular node Metastatic tumours
Granular cell tumour Tumours of the pericardium
Schwannoma Solitary fibrous tumour
Tumours of uncertain behaviour Sarcomas
Inflammatory myofibroblastic tumour Malignant mesothelioma
Paraganglioma Germ cell tumours
Germ cell tumours Metastatic tumours
Teratoma, mature
Teratoma, immature
Yolk sac tumour
99
Appendix 2: International Association for the
Study of Lung Cancer/American Thoracic Society/
European Respiratory Society Classification of
Lung Adenocarcinoma in Resection Specimens
Preinvasive lesions
Atypical adenomatous hyperplasia
Adenocarcinoma in situ (≤3 cm, formerly BAC)
Nonmucinous
Mucinous
Mixed mucinous/nonmucinous
Minimally invasive adenocarcinoma (≤3 cm lepidic predominant tumour with
≤5 mm invasion)
Nonmucinous
Mucinous
Mixed mucinous/nonmucinous
Invasive adenocarcinoma
Lepidic predominant (formerly nonmucinous BAC pattern, with >5 mm invasion)
Acinar predominant
Papillary predominant
Micropapillary predominant
Solid predominant with mucin production
Variants of invasive adenocarcinoma
Invasive mucinous adenocarcinoma (formerly mucinous BAC)
Colloid
Fetal (low and high grade)
Enteric
(BAC = bronchioloalveolar carcinoma)
100
Appendix 2: International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification of Lung Adenocarcinoma in Resection Specimens
Appendix 3: Selected treatment schedules
Non-small cell lung cancer

NON-SMALL CELL LUNG CANCER: STAGE I OR II
Examples of acceptable chemotherapy regimens for adjuvant chemotherapy for stage I or II (goal to complete 4 cycles)
Cisplatin 50 mg/m² i.v. d1 + d15
q 28 d [1, 2, 3, 4, 5, 6]
Vinorelbine 25 mg/m² i.v. d1 + d8 + d15 + d22
OR
Cisplatin 100 mg/m² i.v. d1
q 28 d [1, 2, 3, 4, 5, 6]
Vinorelbine 30 mg/m² i.v. d1 + d8 + d15 + d22
OR
Cisplatin 75-80 mg/m² i.v. d1
q 21 d [1, 2, 3, 4, 5, 6]
Vinorelbine 25-30 mg/m² i.v. d1 + d8
OR
q 28 d [1, 2, 3]
Etoposide 100 mg/m² i.v. d1-3
OR
q 21 d [7]
Gemcitabine 1250 mg/m² i.v. d1 + d8
OR
q 21 d [8]
Docetaxel 75 mg/m² i.v. d1
OR
q 21 d [7] (for non-squamous histologies)
Pemetrexed 500 mg/m² i.v. d1
Patients with comorbidities or patients not able to tolerate cisplatin may alternatively use the following regimen
Carboplatin AUC 6 i.v. d1
q 21 d [9, 10]
Paclitaxel 200 mg/m² i.v. d1
NON-SMALL CELL LUNG CANCER: STAGE III: CONSOLIDATIVE IMMUNOTHERAPY AFTER CHEMO-RADIOTHERAPY
Durvalumab 10 mg/kg i.v. d1 q 2 w (for PD-L1 ≥1%, up to 12 months) [11, 12]
NON-SMALL CELL LUNG CANCER: STAGE IV OR RECURRENT DISEASE: FIRST-LINE CHEMOTHERAPY

Examples of drug regimens, including platinum-based doublets
q 21 d [13, 14]
OR
q 28 d [14]
Gemcitabine 1000 mg/m² i.v. d1 + d8 + d15
OR
q 21 d [15, 16]
OR
q 21 d [8, 14]
OR
q 21 d [14, 17]
Paclitaxel 175-225 mg/m² i.v. d1
OR
q 28 d [18, 19, 20, 21]
Paclitaxel 90 mg/m² i.v. d1 + d8 + d15
OR
Paclitaxel protein bound 100 mg/m² i.v. d1 + d8 + d15
q 21 d [22]
OR
q 21 d [23]
OR
q 21 d [24, 25, 26]
OR
q 28 d [8]
Vinorelbine 25 mg/m² i.v. weekly
OR
q 21 d [15]
Vinorelbine 25 mg/m² i.v. d1 + d8
OR
q 21 d [27]
Vinorelbine 30 mg/m² i.v. d1 + d8
101
NON-SMALL CELL LUNG CANCER: STAGE IV OR RECURRENT DISEASE: FIRST-LINE CHEMOTHERAPY (continued)
Bevacizumab-based chemotherapy for patients who meet eligibility requirements (non-squamous histology, treated brain metastases, no history of haemoptysis)
q 21 d (continue bevacizumab every 21 d after 4-6 cycles are
completed: continue until disease progression) [28, 29]
Bevacizumab 15 mg/kg i.v. d1
OR
q 21 d (continue bevacizumab every 21 d after 4-6 cycles are
completed): continue until disease progression [28]
Bevacizumab 7.5-15 mg/kg i.v. d1
OR
Carboplatin AUC 6 i.v. d1 q 21 d with pemetrexed and bevacizumab continued until disease
Pemetrexed 500 mg/m² i.v. d1 progression (remember folate and B12 supplements along with
dexamethasone premeds for pemetrexed) [30, 31]
Bevacizumab 15 mg/kg i.v. d1
Pemetrexed-based chemotherapy for patients who meet eligibility requirements (non-squamous histology)
Cisplatin 75 mg/m² i.v. d1 q 21 d (remember folate and B12 supplements along with
Pemetrexed 500 mg/m² i.v. d1 dexamethasone premeds for pemetrexed) [32]
OR
Carboplatin AUC 5 i.v. d1 q 21 d (remember folate and B12 supplements along with
Pemetrexed 500 mg/m² i.v. d1 dexamethasone premeds for pemetrexed) [26, 33, 34]
Treatment recommendations for patients with contraindications to carboplatin or cisplatin
q 21 d [35, 36]
OR
Gemcitabine 1000-1200 mg/m² i.v. d1 + d8
q 21 d [27, 37, 38, 39]
Vinorelbine 25-30 mg/m² i.v. d1 + d8
NON-SMALL CELL LUNG CANCER (WILD TYPE): STAGE IV or RECURRENT DISEASE: FIRST-LINE THERAPY
Examples of drug regimen for non-squamous histology (Combination chemotherapy plus immunotherapy)
Cisplatin or 75 mg/m2 i.v. d1 q 21 d (continue pemetrexed + pembrolizumab every 21 d after 4 cycles are
Carboplatin AUC 5 i.v. d1 completed: continue up to a total of 35 cycles or disease progression) [40]
Pemetrexed 500 mg/m2 i.v. d1 q 21 d
Pembrolizumab 200 mg flat dose i.v. d1 q 21 d
OR
Cisplatin or 75 mg/m2 i.v. d1 q 21 d (continue pemetrexed + atezolizumab every 21 d after
Carboplatin AUC 6 i.v. d1 4-6 cycles are completed: continue until disease progression) [41]A
Atezolizumab 1200 mg flat dose i.v. d1 q 21 d
OR
Carboplatin AUC 6 i.v. d1 q 21 d (continue bevacizumab + atezolizumab every 21 d after 4-6 cycles
are completed: continue until clinical benefit) [42]A
Paclitaxel 200 mg/m2 i.v. d1 q 21 d (175 mg/m2 for Asian patients)
Bevacizumab 15 mg/kg i.v. d1 q 21 d
Examples of drug regimen for squamous histology (Combination chemotherapy plus immunotherapy)
Carboplatin AUC 6 i.v. d1 q 21 d (continue pembrolizumab every 21 d after 4 cycles are completed:
continue up to a total of 35 cycles or disease progression) [43]A
Paclitaxel protein bound or 100 mg/m2 i.v. d1 + d8 + d15 q 21 d
Paclitaxel 200 mg/m2 i.v. d1 q 21 d
Pembrolizumab 200 mg flat dose i.v. d1 q 21 d
OR
Carboplatin AUC 6 i.v. d1 q 21 d (continue atezolizumab every 21 d after 4-6 cycles are
completed: continue until clinical benefit) [44]A
Paclitaxel protein bound or 100 mg/m2 i.v. d1 + d8 + d15 q 21 d
Paclitaxel 200 mg/m2 i.v. d1 q 21 d (175 mg/m2 for Asian patients)
Example of drug regimen for NSCLC with TMB ≥10 mutation/Mb (Combination immunotherapy)
Nivolumab 3 mg/kg i.v. d1 q 2 w (continue up to two years or disease progression) [45]A
Ipilimumab 1 mg/kg i.v. d1 q6w
Example of drug regimen for NSCLC with PD-L1 ≥50% (Immunotherapy monotherapy)
Pembrolizumab 200 mg flat dose i.v. d1 q 21 d (continue every 21 d up to two years or disease progression) [46]
Bevacizumab-based chemotherapy for non-squamous histology
Cisplatin 75 mg/m2 i.v. d1 q 21 d (continue bevacizumab+ pemetrexed every 21 d after 4-6 cycles
are completed: continue until disease progression) [47,48]
Bevacizumab 7.5 mg/kg i.v. d1 q 21 d
Examples of drug regimen for squamous histology
Cisplatin 75 mg/m2 i.v. d1 q 21 d SQUIRE (114-115 – 116) (continue necitumumab every 21 d
after 4-6 cycles are completed: continue until disease progression) [49]
Gemcitabine 1250 mg/m2 i.v. d1 q 21 d
Necitumumab 800 mg flat dose i.v. d1 + d8 q 21 d
A
Not EMA approved.
102
NON-SMALL CELL LUNG CANCER: STAGE IV OR RECURRENT DISEASE: EXAMPLES OF SECOND-LINE CHEMOTHERAPY
Docetaxel 75 mg/m² i.v. d1 q 21 d (goal 4-6 cycles) [50, 51, 52, 53, 54]
OR
Pemetrexed 500 mg/m² i.v. d1 (non-squamous q 21 d (goal 4-6 cycles; remember folate and B12 supplements along
histology) with dexamethasone premeds for pemetrexed) [54]
OR
Erlotinib 150 mg PO daily for patients with EGFR mutation or gene amplification; given until
disease progression [7, 17, 55, 56, 57, 58, 59, 60, 61, 62, 63]
Erlotinib alone in second-line and third-line settings remains the standard of care.[64]
NON-SMALL CELL LUNG CANCER (WILD TYPE): STAGE IV or RECURRENT DISEASE: EXAMPLE OF SECOND-LINE REGIMENS
Examples of regimens including immunotherapy
Pembrolizumab 2 mg/kg i.v. d1 q 21 d (for PD-L1 ≥1%, continue until disease progression) [65]
Pembrolizumab 200 mg flat dose i.v. d1 q 21 d [46]
OR
Nivolumab 3 mg/kg i.v. d1 + d15 q 2 w (any PD-L1, continue until disease progression) [66, 67]
Nivolumab 240 mg flat dose i.v. d1 q 2 w [68] (the actual schedule uses)
OR
Atezolizumab 1200 mg flat dose i.v. d1 q 21 d (any PD-L1, continue until disease progression) [69]
Examples of regimen combining chemotherapy with antiangiogenic agents
Docetaxel 75 mg/m2 i.v. d1 q 21 d REVEL (improved efficacy was seen in non-responding patients
to first-line or fast progressing tumours) [70, 71]
Ramucirumab 15 mg/kg i.v. d1 q 21 d
OR
Docetaxel 75 mg/m2 i.v. d1 q 21 d LUME-1 (for adenocarcinoma histology; improved efficacy
was seen in non-responding patients to first-line or fast progressing
tumours) [72,73]
Nintedanib 200 mg PO twice daily q 28 d
OR
Paclitaxel 90 mg/m2 i.v. d1 + d8 + d15 q 28 d (continue both drugs until toxicity or disease progression) [74]A
Bevacizumab 10 mg/kg i.v. d1 + d15 q 28 d
OR
Afatinib 40 mg PO daily q 28 d (for squamous histology; an option for patients unfit for
chemotherapy or immunotherapy) [75]
NON-SMALL CELL LUNG CANCER: STAGE IV OR RECURRENT DISEASE: THIRD-LINE CHEMOTHERAPY

Erlotinib 150 mg PO daily for patients with EGFR mutation or gene amplification; given until disease
progression [7, 17, 55, 56, 57, 58, 59, 60, 61]
NON-SMALL CELL LUNG CANCER (WILD TYPE): STAGE IV or RECURRENT DISEASE: EXAMPLES OF THIRD-LINE REGIMENS
Example of drug regimen after immunotherapy
Docetaxel 75 mg/m2 i.v. d1 q 21 d [8]
Example regimen (prospective trials) for ECOG-PS 0-2 patients treated with immunotherapy
Nivolumab 3 mg/kg i.v. d1 q 2 w [76, 77]
NON-SMALL CELL LUNG CANCER: STAGE IV OR RECURRENT DISEASE: EXAMPLES OF SINGLE-AGENT THERAPY
Paclitaxel 200 mg/m² i.v. d1 q 21 d [78,79]
OR
Docetaxel 35 mg/m² i.v. weekly for 3 wks q 4 wks [36, 50, 53, 80]
OR
Docetaxel 75 mg/m² i.v. d1 q 21 d [50, 51, 52, 53]
OR
Gemcitabine 1000 mg/m² i.v. d1 + d8 + d15 q 4 wks [81, 82]
OR
Gemcitabine 1250 mg/m² i.v. d1 + d8 q 21 d [24, 37]
OR
Vinorelbine 25 mg/m² i.v. weekly [83, 84]
OR
Vinorelbine 30 mg/m² i.v. d1 + d8 q 21 d [36, 85, 86]
OR
Pemetrexed 500 mg/m² i.v. d1 q 21 d [54] (non-squamous histology)
Systemic chemotherapy is not indicated for patients with poor performance status (ECOG 3-4), except for erlotinib in patients who are EGFR-mutation positive. [7]
103
NON-SMALL CELL LUNG CANCER: STAGE IV or RECURRENT DISEASE: FIRST-LINE EGFR-mutated
Examples of drug regimen EGFR TKI in monotherapy
Gefitinib 250 mg PO daily First-generation TKI (given until progression or clinical benefit) [87-92]
OR
Erlotinib 150 mg PO daily First-generation TKI (given until progression or clinical benefit) [93, 94]
OR
Afatinib 40 mg PO daily Second-generation TKI (given until progression or clinical benefit) [95-99]
OR
Dacomitinib 45 mg PO daily Second-generation TKI; in patients without CNS mets (given until
progression or clinical benefit) [100, 101]A
OR
Osimertinib 80 mg PO daily Third-generation TKI, targeting both sensitizing and resistant mutation
(exon 20 T790M ) (given until progression or clinical benefit) [102, 103]
A
Not EMA approved; patients with PS 3 – 4 may also be offered an EGFR TKI.

Examples of drug regimen: combination of chemotherapy + EGFR TKI*
Carboplatin AUC 5 i.v. d1 q 21 d (continue gefitinib daily after 4-6 cycles are completed until
progression or clinical benefit) [104]A
Pemetrexed 500 mg/m2 i.v. d1 q 21 d (remember folate and B12 supplements along with
dexamethasone premeds)
Gefitinib 250 mg PO daily
A
Not EMA approved; *observed worse adverse event included neutropaenia, anaemia, thrombocytopaenia compares to single-agent TKI.

Example of drug regimen: combination of bevacizumab + EGFR TKI
Bevacizumab 15 mg/kg i.v. d1 q 21 d (in these studies patients with CNS mets were excluded) [105-108]
Erlotinib 150 mg PO daily
NON-SMALL CELL LUNG CANCER: STAGE IV or RECURRENT DISEASE: BEYOND FIRST-LINE EGFR-mutated
Examples of drug regimen in pre-treated patients with EGFR TKI agent with exon 20 T790M acquired resistance (around 50% of patients)
Osimertinib 80 mg PO daily (until progression or clinical benefit) [109-111]
Example of drug regimen in pre-treated patients with EGFR TKI agent without exon 20 T790M mutation
Cisplatin 75 mg/m2 i.v. d1 q 21 d (continue with pemetrexed every 21 d until progression) [112]
NON-SMALL CELL LUNG CANCER: STAGE IV or RECURRENT DISEASE: FIRST-LINE ALK-rearranged

Examples of drug regimen with ALK TKI
Crizotinib 250 mg PO BID First-generation TKI (given until progression or clinical benefit) [113-115]
OR
Ceritinib 750 mg PO daily Second-generation TKI (given until progression or clinical benefit) [116]
OR
Ceritinib 450 mg PO daily Second-generation TKI, recommended dose, less toxic with same
efficacy (given until progression or clinical benefit) [117]
OR
Alectinib 300 mg PO BID Third-generation TKI, in Asian patients (given until progression or
clinical benefit) [118]
OR
Alectinib 600 mg PO BID Third-generation TKI, in Caucasian patients (given until progression or
clinical benefit) [119, 120]
OR
Brigatinib 180 mg with a 7-day PO daily
Next-generation TKI (given until progression or clinical benefit) [121]A
run-in at 90 mg
A
Not EMA approved.
104
NON-SMALL CELL LUNG CANCER: STAGE IV or RECURRENT DISEASE: BEYOND FIRST-LINE for ALK-rearranged
Example of drug regimen after first-line chemotherapy
Crizotinib 250 mg PO BID First-generation TKI, after first-line chemotherapy (given until
progression or clinical benefit) [122]
Examples of drug regimen for patients who progressed after first-line crizotinib
Ceritinib 750 mg PO daily Second-generation TKI (given until progression or clinical benefit) [123]
OR
Alectinib 600 mg PO BID Third-generation TKI (given until progression or clinical benefit) [124, 125]
OR
Next-generation TKI (given until progression or clinical benefit) [126]
run-in at 90 mg
OR
Lorlatinib 100 mg PO daily Next-generation TKI (given until progression or clinical benefit) [127-129]
NON-SMALL CELL LUNG CANCER: STAGE IV or RECURRENT DISEASE: BEYOND SECOND-GENERATION RESISTANCE for ALK-rearranged
Examples of drug regimens for patients who progressed after one or more ALK TKI
Next-generation TKI (given until progression or clinical benefit) [126] A
run-in at 90 mg
OR
Lorlatinib 100 mg PO daily Next-generation TKI (given until progression or clinical benefit) [127-129] A
A
Not EMA approved; are recommended if available (e.g. such as compassionate use).
NON-SMALL CELL LUNG CANCER: STAGE IV or RECURRENT DISEASE: ROS1-rearranged

Examples of drug regimens for first-line or pre-treated crizotinib-naïve patients
Crizotinib 250 mg PO BID First-generation TKI (given until progression or clinical benefit) [130-133]
OR
Ceritinib 750 mg PO daily Second-generation TKI (given until progression or clinical benefit) [134]A
Examples of drug regimen for patients treated with crizotinib in first-line
Cisplatin 75 mg/m2 i.v. d1 q 21 d (continue with pemetrexed every 21 d until progression) [130-133]
OR
Lorlatinib 100 mg PO daily Next-generation TKI (ongoing studies) [135]A
A
Not EMA approved.
NON-SMALL CELL LUNG CANCER: STAGE IV or RECURRENT DISEASE: FIRST-LINE BRAF-mutated

Example of drug regimen after BRAF/MEK inhibitors
Dabrafenib 150 mg PO BID BRAF-inhibitor [136-138]
Trametinib 2 mg PO Daily MEK-inhibitor
NON-SMALL CELL LUNG CANCER: STAGE IV or RECURRENT DISEASE: SECOND-LINE BRAF-mutated

Example of drug regimen for treatment-naïve for BRAF-V600E mutation
Cisplatin 75 mg/m2 i.v. d1 q 21 d (continue with pemetrexed every 21 d until progression) [130-131]
Pemetrexed 500 mg/m 2
i.v. d1 q 21 d (remember folate and B12 supplements along with
A
Not EMA approved.
NON-SMALL CELL LUNG CANCER: STAGE IV or RECURRENT DISEASE: Other actionable oncogenic drivers
Example of drug regimen for MET exon 14 mutation (as a resistance mechanism of EGFR or de novo)
Crizotinib 250 mg PO BID First-generation TKI (given until progression or clinical benefit) [139, 140]
Examples of drug regimens for HER2 insertion exon 20 mutation
Afatinib 40 mg PO daily Inhibits EGFR- and HER2-mutant [141]A,B
OR
Poziotinib 16 mg PO daily Next-generation inhibitor of EGFR- and HER2-mutant [142]A,B
OR
Ado-trastuzumab emtansine 3.6 mg i.v. d1 q 21 d targeting HER2-mutation and amplification or protein expression
(TDM1) [143,144]A,B
A
Not EMA approved; B not currently recommended.
Abbreviations: ALK, anaplastic lymphoma kinase; AUC, area under the curve; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth
factor receptor; EMA, European Medicines Agency; HER2, human epidermal growth factor receptor 2; Mb, megabase; PD-L1, programmed death ligand-1, TKI; tyrosine kinase
inhibitor; TMB, tumour mutational burden.
105
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109
SMALL CELL LUNG CANCER: EXAMPLES OF TREATMENT REGIMENS RECOMMENDED FOR LIMITED-STAGE SCLC
Concurrent chemotherapy recommendations with radiation for limited-stage disease
q 21 d for 4 cycles [1]
OR
Cisplatin 25 mg/m² i.v. d1-3
q 21 d for 4 cycles [1, 2, 3]
OR
q 28 d for 4 cycles [4]
OR
Carboplatin AUC 5-6 i.v. d1
q 21 d [5]
Note: Radiotherapy for limited-stage disease should start with cycle 1 or 2 of chemotherapy
SMALL CELL LUNG CANCER: EXAMPLES OF FIRST-LINE CHEMOTHERAPY FOR EXTENSIVE-STAGE DISEASE
Stage IV disease
Cisplatin 60-80 mg/m² i.v. d1
q 21-28 d [6, 7, 8, 9, 10, 11, 12, 13]
Etoposide 80-120 mg/m² i.v. d1-3
OR
q 28 d [13, 14, 15, 16]
Etoposide 80-100 mg/m² i.v. d1-3
OR
q 28 d [8, 11, 12]
Irinotecan 60 mg/m² i.v. d1 + d8 + d15
OR
Cisplatin 30 mg/m² i.v. d1 + d8 (or 80 mg/m² d1)
q 21 d [7, 9]
Irinotecan 65 mg/m² i.v. d1 + d8
OR
q 28 d [14, 16]
OR
q 21 d [17, 18, 19]
Irinotecan 150-200 mg/m² i.v. d1
OR
Cyclophosphamide 800-1000 mg/m² i.v. d1
Doxorubicin 40-50 mg/m² i.v. d1 q 21-28 d [20, 21, 22]
Vincristine 1-1.4 mg/m² i.v. d1
SMALL CELL LUNG CANCER: EXAMPLES OF FIRST-LINE THERAPY FOR EXTENSIVE-STAGE DISEASE
Stage IV disease
Carboplatin AUC 5 i.v. d1 q 21 d (continue with atezolizumab until disease progression or clinical benefit) [23]A
Etoposide 100 mg/m2 i.v. d1,2,3 q 21 d
Atezolizumab 1200 flat dose i.v. d1 q 21 d
A
Not EMA approved.
SMALL CELL LUNG CANCER: EXAMPLES OF SECOND-LINE CHEMOTHERAPY FOR RELAPSED OR REFRACTORY DISEASE
Stage IV disease
Etoposide 50 mg/m² PO daily for 3 wks q 4 wks [24]
OR
Topotecan 2.3 mg/m² PO d1-5 q 21 d [25, 26, 27]
OR
Topotecan 1.5 mg/m² i.v. d1-5 q 21 d [25, 26, 28]
OR
q 28 d [14, 16]
OR
q 21 d [17, 18, 19]
Irinotecan 150-200 mg/m² i.v. d1
OR
q 28 d [29]
OR
q 28 d [8, 12]
OR
Cisplatin 30 mg/m² i.v. d1 + d8 (or 80 mg/m² d1)
q 21 d [7, 9]
Irinotecan 65 mg/m² i.v. d1 + d8
OR
Paclitaxel 80 mg/m² i.v. weekly for 6 wks q 8 wks [30]
OR
Paclitaxel 175 mg/m² i.v. d1 q 3 wks [31]
Abbreviations: AUC, Area under the curve; EMA, European Medicines Agency; SCLC, small cell lung cancer.
110
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3. Daddi N, et al. Eur J Cardiothoracic Surg 2004;26:813-817; 8, 9. Courtesy J. Yao. where they have been unable to trace or obtain permissions and will be glad to
make amendments in future editions.
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Declarations of interest
M-J Ahn: Compensated consultant for AstraZeneca, Boehringer Ingelheim, Lilly, Bristol-Myers Squibb, ONO, Merck,
MSD, Novartis, Takeda, Alpha Pharmaceuticals.
B Besse: Sponsored research at Gustave Roussy Cancer Center, AbbVie, Amgen, AstraZeneca, Biogen, Blueprint
Medicines, Bristol-Myers Squibb, Celgene, Eli Lilly, GSK, Ignyta, Ipsen, Merck KGaA, MSD, Nektar, Onxeo, Pfizer,
PharmaMar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma.
M Bonomi: No conflict of interest.
R Califano: Honoraria for consultancy work from MSD, Bristol-Myers Squibb, Roche, Medimmune/AstraZeneca.
V Calvo: No conflict of interest.
E Capelletto: Advisory boards and consultant activities for Boehringer Ingelheim and AstraZeneca.
GL Ceresoli: Advisory fees: Boehringer Ingelheim, Ipsen, Pfizer; travel expenses: Novocure.
D De Ruysscher: Advisory board for Bristol-Myers Squibb, Merck Serono, Merck/Pfizer, Celgene, Roche/Genentech,
AstraZeneca; industry-funded research for Bristol-Myers Squibb and AstraZeneca.
C Dooms: No conflict of interest.
D Femia: No conflict of interest.
T Finazzi: Advisory board: AstraZeneca.
JF Gainor: Compensated consultant or received honoraria from Bristol-Myers Squibb, Pfizer, Regeneron, Oncorus,
Genentech, Ariad/Takeda, Loxo, Jounce, Agios, Amgen, Incyte, Theravance, Novartis, Merck, Clovis.
M Garassino: Honoraria for speaker, advisory role from: Eli Lilly, Boehringer Ingelheim, Otsuka, Bristol-Myers Squibb,
Celgene, Dephaforum Srl, Takeda; advisory role: Novartis, Pfizer, Inivata; speaker, advisory role, Steering Committee:
MSD, AstraZeneca; speaker: ACCMED, Forum Service Srl, Medscape, McCann Healthcare, S.O.S. Srl, Crems Srl,
Incyte. Institutional financial support for clinical trials (local PI, enrollment in clinical trials): Bristol-Myers Squibb, Roche,
Tiziana Life Sciences, Clovis, Merck Serono, AstraZeneca, Celgene, Otsuka, Bayer, Pfizer, MSD, Eli Lilly, Novartis, Incyte,
AstraZeneca, GlaxoSmithKline S.p.A., Takeda.
L Gianoncelli: Supported by Fondazione Buzzi Unicem, Casale Monferrato (AL), Italy; no conflict of interest.
N Girard: Compensated consultancy and honoraria for lectures for Amgen, AstraZeneca, Boehringer Ingelheim,
Bristol-Myers Squibb, F. Hoffmann-La Roche, Lilly, MSD, Pfizer.
MA Hoda: No conflict of interest.
A Januszewski: No conflict of interest.
W Klepetko: No conflict of interest.
T Klikovits: No conflict of interest.
KHJ Lim: No conflict of interest.
C Merveilleux du Vignaux: No conflict of interest.
S Novello: Speaker bureau for Eli Lilly, MSD, Roche, Bristol-Myers Squibb.
S Peters: Receipt of honoraria or consultation fees: AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim,
Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine,
Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, PharmaMar, Pfizer, Regeneron,
Sanofi, Seattle Genetics, Takeda; gave talks in a company-organised public event: AstraZeneca, Boehringer Ingelheim,
Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Illumina, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi, Takeda;
receipt of grants/research support: (sub)investigator in trials (institutional financial support for clinical trials) sponsored by
Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche, Illumina,
Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer.
S Popat: Compensated consultant to AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology,
Eli Lilly, Guardant Health, MSD, Novartis, Pfizer, Roche, Takeda.
114
M Provencio: Honoraria for consultancy work from MSD, Bristol-Myers Squibb, Roche, Medimmune/AstraZeneca.
S Pusceddu: No conflict of interest.
M Reck: Honoraria for lectures and consultancy: Lilly, Roche, AstraZeneca, MSD, Merck, Bristol-Myers Squibb,
Boehringer Ingelheim, Celgene, Novartis, Pfizer.
N Reinmuth: Personal fees (speakers and consulting honoraria): Bristol-Myers Squibb, F. Hoffmann-La Roche, Lilly,
Novartis, Boehringer Ingelheim, AstraZeneca, Amgen, Pfizer, MSD.
S Senan: Departmental research grants: Varian Medical Systems, ViewRay Inc., AstraZeneca; advisory boards:
AstraZeneca, Celgene, Varian Medical Systems, MSD.
RA Stahel: Honoraria as a consultant at advisory boards from: AbbVie, AstraZeneca, Boehringer Ingelheim,
MSD, Pfizer, Roche, Takeda; honoraria as a speaker from: AstraZeneca, Boehringer Ingelheim, MSD, Roche;
data monitoring committee: Roche and Takeda; financial support of ETOP trials (President and Scientific Chair):
AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech, MSD, Roche, Pfizer.
G Veronesi: Honoraria from AB Medica SpA, Medtronic, Verb Medica.
A Warth: No conflict of interest.
115
Index
Note: Abbreviations used in the index are listed on page x
A second-generation, 60–61, 104, 105

ABCP regimen, advanced NSCLC, 67, 102 third-generation, 61, 104, 105
ABL gene, 62 see also crizotinib
acetylcholine receptors, 7 mutations, 24, 58, 60, 93, 104–105
antibodies, 80 diagnostic assays, 60
acinar growth pattern, 21 features associated, 60
ACP regimen, advanced NSCLC, 67, 102 G1202R, 61
addiction to tobacco products, 7 resistance mutations, 60, 61
adenocarcinoma, lung, 3, 21 alopecia, 36
biomarkers, 12 ALTA-1L study, 61
centrally located, 21 altiratinib, 92
development steps, 8 alveolar duct, 4
diagnosis by low-dose CT, 9 alveolus, 4
gender, prevalence, 3, 5 AMG208, 92
gene mutations and amplifications, 23, 58, 60, 62, 90 amrubicin, 87
HER2 gene (exon 20), 90 anaplastic lymphoma kinase (ALK) see ALK gene
HER2 trans-membrane domain, 91 anethole dithiolethione, 8
high somatic mutational burden, 64 anetumab ravtansine, 77
histochemistry, 22 anti-4-1BB monoclonal antibodies, 95
histomorphological growth patterns, 21 anti-angiogenesis, 48
IASLC/ATS/ERS classification, 100 mesothelioma treatment, 77
immune checkpoint inhibitor therapy, 42, 102 NSCLC treatment, 103
immunohistochemistry, 22 thymic malignancies, 81
invasive mucinous, 93 see also bevacizumab
lymph node metastases, growth patterns, 21 anti-CTLA-4 see CTLA-4 (cytotoxic T-lymphocyte antigen 4)
metastatic, second-line therapy with nintedanib, 48, 103 anti-HGF antibodies, 92
in never-smokers, 3, 5 anti-MET antibodies, 92
pathogenesis, 4 anti-PD-1 see nivolumab; pembrolizumab
precursor lesions, 8, 21 anti-PD-L1 see atezolizumab; avelumab; durvalumab
prevention, aspirin with, 8 anti-VEGF antibody, 42
staging, by PET, 16 anti-VEGFR2 antibody, 48
staining of biopsy material, 20, 22 antibodies, 22
terminal respiratory units, 21 in combination with first-line chemotherapy, 45
WHO classification, 98 lineage-specific, 22
adenocarcinoma in situ (AIS) antigen-presenting cells (APCs), 65, 95
preinvasive, 8 antigens, detection, 22
sublobar resection, 26 AP32788 (EGFR/HER2 inhibitor), 92
adenosquamous carcinoma, lung, 21 apatinib, 62
Adjuvant Lung Cancer Project (Italy), 38 apoptosis, 4, 94
Adjuvant Navelbine International Trial Association, 38 ARCHER trial, 58
adjuvant therapy see chemotherapy (ChT) ARCTIC study, 71
ado-trastuzumab emtansine (T-DM1), 90, 105 aromatic amines, in cigarette smoke, 5
ADOC regimen, 81 arsenic, 5
adrenal metastasis, 14, 18 Asian countries/people
stage IV NSCLC, 30 EGFR gene mutations, 58
adrenocorticotropic hormone (ACTH), 83, 84 lung cancer prevalence, 5
afatinib, 90 SCLC first-line treatment, 51
NSCLC, 58, 90, 105 tegafur-uracil adjuvant therapy in NSCLC, 40
CD75-NRG fusions, 93 aspirin, 8
EGFR exon 20 insertions, 58, 92, 104 asymptomatic pulmonary lesions, 15
HER2 exon 20 mutations, 90, 105 atelectasis, 83
HER2 TMD mutations, 91 atezolizumab, 65
metastatic NSCLC, 58 advanced NSCLC, 67, 68
second-line in advanced NSCLC, 48, 103 first-line therapy, 67, 68, 102
age at diagnosis, lung cancer, 3 schedules, 102, 103
air pollutants, lung cancer risk factor, 5 second-line therapy, 69, 103
AKT1 gene mutation, 23 adverse events, 67, 68, 69
alectinib, 60, 61, 104, 105 disseminated SCLC, 51, 87, 110
ALEX study, 61 PD-L1 expression level in NSCLC and, 67, 69, 70
ALK gene, 24, 60 atypical adenomatous hyperplasia, 8
inhibitors, 60, 93, 104–105 autoantibodies, 12
first-generation (crizotinib), 60, 104, 105 autofluorescence bronchoscopy, 16
resistance, 60, 61 autoimmune disorders, 80, 81
avelumab, 65
116
Index
in mesothelioma, 77 bronchial epithelial cells, 8
AXL gene, 62 bronchiolar cells, exocrine, 21
bronchioles, 4
bronchoalveolar carcinoma, 8
B bronchoscopic laser excision, 84
basal cells, 4
bronchoscopy
4-1BB (CD137), 95, 96
autofluorescence, 16
BCP regimen, immune checkpoint blockade with, 67, 102
neuroendocrine tumours, 84
behavioural support, smoking cessation, 7
video (standard white light), 16
benzene, 5
bronchus, 4
beta-carotene, 8
cell types, 4
bevacizumab, 42
stem cells (putative), 4, 21
adverse effects, 45
budesonide, 8
mesothelioma, 77
bupropion, 7
metastatic NSCLC, 45, 102, 103
ChT with/without, 45, 102
contraindications, 45 C
EGFR-mutated, 42, 104 c-met amplification, 58, 59, 92
immune checkpoint blockade with, 67, 102 C-reactive protein (CRP), 8
schedule, 102, 103 CA184-041 study, 70
neuroendocrine tumours, 85 CA184-156 study, 87–88
Big Lung Trial, 38 cabozantinib, 62, 92, 93
bilobectomy, stage I/II NSCLC, 16, 26 CALGB 9633 study, 39
bioactive amines, hypersecretion, 83 calretinin, 75
biological impact, of minimal invasive lobectomy vs open surgery, 27 canakinumab, 8
biomarkers, lung cancer, 12, 20 CAP regimen, 81
gene, 23 capecitabine, 85
see also specific genes capmatinib, 92
immunohistochemistry and, 22 CAR T cell therapy, 64, 96
PD-L1 expression, 70 targets in solid tumours, 96
prevalence, ADC growth patterns, 21 Carbo-Px regimen, 81
biopsy, lung cancer diagnosis, 18 carboplatin, 34
amount of material for study, 20 advanced/metastatic NSCLC, 44, 45
cytology and histology, 20 CTLA-4 blockade in, 70, 71
endobronchial, 18 EGFR-mutated, 104
endoscopic, 18 first-line therapy, 45, 101, 102
examination, 20 immune checkpoint blockade with, 67, 68, 102
image-guided percutaneous core needle, 18 regimens/schedules, 101, 102, 104
repeat, in NSCLC disseminated SCLC, 51, 87, 110
for ALK-resistance, 59, 61 second-line therapy, 110
for EGFR TKIs, 58, 59 limited-stage SCLC, 110
surgical, 18, 80 locally advanced NSCLC, 34
transbronchial, 18 malignant pleural mesothelioma, 77
bismuth, 5 NSCLC stage I/II, schedule, 101
bleeding, 26, 33, 45 NSCLC stage IV/recurrent disease, 101, 102, 104
blood tests, lung cancer biomarkers, 12 preoperative vs adjuvant, early NSCLC, 41
blood–brain barrier, 59, 60 resected stage IB NSCLC, 39
BLU-667, 62 thymic malignancies, 81
Blueprint PD-L1 IHC Assay Comparison Project, 70 toxicity, 51
BMS-986016, 95 carcinogens
bone-marrow depression, 36 inhaled, lung cancer risk, 4
BRAF gene mutation, 23, 58, 62, 105 in tobacco smoke, 5
V600E, 62, 105 carcinoid syndrome, 84
brain metastasis carcinoid tumours, 21
disseminated SCLC, 52, 55 atypical, 83, 84
asymptomatic, 52 chemotherapy, 85
symptomatic, 52 survival rate, 84
osimertinib activity against, 59 multifocal lesions (bronchopulmonary), 84
Pancoast tumours, 29 thymic, 79
risk reduction in limited-stage SCLC, 36 typical, 83, 84
solitary, stage IV NSCLC, 30 chemotherapy, 85
stereotactic radiotherapy, 33 survival rate, 84
break-apart probes, 24 see also neuroendocrine tumours (lung origin)
brigatinib, 60, 61, 104, 105 carcinoma in situ (CIS), 8
117
Index
carriers (gene), lung cancer susceptibility, 4 combination immunotherapy vs/with, 70, 71, 102
CD5, 79 combination surgery with, 30
CD19, 96 cycle number, optimal, 44
CD28, 65, 96 extending ChT, adverse effects, 44
CD40, 95 first-line ChT, 44, 101–102
CD56, 22 first-line ChT, combination antibodies with, 45
CD74-NRG fusions, 93 first-line ChT, progression and docetaxel/pemetrexed, 47
CD75-NRG fusions, 93 first-line ChT, progression and erlotinib, 47
CD80 (B7-1), 65, 95 first-line ChT, progression and nintedanib, 48
CD86 (B7-2), 65, 95 immune checkpoint inhibitors with/vs, 66, 67, 68, 102, 103
CD117, 79 treatment-naïve, immune checkpoint inhibitors vs, 66
CD137 (4-1BB), 95, 96 perioperative, in NSCLC, 38–39
celecoxib, 8 preoperative, in NSCLC, 40
cell blocks, 20 primary, in thymic malignancies, 81
centromere probe, 24 radiotherapy with see chemoradiotherapy (CRT)
ceritinib, 60, 104, 105 resistance, identification, 41
cetuximab, 45 SCLC, 50–57, 110
CheckMate 017 study, 68 chemosensitivity, 51
CheckMate 026 study, 66 disseminated disease, first-line therapy, 36, 51–52, 110
CheckMate 032 study, 87 disseminated disease, second-line treatment, 53
CheckMate 057 study, 69 drugs used, 50, 87, 110
CheckMate 227 study, 71 immunotherapy with, 51, 87
CheckMate 331 study, 87 limited stage disease, 54, 110
chemoprevention, lung cancer, 8 schedules, 110
phase II trials, 8 in superior vena cava syndrome, 52
phase III trials, agents used in, 8 toxicity, 51
chemoradiotherapy (CRT) thymic malignancies, 80, 81
induction, stage III NSCLC, 28, 101 see also cisplatin
locally advanced NSCLC, 33, 34 chest pain, 14, 80
immunotherapy concurrent, 69 chest X-ray, 9
neoadjuvant, Pancoast tumours, 29 asymptomatic pulmonary lesion, 15
recurrent lung cancer after, 30 lung cancer screening, 9
SCLC, 50 low-dose CT vs, 10
limited-stage, 33, 36, 110 Pancoast tumours, 29
localised, 54 for radiotherapy, 32
stage III NSCLC (N2-positive), 28, 101 chimeric antigen receptor (CAR) T cell therapy, 64, 96
thymic malignancies, 81 chromium, 5
toxicities, 34, 36 chromogenic in situ hybridisation (CISH), 22, 24
chemotherapy (ChT) chromogens, 22
adjuvant, 38–43, 101–102 chromogranin A, 22, 84, 85
bevacizumab with, 42, 45, 102 chromosomal rearrangements detection, 23, 24
biomarker for benefits, 41 see also gene mutations
immunotherapy with, 42, 102 chronic obstructive pulmonary disease (COPD), 5, 7, 34, 35
localised SCLC, 54 chylothorax, 26
NSCLC, 38, 39, 101–102 cigarette smoking see smoking
NSCLC, stage IA, 40, 101 ciliated cells, 4
preoperative vs, in NSCLC, 41 circulating tumour DNA (ctDNA), 61
compliance, preoperative ChT, 41 cisplatin, 34
EGFR TKIs vs in NSCLC, 58 adjuvant, in NSCLC, 38, 39
malignant pleural mesothelioma, 76, 77 disseminated SCLC
neoadjuvant etoposide with, in SCLC, 50, 51, 53, 110
adjuvant ChT vs in NSCLC, 41 irinotecan with, 51, 110
indicative of benefits of adjuvant ChT, 40 second-line therapy, 53, 110
lung-sparing surgery and, 41 topotecan with, 52
mesothelioma, 76 etoposide with, in SCLC, 50, 51, 54, 110
NSCLC, 28, 40–41 localised SCLC, 54, 110
Pancoast tumours, 29 malignant pleural mesothelioma, 77, 88
stage III NSCLC, 28 metastatic NSCLC, 44, 102
neuroendocrine tumours (lung), 85 atezolizumab with/without, 67
NSCLC bevacizumab with/without, 45, 102
schedules, by disease stage, 101–104 immune checkpoint inhibitors with or vs, 66
NSCLC, metastatic, 44 pemetrexed maintenance therapy after, 46
adverse events, 66-68 schedules, 101, 102, 104, 105
second-line therapy after progression, 47
118
Index
NSCLC stage I/II, 39 desmin, 79
schedule, 101 DETERMINE study, 88
NSCLC stage IV/recurrent, schedule, 101, 102, 104, 105 developed countries, lung cancer incidence, 2
perioperative, in NSCLC, 38, 39 diagnosis, lung cancer, 14–19
vinorelbine with, 38 brain metastases at, 52
thymic malignancies, 81 cytology and histology, 20
toxicity, vs carboplatin, 51 with delay, screening-detected cancer, 11
clinical features future perspectives, 12
lung cancer, 3, 14–15 histochemical, 22
Pancoast tumours, 29 histological, 18
malignant pleural mesothelioma, 75 histopathology, 21
thymic malignancies, 80 immunohistochemical, 22
clinical TNM staging, 15 lung cancer stage, 3, 20
CMF therapy, 38 elderly, 3
computed tomography (CT) ethnicity and, 3
cone-beam, 32, 35 screening aim, 9
contrast-enhanced, N-descriptor, TNM staging, 17 molecular, 23–24
4-dimensional (respiration-correlated), RT planning, 32 staging see staging of lung cancer
low-dose see low-dose CT (LDCT) see also screening
mesothelioma staging, 75 diagnosis, malignant pleural mesothelioma, 75
neuroendocrine tumours, 84 diagnosis, thymic malignancies, 79, 80
nodal/extranodal disease detection, 16 diaphragmatic paralysis, 14
non-calcified solitary pulmonary nodule, 15 DNA
NSCLC, 26 adducts, 4
stage III, 28 tumour, cell-free circulating, 12
for radiotherapy delivery, 32 extraction, 23
spiral multi-detector, 9, 16 hyper-methylation, 12
CONVERT study, 56 mutations, 23
cooking vapours, lung cancer and, 5 probes, 24
COSMOS risk model, 11 repair, 4
cough, 14, 75, 80 assays, risk modelling and, 11
counselling, psychosocial, 7 sequencing, 23
cranial magnetic resonance imaging (MRI), 16 docetaxel
crizotinib, 60, 61, 62, 92 adverse events, 68
resistance, 60 metastatic NSCLC, 44, 103
schedule, 104, 105 dose, 47
CRP (C-reactive protein), 8 first-line therapy, 101, 102
cryobiopsy, 18, 20 nintedanib or ramucirumab with, 48
cryosections, 20 second-line therapy, 47, 48, 103
CTLA-4 (cytotoxic T-lymphocyte antigen 4), 64, 95 second-line therapy, atezolizumab vs, 69
inhibitors/mAbs, 65 second-line therapy, nivolumab vs, 68, 69
in NSCLC, 70–71, 102 third-line therapy, 103
tremelimumab, 65, 71, 88 NSCLC stage I/II, schedule, 101
see also ipilimumab NSCLC stage IV/recurrent, schedules, 101, 102, 103
role, 65, 95 doxorubicin
Cushing syndrome, 84 carcinoid tumours, 85
cyclophosphamide in SCLC, 50, 110
SCLC, 50, 110 second-line therapy, 53
disseminated, vs etoposide–cisplatin, 50, 51 thymic malignancies, 81
second-line therapy, 53 DREAM trial, 88
thymic malignancies, 81 DS-6051b, 93
cytisine, 7 durvalumab, 34, 65
cytokeratin 5/6, 22 advanced NSCLC, tremelimumab with, 71
cytokine release syndrome (CRS), 96 adverse events, 69
cytology of lung cancer, 20 locally advanced NSCLC, 34, 69, 101
cytotoxic T-lymphocyte antigen 4 (CTLA-4) see CTLA-4 mesothelioma, 88
PD-L1 expression level in NSCLC and, 70
stage III NSCLC treatment schedule, 101
D dysphagia, 14
dabrafenib, 62
dysplasia, 8, 21
dacomitinib, 58, 90, 104
dyspnoea, 14, 75, 80
DCC-2701, 93
dendritic cells (DCs), 65
119
Index
E ERBB family, 90
early stage lung cancer erlotinib, 42, 46, 58
diagnosis at, percentage, 3 metastatic NSCLC
surgery, 12 EGFR-mutated, 42, 58, 104
see also specific cancer types maintenance therapy, 46
Eastern Cooperative Oncology Group (ECOG), 38 second-line therapy, 47, 48, 103
EBUS-controlled transbronchial needle aspiration (EBUS-TBNA), 18 third-line therapy, 103
EGFR (epidermal growth factor receptor), 90 resistance, EGFR-mutant NSCLC, 58, 92
antibodies/inhibitors ethnic factors, lung cancer diagnosis, 3
adverse effects, 45 etoposide, 34
EGFR/HER2 inhibitor (AP32788), 92 NSCLC, 34, 38
first-/second-generation TKIs, 58 stage I/II, schedule, 101
multikinase inhibitors, 62 SCLC, 50, 51, 87, 110
second-line therapy, 47 extensive-stage disease, 51, 87, 110
squamous NSCLC, 45 localised disease, 54, 110
third-generation TKIs, 59 second-line therapy, 53, 110
see also afatinib; erlotinib; gefitinib thymic malignancies, 81
EGFR sensitising aberrations, NSCLC, 58, 59 etretinate, 8
expression by squamous NSCLC, 45, 47 Europe
gene mutations, 23, 42, 58, 59 disseminated SCLC therapy, 51
C797S, 59 lung cancer and low-dose CT screening, 10
exon 19 and L858R (exon 21), 47, 58 lung cancer mortality, 2
exon 20 insertions, 90, 92 malignant pleural mesothelioma diagnosis, 75
first-/second-generation TKIs targeting, 58 European Thoracic Oncology Platform (ETOP), 90
frequency in NSCLC, 58 EURTAC trial, 58
NSCLC, adjuvant ChT, 42 everolimus, 81, 85
NSCLC, second-line therapy response, 42, 47 excision repair cross-complementation group 1 (ERCC1) enzyme, 41
NSCLC treatment schedules, 103, 104 external beam radiotherapy see radiotherapy (RT)
T790M, 59 extrapleural pneumonectomy (EPP), 76
targeted therapy in NSCLC, 58–59
third-generation TKIs, 59 F
TKI resistance, 23, 58, 59 familial factors, lung cancer pathogenesis, 4
wild-type, maintenance therapy in NSCLC, 46 FDG (fluorodeoxyglucose), 16, 17, 28, 56, 84
Elastica van Gieson (EvG) stain, 20, 22 see also positron emission tomography (PET)
elderly fenretinide, 8
lung cancer diagnosis, 3 FGFR1 inhibitors, 24
malignant pleural mesothelioma, 75 fibroblast activation protein (FAP), 96
stereotactic ablative radiotherapy, 35 fibroblast growth factor receptor (FGFR), inhibition, 48, 62
emerging targets/agents in lung cancer, 90–97 fibroblast growth factor receptor 1 (FGFR1), gene amplification, 24
see also NSCLC, drugs in development fibrosis, radiation, 34
emibetuzumab, 92 ficlatuzumab, 92
emphysema, 9, 11 field cancerisation, 21
endobronchial biopsy, 18 FLEX trial, 45
endobronchial staging, 16 FLT3 gene, 62
endobronchial ultrasound (EBUS), 17 fluorescent in situ hybridisation (FISH), 22, 24, 42, 60
endocrine features, paraneoplastic syndrome, 14 5-fluorouracil, 85
endoscopic biopsy, lung cancer diagnosis, 18 fluticasone, 8
endoscopic-guided fine needle aspiration (EUS-FNA),18 folate, 8, 102, 103, 104, 105
endoscopic ultrasound (EUS), 17 follow-up, 15
endosonography, 17 after CRT in locally advanced NSCLC, 34
entrectinib (RXDX-101), 93 after SABR, 35
environmental tobacco smoke exposure, 5 extensive-disease SCLC, 36
EORTC, RT for localised SCLC, 56 4-1BB (CD137), 95, 96
epacadostat (Incyte), 94 forceps biopsy, 18, 20
epidemiology of lung cancer, 1–2 fusion strategy, in situ hybridisation, 24
Asian countries, 5
Europe and worldwide, 2
in non-smokers, 3, 5 G
risk modelling and, 11 gefitinib
USA, 1 in NSCLC, 58, 104
epidermal growth factor receptor (EGFR) see EGFR resistance, EGFR-mutant NSCLC, 58, 92
epirubicin, SCLC, disseminated, vs etoposide/cisplatin, 51 gemcitabine
epithelial mesenchymal transition (EMT), 58 cisplatin with, in metastatic NSCLC, 44, 45
mesothelioma, 77
120
Index
metastatic NSCLC, 44, 101, 102, 103 immunotherapy and, 71
bevacizumab with, 45, 102 metastatic, ALK rearrangement with, 60
NSCLC stage I/II, schedule, 101 metastatic, first-line ChT and, 44, 45
NSCLC stage IV/recurrent, schedules, 101, 102, 103 metastatic, second -line ChT and, 48
gender thymic malignancies, 79
adenocarcinoma (lung) prevalence, 3 histomorphological changes, 20, 22
lung cancer diagnosis, age at, 3 histomorphological growth patterns, 21
lung cancer incidence, 1 histopathology of lung cancer, 20–22
lung cancer mortality histotypes, lung cancer, 3, 5, 21
Europe, 2 in never-smokers, 3, 5
USA, 1 hoarseness, 14
mesothelioma mortality, 75 Horner’s syndrome, 14, 29
smoking prevalence, 1 host susceptibility, to lung cancer, 4
gene amplification, 23, 24 human epidermal growth factor receptor 2 (HER2) gene see HER2 gene
MET gene, 58, 59, 92 Hungary, lung cancer incidence, 2
in NSCLC see NSCLC hydroxyindoleacetic acid (HIAA), 84
gene mutations hypercholesterolaemia, 61
detection, 23 hypertriglyceridaemia, 61
lung ADC, 23
NSCLC see under NSCLC
see also individual genes
I
IALT (International Adjuvant Lung Cancer Trial), 38, 39
gene of interest, 24
I-ELCAP study, 9
gene rearrangements, 24
IDO (indoleamine 2,3-dioxygenase), 94
gene translocation, 24
inhibitors, 94
general secretory pathway (GSP), 90
overexpression, immune tolerance, 94
genetic factors
IFCT-0002 study, 41
lung cancer pathogenesis, 4
ifosfamide, thymic malignancies, 81
lung cancer risk factor, 5
iloprost, 8
genomic alterations, 4, 23
image-guided percutaneous core needle biopsy, 18
lung adenocarcinoma, 23
immune adjuvant, 95
germ cell tumours, 80, 98, 99
immune checkpoint(s), 64
golvatinib, 92
binding to receptors, self-tolerance, 65
Grays (Gy), 33
role, 65
ground-glass opacity, 15, 26
immune checkpoint inhibitors, 34, 42, 64, 65
growth patterns, lung adenocarcinoma, 21
chemotherapy with, 66, 67, 102
locally advanced NSCLC, consolidative treatment with, 34
H mesothelioma treatment, 77, 88
haematological toxicity, 34 SCLC, 87–88
haematoxylin–eosin (HE) stain, 20, 22, 23 second-line in advanced NSCLC, 103
haemoptysis, 14, 45 toxicity, 67
‘hallmark of cancer’, 64 treatment-naïve advanced NSCLC, 66–68, 102
heart, tumours, WHO classification, 99 see also CTLA-4 (cytotoxic T-lymphocyte antigen 4); PD-1 (programmed
hepatocyte growth factor (HGF), 92 cell death protein 1); PD-L1 (programmed death-ligand 1); specific
HER2 gene, 90 agents
amplification, 58 immune evasion by cancer cells, 64, 65, 94
mutations, 23, 58 immune system/response, 64, 65
exon 20 mutations, 90, 92 IDO overexpression effect, 94
G660D in exon 17, 91 immune tolerance, 64, 94
kinase domain, 91 immunoediting, 64
in NSCLC, 23, 58, 90, 91, 92 immunohistochemistry (IHC), 22
trans-membrane domain (TMD), 91 ALK gene rearrangements, 60
V659E, 91 direct and indirect methods, 22
hereditary factors, lung cancer pathogenesis, 4 NSCLC, 22
HGF, antibodies, 92 PD-L1 expression assay, 70
high-risk patients, low-dose CT screening, 10 subtyping, 20
histochemistry, 22 thymic malignancies, 79
histology, 20 immunophenotyping, 22
bronchi (normal), 4 immunosuppression, 64
diagnosis of lung cancer, 18, 20 immunosurveillance, 64
malignant pleural mesothelioma, 75 immunotherapy, 64–72
neuroendocrine tumours, 83 NSCLC, 42, 64–72
NSCLC SCLC, 87–88
adjuvant ChT and, 39, 40 thymic malignancies, 81
121
Index
see also CTLA-4 (cytotoxic T-lymphocyte antigen 4); immune checkpoint kynurenine pathway, 94
inhibitors; NSCLC (non-small cell lung cancer)
IMP321, 95
IMpower 130 study, 67
L
LAG-3 (lymphocyte-activation gene 3), 95
blockade, 95
LAG-3Ig fusion protein (IMP321), 95
LAG525, 95
lapatinib, 91
in situ hybridisation (ISH), 24
large cell carcinoma, lung, 21
incidence
prevalence, 3
lung cancer
large cell neuroendocrine tumours (LCNEC) see neuroendocrine tumours
Europe, 2
(lung origin)
gender and, 1, 2, 3
laser excision, bronchial NETs, 84
USA, 1
lead-time bias, 10
malignant pleural mesothelioma, 75
lenvatinib, 62
neuroendocrine tumours (lung origin), 83
lepidic growth pattern, 21
Pancoast tumours, 29
Li-Fraumeni syndrome, 91
indoleamine 2,3-dioxygenase (IDO) see IDO (indoleamine 2,3-dioxygenase)
lineage of neoplastic cells, 22
induction treatment
linear accelerator (LINAC), 32, 35
NSCLC, immunotherapy as, 42
lobectomy
stage I/II NSCLC, surgery after, 27
minimal invasive, in NSCLC, 27
stage III NSCLC, 28
neuroendocrine tumours, 84
thymic malignancy, 81
stage I/II NSCLC, 26, 27
intensity-modulated radiotherapy (IMRT), malignant pleural mesothelioma,
minimal invasive surgery vs, 27
76
preoperative ChT and, 41
interferon (IFN), 65
sleeve lobectomy, 27
interferon-γ (IFN-γ), 65
stage III NSCLC, 28
interleukin-1 beta inhibitor, 8
locoregional failure, of SABR, 35
interleukin-2 (IL-2), 65
lorlatinib, 61, 105
International Adjuvant Lung Cancer Trial (IALT), 38, 39
adverse effects, 61
International Agency for Research on Cancer (IARC), carcinogens in tobacco
low-dose CT (LDCT)
smoke, 5
no-contrast, limitations, 9
International Association for the Study of Lung Cancer (IASLC)
over-diagnosis of lung cancer, 11
adenocarcinoma classification, 100
false-positives/negatives, 11
lymph node map, 17
performance and risk modelling, 11
intracranial hypertension, 52
risk modelling and, 11
intratumoural cavitation, 30
risks, 11
ipilimumab, 65
screening for lung cancer, 9
advanced NSCLC
cancer mortality reduction, 9, 10
combination therapy, 71
chest X-ray vs, 10
schedules, 102
guidelines, 10
squamous cell, 70
randomised studies, 10
treatment-naïve, nivolumab with, 71
volume doubling time of lung cancer, 11
mesothelioma, 77, 88
LOXO-101, 93
recurrent NSCLC, schedules, 102
LOXO-292, 62
safety profile, 87
LUME-Meso study, 77
SCLC, 87
lung adenocarcinoma see adenocarcinoma, lung
irinotecan, disseminated SCLC, 51, 110
Lung Adjuvant Cisplatin Evaluation (LACE), 38, 39
IUNO trial, 46
lung biopsy see biopsy
lung cancer
J advanced stage, diagnosis at, percentage, 3
J-ALEX study, 61 chemoprevention, 8
Japanese patients, adjuvant ChT in stage I NSCLC, 40 clinical features, 3, 14–15
JBR.10 trial, 38, 39 diagnosis, 14-19
epidemiology, 1–2, 5
immune system and, 64
K non-small cell see NSCLC
KEYNOTE-010 study, 68
pathogenesis, 4
prevention, 7–8
risk factors, 5
screening, 8–11
smallcell see SCLC (small cell lung cancer)
KIT gene, 62
staging, 15–17
KRAS gene mutation, 23
122
Index
survival expectancy, 3, 9 second-line, 77, 88
WHO classification, 98 TNM staging, 75
see also specific topics/cancers MAPK activation, 59
lung neuroendocrine tumours see neuroendocrine tumours (lung origin) MAPS2 study, 77, 88
lung nodules MARS trial, 76
benign vs malignant, 9 Masaoka–Koga staging, 79, 81
detection by CT, 9 Mayo Lung Project, 9
indeterminate, low-dose CT screening, 11 mediastinal lymph nodes
non-calcified solitary pulmonary nodule (SPN) 15 dissection, lobectomy with, 26
over-diagnosis by low-dose CT, 11 false-positive/negative PET, 17
peripheral, low-dose CT detection, 9 lymphadenectomy in NSCLC, 26
small/PET-negative, management, 12 NSCLC
lung resection see resections, lung postoperative radiotherapy, 41
LUX-Lung 3 and LUX-Lung 6 trials, 58 stage III, 28
Lyell’s syndrome, 81 staging, endosonography, 17
lymph node dissection, 12 surgical staging, 17
neuroendocrine tumours, 84 mediastinal masses, anterior, 80
NSCLC stage I and II, lobectomy with, 26 differential diagnosis, 80
lymph node involvement see also thymic malignancies
ADC growth patterns, 21 mediastinum, anterior, epithelial tumours see thymic malignancies
detection by CT, 16, 17 MEK inhibitor, 62
detection by PET, 16 MEK1 gene, 58
IASLC node map, 17 MESOT-TREM-2008 trial, 88
mediastinal see mediastinal lymph nodes MESOT-TREM-2012 trial, 88
neuroendocrine tumours, 83, 84 mesothelin, 77, 96
lymphadenectomy, mediastinal, in NSCLC, 26 mesothelioma see malignant pleural mesothelioma (MPM)
lymphocyte-activation gene 3 (LAG-3) see LAG-3 MesoVATS trial, 76
MET gene, 62
antibodies and agents targeting MET, 92
M copy number gain, 58, 59, 92
MAGE-A3 antigen-specific vaccine, 42
MET pathway
magnetic resonance imaging (MRI)
agents in development targeting, 92
brain, 16
dysregulation in lung cancer, 92
crizotinib resistance in NSCLC, 60
meta-analyses
extensive-disease SCLC, 36
addition of thoracic RT to ChT in localised NSCLC, 54
surveillance, for brain metastases in SCLC, 52
ChT in metastatic NSCLC, 44
maintenance therapy
effect of adjuvant treatment with UFT plus surgery vs surgery alone, 40
localised SCLC, 51, 54
effect of daily aspirin on long-term risk of cancer death, 8
NSCLC, 46, 47
IPD study on preoperative ChT, 40
continuous maintenance, 46
video-thoracoscopic screening in lung cancer, 12
see also NSCLC
metastases
switch maintenance, 46
after SABR for early-stage NSCLC, 35
major histocompatibility complex (MHC), 65, 95
brain see brain metastasis
malignant pleural effusion (MPE), in NSCLC, 30
distant
malignant pleural mesothelioma (MPM), 75–78
detection by PET, 16
biphasic, 75
symptoms, 14
clinical presentation, 75
lung cancer, survival rate, 3
epithelioid, 75
lymph nodes, 21
histological subtypes, 75
neuroendocrine tumours, 83, 84, 85
immune checkpoint blockade, 77, 88
NSCLC see NSCLC, metastatic
incidence, 75
SABR treatment, 35
multimodality treatment, 76
SCLC see SCLC, disseminated
pathology, 75
vertebral, palliative radiotherapy, 33
PD-1/PD-L1 inhibitor therapy, 77, 88
see also Tumour, Node, Metastasis (TNM) staging
prognostic factors, 75
MGCD265, 92
radiotherapy, 76
MGCD516, 93
response assessment, RECIST method, 75
microdissection, for molecular diagnosis, 23
sarcomatoid, 75
micropapillary growth pattern, 21
surgery, 76
minimal invasive thoracic surgery
survival
in NSCLC, 27
after ChT, 77
talc pleurodesis, 30
after immunotherapy, 77, 88
mitomycin, 38
after surgery, 76
mitotic index, 83
systemic treatment, 77
123
Index
mobilisation of patients, 27 WHO classification, 83, 98
molecular changes, 20 see also carcinoid tumours
molecular diagnosis, 23–24 neurological features, paraneoplastic syndrome, 14
monoclonal antibodies, 64, 65 neuron-specific enolase (NSE), 85
see also specific drugs neurotransmitters, 7
morbidity neutropaenia, 45
after lobectomy in NSCLC, 26, 27 never-smokers, lung cancer histotype/prevalence, 3, 5
after salvage resection for recurrent lung cancer after CRT, 30 next generation sequencing (NGS), 23, 60
extrapleural pneumonectomy, 76 NIBIT-MESO-1 trial, 88
mortality, cancer-related (all cancer), 1, 2 NICHE trial, 90
lung cancer percentage, 1 nicotine, 7
malignant pleural mesothelioma, 75, 76 nicotine receptor partial agonists, 7
mortality of lung cancer nicotine replacement therapy (NRT), 7
after pneumonectomy, stage III NSCLC, 28 nintedanib, 48, 77, 103
Europe, 2 N-nitrosamines, in cigarette smoke, 5
reduction by low-dose CT screening, 10 nivolumab, 65
sleeve lobectomy in NSCLC, 27 adverse events, 66, 68, 87
USA, 1 LAG525 with (melanoma), 95
mTOR inhibitor, 85, 93 mesothelioma, 77, 88
mucous cells, 4 NSCLC
multi-tyrosine kinase inhibitor, 48, 62 advanced, schedules, 102, 103
multikinase inhibitors (MKIs), 62 advanced, second-line therapy, 68, 69, 103
multiple endocrine neoplasia type 1 (MEN-1), 83 advanced, third-line therapy, 103
musculoskeletal features, paraneoplastic syndrome, 14 advanced, treatment-naïve, 66, 102
mutational burden, of tumours, 64, 70, 71 CTLA-4 blockade with, 71, 102
malignant pleural mesothelioma, 77 PD-L1 expression level and, 66, 68, 69, 70, 71
SCLC, immunotherapy, 87 perioperative, 42
myasthenia gravis, 80, 81 SCLC, 87
myo-inositol, 8 nodules, lung see lung nodules
MYSTIC study, 71 non-calcified solitary pulmonary nodule (SPN), 15
non-small cell lung cancer see NSCLC (non-small cell lung cancer)
NRAS gene mutation, 23
N NRG1 fusions, 93
nab-paclitaxel, in metastatic NSCLC, 67, 68
NSCLC (non-small cell lung cancer), 21
napsin A, 22
adenocarcinoma see adenocarcinoma, lung
National Lung Screening Trial (NLST), USA, 10
adjuvant therapy
natural killer (NK) cells, 94
chemotherapy, 38–41, 101–102
NCT02000947 study, 71
non-ChT approaches, 42
necitumumab, 45, 102
ALK gene rearrangements, 24, 60
needle core biopsy, 18, 20
ALK inhibitor therapy, 60–61, 104–105
NEJ002 trial, 58
BRAF gene mutations, 23, 58, 62, 105
NELSON study, 10, 11
CAR T cell therapy, 64, 96
neoadjuvant chemotherapy see chemotherapy (ChT)
centrally located, parenchyma-sparing sleeve resection, 27
neoantigens, 64, 65
chemotherapy
neratinib, 90
adjuvant, 38–41, 101–102
neuroendocrine cells, 4
combination immunotherapy vs, 71
neuroendocrine tumours (lung origin), 83–86
crizotinib therapy, comparisons, 60
clinical presentation, 83
first-line treatment, schedules (by stage), 101–102
histology, 21, 83
HER2 expression and, 90
immunohistochemistry, 22, 84
immune checkpoint inhibitors vs, 66, 68
incidence, 83
immune checkpoint inhibitors with, 66, 67, 68, 102
investigations, 84
neoadjuvant, 28, 40–41
large cell, 21, 79, 83, 84
number of cycles, 38–39
survival rate, 84
pembrolizumab vs, 66
metastatic, 83, 84, 85
perioperative, 38–39
nodal status, 83
preoperative, 40
pathology, 83
second-line regimens, 103
prognostic factor, 83
third-line regimens, 103
small cell see SCLC
CNS relapse, crizotinib and, 60
staging, 84
cT1N0M0, sublobar resection, 12
surgery, 84
CTLA-4 blockade, 70–71, 102
survival, 83, 84, 85
drugs in development, targets, 90–97
systemic treatment, 84, 85
4-1BB (CD137), 95
thymic, 79, 99
CAR T cells, 96
124
Index
EGFR exon 20 insertions, 92 continuous maintenance therapy, 46
HER2 exon 20 mutations, 90, 105 EGFR wild-type, maintenance therapy, 46, 103
HER2 trans-membrane domain mutations, 91 first-line ChT, 44, 101–102
IDO, 94 first-line ChT with antibodies, 45, 102
LAG-3, 95 immune checkpoint blockade, 66–68, 102
MET copy number gain, 92, 105 immune checkpoint inhibitors see above
NRG1, 93 maintenance therapy, 46, 67
NTRK1-3, 93 nintedanib response, 48
TRK fusions, 93 oncogene-addicted, 58–63
early-stage second-line therapy, 47–48, 103
recurrences after SABR, 35 second-line therapy vs erlotinib maintenance therapy, 46
stereotactic ablative radiotherapy, 12, 33, 35 second-line therapy with antibodies, 48, 103
EGFR TKI therapy, responses, 42, 58, 90, 103, 104 switch maintenance therapy, 46
first- vs second-generation TKIs, 58 targeted therapy see targeted therapy (below)
resistance development, 58, 59, 105 multiple synchronous, in smokers, 21
third-generation TKIs, 59, 90 N2-positive disease, treatment, 28
gene mutations and amplifications, 23, 47, 58, 59, 62 oligometastatic disease, treatment, 30, 35
CD74-NRG fusions, 93 palliative treatment, 30
EGFR C797S, 59 Pancoast tumours see Pancoast tumours
EGFR gene, 23, 47, 58, 59, 90, 92 PD-L1 expression see PD-L1
EGFR gene (exon 19 and 21), 47, 58 perioperative therapy, 38–39
EGFR gene (exon 20 insertions), 90, 92 recurrent
HER2 gene (kinase domain), 23, 58, 90, 91, 105 docetaxel with/without nintedanib, 48
HER2 trans-membrane domain (TMD), 91 first-line ChT schedule, 101
MET amplification, 92, 105 treatment schedules, 102–105
NTRK1-3 genes, 93 somatic mutational burden, 64
RET gene, 23, 58, 62 squamous see squamous cell carcinoma, lung
ROS1 gene, 23, 24, 58, 62, 105 stage I, 26
T790M and EGFR TKI resistance, 58, 59 minimal invasive surgery, 27
TRK fusions, 93 perioperative ChT, 38, 39
see also ALK gene; EGFR surgery, 26, 27
heterogeneity/molecular subsets, 58 tegafur-uracil adjuvant therapy, 40
high mutational burden, 64, 70 treatment schedule, 101
histotypes, 3, 21 stage IA
immune checkpoint(s), 65, 66 adjuvant ChT, 38, 39, 40
immune checkpoint blockade, 102, 103 mortality risk after resection, qPCR identification, 41
atezolizumab, 67, 68, 69, 102 preoperative ChT, 41
bevacizumab, 67 surgery, 27
chemotherapy vs, 66, 68 stage IB
chemotherapy with, 66, 67, 68, 102 adjuvant ChT, 38, 39
durvalumab, 69, 70, 71, 101 mortality risk after resection, qPCR identification, 41
durvalumab and CTLA-4 blockade, 71 paclitaxel/carboplatin ChT, 39
nivolumab, 66, 68, 69, 71, 102, 103 preoperative ChT, 41
nivolumab and CTLA-4 blockade, 71, 102 stage II, 26
pembrolizumab, 66, 67, 68, 102 adjuvant ChT, 38, 39, 40
stage IV/recurrent disease, 102, 103 minimal invasive surgery, 27
toxicities, 66, 67, 68, 69 perioperative ChT, 38, 39
treatment-naïve advanced NSCLC, 66–68 preoperative ChT, 41
immunotherapy, 64–72, 102, 103 surgery, 26, 27, 40
advanced squamous NSCLC, 70 treatment schedule, 101
CTLA-4 blockade, 70–71, 102 stage III, 28
CTLA-4 blockade and immune checkpoint inhibitor, 70–71, 102 adjuvant ChT, 38, 39
immune checkpoint blockade see above N2-positive, treatment, 28
locally advanced NSCLC, 69 perioperative ChT, 38, 39
second-line therapy, 68–69, 103 planning CT for radiotherapy, 32
treatment-naïve advanced NSCLC, 66–68, 71 surgery, 28
locally advanced, 28, 69 treatment schedule, 101
chemoradiotherapy, 33, 34 unresectable, immunotherapy, 69
immunotherapy, 69 stage IIIB
malignant pleural effusion, 30 first-line ChT, 44
MET copy number gain, 92 first-line ChT with antibodies, 45
MET-directed therapy, 92, 105 maintenance therapy, 46
metastatic, treatment, 44–49 second-line therapy, 47–48
ChT dose, 38
125
Index
stage IV, 30 O
ALK-rearranged, 104–105 OAK study, 69
BRAF-mutated, regimens, 105 occupational exposures, lung cancer risk factor, 5
EGFR-mutated, regimens, 104 octreotide, 81
first-line ChT, 44, 101 long-acting release (LAR), 85
first-line ChT with antibodies, 45, 102 oesophagitis, 34, 36, 56
maintenance therapy, 46 onartuzumab, 92
oncogenic drivers, regimens, 105 oncogenes, 4, 58
ROS1-rearranged, 62, 105 OPTIMAL trial, 58
second-line therapy, 47–48, 103 osimertinib, 59
single-agent therapy, 103 EGFR exon 20 insertions NSCLC, 92, 104
surgery, 30 EGFR mutation and MET amplification, 92
third-line regimens, 103 resistance, 59, 92
see also NSCLC, metastatic over-diagnosis of lung cancer, 10, 11
surgery, 26–31
5-year survival, 27
adjuvant ChT vs, 41 P
cisplatin-based perioperative therapy, 38 p40, 22
locally advanced disease, CRT vs, 34 p63, 22
minimal invasive thoracic surgery, 27 PACIFIC study, 69
mortality risk after, qPCR identification, 41 paclitaxel
preoperative ChT vs, 41 CTLA-4 blockade with in NSCLC, 70
stage I, 26, 27, 40 HER2 V659E mutation and, 91
stage II, 26, 27 locally advanced setting, chemoradiotherapy in, 34
stage III, 28 metastatic NSCLC, 44, 45, 101, 102, 103
stage IV, 30 immune checkpoint blockade with, 67, 68
timing of ChT after, 38 NSCLC stage I/II, 101
surgical staging, 26 NSCLC stage IV/recurrent disease, 101, 102
survival first-line therapy, 101, 102
adjuvant ChT benefit, 38, 39 second-line therapy, 103
erlotinib adjuvant therapy, 42 resected stage IB NSCLC, 39
first- vs second-generation EGFR TKIs, 58 SCLC, relapsed/refractory, 110
immune checkpoint inhibitor therapy, 66–69 thymic malignancies, 81
locally advanced, after CRT, 34 palliative radiotherapy
metastatic, after ChT, 44 NSCLC, 32, 33
metastatic, after ChT and bevacizumab, 45 SCLC, 36, 50
metastatic, maintenance therapy, 46 palliative surgery, stage IV NSCLC, 30
metastatic, second-line therapy, 47 pan-TRK inhibitors, 93
oligometastatic NSCLC, 30 Pancoast syndrome, 14, 29
perioperative ChT benefit, 38, 39 Pancoast tumours, 29
postoperative radiotherapy after surgery, 41 anterior vs posterior, surgery, 29
preoperative ChT, 40 clinical features, 29
second-line immunotherapy, 68–69 incidence, 29
stage IA, 38 treatment and prognosis, 29
stage IA, minimal invasive lobectomy, 27 pancytokeratin, 79
stage IB, 39 papillary growth pattern, 21
stage III, neoadjuvant therapy and surgery, 28 paraffin-embedded tissue, 20
stage IIIA, 38 paraneoplastic syndrome, symptoms, 14
stage IV, salvage resection, 30 passive smoking, 5
targeted therapy pathogenesis of lung cancer, 4
ALK inhibitors, 60–61 pathological response, definition, 42
for BRAF mutations, 62 pathology, 20
EGFR TKIs, 48, 58–59, 90, 92 lung cancer, 20–22
multikinase inhibitors, targets, 62 malignant pleural mesothelioma, 75
for RET mutations, 62 neuroendocrine tumours (lung), 83
for ROS1 rearrangements, 62 thymic malignancies, 79
see also drugs in development targeting (above) see also histology
TKI sensitivity, 59, 90 PD-1 (programmed cell death protein 1), 64, 65
see also adenocarcinoma, lung; squamous cell carcinoma, lung inhibitors/mAbs, 42, 64, 65, 70
NTRK1 gene, 58, 93 LAG-3-directed therapy with, 95
NTRK2 gene, 93 in mesothelioma, 77
NTRK3 gene, 93 see also nivolumab; pembrolizumab
LAG-3 co-expression, 95
role, 65
126
Index
PD-L1 (programmed death-ligand 1), 64, 65 pneumocytes
assays, 70 type I, 4
as biomarker, 70 type II, 4, 21
expression in NSCLC, 64, 65, 66, 67, 68, 69, 70, 71 pneumonectomy
as biomarker for immunotherapy, 70 avoidance in neuroendocrine tumours, 84
CTLA-4 blockade and nivolumab, 70 extrapleural, 76
heterogeneity, 70 stage I/II NSCLC, 26, 27
nivolumab second-line therapy and, 68, 69 preoperative ChT and, 41
pembrolizumab therapy, 66, 68 stage III NSCLC, 28
inhibitors/mAbs, 34, 42, 64, 65, 66 pneumonia, 83
in mesothelioma, 77 pneumonitis, radiation, 34, 36, 56
in NSCLC see NSCLC (non-small cell lung cancer), immune polonium, 5
checkpoint blockade polycyclic aromatic hydrocarbons (PAHs), 5
in SCLC, 87–88, 110 polymerase chain reaction (PCR), 23
see also atezolizumab; avelumab; durvalumab mutation analysis methods, 23
role, 65, 95 quantitative, NSCLC at risk of mortality after surgery, 41
in SCLC, 87–88, 110 ponatinib, 62
disseminated, with carboplatin-etoposide, 51 POPLAR study, 69
pembrolizumab response, 88 positron emission tomography (PET), 11, 15
PD-L2 (programmed death-ligand 2), 65 neuroendocrine tumours, 84
PE regimen, 81 staging of lung cancer, 16
pembrolizumab, 65, 66 false-negative findings, 17
adverse events, 66, 67, 88 N-descriptor, 17
ChT with, or compared to, 66, 67 positron emission tomography-CT (PET-CT), 11
epacadostat with in NSCLC, 94 radiotherapy in localised SCLC and, 56
in mesothelioma, 77 stage III NSCLC, 28
NSCLC (advanced) staging of lung cancer, 16, 84
second-line therapy, 68, 103 N-descriptor, 17
treatment-naïve (first-line), 66, 67, 102 postoperative complications
NSCLC stage IV/recurrent, schedule, 102, 103 lobectomy in NSCLC, 26
PD-L1 expression level in NSCLC and, 66, 67, 68, 70 minimal invasive vs open lobectomy, 27
SCLC after ChT, 88 postoperative radiotherapy (PORT) see radiotherapy (RT)
pemetrexed poziotinib, 105
cisplatin or carboplatin with, in locally advanced NSCLC, 34 precursor lesions, lung adenocarcinoma, 8, 21
cisplatin with, in metastatic NSCLC, 44, 46, 105 preoperative work-up, stage I/II NSCLC, 27
atezolizumab with/without, 67 prevention of lung cancer, 7–8
continuous maintenance therapy, 46 PROFILE 1001 study, 62
third-generation EGFR TKI vs, 59 PROFILE 1014 study, 60
EGFR-mutated metastatic NSCLC, 104 prognostic factors
first-generation ALK inhibitor vs, 60 lung adenocarcinoma growth pattern, 21
malignant pleural mesothelioma, 77, 88 lung cancer stage (TNM), 15
NSCLC stage I/II, schedule, 101 malignant pleural mesothelioma, 75
NSCLC stage IV/recurrent, schedule, 102, 103, 104 neuroendocrine tumours, 83
pembrolizumab with, NSCLC, 66 Pancoast tumours, 29
second-line therapy in metastatic NSCLC, 47 thymic malignancies, 79, 81
periodic acid-Schiff (PAS) stain, 20, 22 programmed cell death protein 1 (PD-1) see PD-1
perioperative therapy, NSCLC, 38–39 programmed death-ligand 1 (PD-L1) see PD-L1
peripheral neuropathy, 61 programmed death-ligand 2 (PD-L2), 65
pharmacotherapy, smoking cessation, 7 PROMID trial, 85
PIK3CA gene mutation, 23, 58 prophylactic cranial irradiation (PCI), 36
PIT trial, 76 adverse effects, 36
plasma genotyping, 59 in disseminated SCLC, 52
platelet-derived growth factor receptor (PDGFR), inhibition, 48, 62 hippocampus avoidance, 56
platinum-based ChT in localised SCLC
NSCLC see carboplatin; cisplatin after ChT and RT, 55
SCLC, 87 after surgery, 54
pleura, EvG staining, 22 standard vs higher dose, 56
pleural effusion, malignant timing, 55
mesothelioma, 75, 76 neurocognitive impairment after, 55
NSCLC, 30 proteinuria, 45
pleural node/mass, biopsy, 18 psychosocial counselling, 7
pleural tumours, WHO classification, 98 pulmonary adenocarcinoma see adenocarcinoma, lung
pleurectomy/decortication (P/D), 76 pyrosequencing, 23
PLX7486, 93
127
Index
Q salvage resection for, 30
quality of life SCLC, 53, 56
impaired, extended ChT in metastatic NSCLC, 44 thymic malignancies, treatment, 81
impaired, malignant pleural effusion, 30 resections
PCI adverse effect, 36 malignant pleural mesothelioma, 76
pembrolizumab in advanced NSCLC, 66 Pancoast tumours, 29
thymic malignancies, 79, 80
resections, lung, 12
R localised SCLC, 54
RADIANT-4 trial, 85 neuroendocrine tumours, 84
RADIANT study, 42 parenchyma-sparing sleeve, 27
radiation fibrosis, 34 salvage, stage IV NSCLC, 30
radiation pneumonitis, 34, 36, 56 sleeve, neuroendocrine tumours, 84
radiography see chest X-ray specimen, histology, 20
radiotherapy (RT), 32–37 stage I and II NSCLC, 26
chemotherapy with see chemoradiotherapy (CRT) cisplatin-based perioperative therapy, 38
chest stage III NSCLC, 28
disseminated SCLC, 52 cisplatin-based perioperative therapy, 38
localised SCLC, 54, 55 stage IV NSCLC, 30
conformal techniques, 81 sublobar, 12, 26
curative, 4-dimensional CT for, 32 Response Evaluation Criteria in Solid Tumours (RECIST), 75
dose coverage, 32 RET gene mutation, 23, 58, 62
dose-fractionation schemes, 33 13-cis-retinoic acid, 8
elective nodal irradiation, localised SCLC, 56 retinyl palmitate, 8
external beam, 32 REVEL trial, 48
image-guided, 32 rilotumumab, 92
NSCLC risk factors
locally advanced, 34 lung cancer, 5
postoperative, 41 modifiable, for lung cancer, 5
stage III, planning CT for, 32 screening for high-risk patients, 10
palliative, 33 risk modelling, lung cancer, 11
extensive-disease SCLC, 36 risk prediction models, 11
postoperative RNA probes, 24
mesothelioma, 76 robotic-assisted thoracic surgery (RATS), stage I/II NSCLC, 27
NSCLC, 41 robotic surgery, 12
thymic malignancies, 81 ROS1 gene mutation, 23, 24, 58, 62
prophylactic, in mesothelioma, 76 NSCLC treatment, 62, 93, 105
prophylactic cranial irradiation see prophylactic cranial irradiation (PCI)
SCLC, 36, 50–57
disseminated disease, 52 S
limited-stage disease, 33, 36 SABR see stereotactic ablative radiotherapy (SABR)
localised disease, 54, 55, 56 salivary gland tumours, 21
modified vs conventional RT, 56 Sanger sequencing, 23
schedule, 56 sarcomatoid carcinoma, 21
toxicity, 55, 56 SCLC (small cell lung cancer), 21, 50–57, 83
treatment time and dose, 55, 56 brain metastases, 52, 55
stereotactic ablative (SABR) see stereotactic ablative radiotherapy frequency, 55
(SABR) surveillance for and PCI, 52
thymic malignancies, 80, 81 WBRT and ChT, 52
treatment plan, 32 chemosensitivity, 51, 53
localised SCLC, 56 chemotherapy, 36, 50–57, 110
whole-brain, 33 immunotherapy with, 87
disseminated SCLC, 52 clinical presentation, 50
radon, 5 disseminated
ramucirumab, 48, 103 brain metastases, management, 52
rapamycin, 85, 93 brain metastases, prevention, 52, 55
rational tissue processing, 20 first-line treatment, 51–52, 110
RECIST method, 75 immunotherapy, 87–88
recurrence MRI surveillance, 52
lung cancer platinum derivative with etoposide, 51
after SABR for eary-stage NSCLC, 35 prophylactic cranial irradiation, 52
after sublobar resection vs lobectomy in AIS, 26 relapse after first-line ChT, 53, 87, 88
local, after CRT in locally advanced NSCLC, 34 second-line treatment, 53, 87, 88, 110
NSCLC see NSCLC (non-small cell lung cancer) early stage, 54
128
Index
extensive-disease, treatment, 36, 110 smoking
immunotherapy, 87–88, 110 cessation
histology, 83 benefits, 7
immunotherapy, 87–88 low-dose CT screening and, 10
after chemotherapy, 87, 88 methods, success and symptoms, 7
chemotherapy with, 87, 110 in survivors of limited-stage SCLC, 36
immune checkpoint blockade, 87–88, 110 diseases related, low-dose CT detection, 9
investigations, 84 lung cancer histotype, 3
limited-stage (stage I–III) lung cancer mortality association, 1, 2
chemotherapy with radiotherapy, 33, 36, 50, 110 lung cancer pathogenesis, 4, 21
cisplatin/etoposide with RT, 50 lung cancer risk factor, 5
second lung cancer after, 36 prevalence, decline, 1
treatment regimens, 110 SCC pathogenesis, 21
localised, treatment, 54–56, 110 solid growth pattern, 21
concurrent ChT and RT, 54 solitary brain metastasis (SBM), in stage IV NSCLC, 28
maintenance therapy, 54 solitary pulmonary nodule (SPN), 50
radiotherapy, 54, 55, 56 non-calcified, 15
recurrence frequency after RT, 56 soluble LAG-3 (sLAG-3), 95
RT timing after ChT, 55 somatic mutational burden, 64
surgery, 54 somatostatin analogues, 85
metastatic (stage IV), 50 somatostatin receptor scintigraphy, 84
neuroendocrine nature, 79, 83 sputum screening, 9
pathogenesis, 4 squamous cell carcinoma, lung, 21
radiotherapy, 36, 50–57 advanced, immunotherapy, second-line, 68
localised disease, 54, 55, 56 biomarkers, 12
localised disease, schedule, 56 CTLA-4 blockade therapy, 70
palliative, 50 development steps, 8
refractory, 53, 110 EGFR expression, 45
relapse, 53 FGFR1 gene amplification, 24
immunotherapy after, 87, 88 high somatic mutational burden, 64
sensitive vs resistant, 53 histopathology, 21
treatment, 53, 110 immune checkpoint inhibitor therapy, 42, 66
stage I (solitary nodule), 50 immunohistochemistry, 22
staging, 84 metastatic
surgery, 50, 54 first-line ChT and bevacizumab, 45
survival, 84 second-line therapy, 47, 48
after first-line therapy, 51, 52 pathogenesis, 4, 21
brain metastases, 52, 55 precursor lesions, 8
chemotherapy and radiotherapy, 50 prevalence, 3
ChT with immunotherapy, 87 WHO classification, 98
disseminated, first-line therapy, 51, 52 squamous cell carcinoma, thymic, 79
limited-stage SCLC after CRT, 36 squamous metaplasia, 21
localised disease, 54 SQUIRE trial, 45
PCI benefit, 55 staging of lung cancer, 15–17
by TNM stage, 54 bronchoscopy, 16
TNM stages, 54 CT and MRI scans, 16, 17
transformation, EGFR TKI resistance, 58, 59 endobronchial, 16
screening for lung cancer, 8, 9, 14 endosonography, 17
benefits, 9, 12 intraoperative, 26
biomarkers, 12 N-descriptor, 17
low-dose CT see low-dose CT (LDCT) PET scans, 16, 17
risks, 11 surgical, of NSCLC, 26
segmentectomy, lung, 26 T-descriptor, 16
selenium, 8 Tumour, Node, Metastasis (TNM) staging, see TNM staging
self-tolerance, 65 staining, biopsy material, 20, 22
semi-quantitative assessment, adenocarcinoma, 21 stem cells, 4, 21
shoulder pain, 14, 29 stereotactic ablative radiotherapy (SABR), 12, 33, 35
sleeve lobectomy, 27 cone-beam CT with, 35
sleeve resection, 27, 84 early-stage NSCLC, 12, 33, 35
small cell lung cancer see SCLC (small cell lung cancer) in elderly, 35
SMART trial, 76 increasing use in USA by year, 35
smoke, tobacco, carcinogens in, 5 ‘risk adapted’ dosing schemes, 35
toxicity, 35
129
Index
sternotomy, 80 chemoradiotherapy, 81
streptozotocin, 85 chemotherapy, 81
stridor, 14 postoperative radiotherapy, 81
‘suicide gene’, 96 thymic malignancies, 79–82
sunitinib, 62, 81 chemotherapy, 80, 81
superinfection, 30 classification, 79
superior pulmonary sulcus tumours (SSTs) see Pancoast tumours clinical features, 80
superior vena cava syndrome, 14, 52 diagnosis, 80
surgery differential diagnosis, 80
early stage cancer, after screening, 12 epithelial, 79, 80
future perspectives, 12 immunotherapy, 81
less extensive lung resections, 12 Masaoka–Koga staging, 79, 81
lung biopsy, 18 pathology, 79
malignant pleural mesothelioma, 76 prognostic factors, 79, 81
mediastinal nodal staging, 17 radiotherapy, 80, 81
minimal invasive thoracic, stage I/II NSCLC, 27 recurrence, treatment, 81
NSCLC see NSCLC resection, prognosis, 79
Pancoast tumours, 29 surgery, 80
SCLC, 50 TNM staging, 79
localised disease, 54 treatment, 80
spiral contrast-enhanced multi-detector CT benefit, 16 WHO classification, 99
thymic malignancies, 79, 80 thymoma, 79, 81
video-thoracoscopic vs open thoracotomy, 12 chemotherapy, 81
see also specific procedures (e.g. lobectomy) diagnosis and immunological check-up, 80
survival subtypes, 79, 99
carcinoid tumours, 84 thyroid transcription factor 1 (TTF1), 22
lung cancer, 3, 9 tisagenlecleucel, 96
malignant pleural mesothelioma, 76, 77, 88 tivantinib, 92
neuroendocrine tumours, 83, 84, 85 TNM staging, 15
NSCLC see NSCLC (non-small cell lung cancer) lung cancer
Pancoast tumours, 29 endobronchial lesions, 16
prediction, lung adenocarcinoma growth pattern, 21 N-descriptor, CT and PET-CT, 17
SCLC see SCLC (small cell lung cancer) T-descriptor, methods, 16
switch maintenance, 46 time point for evaluation, 15
symptoms of lung cancer, 14 malignant pleural mesothelioma, 75
synaptophysin, 22 NSCLC
6th vs 8th edition, ChT and, 39
8th edition, 15, 39
T Pancoast tumours, 29
T cell(s), 65
thymic malignancies, 79
activation, 64, 65, 95
tobacco consumption, global, 2
4-1BB upregulation, 95
tobacco dependence, 7
anergy, 65
tobacco smoke
CAR-modified, 64, 96
carcinogens in, 5
CD8+ cytotoxic, 65
see also smoking
effector (Teff), 67
topoisomerase I enzyme, 51
immature (TdT), 79
topotecan
LAG-3 blockade effect, 95
disseminated SCLC, 52, 87, 110
regulatory, CTLA-4 on, 65
resistant relapse in SCLC, 53, 110
suppression, IDO overexpression, 94
trametinib, 62, 105
T cell immunoglobulin and mucin domain 3 (TIM-3), 95
transbronchial lung biopsy, 18
T cell receptor (TCR), 65, 95
trastuzumab, 90
talc pleurodesis, 30, 76
treatment of lung cancer see specific cancers, treatment modalities
targeted therapy, metastatic NSCLC see NSCLC (non-small cell lung cancer)
treatment plan, 32
tegafur-uracil (UFT), 40
tremelimumab, 65, 71, 88
temozolomide, 85
TRK (tropomyosin receptor kinase) inhibitors, 93
tepotinib, 92
TRKA-C proteins, 93
thoracic pain, 75
tropomyosin receptor kinase (TRK), 93
thoracotomy
tryptophan, 94
muscle-sparing anterolateral, 26
TSR-011, 93
muscle-sparing posterior, 26
tumour-associated antigens, 65
open, video-thoracoscopy vs, 12
tumour biological behaviour, 21
thymectomy, 80
tumour infiltrating lymphocytes, 95
thymic carcinoma, 79, 99
Tumour, Node, Metastasis (TNM) staging see TNM staging
130
Index
tumour suppressor genes, 4 W
tunnelled pleural catheters (TPCs), 30 wedge resection, stage I/II NSCLC, 26
tyrosine kinase inhibitors (TKIs), 42, 48, 90 weight loss, 14
ALK TKIs, 60, 61 wheezing, 14, 83
first-generation EGFR, 58 whole-brain radiotherapy (WBRT), disseminated SCLC, 52
HER2 mutations, 90 WJTOG-3405 trial, 58
multi-kinase MET TKIs, 92 World Health Organization (WHO)
pan-HER irreversible, 90, 92, 93 2015 classification, 98–99
see also afatinib lung cancer mortality, 2
resistance, 23, 58, 59 neuroendocrine tumours (lung) classification, 83
second-generation EGFR, 58 thymic malignancy classification, 79
selective MET TKIs, 92
third-generation EGFR, 59
treatment schedules in stage IV NSCLC, 104, 105
U
ultrasound
endobronchial, 17
endoscopic, 17
uracil, tegafur with, 40
urelumab, 95
USA
disseminated SCLC therapy, 51
lung cancer incidence and mortality, 1
lung cancer mortality reduction by low-dose CT, 10
lung cancer stage at diagnosis, 3
smoking cessation methods, 7
survival rates, 3
USA National Lung Screening Trial (NLST), 10
utomilumab, 95
V
vandetanib, 54, 62
varenicline, 7
vascular endothelial growth factor (VEGF), 42
vascular endothelial growth factor receptor (VEGFR), antibodies/inhibitors,
48, 62
vemurafenib, 62
vertebral body, involvement, Pancoast tumours, 29
vertebral metastases, palliative radiotherapy, 33
video-assisted thoracoscopic surgery (VATS), 17, 18
mesothelioma staging, 75
stage I/II NSCLC, 27
video bronchoscopy, staging of lung cancer, 16
video thoracoscopy, open thoracotomy vs, 12
videomediastinoscopy, 17
vincristine
SCLC, disseminated, 110
second-line therapy, 53
thymic malignancies, 81
vinorelbine
mesothelioma, 77
NSCLC
cisplatin with, 34, 38
stage I/II, schedule, 101
stage IV/recurrent disease, 101, 102, 103
vinyl chloride, 5
VIP regimen, 81
vitamin B12, 8
vitamin E, 8
volatile compounds, in breath, 12
volume doubling time (VDT), 9, 11
software-calculated, NELSON study, 11
131
Index
www.esmo.org www.esmo.org
Rolf A. Stahel · Solange Peters · Marina Garassino

edited by
Rolf A. Stahel
THORACIC TUMOURS THORACIC TUMOURS Solange Peters

Marina Garassino
SECOND EDITION
E S S E N T I A L S forC L I N I C I A N S SECOND EDITION
THORACIC TUMOURS
edited by
Rolf A. Stahel
Solange Peters
Marina Garassino
Thoracic Tumours: Essentials for Clinicians
is intended primarily to be read by young oncologists
(residents at the beginning of their career) and provides the reader
with the essential information or ‘What every oncologist
SECOND EDITION
should know’. In addition to more common cancers such as
non-small cell lung cancer, the title also discusses rarer tumour types,
such as extragonadal germ cell tumours. This second edition includes
new chapters on targeted therapy for oncogene-addicted tumours and
immunotherapy for advanced NSCLC. In addition
to the essentials, the book also introduces more advanced
knowledge for those who wish to explore the topic further.
As with all titles in the Essentials for Clinicians series,
the subject is presented in a very visual and didactic
format to enable the reader to easily assimilate the information
and includes revision questions to test the acquired knowledge.
ISBN 978-88-941795-8-3
Series Editor ESMO Press · ISBN 978-88-941795-8-3
Michele Ghielmini
ESMO Press
9 788894 179583
ESMO Press ESMO Press

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Rolf A. Stahel · Solange Peters · Marina Garassino

THORACIC TUMOURS THORACIC TUMOURS Solange Peters

Marina Chiara Garassino

© 2019 European Society for Medical Oncology

Printed through s | s | media limited, Rickmansworth, Hertfordshire, UK

B. More advanced knowledge

Image sources 112

Professor Rolf Stahel

Solange Peters, MD, PhD

Marina Chiara Garassino, MD

ABCP Atezolizumab/bevacizumab/carboplatin/paclitaxel LCNEC Large cell neuroendocrine carcinoma

What every oncologist should know

Lung cancer is the leading cause of cancer-related Estimated New Cases

genders, after prostate cancer in men and breast cancer Leukemia

in women. All Sites 870,970 100% All Sites 891,480 100%

prostate and breast cancer mortality. Colon & rectum

In both genders, USA lung cancer incidence rates

Incidence is now beginning to decline, possibly due

Cigarette smoking prevalence peaked about 20 years

Lung cancer death rates have followed the same trend as

European predictions for the year 2018 in men and 60

women, estimated 267 000 and 121 000 lung cancer-

20% of total cancer deaths in both sexes combined.

Lung cancer is the primary cause of cancer-related deaths

in men in Europe and is second only to breast cancer

in women, with a very slight difference in the number of 10

1980s in men and began declining later, while in women, Stomach

in contrast to the USA scenario, mortality continues to 00 00

trend has been observed in breast cancer. Fig. 1.4

An evaluation performed in 2018 revealed that the lung

Belgium 78.1 39.7

Bosnia Herzegovina 89.4 19.3

United Kingdom 55.0 45.6

Hungary 111.6 58.7

Lung cancer rates in underdeveloped countries are lower

Worldwide, every year, as many people die from

In a large percentage of cases, lung cancer is diagnosed

combined is about 18%. 5 5 5

Stage at Diagnosis Stage at Diagnosis

Stage distribution 5-year relative

Lung cancer in both sexes is predominantly diagnosed

Compared with men, women are less likely to have a

Adenocarcinoma accounts for 38.5% of all lung cancer

Lung adenocarcinoma is also the most represented

Inhaled air and potentially dangerous substances are Mucous cell

conducted to the alveoli through a network of bronchi

which are believed to give rise to the differentiation of bronchus

ciliated, mucous and neuroendocrine cells. Bronchiole

peripheral (adenocarcinoma) airway compartment. Respiratory

The interaction between inhaled carcinogens and the

Repair processes may remove the DNA adducts and

If DNA adducts persist or are misrepaired, they result in a

Lung cancer pathogenesis is also affected by a genetic Carrier Healthy

The addition of smoking to this genetic inheritance is

Carrier Carrier Healthy Healthy Fig. 1.12

Smoking is considered the principal risk factor in lung

Non-smoking-related risk factors include occupational

The main modifiable risk factors for cancer pathogenesis

vegetables in the diet.

COPD, Chronic obstructive pulmonary disease

An estimated 10%–25% of lung cancers worldwide

Nicotine dependence – also called tobacco dependence

• VATS for sampling of