ESMO Essentials Clinicians Thoracic Tumours 2014

www.esmo.
org
www.esmo.org
Rolf A. Stahel Solange Peters Marina Garassino
THORACIC TUMOURS
E S S E N T I A L S forC L I N I C I A N S
Rolf A. Stahel
Solange Peters
Series Editor
Central compartment
Large bronchus
Ciliated cell
Mucous cell
Primary
bronchus
Neuro-endocrine
cell
Basal cell
Secondary
bronchus
Tertiary
bronchus
Basement membrane
>
Peripheral compartment
Respiratory bronchiole
Bronchiole
Terminal
bronchiole
Alveoli
Alveolus
Clara cell
Respiratory
bronchiole
Ciliated cell
Basement
membrane
Interstitium
Alveolar
duct
Alveolus
Alveolus
Type I
pneumocyte
Type II
pneumocyte
Alveolus
ISBN 978-88-906359-4-6
9 788890 635946
ESMO Press
CM 28 ESMO Essentials Thoracic sponsored cover v03.indd 1
ESMO Press ISBN 978-88-906359-4-6
Michele Ghielmini
ESMO Press
Rolf A. Stahel
Solange Peters
Marina Garassino
THORACIC TUMOURS
E S S E N T I A L S fo r C L I N I C I A N S
Thoracic tumours include cancers ranging from some

of the most common - such as non-small cell lung cancer to the most rare, such as extragonadal germ cell tumours.
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 should know. Other interested readers
will include more advanced doctors or students, who may have
never dealt with this topic and who wish to understand the
core concepts of management of these tumours.
It 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.
In addition to the essentials, this volume also gives
an introduction to more advanced knowledge for those
who wish to explore the topic further.
Marina Garassino
THORACIC TUMOURS
edited by
edited by
ESMO Press
31/08/2014 17:52
Thoracic Tumours
Essentials for Clinicians
Thoracic Tumours
Essentials for Clinicians
Edited by
Rolf A. Stahel
Laboratory of Molecular Oncology, Clinic and Policlinic for Oncology
University Hospital Zurich, Zurich, Switzerland
Solange Peters
Department of Oncology, University of Lausanne
Lausanne, Switzerland
Marina Chiara Garassino

Thoracic Oncology Unit, Department of Medical Oncology
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
2014 European Society for Medical Oncology
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Contents
Preface vii
Contributors viii
Abbreviations x
Disclosures
xi
A. W
hat every oncologist should know
1. Epidemiology, pathogenesis, and risk factors
E Capelletto & S Novello
2. Prevention and screening of lung cancer

G Veronesi
3. Diagnosing lung cancer

C Dooms
14
4. Histopathological and molecular characterisation of lung cancer

A Warth
20
5. Principles of surgery of non-small cell lung cancer

MA Hoda & W Klepetko
26
6. Principles of radiotherapy of thoracic tumours

S Senan
32
7. Adjuvant and neoadjuvant therapy

B Besse
38
8. Treatment of metastatic non-small cell lung cancer

N Reinmuth & M Reck
44
9. Treatment of small cell lung cancer: chemotherapy and radiotherapy

D De Ruysscher
51
B. More advanced knowledge

10. Malignant pleural mesothelioma
GL Ceresoli, G Pasello, & F Calabrese
61
11. Thymic malignancies

N Girard
65
12. Neuroendocrine tumours of lung origin

MC Garassino, A Bill, & S Pusceddu
69
13. Emerging targets and new agents in lung cancer

TA Yap & SB Popat
73
Appendices
1. WHO Classification
77
2. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory
Society Classification of Lung Adenocarcinoma in Resection Specimens
79
3. Selected treatment schedules
80
Image sources
86
Index
87
v
Contents
vi
Preface
After many years of stagnation, big leaps have been made in improving the diagnosis and therapy of
thoracic malignancies. This volume of the series 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 Doctors 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, radio-oncology,
and medical oncology. The topics range from pathology to early diagnosis and screening to the current
therapeutic options of lung cancer. In addition, essential knowledge 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
Zurich, Switzerland
vii
Preface
Contributors
B Besse
Department of Cancer Medicine, Gustave Roussy, Villejuif, France
A Bill
Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
F Calabrese
Department of Cardiothoracic and Vascular Sciences, University of Padova Medical School, Padova, Italy
E Capelletto
Department of Oncology, University of Turin, AOU San Luigi-Orbassano, Orbassano, Italy
GL Ceresoli
Thoracic and GU Oncology Unit, Medical Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy
D De Ruysscher
University Hospitals Leuven/KU Leuven, Leuven, Belgium
C Dooms
University Hospitals Leuven, Respiratory Division, Leuven, Belgium
MC Garassino
Thoracic Oncology Unit, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
N Girard
Universit Claude Bernard Lyon 1, Hpital Louis Pradel, Hospices Civils de Lyon, Lyon, France
MA Hoda
Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Centre Vienna,
Medical University of Vienna, Vienna, Austria
W Klepetko
Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Centre Vienna,
Medical University of Vienna, Vienna, Austria
S Novello
Department of Oncology, University of Turin, AOU San Luigi-Orbassano, Orbassano, Italy
G Pasello
Thoracic Oncology Unit, Medical Oncology II, Istituto Oncologico Veneto, Padova, Italy
SB Popat
Department of Medicine, The Royal Marsden NHS Foundation Trust, London, UK
S Pusceddu
Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
M Reck
Department of Thoracic Oncology, LungenClinic, Grosshansdorf, Germany;
Member of the German Center for Lung Research (DZL), Germany
viii
Contributors
N Reinmuth
Department of Thoracic Oncology, LungenClinic, Grosshansdorf, Germany;
Member of the German Center for Lung Research (DZL), Germany
S Senan
Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands
G Veronesi
Lung Cancer Early Detection Unit, Division of Thoracic Surgery, European Institute of Oncology, Milan, Italy
A Warth
Institute for Pathology, University Hospital Heidelberg, Heidelberg, Germany
TA Yap
Department of Medicine, The Royal Marsden NHS Foundation Trust, London, UK
ix
Contributors
Abbreviations
AC
Atypical carcinoid
ACTH
Adrenocorticotrophic hormone
ADC Adenocarcinoma
AIS
Adenocarcinoma in situ
ALK
Anaplastic lymphoma kinase
BSC
Best supportive care
CDDP Cisplatin
CI
Confidence interval
CIS
Carcinoma in situ
CISH
Chromogenic in situ hybridisation
COPD
Chronic obstructive pulmonary disease
CT
Computed tomography
DFS
Disease-free survival
EBUS
Endobronchial ultrasound
EGFR
Epidermal growth factor receptor
EPP
Extrapleural pneumonectomy
EUS
Endoscopic ultrasound
FDG Fluorodeoxyglucose
FEV1%pred Predicted % forced expiratory volume in 1 minute
FFPE
Formalin-fixed, paraffin-embedded
FGFR
Fibroblast growth factor receptor
FISH
Fluorescence in situ hybridisation
FNA
Fine needle aspiration
GEP Gastroenteropancreatic
GI Gastrointestinal
Gy Gray
HCG
Human chorionic gonadotrophin
HDAC
Histone deacetylase
HPF
High-power field
HR
Hazard ratio
IARC
International Agency for Research on Cancer
IGF-1R
Insulin-like growth factor 1 receptor
IHC Immunohistochemistry
IMRT
Intensity modulated radiotherapy
IPD
Individual patient-based
ISH
In situ hybridisation
ITMIG
International Thymic Malignancy Interest Group
LCNEC
Large cell neuroendocrine carcinoma
LDCT
Low-dose computed tomography
LINAC
Linear accelerator
LN
Lymph node
mAb
Monoclonal antibody
MEK
Mitogen-activated protein kinase
MEN-1
Multiple endocrine neoplasia type 1
MMT
Multimodality treatment
MPM
Malignant pleural mesothelioma
mTOR
Mammalian target of rapamycin
nAChR
Nicotinic acetylcholine receptor
NET
Neuroendocrine tumour
NRT
Nicotine replacement therapy
NSCLC
Non-small cell lung cancer
NSE
Neurone-specific enolase
ORR
Overall response rate
OS
Overall survival
P/D Pleurectomy/decortication
PAHs
Polycyclic aromatic hydrocarbons
PCI
Prophylactic cranial irradiation
PCR
Polymerase chain reaction
PD
Progressive disease
PDGFR
Platelet-derived growth factor receptor
PET
Positron emission tomography
PFS
Progression-free survival
PORT
Postoperative radiotherapy
PR
Partial response
PS
Pathological stage
PTH
Parathyroid hormone
RCT
Randomised clinical trial
ROC
Receiver operating characteristic
RR
Response rate
SABR
Stereotactic ablative radiotherapy
x
Abbreviations
SBM
Solitary brain metastasis
SCLC
Small cell lung cancer
SD
Stable disease
SIADH
Syndrome of inappropriate antidiuretic hormone secretion
SPN
Solitary pulmonary nodule
SQCC
Squamous cell carcinoma
SR
Sleeve resection
SST
Superior sulcus tumour
TBNA
Transbronchial needle biopsy
TC
Typical carcinoid
TKI
Tyrosine kinase inhibitor
TNM
Tumour, lymph nodes, distant metastases classification
TPC
Tunnelled pleural catheter
TSH
Thyroid stimulating hormone
TTF1
Thyroid transcription factor 1
TTP
Time to progression
UFT Tegafururacil
VATS
Video-assisted thoracoscopic surgery
VDT
Volume doubling time
VEGFR
Vascular endothelial growth factor receptor
VP16 Etoposide
WBRT
Whole-brain radiotherapy
Disclosures
B Besse: no conflict of interest
A Bill: no conflict of interest
F Calabrese: no conflict of interest
E Capelletto: no conflict of interest
GL Ceresoli: no conflict of interest
D De Ruysscher: no conflict of interest
C Dooms: no conflict of interest
MC Garassino: no conflict of interest
N Girard: no conflict of interest
MA Hoda: no conflict of interest
W Klepetko: no conflict of interest
S Novello: no conflict of interest
G Pasello: no conflict of interest
SB Popat: Uncompensated consultant to: AstraZeneca, Roche, Boehringer-Ingelheim, Lilly, Pfizer, GlaxoSmithKline,
Pierre Fabre; Research funding: Pierre Fabre, Roche, Boehringer-Ingelheim
S Pusceddu: no conflict of interest
M Reck: Consultant to Hoffmann-La Roche, Lilly, Bristol-Myers Squibb, Novartis, Boehringer-Ingelheim, Pfizer,
AstraZeneca; Speaker honoraria from Hoffmann-La Roche, Lilly, Bristol-Myers Squibb, Novartis, Boehringer-Ingelheim,
Pfizer, AstraZeneca
N Reinmuth: Consultant to Hoffmann-La Roche, Lilly, Amgen, Bristol-Myers Squibb; Speaker honoraria from
Hoffmann-La Roche, Lilly, Novartis, Boehringer-Ingelheim, Otsuka, Bristol-Myers Squibb
S Senan has received speakers honoraria from Varian Medical Systems, and is also a member of the Trial Management
Group for a phase III study in lung cancer sponsored by Lilly Oncology
G Veronesi: no conflict of interest
A Warth: no conflict of interest
TA Yap: no conflict of interest
xi
Disclosures
What every oncologist should know
Epidemiology, pathogenesis, and risk factors
US Incidence and mortality

Lung cancer is the leading cause of cancer-related
death in both genders worldwide, expected to account
for 224 210 new cases and 159 260 deaths in the USA,
for the year 2014.
It is the second most common solid tumour type in both
genders, after prostate cancer in men and breast cancer
in women.
Lung cancer is the cause of 28% and 26% of all male and
female cancer-related deaths, respectively, exceeding
prostate and breast cancer mortality.
Lung cancer US incidence rates in both genders have

been increasing from the 1970s, until the mid 1980s in
men and the late 1990s in women.
Incidence is now beginning to decline, possibly as
a consequence of a reduced 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.
US lung cancer death rates 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 described in both sexes, as a result of combined
improvements in primary prevention, control of associated
risk factors, and treatment.
REVISION QUESTIONS
1. What is the trend of lung cancer incidence in the USA in the last 15 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 2014 in men and
women, respectively, estimate over 187 000 (25% of all
cases) and 84 000 lung cancer-related deaths.
Men
Europe
Western Europe
Serbia
FYR Macedonia
Montenegro
Croatia
Slovenia
Spain
Greece
Albania
Bosnia Herzegovina
Italy
Malta
Portugal
Cyprus
Central & Eastern Europe
Northern Europe
Southern Europe
EU27
The Netherlands
Belgium
France
Luxembourg
Germany
Switzerland
Austria
26
66
45
83
28
74
28
60
27
57
25
52
30
54
28
99
Lung
30
20
Colorectum
10
Prostate
Pancreas
Stomach
Leukemias
15
Breast
Lung
10
Colorectum
Pancreas
Uterus
Stomach
Leukemias
0
1970 1980 1990 2000 2010 2020
Calendar year
1970 1980 1990 2000 2010 2020
Calendar year
33
102
19
86
On the contrary, the incidence rate for women was

highest in Northern European countries and lowest in
Eastern Europe.
26
85
22
79
25
77
16
75
13
54
25
65
15
59
19
58
11
49
12
38
11
63
55
55
For both sexes combined, the lowest rates were seen in

Cyprus and the highest in Hungary, with a range varying
from 49 to 156 cases/100 000.
40
53
39
48
43
52
38
84
12
81
10
71
14
45
18
29
28
109
47
90
31
75
26
83
16
70
20
73
12
82
9
74
10
61
12
67
120
40
An evaluation performed in 2012 revealed that the lung

cancer incidence rate for men was highest in Central
and Eastern European countries and lowest in
Northern Europe.
22
66
Denmark
Ireland
United Kingdom
Iceland
Norway
Latvia
Lithuania
Estonia
Finland
Sweden
Hungary
Poland
Czech Republic
Romania
Slovakia
Bulgaria
Belarus
Russian Federation
Moldova
Ukraine
Women
68
20
Deaths per 100 000 population
European mortality for lung cancer peaked in the late

1980s for men and began declining later, while, for women,
differently to the US scenario, mortality continues to
increase with a prediction of 14.1 cases/100 000 in 2014.
An opposite trend has been observed for breast cancer.
EU female
50
Deaths per 100 000 population
Lung cancer is the primary cause of cancer-related

deaths for men in Europe, being second only to breast
cancer for women.
EU male
60
100
80
60
40
20
20
40
60
80
100
Agestandardized incidence (E) per 100,000
The lung cancer rate in underdeveloped countries is lower

than in developed ones, although incidence and mortality
are slowly increasing.
The World Health Organisation estimates that lung cancer
deaths worldwide will continue to rise, largely as a result
of an increase in global tobacco use.
Worldwide, every year, as many people die from
lung cancer as the cumulative number resulting from
prostate, breast, and colon cancers.
REVISION QUESTIONS
1. Are there differences in 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
Clinical features and survival expectancy

Only 15% of all lung cancer cases is diagnosed at an
early stage, with a 5-year survival rate higher than 50%.
n African American
Percent
Five-year survival rate for all lung cancer stages combined

is about 17%.
n White
Percent
In a large percentage of cases, lung cancer is diagnosed

at an advanced stage with distant metastases and a
5-year survival rate of about 4%.
n All Races
Stage at Diagnosis
Stage distribution
by race, United States,
2003 to 2009
Stage at Diagnosis
5-year relative
survival rates by race and stage
at diagnosis, United States,
2003 to 2009
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.
Adenocarcinoma of the lung is the most common
histological subtype among women.
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.
In the past decades, adenocarcinoma incidence has
progressively increased, and nowadays it has replaced
squamous cell carcinoma as the most prevalent histotype
of non-small cell lung cancer.
Adenocarcinoma of the lung is also the most
represented histotype among never-smokers.
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:
inhaled air and potentially dangerous substances are
conducted to the alveoli through a network of bronchi
and bronchioles.
Central compartment
Large bronchus
Ciliated cell
Mucous cell
Primary
bronchus
The putative stem cells of the bronchus are the basal

cells, which are believed to give rise to the differentiation
of ciliated, mucous, and neuroendocrine cells.
Secondary
bronchus
Tertiary
bronchus
Lung cancer may arise from all these differentiated

and undifferentiated cells, from either the central (small
cell lung cancer and squamous cell carcinoma) or the
peripheral (adenocarcinoma) airway compartment.
Terminal
bronchiole
Neuro-endocrine
cell
Basal cell
Basement membrane
Bronchiole
Alveoli
Alveolus
Clara cell
Respiratory
bronchiole
Ciliated cell
Basement
membrane
Interstitium
Alveolar
duct
Alveolus
Alveolus
Type I
pneumocyte
Type II
pneumocyte
Alveolus
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, key events
in lung cancer pathogenesis, especially if they occur in
critical oncogenes and tumour suppressor genes.
Lung cancer pathogenesis is also affected by a genetic
component: it relates to the host susceptibility to lung
cancer, with or without exposure to certain carcinogens.
Carrier
Healthy
Normal gene
Studies on familial aggregation have supported the

hypothesis that a multifactorial hereditary component is
possible for this disease, even if a clear mechanism of
familial transmission is still not described.
Mutated gene
Cancer susceptibility
The addition of smoking to this genetic inheritance is

associated with a 3-fold increased risk of lung cancer.
Carrier
Carrier
Healthy
Healthy
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 for lung
cancer, causing more than 80% of all cases.
Common risk factors for lung cancer
Non-smoking-related risk factors include occupational

exposure to asbestos, chromium, arsenic, cadmium,
silica, and nickel, as well as second-hand smoke,
outdoor air pollutants, previous lung diseases, radon
exposure, and dietary factors.
In the absence of such risk factors, the genetic
susceptibility to lung cancer remains the only other
parameter predisposing to the onset of the disease.
Acetone
(solvent)
*Naphthylamine
Methanol
Cyanhydric acid
(was used in the gas chambers)
Ammoniac
(detergent)
(used as rocket fuel)
*Pyrene
*Urethane
Naphthalene
Toluene
Nicotine
Arsenic
(moth-repellent)
(used as a herbicide and insecticide)
*Cadmium
(used in batteries)
Carbon monoxide
(found in exhaust fumes)
Vinyl chloride
(used in plastic materials)
(industrial solvent)
(lethal poison)
*Dibenzacridine
*Polonium 210
(a radioactive element)
Occupation
(miners,
heavy metal
workers)
Radon gas
Ageing
Other
illnesses
(such as COPD,
tuberculosis,
etc)
Family
history
Exposure to
radiation
Pollution
The relative risk of lung cancer in long-term smokers has

been estimated as 10- to 30-fold higher compared with
non-smokers.
The International Agency for Research on Cancer (IARC)
has identified at least 50 carcinogens in tobacco smoke,
targeting both central and peripheral airways.
The most potent carcinogens of cigarette smoke are
the polycyclic aromatic hydrocarbons (PAHs) and the
aromatic amines, N-nitrosamines, but it also contains
benzene, vinyl chloride, arsenic, chromium, radon, and
its decay products, bismuth and polonium.
(insecticide)
*Known carcinogenic substances
Cancers arising in never-smokers predominantly target

the distal airways, favouring adenocarcinoma histology
and female gender. One of the most relevant risk factors
is environmental tobacco smoke exposure.
Lung cancer prevalence in never-smokers is higher in
Asian countries, especially in women, probably due
to the inhalation of cooking oil vapours and particles
emitted by domestic use of coal for cooking and heating.
All
2
Male
Europe (n = 22,742)
10
22
23
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?
US (n = 15,181)
East Asia (n = 20,206)
South Asia (n = 1,166)
11
15
15
Female
REVISION QUESTIONS
Second-hand
smoke
DDT
An estimated 1025% of lung cancers worldwide occur in

never-smokers, defined as individuals who have smoked
less than 100 cigarettes in their lifetime.
Smoking/
tobacco
20
21
61
40
60
83
80
Proportion of lung cancer cases (%)
100
Summary: Epidemiology, pathogenesis, and risk factors

Lung cancer is the leading cause of cancer-related death worldwide in both genders, surpassing prostate and breast
cancer mortality
US 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 for women are secondary only to breast cancer and, differently to the US
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 together
Only 15% of all lung cancer cases are diagnosed at an early stage, while the majority present with distant metastases
at diagnosis with a 5-year survival rate of about 4%
Median age at diagnosis is 71 years and adenocarcinoma is nowadays the most prevalent histotype
Lung cancer may arise from all the differentiated and undifferentiated cells of the upper and lower airways, and 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: long-term smokers have a 10- to 30-fold higher risk compared with
non-smokers
Non-smoking-related risk factors include occupational exposure to carcinogens, second-hand smoke, pollution,
dietary factors, radon exposure, and genetic susceptibility to cancer
Further Reading
Boffetta P. Classic epidemiology of lung cancer. Chapter 3 in: Multidisciplinary Approach to Thoracic Oncology, 2014. Aurora,
Colorado: IASLC.
Couraud S, Zalcman G, Milleron B, et al. Lung cancer in never smokers a review. Eur J Cancer 2012; 48:12991311.
Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med 2011; 32:605644.
Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries
in 2012. Eur J Cancer 2013; 49:13741403.
Gazdar AF, Zhou C. Lung cancer in never smokers: a different disease. Chapter 4 in: Multidisciplinary Approach to Thoracic
Oncology, 2014. Aurora, Colorado: IASLC.
Malvezzi M, Bertuccio P, Levi F, et al. European cancer mortality predictions for the year 2014. Ann Oncol 2014 Apr 23
[Epub ahead of print].
Nielsen LS, Blum J, Rasmussen J, et al. Occupational asbestos exposure and lung cancer a systematic review of the literature.
Arch Environ Occup Health 2014, 69:191206.
Novello S, Stabile LP, Siegfried JM. Gender-related differences in lung cancer. Chapter 5 in: Multidisciplinary Approach to Thoracic
Oncology, 2014. Aurora, Colorado: IASLC.
Pallis GA, Syrigos KN. Lung cancer in never smokers: disease characteristics and risk factors. Crit Rev Oncol Hematol 2013;
88:494503.
Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014; 64:929.
Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers a different disease. Nature Rev Cancer 2007; 7:778790.
Torres-Durn M, Barros-Dios JM, Fernndez-Villar A, et al. Residential radon and lung cancer in never smokers. A systematic review.
Cancer Lett 2014; 345:2126.
6
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.
2-FA-PET imaging of nAChR occupancy from cigarette smoke exposure
Nicotine binds nicotinic acetylcholine receptors

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

psychosocial counselling (also called behavioural support)
and pharmacotherapy. Combining the two enhances the
success rate.
0.3 Cigarette
kBq/mL
MRI
1.0 Cigarette
3.0 Cigarette
Three categories of first-line treatment are approved in

the USA and many other countries: nicotine replacement
therapy (NRT), bupropion (atypical antidepressant), and
varenicline (selective nicotine receptor partial agonist).
Tailored online support

One-to-one support
Group support
Varenicline, the newest product to market, is effective

but enthusiasm has been tempered by post-marketing
concerns about psychiatric side effects and possible
increased risk of cardiovascular events.
Telephone support
NRT alone
NRT/bupropion +
support
Varenicline + support
0 5 10 15 20
Smoking cessation is associated with anger, anxiety,

depression, impaired concentration, impatience,
insomnia, and restlessness. These symptoms peak within
the first week and last 24 weeks.
The table summarises the immediate and late benefits
of smoking cessation. The risk of cardiovascular
events reduces rapidly after cessation, while
oncological risks remain higher than those of never
smokers for 15 years.
The figure shows percentage increases in success

rate for smoking cessation at six months compared to
unaided attempts for each type of cessation support.
Within 20 min, blood pressure and heart rate decrease

Within 12 hours, carbon monoxide levels in the blood decrease to normal
Within 48 hours, nerve endings and sense of smell and taste start recovering
Within 3 months, circulation and lung function improve
Within 9 months, coughing and shortness of breath decrease
Within 1 year, the risk of coronary heart disease is cut by half
Within 5 years, the risk of stroke falls to that of a non-smoker, and the risks of
developing several cancers (mouth, throat, oesophagus, bladder, uterine cervix)
fall significantly
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
REVISION QUESTIONS
1. What are the two main categories of treatment 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
The figure illustrates the steps in the development of
squamous cell lung cancer: cells of the bronchial epithelium
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.
Endpoint
Metaplasia, dysplasia
Metaplasia
Sputum atypia
Sputum atypia
Sputum atypia
n
100
82
150
1067
73
Budesonide
Dysplasia
112
Budesonide
Fluticasone
Nodule size
Nodule size and number
202
201
Anethole dithiolethione New dysplastic lesions
101
Iloprost
Dysplasia
152
Celecoxib
Ki-67
Ki-67
204
101
Myo-inositol
Dysplasia
26
Outcome
Negative
Negative
Negative
Negative
Negative
Negative for primary endpoint;
fewer nodules in treatment group
Negative
Negative
Negative for primary endpoint; rate of
worsening lower in treatment group
Positive in former smokers only
(improved endobronchial histology)
Positive (decreased Ki-67 labelling
index in former smokers)
Positive (decreased Ki-67 labelling
index in former smokers)
Promising: a phase I trial with
historical control
While most studies in the past 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).
Following publication of a meta-analysis on the effect of daily
aspirin on long-term risk of cancer death, aspirin is considered
one of the most promising investigational cancer prevention
agents. Aspirin was associated with reduced death risk for
adenocarcinoma affecting several distinct organs.
In particular, patients receiving aspirin experienced a
40% reduction in lung adenocarcinoma death compared
to controls.
Phase III trials of lung cancer prevention have

tested aspirin, retinyl palmitate, 13-cis-retinoic
acid, vitamin E, multivitamin supplement,
mineral supplement, selenium, and betacarotene. All were ineffective. Beta-carotene
was harmful to current smokers.
Phase II cancer prevention trials rely on
intermediate biological endpoints as surrogates
of cancer incidence and mortality.
The table shows the main published phase II
trials, types of agent used, number of cases, and
results. No trial has shown a clear benefit for a
chemopreventive agent compared to placebo.
5
Risk of cancer death (%)
Intervention
13-cis-retinoic acid
Fenretinide
Etretinate
Beta-carotene
Vitamin B12/folate
Control
Aspirin
4
3
2
1
0
0 5 10 15 20
Year to death
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
Chest X-ray and low-dose computed tomography
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.
Number of deaths
The aim of screening is to detect lung cancer at a stage

when it is not causing symptoms and when treatment is
most successful.
Survival (%)
In the 1970s chest X-ray and sputum screening trials

showed no mortality reduction in the screening
compared to no-screening arms. The results of the
Mayo Lung Project, on over 10 000 high-risk men, are
shown in the figure.
100
Resected clinical stage I cancer, 92% (95% CI, 8895)
80
All lung cancers, 80% (95% CI, 7485)
60
40
20
0
12
24
36
48
60
72
84
96
108
120
50
34
28
18
16
12
9
7
2
1
Months
No. at Risk
All participants
Participants
undergoing
resection
484
302
433
280
356
242
280
191
183
120
90
59
The introduction of spiral multi-detector computed

tomography (CT) of the chest has made it possible to
reduce the radiation dose to 1020% of that of standard
CT, maintaining high sensitivity for small nodules.
The single arm I-ELCAP study used low-dose CT
(LDCT) screening to detect 484 lung cancer cases
among 31 000 participants. Overall cancer-specific
survival was encouragingly high at 80%.
Other single-arm studies have shown similarly high
survival, as well as favourable stage distribution and small
mean size of diagnosed cancers.
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.
LDCT with no contrast has limited resolution for
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 for peripheral nodules.
In fact most cancers diagnosed by LDCT screening are
peripheral stage I adenocarcinomas.
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 screeningdetected lung cancers compared to historical controls.
To overcome these biases and determine mortality
reduction in LDCT-screened populations compared to
controls, a number of randomised trials were started in
Europe and the USA.
Most of the published European studies did not find a
reduction in mortality, most likely because they were
underpowered. The definitive results of the European
NELSON trial are not yet available.
Cumulative No. of Lung-Cancer Deaths
Death from Lung Cancer

500
Chest radiography
400
NLST enrolled 53 454 high-risk participants aged

5574 years who had at least a 30-pack-year
smoking history.
Low-dose CT
300
200
100
0
The US National Lung Screening Trial (NLST) was a

prospective, randomised lung cancer screening trial
comparing annual LDCT scan to annual chest X-ray
for 3 years.
NLST found a 20% reduction in lung cancer-specific

mortality and a 7% reduction in all-cause mortality in
the screened arm after 5 years.
Years since Randomization
As a consequence of the NLST findings,

most scientific organisations have
recommended LDCT lung cancer
screening implementation in high-risk
individuals.
High-risk populations are defined
according to 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 quality and
effectiveness control procedures in place.
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Lung Cancer Screening V.1.2015. 2014 National
Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines and illustrations herein may not be reproduced in any form for any purpose without the
express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE
CANCER NETWORK, NCCN, NCCN GUIDELINES, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
REVISION QUESTIONS
1. What are the potential biases of single-arm screening studies with LDCT?
2. Was the US National Lung Screening Trial 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
Limitations 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: 025% of positive
nodules are diagnosed as benign in published studies.
89% of screening-detected lung cancers are estimated
as diagnosed with delay, due to central position or fastgrowing disease.
To lower the proportions of false-positive and falsenegative nodules, diagnostic protocols have been
developed to manage the high number of indeterminate
nodules detected by CT screening.
A 5 mm size threshold has been widely adopted:
>5 mm nodules require further investigation; smaller
nodules are investigated at the next annual scan.
PET-CT can reduce use of more invasive procedures
to diagnose benign disease.
The NELSON study introduced software-calculated VDT
into the nodule management algorithm.
Author,
publication year
Country
Lung
cancer
cases
Variables included in lung cancer risk

prediction model
Models have been developed to

estimate the risk of individuals
developing lung cancer: to reduce both
costs and the number of potentially
harmful screening CT scans.
Bach et al, 2003
USA
1070
Age, sex, asbestos exposure history, smoking history 0.72
Spitz et al, 2008
USA
725
Smoking history, emphysema, dust exposure,

family history of cancer, asbestos exposure history,
hayfever, DNA repair capacity, bleomycin treatment
Former smokers: 0.70

Current smokers: 0.73
Cassidy et al, 2008
UK
579
Smoking history, pneumonia, asbestos exposure

history, previous cancer, family history of cancer
0.70
Young et al, 2009
New Zealand
239
Panel of 20 single nucleotide polymorphisms, age,

family history of lung cancer
0.77
The table summarises efficacy (area

under ROC curve) of published
risk models. Most models use
epidemiological variables to estimate
risk; some combine epidemiological
risk factors with DNA repair assays.
Calabro et al, 2010
Italy
57
FEV1%pred
0.70
0.75
The COSMOS risk model incorporated

epidemiological variables with first
screening CT findings. Validation is
ongoing. Low-risk individuals identified
by this model may benefit from
increased interval between screenings.
Model prediction
accuracy: area under
the ROC curve
Raji et al, 2010
UK
200
Smoking history, pneumonia, asbestos exposure

history, previous cancer, family history of cancer
+ SEZ6L genotype
Maisonneuve et al,
2011
Italy
55
Model 1: Age, sex, asbestos exposure history,

and smoking history
Model 2: As model 1 + CT findings
Model 1: 0.62
Model 2: 0.76
Tammemagi et al,
2011
Multinational
10 sites
1040
Age, education, body mass index, family history of

lung cancer, COPD, recent chest X-ray, smoking
history
Model 1: 0.78
Model 2: 0.84
Hoggart et al, 2012 Multinational

Europe
1250
Smoking history
Former smokers: 0.83

Current smokers: 0.82
Ever smokers: 0.84
Lin et al, 2012
633
Sex, lung disease history, occupational exposure,

family history, smoking history
0.71
0.64
0.87
China
Li et al, 2012
China
2283
Smoking status + genetic score based on 5 single

nucleotide polymorphisms (rs2736100, rs402710,
rs1051730, rs4083914, rs4488809)
Park et al, 2013
Korea
10 007
Smoking history, body mass index, physical activity,

fasting glucose levels
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

Biomarkers for lung cancer could gain a potential role
in risk stratification and detection of early-stage disease.
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, and proteomic methods.
More recently, serum microRNAs have emerged as
promising potential screening markers.
Screening detects more cancers at an earlier stage,

where less invasive surgery is justified, associated with
less postoperative pain and fewer complications as
compared with traditional open thoracotomy.
A meta-analysis found that the video-thorascopic
approach was associated with improved oncological
outcomes compared to open thoracotomy.
Robotic surgery is a fast-growing development of the
video-thorascopic 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.
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 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.
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, nicotine replacement therapy, or bupriopion 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 US NLST showed that annual LDCT can reduce 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
Diagnostic algorithms should be used to manage indeterminate nodules and reduce false positives
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; 3:495503.
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; 355:17631771.
Keith RL, Miller YE. Lung cancer chemoprevention: current status and future prospects. Nat Rev Clin Oncol 2013; 10:334343.
Lemmens V, Oenema A, Knut IK, et al. Effectiveness of smoking cessation interventions among adults: a systematic review of reviews.
Eur J Cancer Prev 2008; 17:535544.
Maisonneuve P, Bagnardi V, Bellomi M, et al. Lung cancer risk prediction to select smokers for screening CTa model based on the
Italian COSMOS trial. Cancer Prev Res (Phila) 2011; 4:17781789.
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; 365:395409.
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; 377:3141.
van Klaveren RJ, Oudkerk M, Prokop M, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med 2009;
361:22212229.
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; 157:776784.
Wender R, Fontham ET, Barrera E Jr, et al. American Cancer Society lung cancer screening guidelines. CA Cancer J Clin 2013;
63:107117.
13
Veronesi
Diagnosing lung cancer

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.
Cough with
haemoptysis
Screen-detected
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, or Pancoast
syndrome (shoulder pain, Horner,
upper extremity muscle wasting).
Symptoms as a result of distant metastasis: brain, bone,

liver, adrenal gland; constitutional symptoms (loss of
appetite, weight loss, fatigue, malaise).
Symptoms of paraneoplastic syndrome in 10% of
lung cancer patients.
Endocrine
SIADH/hyponatraemia; PTH/hypercalcaemia; ACTH/Cushing;

b-HCG/gynaecomastia; insulin-like factor/hypoglycaemia;
growth hormone/acromegaly; TSH/hyperthyroidism;
prolactin/galactorrhoea
Musculoskeletal
Hypertrophic osteoarthropathy; clubbing; polymyositis;

dermatomyositis; myopathy
Neurological
Lambert-Eaton myasthenia; cerebellar degeneration;

peripheral, encephalitis, or autonomic neuropathy
Other
Haematological (anaemia, thrombocytosis, leucocytosis,

non-bacterial thrombotic endocarditis); skin (pruritus,
erythema multiforme, acanthosis nigricans)
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
Clinical presentation
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
CT scan with at least two thirds of its margins
surrounded by normal lung parenchyma
and not associated with intrathoracic lymph
nodes or a pleural effusion.
5 mm
No follow-up (FU)
>5 mm
Follow-up CT
8 mm
Fleischner
>8 mm
Pretest
probability
calculation
Clinical evaluation of an SPN is dependent on:

1. Appearance and size
2. Calculation of pretest probability of malignancy,
based on size, margin, cancer and smoking history,
age, location.
GGO*
(partial)
solid
<5%: FU CT
*Ground-glass opacity
560%: PET
>60%: Tissue
Further reading: MacMahon et al. 2005; Naidich et al. 2013
Staging of lung cancer

Tumour-Node-Metastasis staging = a multidisciplinary
process involving physical examination and
endoscopic, imaging, and surgical techniques to
establish the TNM category and stage group.
Stage group
TNM
Stage group
TNM
TisN0M0
IIIA
T1-3N2M0
IA
T1a-1bN0M0
IB
T2aN0M0
IB
T4N0-1M0
The TNM 7th edition paradigm is based solely on anatomy.
IIA
T1-2aN0M0
IIIB
T4N2M0
Different types of TNM categories are used dependent on

the time point of evaluation: c, clinical before any therapy;
y, restaging after systemic therapy; p, pathological after
surgical resection; r, at disease relapse.
The disease stage is the most important prognostic factor
in lung cancer to date.
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
T3N1M0
T2bN0M0
IIB
T2bN1M0
T3N0M0
T1-4N3M0
IV
T1-4N0-3M1a
T1-4N0-3M1b

Standard white light videobronchoscopy and
autofluorescence bronchoscopy: in addition to pathological
confirmation, it also permits endobronchial staging, i.e.
detection of synchronous radio-occult endobronchial
lesions or extension of the primary tumour; T-descriptor:
eT1a: tumour 2 cm not extending into main bronchus
eT2a: tumour involving main bronchus 2 cm distal to
main carina
eT3: tumour involving main bronchus <2 cm from
main carina
eT4: tumour involving main carina and/or distal trachea
Resectable by bilobectomy
superior (fissure) with sleeve
of pulmonary artery
Right upper lobe bronchus

tumour 2 cm not extending into
main bronchus
CT scan of chest and upper abdomen are done in all

patients to detect nodal and extranodal disease. Cranial
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).
PET has a complementary role to CT for two reasons:

Detection of unexpected lymph node involvement
or distant metastatic organ spread in 412% of
stage I-III lung cancer. The overall evidence points at
significantly more accurate TNM staging with PET-CT.
Lung adenocarcinoma
cT2aN1M1b (solitary right
scapula)
Determination of 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.
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 FDG-PET/CT?
16

For the N-descriptor, contrastenhanced CT is accurate in delineating
LN enlargement (defined as 10 mm
short axis) and helps to allocate the
nodal stations as defined in the new
lymph node map (Rusch 2009).
azygos vein
station 4L LN
station 11Rs
station 4L LN
station 10R LN
azygos vein
station 7
station 12L
station 12L
station 11Ri
For the N-descriptor, integrated PET-CT has a pooled

weighted sensitivity of 0.76 (95% CI 0.650.84) and
specificity of 0.88 (95% CI 0.820.92).
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 to
the fact that FDG uptake is not tumour specific.
Invasive mediastinal nodal staging

starting with endosonography
(EBUS and EUS) and if negative
surgical staging has been proven to
detect significantly more mediastinal
nodal disease compared to
mediastinoscopy alone.
The negative likelihood ratio of
endosonography alone is 0.130.15.
Therefore in routine practice a
preoperative surgical staging procedure (videomediastinoscopy or 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
LN
aorta
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
local expertise available
Endoscopic biopsy:
endobronchial biopsy (forceps biopsy or cryobiopsy)
transbronchial lung biopsy guidance by radial endobronchial ultrasound (EBUS) miniprobe
EBUS-controlled transbronchial needle biopsy (EBUS-TBNA)
oesophageal-guided fine needle aspiration (EUS-FNA)
thoracocentesis or medical pleuroscopy
Image-guided percutaneous core

needle biopsy:
= CT-guided biopsy or ultrasoundguided biopsy of
supraclavicular LN
pulmonary lesion: parenchymal
or pleural node/mass
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,
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, radiation oncologist, thoracic radiologist and nuclear
clinician, pulmonologist
Staging of (suspected) lung cancer:
TNM 7 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 J, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy versus endosonography for mediastinal nodal staging of lung cancer:
a randomized trial. JAMA 2010; 304:22452252.
Dooms C, Muylle I, Yserbyt J, et al. Endobronchial ultrasound in the management of non-small cell lung cancer. Eur Respir Rev 2013;
22:169177.
Fischer B, Lassen U, Mortensen J, et al. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med 2009; 361:3239.
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. J Thorac Oncol 2007; 2:706714.
MacMahon H, Austin J, Gamsu G, et al. Guidelines for management of small pulmonary nodules detected on CT scans:
A statement from the Fleischner society. Radiology 2005; 237:395400.
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; 266:304317.
Ost DE, Gould MK. Decision making in patients with pulmonary nodules. Am J Respir Crit Care Med 2012; 185:363372.
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; 143:825839.
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; 4:568577.
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; 76:118.
Yeung S, Habra MA, Thosani SN. Lung cancer induced paraneoplastic syndromes. Curr Opin Pulm Med 2011; 17:260268.
19
Dooms
Histopathological and molecular

characterisation of lung cancer
Introduction cytology and histology
Tissue processing
for intraoperative
cryosections
Cutting of paraffinembedded tissue specimens

with a microtome
After
deparaffinisation the slides
are stained with HE
HE and EvG
(green label) stained slides
of a lobectomy specimen
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 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 25 m slides, and stained with
haematoxylineosin (HE) or other useful stains (e.g.
periodic acid-Schiff [PAS], Elastica van Gieson [EvG]).
Lung cancer is usually diagnosed in advanced stages.

Thus, in the majority of cases, only cytology or small
biopsy material is 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.
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
are usually superior to forceps biopsies with respect to
tumour amount.
Cell block
Forceps biopsy
Needle core biopsy
Resection specimen
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.
The group of NSCLC is further categorised into
adenocarcinomas (ADC), squamous cell carcinomas
(SQCC), adenosquamous carcinomas, large cell
carcinomas, and sarcomatoid carcinomas. Lung tumours
can show a combination of different histotypes.
A: Squamous cell carcinoma
Adenocarcinoma
Squamous cell
carcinoma
Adeno-squamous
carcinoma
SCLC
Large cell
carcinoma
Sarcomatoid
carcinoma
Surgical resection (only early stages)
Chemotherapy
B: Small cell carcinoma
ADC seem to have different precursors. Centrally

located ADC are thought to arise from the surface
or glandular epithelium of bronchi, in contrast to the
terminal respiratory unit ADC, for which the stem
cells are likely to be exocrine bronchiolar cells and
type II pneumocytes.
SQCC 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.
C: Combined large cell neuroendocrine (left) and adenocarcinoma (right)
ADC are characterised by various histomorphological

growth patterns. Semi-quantitative assessment
(subtyping) of these patterns provides relevant clues for
optimised treatment decisions.
Lymph node metastasis based on predominant pattern

of pulmonary adenocarcinomas
The predominant ADC growth pattern is associated with

the patients prognosis and has been demonstrated to be
a stage-independent predictor of survival.
Specific ADC growth patterns are associated with
a distinct tumour biological behavior, prevalence of
predictive biomarkers, and lymph node metastasis.
REVISION QUESTIONS
1. How is lung cancer classified? What is the rationale behind this classification?
2. How do squamous cell carcinomas arise in the respiratory epithelium?
3. What is the clinical impact of morphological adenocarcinoma subtyping?
21
Warth
Lepidic:
7%
Acinar:
46%
Papillary:
43%
Solid:
51%
Micropapillary:
76%
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
(PAS-positive intracytoplasmic mucin droplets).
EvG staining is used to identify elastic fibres (dark black)
and is recommended to specifically assess tumour
infiltration of the visceral and parietal pleura.
Secondary antibody labelled

with chromogens (purple)
Primary antibody
Antigen
Tumor cell
For reliable tumour diagnoses, lineage-specific

antibodies are required. Thyroid transcription factor
1 (TTF1) and Napsin A are frequently used to confirm
pulmonary ADC; p63 (p40) and cytokeratin 5/6 are
used as markers for SQCC.
A neuroendocrine differentiation is confirmed with
antibodies against Chromogranin A, Synaptophysin,
or CD56.
IHC staining requires a careful correlation with
the morphological findings to define lineage and
immunophenotype of the neoplastic cells.
HE staining (left) and EvG staining (right) of a pulmonary adenocarcinoma.

The elastic layers of the pleura are delineated in black and thus allow optimised
tumour staging.
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
morphologically unclear cancers.
IHC allows the visualisation of an antigen by means
of primary monoclonal or polyclonal antibodies and a
detection system.
A primary (direct method) or secondary antibody
(indirect method; more sensitive) is therefore labelled
with a chromogen. Counterstains are used to provide
contrast that helps the primary stain stand out.
Step 1:
Morphology (HE, PAS)
Step 2:
Immunohistochemistry
- squamous: CK5/6, p40, p60
- non-squamous: CK7, TTF1, Napsin
Step 3:
Immunohistochemistry
- FISH, CISH
- IHC
- PCR (Sequencing)
unclear
morphology
(NSCLC NOS)
clear
morphology
(ADC, SQCC)
unclear
immunophenotype
(NSCLC NOS)
clear
immunophenotype
(ADC, SQCC)
Predictive Biomarker
Analysis
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 SQCC and ADC?
22
Molecular diagnostics polymerase chain reaction (PCR) and sequencing

Polymerase chain reaction (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
non-neoplastic cells.
Identification of areas with high tumour cell content after HE staining (left) and
the same slide after microdissection (right)
Frequent alterations in adenocarcinomas

Unknown
K-RAS
EGFR
NRAS
HER2
BRAF
PIK3CA
AKT1
ROS1
In NSCLC, especially in ADC, a still-increasing number

of potentially druggable mutations and amplifications
have been identified.
For each biomarker, reliable diagnostic methods (e.g.
immunohistochemistry, PCR-based mutation analysis, in
situ hybridisation) and respective cutoff values for clinical
decisions need to be established.
Various methods for PCR-based mutation analyses are
available. Targeted detection PCR, Sanger sequencing,
pyrosequencing, or next generation sequencing
approaches are used in pathological institutions.
RET
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.
For reliable Sanger sequencing a tumour cell
concentration of 30% is required to detect all types of
mutations.
Pyrosequencing and next generation sequencing have
a higher sensitivity when only sparse tumour material is
available.
c.2573T>G (p.L858R)
c.2237_56delinsTT (p.E746_S752delinsV)
Upper left: Common point mutation of EGFR (arrow). Upper right: Point mutation
in EGFR resulting in tyrosine kinase inhibitor resistance. The lower sequence
demonstrates a complex EGFR deletion/insertion mutation. Note the sequence
shift of the mutated allele compared to the wild-type allele
REVISION QUESTIONS
1. Why is polymerase chain reaction 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
c.2369C>T (p.T790M)
Molecular diagnostics in situ hybridisation (ISH)

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
(single red and green signals) indicate a translocation.
ISH analyses require high tissue quality and tailored
handling procedures. Interpretation of the results should
be performed by specifically trained personnel.
Normal chromosome with juxtaposed

red and green probes flanking ALK
Fluorescence (FISH; left) and chromogenic in situ hybridisation (CISH; right)

demonstrating a translocation of the ALK gene locus with juxtaposed probes of
the normal chromosome (yellow in FISH, brown in CISH) and rearranged probes
(single red or green signals)
ISH with break-apart strategy is used to detect

rearrangements of the investigated gene, without
knowing the partner involved in the translocation.
For ISH fusion strategies, the fusion partners must be
known.
Inversion of the ALK gene and fusion

with EML4 (split of red and green signal)
Since yet clinically relevant chromosomal rearrangements

in NSCLC (for example, translocations of ALK or ROS1)
involve multiple fusion partners, break-apart probes are
more commonly used in daily practice.
Amplification of a specific gene is another relevant finding

to be analysed by ISH. For example, in 2025% of SQCC,
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.
Amplification of the FGFR1 gene locus (green) in relation to the centromere
probe (red) in a SQCC
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 adenocarcinomas, squamous cell carcinomas, adenosquamous carcinomas, large
cell carcinomas, and sarcomatoid carcinomas
Whereas cryosections are required for intraoperative diagnosis, most biopsy and resection specimens are formalinfixed, 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, polymerase chain reaction 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). Spencers 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 Ackermans 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; 6:244285.
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; 30:14381446.
25
Warth
Principles of surgery of non-small cell lung cancer
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,
lobectomy, bilobectomy, or pneumonectomy.
A muscle-sparing anterolateral thoracotomy is the

most common approach.
The role of sublobar resection, anatomical
segmentectomy, or wide-wedge resection is being
reconsidered for very early lung cancer and is currently
being evaluated in ongoing 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.
Lobectomy with mediastinal lymph node dissection

is considered the standard surgical treatment for all
tumours >2 cm and tumours <2 cm that have a solid
appearance on chest computed tomography (CT).
Right Upper Lobectomy
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 36%.
Typical complications are prolonged air leak, bleeding,
chylothorax, and recurrent nerve palsy.
Normal
Lymph Nodes
Right Upper Lobe

Containing Tumour and
Lymph Nodes
Right Lung
Left Lung
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
VATS (video-assisted thoracoscopic surgery) lobectomy and

parenchyma-sparing resections
The current evidence indicates that VATS lobectomy
for early-stage NSCLC is associated with fewer
postoperative complications than open lobectomy.
Current data strongly also suggest oncological
equivalence of VATS versus open lobectomy for patients
with early-stage NSCLC.
VATS lobectomy should be performed at experienced
centres. Patients should undergo an accurate preoperative
work-up to exclude locally advanced disease.
In recent reports, the 5-year survival for VATS

lobectomy in stage IA NSCLC is near 80%, similar to
that for open lobectomy.
VATS 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.
In case of a centrally located tumour, a parenchymasparing 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 parenchymasparing SR can even be safely performed after induction
treatment.
REVISION QUESTIONS
1. Is VATS lobectomy associated with fewer postoperative complications?
2. Is the long-term outcome of VATS lobectomy comparable to standard lobectomy?
3. In centrally located tumours, what is the alternative to pneumonectomy?
27
Hoda & Klepetko
Stage III non-small cell lung cancer

Stage III NSCLC is a heterogeneous
disease, which can be subclassified
into locally advanced primary tumours
(T3N1, T4N0-1) and N2-positive NSCLC.
CT
FDG-PET CT
In case of locally advanced lung cancer

(T3N1, T4N0-1), radical resection can
be achieved with or without induction
treatment.
FDG-PET, 18F-Fluorodeoxyglucose positron emission tomography
Patients with limited mediastinal lymph

node involvement undergoing induction
treatment can be eligible for radical
resection after down-staging.
Patients with N2 disease undergoing surgery

after induction had a significantly longer progressionfree survival compared to those receiving
chemoradiotherapy alone.
CT/RT/S
CT/RT
100
Patients alive without progression (%)
HR 077 (95% CI 062096); p=0017
75
Patients undergoing induction chemoradiotherapy and

lobectomy had an improved overall survival compared to
patients with chemoradiotherapy alone.
50
This result could not be confirmed for patients undergoing

pneumonectomy due to unusually high mortality.
25
Number at risk
CT/RT/S 202
CT/RT 194
102
88
63
43
51
31
40
21
32
13
However, pneumonectomy after induction

chemoradiotherapy can obtain favourable outcomes
when performed at experienced centres.
100
CT/RT/S
CT/RT
Patients have to be selected very carefully with regard to

their performance status and must be staged accurately
in order to exclude more advanced disease.
However, clear evidence-based treatment protocols for
patients with N2-positive NSCLC cannot be defined on
the basis of the current literature.
Patients alive (%)
75
50
25
Number at risk
CT/RT/S 90
CT/RT 90
73
60
56
39
40
24
28
17
21
10
REVISION QUESTIONS
1. Does surgery play a role in patients with proven N2 disease?
2. Does every patient with T4N0 NSCLC need to undergo induction treatment?
3. Should pneumonectomy be avoided in N2-positive patients even after induction treatment?
28
Pancoast tumours
Pancoast or superior pulmonary sulcus tumours
(SST) are a rare subset of NSCLCs, occurring with an
incidence of less than 5% of all lung cancers.
The clinical picture consists of typical symptoms (pain
down the arm, Horners syndrome) and radiographic
evidence of first rib and/or vertebral body destruction.
Pancoasts Syndrome
Brachial plexus
(arm and
shoulder pain)
Vertebral body
Sympathetic trunk
(Horners
syndrome)
Subclavian
artery
and vein
Recurrent nerve
(vocal cord paralysis)
Vagus nerve
Induction chemoradiotherapy 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
in the superiour sulcus
Vascular, neural, and

vertebral body involvement
can be managed with advanced
surgical techniques and
interdisciplinary
approaches
Surgery requires expertise and should

be performed only in specialised centres
by an experienced team, including also a
neurosurgeon or orthopaedic surgeon.
The distinct anatomical location of SST
has required the development of special
surgical approaches for adequate
resection of the tumour and involved
adherent structures.
A 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.
The three most important prognostic factors for tumour

recurrence are completeness of resection, T status, and
N status of the tumour.
For SST the expected incidence of brain metastasis as
a first site of recurrence has been described as high as
24%, but occurrence of brain metastasis did not impact
on survival.
5-year survival
90
80
5-year survival (%)
Combined treatment schedules have led to

improvements in completeness of resection, clinical
and pathological response rates resulting in improved
long-term survival.
70
60
50
40
30
20
10
0
n=18
n=23
n=10
RT
RT+Surgery
CT+RT+
Surgery
REVISION QUESTIONS
1. Which therapy modality has become the modern treatment standard for superior sulcus tumours?
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 & Klepetko
Data pooled from

different publications reporting
long-term survival rates after
different therapeutic
modalities
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.
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.
In NSCLC, malignant pleural effusion is also a terminal

condition diminishing quality of life and requiring multiple
hospital admissions and interventions.
Salvage resections can be indicated in patients with

intratumoural cavitation and superinfection, for whom
any other treatment modality is not appropriate.
Salvage resection can also be performed for recurrent
lung cancer following definitive chemoradiotherapy, with
acceptable morbidity and mortality rates.
For both patient groups, careful selection and
preoperative assessment as well as postoperative care
can result in overall survival up to 30 months.
Suggested Placement Procedure
Tunnelled pleural catheters (TPCs) became popular as

a less invasive, outpatient modality in malignant pleural
effusion management in NSCLC.
TPCs are particularly preferred for patients with trapped
lung or those who are not considered candidates for
pleurodesis because of short life-expectancy.
Tunneled
portion of
catheter
External portion
of catheter
First Incision:
Guidewire
insertion site
Second
Incision:
Catheter
exit site
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 chemoradiotherapy?
3. Do NSCLC patients need any surgical intervention for recurrent malignant pleural effusion?
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
Video-assisted 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 induction treatment
Pancoast tumours: induction chemoradiotherapy 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
chemoradiotherapy
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; 374:379386.
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; 86:16321638.
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; 60:615622.
Pfannschmidt J, Dienemann H. Surgical treatment of oligometastatic non-small cell lung cancer. Lung Cancer 2010; 69:251258.
Predina JD, Kunkala M, Aliperti LA, et al. Sleeve lobectomy: current indications and future directions. Ann Thorac Cardiovasc Surg 2010;
16:310318.
Rueth NM, Andrade RS. Is VATS lobectomy better: perioperatively, biologically and oncologically? Ann Thorac Surg 2010;
89:S2107S2111.
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; 6:762767.
Tamura M, Hoda MA, Klepetko W. Current treatment paradigms of superior sulcus tumours. Eur J Cardiothorac Surg 2009; 36:747753.
Van Schil PE, Asamura H, Rusch VW, et al. Surgical implications of the new IASLC/ATS/ERS adenocarcinoma classification. Eur Respir J
2012; 39:478486.
Yanagawa J, Rusch VW. Current surgical therapy for stage IIIA (N2) non-small cell lung cancer. Semin Thorac Cardiovasc Surg 2011;
23:291296.
31
Hoda & Klepetko
Principles of radiotherapy of thoracic tumours
Background
External beam radiotherapy 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
Example of 3D imaging (A) and 4D imaging (B) for the same tumour.
(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
LINAC yellow simulates the radiation beam, while green simulates the X-rays
used for imaging patient anatomy
A planning CT scan is performed before high-dose

radiotherapy, 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 CT (or respiration-correlated CT) scan is
the preferred technique for curative radiation, as it allows
for motion to be visualised for tailored delivery.
Any changes in tumour position can be accounted for

by adapting the initial plan in order to ensure dose
coverage.
Target coverage can be improved by performing

cone-beam CT scans with the patient on the
LINAC couch.
Repeated imaging during treatment delivery is a

component of modern image-guided radiotherapy.
Planning CT (A) and cone-beam CT scans performed during treatment (B)
REVISION QUESTIONS
1. Can radiation cure patients with lung cancer?
2. How is radiotherapy delivered to patients?
3. What is imaging-guided radiotherapy?
32
Dose-fractionation schemes
Simple field for vertebral metastases
The radiation dose delivered at each session is

measured in units called Grays (Gy).
Palliation often involves use of doses ranging from 8 Gy to
4 Gy, delivered in 15 fractions. High response rates are
seen for symptoms like pain and bleeding.
If required, palliative radiotherapy can be repeated.
Stereotactic radiotherapy (RT) for brain metastasis
Stereotactic radiotherapy is a form of high-dose,

high-precision delivery that requires special equipment.
In patients with 12 brain metastases, superior local
control is obtained with single doses of 1824 Gy using
stereotactic radiotherapy rather than conventional doses.
Stereotactic radiotherapy is widely used for treatment
of early-stage non-small cell lung cancer (NSCLC),
where local control rates of 90% can be achieved
using 1118 Gy given in 53 fractions.
Pre-treatment
6 months post-treatment
In locally advanced NSCLC, once-daily fractions of

2 Gy are used during concurrent therapy as the large
treatment fields required are potentially more toxic.
For limited-stage small cell lung cancer (SCLC), use of
twice-daily fractions of 1.5 Gy in 30 treatments were
superior to use of once-daily fractions.
If radiotherapy follows chemotherapy, e.g. in less fit
patients, higher dose fractions (e.g. 2.63 Gy) are used
to shorten treatment times and improve survival.
REVISION QUESTIONS
1. How many treatment fractions are used to deliver palliative radiotherapy?
2. What are the features of stereotactic radiotherapy?
3. How frequently are patients irradiated for locally advanced lung tumours?
33
Senan
Large radiation field for a locally advanced lung cancer
Locally advanced non-small cell lung cancer (NSCLC)

In appropriately staged and fit
patients, concurrent radiotherapy
and platinum-based chemotherapy
is the standard of care.
Meta-analysis of concurrent vs sequential CT-RT showing survival curves (A) and progression-free survival curves (B)
Radiotherapy doses used are in

the range of 6066 Gy, delivered in
once-daily doses of 2 Gy. Higher total
radiation doses have led to improved
survival.
100
100
RT + concRTCT
+ conc CT
RT + seq RT
CT+ seq CT
100
B
100
80
80
60
60
60
60
40
40
40
40
35.6
35.6
Percent
80
Percent
80
Percent
The most widely studied concurrent

chemotherapy schemes are cisplatin
etoposide or cisplatinvinorelbine.
Percent
RT + concRTCT
+ conc CT
RT + seq RT
CT+ seq CT
HR = 0.90HR
(95%CI,
= 0.900.79
(95%CI,
to 1.01)
0.79 to 1.01)
P = .07 P = .07
40.5
37.9
30.3
20
30.3
23.8
20
18.1
HR = 0.84HR
(95%CI,
= 0.840.74
(95%CI,
to 0.95)
0.74 to 0.95)
P = .004 P = .004
1 2
2 3
23.8
18.4
18.4
15.1
22.7
15.1
20
3 4
10.6
4 5
Deaths/Person-Years
Deaths/Person-Years
by Periodby Period
0y 1y 0y 1y 2y 1y 2y 3y 2y 3y 4y 3y 4>y 4y
> 4y
RT+ concRT+
CT (n
conc
= 603)
CT (n = 603)
240/498 240/498
147/276 147/276
67/171 67/171
30/116 30/116
37/186 37/186
RT+ seq CT
RT+(nseq
= 602)
CT (n = 602)253/491 253/491
171/242 171/242
70/129 70/129
30/ 83 30/ 23/126
83
23/126
19.5
13.1
1 2
2 3
16.0
13.7
13.711.6
11.6
13.1
10.6
10.6 9.4
9.4
3 4
4 5
Time Time
SinceSince
Random
Random
Assignment
Assignment
(years)
(years)
Time Time
SinceSince
Random
Random
Assignment
Assignment
(years)
(years)
Radiation plan showing large fields. High-dose regions in mediastinum and left lung
16.0
19.5
12.8
10.6
22.7
20
18.1
12.8
40.5
37.9
Deaths/Person-Years
Deaths/Person-Years
by Periodby Period
0y 1y 0y 1y 2y 1y 2y 3y 2y 3y 4y 3y 4>y 4y
> 4y
RT+ concRT+
CT (n
conc
= 595)
CT (n = 595)
365/408 365/408
98/170 98/170
36/104 36/104
12/80 12/80
21/134 21/134
RT+ seq CT
RT+(nseq
= 589)
CT (n = 589)391/399 391/399
90/133 90/133
33/80 33/80
13/58 13/58
12/100 12/100
Acute toxicities of the treatment include pain with

swallowing (oesophagitis), haematological toxicity, and
radiation pneumonitis.
Dietary advice and painkillers can mitigate symptoms
of oesophagitis, but a feeding tube may be required.
Symptomatic radiation pneumonitis may occur in up to
30% of patients, but fatal pneumonitis is uncommon.
Post-treatment response evaluation can be difficult due

to fibrosis, but 30% of patients may develop a local
recurrence versus 50% or more with distant failures.
In prospective randomised trials, the addition of surgery

to standard chemoradiotherapy has not led to improved
overall survival in the surgical arm.
All patients should undergo long-term follow-up to identify
and treat complications, comorbidities such as COPD,
and second tumours.
Pre- and post-treatment

images showing radiation
pneumonitis
Pre-treatment
6 months post-treatment
REVISION QUESTIONS
1. What is the chemotherapy of choice with concurrent radiotherapy?
2. Name two common toxicities of concurrent thoracic radiotherapy.
3. What proportion of patients develop distant disease failures after chemoradiotherapy?
34
Stereotactic radiotherapy
Stereotactic radiotherapy is associated with

low toxicity in patients with COPD and the
elderly, and improves population-based
survival in elderly patients.
1999-2001
2002-2004
2005-2007
0.75
0.50
0.25
Log-rank test (2005-2007 v 1999-2001): P < .001
274
254
347
18
24
191
188
283
153
151
238
125
116
174
98
94
118
30
36
83
83
76
0.75
0.50
0.25
Log-rank test (2005-2007 v 1999-2001): P = .0056
12
18
24
30
36
Time Since Diagnosis (months)

71
82
146
66
73
137
50
58
121
38
41
86
30
32
57
21
29
36
15
24
19
1999-2001
2002-2004
2005-2007
0.75
0.50
0.25
Log-rank test (2005-2007 v 1999-2001): P = .1995
99
90
110
18
24
79
76
93
74
63
83
69
58
67
55
50
49
1.00
30
36
51
45
35
49
41
23
1999-2001
2002-2004
2005-2007
0.75
0.50
0.25
Log-rank test (2005-2007 v 1999-2001): P = .2152
0
No. at risk
1999-2001
2002-2004
2005-2007
12
No. at risk
1999-2001
2002-2004
2005-2007
69
72
45
1999-2001
2002-2004
2005-2007
1.00
1.00
0
No. at risk
1999-2001
2002-2004
2005-2007
12
No. at risk
1999-2001
2002-2004
2005-2007
Overall Survival (probability)
So-called risk adapted dosing schemes

are used to deliver a biologically equivalent
tumour dose of 100 Gy, in 38 fractions.
1.00
Changes in population survivals in elderly after introduction of stereotactic ablative radiotherapy

(SABR). (A) All patients; (B) patients treated with surgery; (C) patients treated with radiotherapy;
(D) untreated patients
Stereotactic radiotherapy is the nonsurgical treatment of choice for earlystage NSCLC, and local control rates in
excess of 90% are obtained.
12
18
24
30
36

104
82
91
46
39
53
29
30
34
18
17
21
13
12
12
11
9
5
5
7
3
Recurrences after SABR

Pre-SABR
6 months
Patients are treated on LINACs in an outpatient setting,

and each session can take as little as 20 minutes in total.
12 months
21 months
21.5 months
Pre-treatment, on-couch image guidance utilises

cone-beam CT scans on the treatment table and, less
commonly, tracking of implanted fiducial markers.
Stereotactic radiotherapy for lung cancer can be delivered
on many different treatment machines, or platforms.
HRFs: E nlarging Opacity

Craniocaudal Growth
Sequential Enlargement
Enlargement after 12 months
Linear Margin Disappearance
Bulging Margin
Loss of Air Bronchogram
Post-SABR fibrosis
Careful follow-up is required after stereotactic

radiotherapy in order to distinguish benign fibrosis,
which is common, from an in-field recurrence.
20% of patients develop disease recurrence, with the
majority having out-of-field, isolated distant recurrences at
a median of 9.6 months post-treatment.
Long-term follow-up can identify both locoregional failures
and primary tumours (in 6%), both of which are suitable
for curative therapies.
REVISION QUESTIONS
1. What is the local control rate after stereotactic radiotherapy for early-stage lung tumours?
2. What is the predominant pattern of disease recurrence after stereotactic radiotherapy?
3. What is the aim of follow-up after treatment of early-stage lung cancer?
35
Senan
Small cell lung cancer (SCLC)

Survival after prophylactic cranial irradiation in extensive-stage SCLC
Both chemotherapy and radiotherapy are essential in

the treatment of both early-stage and advanced SCLC.
100
90
80
Overall Survival (%)
Patients with extensive disease SCLC who have no

brain metastases have a survival benefit from receiving
prophylactic brain radiotherapy.
The standard treatment for a patient with limited-stage
SCLC is chemoradiotherapy to the thorax using a
platinum-based scheme and brain radiotherapy.
70
60
50
40
P=0.003
30
20
Control
Irradiation
10
0
12
15
18
21
3
17
2
11
1
6
24
Months
No. at Risk
Control
Irradiation
143
143
115
119
58
67
36
44
15
26
Immobilisation mask and simulation radiograph for delivery of conventional brain irradiation
Prophylactic brain radiotherapy is performed

after the delivery of chemotherapy in order to
minimise risks of neurotoxicity.
Prophylactic brain radiotherapy is delivered
in 10 fractions of 2.5 Gy, and is associated
with alopecia and a short-term decrease in
quality of life.
Concurrent chemoradiotherapy to the thorax
is associated with oesophagitis, bone-marrow
depression, and radiation pneumonitis.
The median survival in patients with limited-stage

SCLC following concurrent chemoradiotherapy is
around 20 months, with 5-year survival around 20%.
Long-term survivors of limited-stage SCLC are at risk
for a second lung cancer, and should be counselled on
smoking cessation.
Survival for limited disease in both study arms of a landmark study

1.0
Probability of Survival
Although one study suggested a survival benefit for

twice-daily fractionation to the thorax, this is not widely
practised due to patient convenience.
0.8
P=0.04 by log-rank test
0.6
0.4
Twice-daily radiotherapy
0.2
Once-daily radiotherapy
0.0
10
20
30
40
50
60
70
80
90
100
Months
TREATMENT G ROUP
020 Mo
Once daily
Twice daily
108/206
100 /211
2040 Mo
4060 Mo
6080 Mo
no. of deaths/no. at risk
48/96
47/109
15/47
7/62
4 /21
5 /42
80100 Mo
0/5
1/14
REVISION QUESTIONS
1. Can use of prophylactic brain radiotherapy improve survival in SCLC?
2. What are common side effects of prophylactic brain radiotherapy?
3. Are survivors of SCLC at risk of developing other lung tumours?
36
Summary: Principles of radiotherapy of thoracic tumours

Radiotherapy is used in both the curative and palliative treatment of thoracic tumours
Small, peripherally located lung tumours can be cured using SABR, which is delivered in an outpatient setting
In limited-stage small cell lung cancer, and locally advanced non-small cell lung cancer, concurrent chemoradiotherapy
offers the best chance of cure
Prophylactic brain irradiation improves the survival of patients whose disease does not progress following
chemotherapy
Precise targeting of tumours using image-guided radiotherapy can minimise the risk of normal tissue damage
4-dimensional CT scans can improve radiotherapy delivery in thoracic tumours
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; 374:379386.
Auprin A, Le Pchoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced
non-small-cell lung cancer. J Clin Oncol 2010; 28:21812190.
Dahele M, Palma D, Lagerwaard F, et al. Radiological changes after stereotactic radiotherapy for stage I lung cancer. J Thorac Oncol
2011; 6:12211228.
De Ruysscher D, Faivre-Finn C, Nestle U, et al. European Organisation for Research and Treatment of Cancer recommendations for
planning and delivery of high-dose, high-precision radiotherapy for lung cancer. J Clin Oncol 2010; 28:53015310.
Palma D, Visser O, Lagerwaard FJ, et al. Impact of introducing stereotactic lung radiotherapy for elderly patients with stage I non-smallcell lung cancer: a population-based time-trend analysis. J Clin Oncol 2010; 28:51535159.
Senthi S, Lagerwaard FJ, Haasbeek CJ, et al. Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage
non-small-cell lung cancer: a retrospective analysis. Lancet Oncol 2012; 13:802809.
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; 357:664672.
van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet 2011; 378:17411755.
van Meerbeeck JP, Kramer GW, Van Schil PE, et al; European Organisation for Research and Treatment of Cancer-Lung Cancer Group.
Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer.
J Natl Cancer Inst 2007; 99:442450.
Vansteenkiste J, De Ruysscher D, Eberhardt WE, et al; ESMO Guidelines Working Group. Early and locally advanced non-small-cell lung
cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24 (Suppl 6):vi8998.
37
Senan
Adjuvant and neoadjuvant therapy

Five-year survival rates of resected non-small cell lung
cancer (NSCLC) range between 73% for pathological
stage (PS) IA and 25% for PS IIIA.
Cisplatin-based CT
NSCLC
Absolute OS benefit
at 5 years
5.3% 1.6%
Toxic death
0.8 to 2%

No. at Risk
Chemotherapy
Control
Chemotherapy (469 deaths)
80
60
40
20
0
The 5-year survival rate was 45% in the CT arm vs 40%

in the control arm (HR 0.86, 95% CI 0.760.98; p <0.03).
These results are consistent with other tumours, i.e.
breast cancer.
Probability of Overall Survival
+ 4% at 5 yrs
100
IALT is the first randomised study to show a benefit

for a cisplatin-based chemotherapy (CT) regimen after
complete surgical resection in patients with stage I to
III NSCLC.
CMF ADJUVANT
Breast Cancer
Control (504 deaths)

P<0.03
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1 2 3 4 5
Years
932
935
775
774
624
602
450
432
308
286
181
164
First positive study

in NSCLC
CMF
P 0.03 (adjusted)
Control
5 10 15 20
Years after Mastectomy
5 yrs
First positive study

in breast cancer
The LACE pooled analysis included 4584 patients

accrued in 5 large cisplatin-based adjuvant trials.
Adjuvant chemotherapy had a 5.3% improvement in
overall survival (OS) and 5.2% disease-free survival
(DFS) at 5 years.
The treatment should ideally begin within 2 months
after surgery in PS 0-1 patients without postoperative
complications and less than 75 years of age.
Three to 4 cycles of chemotherapy should be offered,
although the duration of chemotherapy is still challenging.
Vinorelbine is the most validated compound

in combination with cisplatin in the adjuvant
setting. Other third-generation cytotoxics
have not been compared with vinorelbinecontaining regimens.
Three out of 5 studies included in LACE
offered in the experimental arm 4 cycles
of high-dose cisplatin (100 mg/m every 4
weeks) and vinorelbine (2530 mg/m every
week, up to 16 weeks).
However, in the metastatic setting the high
dose is similar to an alternative lower dose
regimen: 7580 mg/ m, which is more
frequently prescribed in the adjuvant setting
although it has not been formally validated.
Inclusion
criteria
Chemotherapy (No. of cycles, dose of

cisplatin by cycle, daily dose No. of
doses for other drugs)
Radiotherapy
Inclusion period
No. of
patients
included
JBR.10
pT2pN0 or
pT1-2pN1
4 cycles, cisplatin (50 2) mg/m2

Vinorelbine 25 mg/m2 16
No radiotherapy
19942001
482
Stage I,
II, IIIA
Adjuvant Lung
Cancer Project
Italy
3 cycles, cisplatin 100 mg/m

Mitomycin 8 mg/m2 3, vindesine
3 mg/m2 6
Optional after
chemotherapy
19941999
1088
Adjuvant
Navelbine
International
Trialist
Association 01
Stage I,
II, IIIA
4 cycles, cisplatin 100 mg/m2

Vinorelbine 30 mg/m2 16
Optional for
pN+ after
chemotherapy
19942000
840
International
Adjuvant Lung
Trial
Stage I,
II, III
3 cycles, cisplatin 100 or 120 mg/m2 or

4 cycles, cisplatin 80 or 100 mg/m2
Vindesine 3 mg/m2 6-8, or
Vinblastine 4 mg/m2 6-8, or
Vinorelbine 30 mg/m2 weekly 13, or
Etoposide 100 mg/m2 9-12
Optional
according
to pN after
chemotherapy
19952001
1867
Big Lung Trial
Stage I,
II, III
3 cycles, cisplatin 80 mg/m2 (bitherapies)

or 50 mg/m2 (tritherapies)
Vindesine 3 mg/m2 6, or
Vinorelbine 30 mg/m2 6, or
Mitomycin 6 mg/m2 3 and ifosfamide
3 g/m2 3, or
Mitomycin 6 mg/m2 3 and vinblastine
6 g/m2 3
Optional after
chemotherapy
19952001
307
Trial name
REVISION QUESTIONS
1. What is the 5-year benefit of adjuvant chemotherapy?
2. What are the characteristics of the patients eligible for adjuvant chemotherapy?
3. What number of cycles should be given in the adjuvant setting?
38

Histology is not a predictive factor for the benefit of
adjuvant chemotherapy.
Stage II and III NSCLC patients are candidates for
adjuvant chemotherapy: the risk reduction is 17%.
There was a negative effect of adjuvant chemotherapy for
stage IA.
The risk reduction was 8% for stage IB, in which adjuvant
chemotherapy is still debated.
CALGB STAGE IB TRIAL

Paclitaxel 200 mg/m and carboplatin
AUC 6 q3w
4 cycles
4cm
The CALGB study, which was terminated prematurely,

compared 4 cycles of paclitaxelcarboplatin in patients
with resected stage IB NSCLC. There was a significant
benefit for tumours 4 cm.
In the JBR.10 study, patients with tumours 4 cm derived
clinically meaningful benefit from chemotherapy (HR 0.66,
95% CI 0.391.14; p = 0.13) as opposed to those with
tumours <4 cm (HR 1.73, 95% CI 0.983.04; p = 0.06).
<4cm
Most of the ongoing adjuvant trials include patients with

stage IB 4 cm, stage II and stage III NSCLC.
Three large adjuvant chemotherapy 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 chemotherapy
regimens, particularly for vascular disease, could explain
this fading effect.
REVISION QUESTIONS
1. When can adjuvant chemotherapy 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 chemotherapy a concern?
39
Besse

A 2-year adjuvant treatment with tegafururacil (UFT)
showed benefit versus surgery alone in Japanese patients
with stage I.
A meta-analysis of 2003 eligible patients showed an
increase in survival rates at 5 and 7 years in favour of
UFT + surgery versus 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.
Events Totals
S alone 1729 4142
S+CT 1594 4305
1.0
0.9
0.8
+ 4% at 5 years
Survival
0.7
0.6
0.5
0.4
N=8447
0.3
0.2
0.1
0
0 1 2 3 4 5 6 7 8
Years
Number at risk
4142 3648 3102 2584 2083 1601 841 407 148
S alone
4305 3809 3261 2746 2278 1785 936 473 165
S+CT
The individual patient-based (IPD) meta-analysis

(8447 patients) showed an absolute benefit in OS at
5 years of 4% in all stages of adjuvant treatment.
Platinum-based chemotherapy was used in 18 trials. In
stage I patients, which represent 65% of the cohort, the
meta-analysis is not conclusive for stage IA.
Most adjuvant studies used the 6th TNM classification,
where stage IB was defined as tumours 3 cm. This may
suggest that the 5-year survival of 5% is not applicable
with the 7th TNM classification.
HR 0.87, 95% CI 0.810.93; p <0.000001
The IPD meta-analysis of 15 trials (2385 patients) showed

that preoperative chemotherapy significantly increased
survival (HR 0.87, 95% CI 0.780.96; p = 0.007).
When preoperative chemotherapy induces a response,

there is a trend for larger benefit when adjuvant
chemotherapy is given (HR 0.78, 95% CI 0.640.95;
p = 0.02).
0.9
No preoperative chemotherapy
Preoperative chemotherapy
Events Totals
745 1207
682 1178
0.8
0.7
Survival
No subgroup of patients was identified who derived more

benefit from preoperative chemotherapy based on age,
performance status, sex, histology, and stage.
1.0
+ 5% at 5 years
0.6
0.5
0.4
0.3
0.2
0.1
0
N=2385
0 1 2 3 4 5 6 7 8
Time from randomisation (years)

Number at risk
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 0.780.96; p = 0.007
REVISION QUESTIONS
1. Who are the patients eligible for adjuvant UFT?
2. W
hat are the HRs between surgery and surgery + neoadjuvant or postoperative surgery in the 2 meta-analyses based on
individual patients data?
3. Is there a group of patients who would derive more benefit from adjuvant chemotherapy compared with preoperative chemotherapy?
40
Compliance is improved with preoperative chemotherapy.

In the IFCT-0002 study, 90.4% of patients received
4 cycles of preoperative chemotherapy in one arm
compared to 75.2% in the other arm (2 cycles before
and 2 cycles after surgery).
Preoperative chemotherapy does not promote lungsparing surgery, meaning that it does not decrease the
rate of pneumonectomy vs lobectomy.
Preoperative chemotherapy v Surgery alone:

HR = 0.96 (95% CI, 0.84 to 1.1); P = .56
Adjuvant chemotherapy v Surgery alone:
HR = 0.99 (95% CI, 0.75 to 1.3); P = .93
Events: Preoperative chemotherapy 99 (49.7%)
Adjuvant chemotherapy 102 (48.6%)
Surgery 109 (51.9%)
1.0
Phase III
624 patients
IA (>2 cm),
IB, II, T3N1
Arm 1 : surgery
Arm 2 : 3XPC then surgery
Arm 3 : surgery then 3XPC
Disease-Free Survival
(probability)
Only one phase III trial has compared preoperative

or adjuvant chemotherapy to surgery alone, without
pointing out a better setting based on DFS.
0.8
0.6
0.4
0.2
Preoperative chemotherapy
Adjuvant chemotherapy
Surgery alone

0 1 2 3 4 5 6
Time (years)
No. at risk
165 131 99 71 45 31
Preoperative
Adjuvant 161 121 90 65 40 29
Surgery 168 131 105 72 40 27
PC = paclitaxel 200 mg/m + carboplatin AUC 6 q3w
The figure shows the proportion of patients with

surgically resected NSCLC diagnosed in Ontario
who received adjuvant chemotherapy.
~25%!
Adjuvant chemotherapy uptake is still very low, mostly

due to the toxicity of the treatment leading to a drastic
patient selection.
Alternative treatments have been explored, such as the
use of targeted therapies or vaccine strategies, which are
less toxic.
Ontario database (n=6304) from 2001 to 2006
Postoperative radiotherapy (PORT) remains controversial

in completely resected NSCLC patients with
pathologically involved mediastinal lymph nodes (N2),
whereas it is not a standard for stage I and II.
PORT Improves Overall Survival
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
REVISION QUESTIONS
1. How can you increase the perioperative chemotherapy compliance?
2. Are pneumonectomies a contraindication to perioperative chemotherapy?
3. Is mediastinal radiotherapy a standard treatment for resected N2 NSCLC patients?
41
Besse

No biomarker has been fully validated as able to identify
subgroups of patients for whom adjuvant treatment would
be of particular benefit.
This high-risk group
might benefit from adjuvant
chemotherapy. Clinical trials
stratified on multigene
assays are ongoing
Despite great efforts, no validated tools are available for

identifying resistance to chemotherapy (i.e. the excision
repair cross-complementation group 1 [ERCC1] enzyme).
The figure shows an example of a 14-gene expression
assay that uses quantitative polymerase chain
reaction (qPCR) to identify patients with early-stage
non-squamous NSCLC at high risk for mortality after
surgical resection.
Overall survival for 330 patients with American Joint Commission on Cancer stage IA and
IB disease considered to be low risk as per conventional pathological criteria (National
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
The RADIANT study explored the activity of 2-year

treatment with erlotinib (150 mg/d) in patients with
immunohistochemically or FISH-evaluated
EGFR-positive tumours.
There was no difference in DFS (HR 0.90, 95%
CI 0.7411.104; p = 0.0391) or OS in the overall
population (HR 1.13, 95% CI 0.081.44; p = 0.33).
In mutated patients, DFS was not significantly
increased (HR 0.61, 95% CI 0.30.9; p = 0.03) and
OS was similar (HR 1.09, 95% CI 0.52.1; p = 0.81).
The use of EGFR tyrosine kinase inhibitors (TKIs) in this
setting is not validated.
The use of the anti-vascular endothelial growth factor

(VEGF) antibody bevacizumab (15 mg/kg every 3 weeks
for 1 year) is under investigation (ECOG 1505 trial).
Other non-chemotherapy approaches include the
MAGE-A3 antigen-specific vaccine, which has not shown
any advantage in 2 of the 3 coprimary endpoints after
accrual of > 2000 patients.
Among the other promising drugs for the adjuvant setting
are the checkpoint inhibitors (such as anti-PD1 antibodies)
that are being evaluated in the metastatic setting.
REVISION QUESTIONS
1. Which biomarker is mandatory for the adjuvant chemotherapy indication?
2. Is cisplatin-based chemotherapy 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 chemotherapy improves survival in resected NSCLC patients
Meta-analysis of preoperative chemotherapy and adjuvant chemotherapy demonstrated a benefit that is in the same
range in both settings
Standard: cisplatin-based chemotherapy
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
chemotherapy
Never use targeted therapy (erlotinib, gefitinib, bevacizumab)
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; 350:351360.
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; 28:34723478.
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; 2:706714.
Goss GD, OCallaghan 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; 31:33203326.
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; 350:17131721.
Kratz JR, He J, Van Den Eeden SK. A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung
cancer: development and international validation studies. Lancet 2012; 379:823832.
Le Pchoux C. Role of postoperative radiotherapy in resected non-small cell lung cancer: a reassessment based on new data.
Oncologist 2011; 16: 672681.
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;
375:12671277.
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; 383:15611571.
Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group.
J Clin Oncol 2008; 26:35523559.
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; 26:50435051.
Wakelee HA, Dahlberg SE, Keller SM, et al. Interim report of on-study demographics and toxicity from E1505, a phase III randomised
trial of adjuvant (adj) chemotherapy (chemo) with or without bevacizumab (B) for completely resected early-stage non-small cell lung
cancer (NSCLC). J Clin Oncol 2011; 29 (suppl; abstr. 7013).
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; 49:26542664.
43
Besse
Treatment of metastatic non-small cell lung cancer
Introduction
Chemotherapy in metastatic non-small cell lung cancer
(NSCLC) has reached a plateau.
Cisplatin and paclitaxel

Cisplatin and gemcitabine
Cisplatin and docetaxel
Carboplatin and paclitaxel
100
A total of 1207 patients were randomly assigned to

cisplatin and paclitaxel, cisplatin and gemcitabine,
cisplatin and docetaxel, or carboplatin and paclitaxel.
Survival (%)
80
The overall survival (OS) of all regimens was

7.48.1 months. There was no significant difference
between the 4 treatment regimens.
60
40
20
0
10
Planned subgroup analysis
Survival Probability
0.9
CP
CG
0.8
0.7
CP v CG
0.6
30
40
In 1725 chemotherapy-naive patients with stage IIIB or

IV NSCLC, cisplatinpemetrexed (CP) provided similar
efficacy compared to cisplatingemcitabine (CG).
Median; 95% CI
1.0
20
11.8; 10.4, 13.2

10.4; 9.6, 11.2
In the intent-to-treat population, overall survival for CP was

non-inferior to CG (median survival, 10.3 vs 10.3 months,
respectively, hazard ratio [HR] 0.94, 95% CI 0.841.05).
Adjusted HR; 95% CI

0.81; 0.70, 0.94
0.5
0.4
In a prespecified subgroup analysis, CP-treated patients

with non-squamous histology had a significantly better
survival than CG-treated patients.
0.3
0.2
0.1
0
12
18
24
Meta-analysis included 13 RCTs and

3027 patients receiving first-line (largely
platinum-based) chemotherapy for
34 cycles versus continuation of the
same chemotherapy for 6 cycles or until
disease progression.
Extending chemotherapy improved
progression-free survival (PFS)
substantially (HR 0.75, 95% CI 0.690.81;
p <0.00001) and showed no significant
improvement of OS (HR 0.94, 95% CI
0.861.01; p = 0.10).
30
Study (Year
published)
Zarogoulidis (1995)
Buccheri (1989)
Barata (2007)
Ciuleanu (2008)
Fidias (2007)
Brodowicz (2006)
Smith (2001)
Socinski (2002)
Belani (2003)
von Plessen (2006)
Westeel (2005)
Park (2007)
Tourani (1990)
Extended
duration
36
38
110
441
153
138
153
116
65
147
91
158
12
Standard
duration
Hazard ratio (fixed)

95% CI
Weight
%
38
36
110
222
154
68
155
114
65
150
90
156
11
Total (95% CI)

1,658
1,369
Test for heterogeneity: 2 = 12.68, df = 12 (P = .39), I 2 = 5%
Test for overall effect: z = 2.18, P = .03
Extending chemotherapy was associated

with higher toxicity and impaired
quality of life.
0.5
0.7
Extended better
1.5
Hazard ratio (fixed)

95% CI
3
2
7
10
9
2
15
23
3
10
6
6
4
0.71 (0.45 to 1.12)

0.73 (0.46 to 1.17)
0.77 (0.59 to 1.01)
0.79 (0.63 to 1.01)
0.84 (0.65 to 1.08)
0.84 (0.52 to 1.38)
0.88 (0.72 to 1.07)
0.96 (0.82 to 1.12)
1.02 (0.66 to 1.57)
1.04 (0.82 to 1.32)
1.08 (0.79 to 1.48)
1.11 (0.82 to 1.48)
1.26 (0.85 to 1.86)
100
0.92 (0.85 to 0.99)
Standard better
Overall survival analysis:

extending chemotherapy
beyond a standard
duration
REVISION QUESTIONS
1. What is the best chemotherapy regimen for first-line therapy?
2. What is the optimal duration of first-line chemotherapy?
3. Is the histological subgroup important?
44
Molecular testing
In adenocarcinoma, multiple driving mutations can be detected. Similarly,
increasing mutations are also found in squamous cell lung cancers.
Several compounds are being tested against specific driver mutations.
However, despite impressive response rates for some agents, the tumour cells
will ultimately develop resistance mechanisms resulting in cancer regrowth.
K-RAS
Molecular testing of therapy-naive tumours as well as re-testing of

progressing tumours is necessary in order to detect driver mutations that
may result in defined treatment options.
Unknown
EGFR
EML4ALK HER2
BRAF
PI3KCA
AKT1
MET MAP2K1
EGFR mutation testing in NSCLC is an

important molecular pathological diagnostic
assay that is predictive of response to
anti-EGFR therapy. Several methods may
be used for testing of EGFR mutations.
Most frequent are deletions in exon 19
and L858R point mutation in exon 21,
resulting in activated EGFR signalling.
Mutations may also occur in exons 18
and 20, resulting in various effects on
EGFR function including resistance to
some EGFR TKIs (such as T790M).
Several guidelines recommend testing of
all NSCLC tumours for EGFR mutations
at least cancers without predominant
squamous histology, where EGFR
mutations occur in 1216%.
In a phase III study, 347 patients with ALK-positive

NSCLC who had received one prior platinum-based
regimen were treated with chemotherapy (docetaxel
or pemetrexed) or crizotinib, an ALK-targeting TKI.
The response rates were 65% (crizotinib) and 20%
(chemotherapy) (p <0.001).
The median PFS was 7.7 months in the crizotinib group
and 3.0 months in the chemotherapy group (HR 0.49, 95%
CI 0.370.64; p <0.001). Median OS was not significantly
different, possibly due to crossover of 64% of patients.
Progression-free survival with crizotinib vs pemetrexed or docetaxel

Probability of Progression-free
Survival (%)
Another example of driving alterations that offers the

chance of specific treatment is the identification of EML4
ALK translocations. Several EML4-ALK fusion proteins
have been described, leading to ALK over-activation.
100
Crizotinib
80
Hazard ratio for progression or death,

0.30 (95% CI, 0.210.43)
P<0.001 (vs. docetaxel)
60
40
Pemetrexed
20
0
Docetaxel
0
10
15
20
25
11
3
1
2
1
0
0
0
No. at Risk
Crizotinib
Pemetrexed
Docetaxel
172
99
72
1. Which driving mutations have gained interest recently?

2. Who should be tested for EGFR mutations and EML4ALK translocations?
3. Is there a clinical benefit in targeting EGFR mutations and/or EML4ALK translocations?
Reinmuth & Reck
Months
REVISION QUESTIONS
45
Hazard ratio for progression or death,

0.59 (95% CI, 0.430.80)
P<0.001 (vs. pemetrexed)
93
36
13
38
2
3
EGFR inhibitors
In a landmark study, 1217 previously untreated patients
(Asian, never-smokers, and former light-smokers) with untreated
stage IIIB/IV pulmonary adenocarcinoma were treated with
gefitinib or carboplatinpaclitaxel.
The median PFS was 5.7 months in the gefitinib group and
5.8 months in the carboplatinpaclitaxel group, approximately
coinciding with crossing of the KaplanMeier curves.
In the subgroup of 261 patients with EGFR gene mutations, PFS
was significantly longer for those who received gefitinib (HR 0.48,
95% CI 0.360.64; p <0.001), whereas, in the subgroup of 176 EGFR
wild-type patients, PFS was significantly longer for chemotherapytreated patients (HR 2.85, 95% CI 2.053.98; p <0.001). With a
high proportion of chemotherapy-treated patients receiving gefitinib
subsequently, OS (954 deaths) was similar for both treatment arms
(HR 0.90, 95% CI 0.791.02; p = 0.109).
1.0
Erlotinib (n=86)
Chemotherapy (n=87)
HR 0.37 (95% CI 0.25-0.54); log-rank p<0.0001
PFS probability
0.8
0.6
0.4
Erlotinib
(n=86)
0.2 Chemotherapy
(n=87)
12
15 18 21
Time (months)
24
27
30
33
36
Number at risk
Erlotinib 86
63 54 32 21 17 9 7 4 2 2 0 0
Chemotherapy 87
49 20 8 5 4 3 1 0 0 0 0 0
Probability of Progression-free
Survival
EGFR mutationpositive
1.0
Hazard ratio, 0.48 (95% CI, 0.360.64)

P<0.001
Events: gefitinib, 97 (73.5%); carboplatin
plus paclitaxel, 111 (86.0%)
0.8
0.6
0.4
Carboplatin
plus
paclitaxel
0.2
0.0
Gefitinib
12
16
20
24
Months since Randomization

No. at Risk
Gefitinib
132
Carboplatin plus 129
paclitaxel
108
103
71
37
31
7
11
2
3
1
0
0
In a Caucasian collective, 174 chemo-naive patients with

stage IIIB/IV NSCLC and harbouring EGFR mutations
were treated with erlotinib or 4 cycles of platinum-based
doublet chemotherapy.
PFS was significantly different and in favour of the
erlotinib arm (10.4 vs 5.1 months, HR 0.34, 95%
CI 0.23410.4944; p <0.0001). Overall survival was
similar between both treatment arms, possibly due to
crossover (HR 0.9319; p = 0.7149).
Molecular analyses displayed frequent pre-therapeutic
occurrence of T790M mutations, EML4ALK and BIM
expression using highly sensitive PCR techniques.
Finally, afatinib, another TKI binding irreversibly to the

EGFR, was compared with pemetrexedcisplatin in
a phase III study in therapy-naive patients with EGFR
mutation-positive advanced lung adenocarcinoma.
345 patients were randomised (230 for afatinib; 115
for chemotherapy). The median PFS was in favour of
afatinib-treated patients (11.1 vs 6.9 months, HR 0.58,
95% CI 0.430.78; p = 0.0004). This efficacy was
consistent in all relevant subgroups.
Afatinib
Cisplatin/pemetrexed
Moreover, there was a significant delay in time to

deterioration of cancer-related symptoms and significant
improvements in the global health status/quality of life
with afatinib vs pemetrexedcisplatin.
REVISION QUESTIONS
1. Which patients should receive EGFR TKI?
2. With therapy with EGFR TKI, what OS can be expected in patients with EGFR mutations?
3. Are there data on which EGFR TKI is superior compared to the others?
46
Antiangiogenic therapy
The median survival was superior for the bevacizumabcontaining regimen (12.3 vs 10.3 months, HR 0.79;
p = 0.003). Similarly, PFS was improved (6.2 vs 4.5
months, HR 0.66; p <0.001) with corresponding response
rates of 35% and 15% (p <0.001). In this study, rates
of clinically significant bleeding were 4.4% and 0.7%,
respectively (p <0.001).
100
Hazard ratio, 0.79
P=0.003
80
878 NSCLC patients (stage IIIB or IV) were treated with

paclitaxelcarboplatin with or without bevacizumab. After
6 cycles, bevacizumab was administered every 3 weeks
until disease progression.
Progression-Free
Survival (probability)
Placebo + CG (n = 347)
Bevacizumab 15 mg/kg + CG (n = 351)
0.8
HR (95% CI) = 0.82 (0.68 to 0.98)

P = .03
0.6
0.4
12
15
PC group
(344 events in
433 patients)
228
238
122
148
36
46
12
16
3
5
0
0
1314 patients with histologically or cytologically

confirmed stage IIIB/IV or recurrent NSCLC were
randomised to therapy with docetaxel with or without
nintedanib. All NSCLC histologies were included.
PFS and OS data are displayed.
Interestingly, adenocarcinoma patients with progressive
disease under first-line therapy benefitted most from the
addition with nintedanib. So far, there is no biomarker for
antiangiogenic treatment.
18
24
30
36
42
PC, paclitaxel and carboplatin; BPC, paclitaxel and carboplatin plus bevacizumab
In a three-arm phase III study, 1043 patients received

cisplatin and gemcitabine with or without low-dose
(7.5 mg/kg) or high-dose bevacizumab (15 mg/kg).
The rates of grade 3 hypertension, bleeding, and
proteinuria were modestly higher in the bevacizumab
arms than in the placebo arm.
Median OS was >13 months in all treatment groups;

OS was not significantly increased with the addition of
bevacizumab. Most patients (62%) received multiple lines
of post-study treatment.
Nintedanib+ Placebo+
docetaxel docetaxel
HR (95% CI)
p value
PFS, months
All patients
Adenocarcinoma
SCC
3.4
4.0
2.2
2.7
2.8
2.6
0.79 (0.680.92) 0.0019

0.77 (0.620.96) 0.0153
0.77 (0.620.96) 0.0200
OS, months
All patients
Adenocarcinoma
SCC
10.1
12.6
8.6
9.1
10.3
8.7
0.94 (0.831.05) 0.2720

0.83 (0.700.99) 0.0359
1.01 (0.851.21) 0.8907
REVISION QUESTIONS
1. What is the benefit of adding antiangiogenic therapy to chemotherapy?
2. Which NSCLC patients can be treated with antiangiogenic therapy?
3. Do TKIs targeting VEGFR show clinical benefit?
Reinmuth & Reck
12
Month
Nintedanib is a multi-TKI inhibiting VEGFR, PDGFR, and

FGFR. This is the first study with a multi-TKI demonstrating
benefit in PFS and OS, at least in pre-planned histological
subgroup analyses, in second-line treatment.
47
18
Time (months)
No. of patients at risk
Placebo + CG
347
Bev 15 mg/kg + CG 351
40
PFS was significantly prolonged (low-dose group: median

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).
0.2
60
20
Patients with squamous cell tumours, tumour infiltration of

large central vessels, and clinically significant haemoptysis
should not receive bevacizumab.
1.0
BPC group
(305 events in
417 patients)
Maintenance therapy
Pemetrexed significantly improved PFS (4.3 vs 2.6 months,

HR 0.50, 95% CI 0.420.61; p <0.0001) and OS (13.4 vs
10.6 months, HR 0.79, 95% CI 0.650.95, p = 0.012).
Subgroup of EGFR
wild-type patients
1.0
0.8
08
07
HR 050 (95% CI 042061); p<00001
06
05
04
03
02
01
0
12
18
24
122
19
33
3
9
1
1
0
Number at risk
Pemetrexed 441
Placebo 222
NSCLC patients without disease progression after

first-line therapy received erlotinib (n=438) or placebo
(n=451) until progression or unacceptable toxicity.
0.6
0.4
0.2
HR=0.78 (0.63-0.96); p=0.0185
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
165
158
91 79 57
43 37
29
17 15 11 8 7 7 5 5 5 4 2 2 1 0 0
Erlotinib
163
158
82 55 37
26 22 17
11 10 9 8 7 7 6 5 3 3 1 1 1 1 1
Placebo
In contrast to switch maintenance where a third agent is

initiated after 4 cycles of platinum-based double-agent
chemotherapy, continuous maintenance uses an agent
that was already part of the first-line treatment.
After 4 cycles of pemetrexed plus cisplatin, 539 stage
IIIB/IV NSCLC patients received continuation maintenance
with pemetrexed (n=359) or placebo (n=180).
Patients in the pemetrexed arm had a superior PFS
(4.1 vs 2.8 months; p <0.0001) and OS (16.9 vs
14 months; p = 0.0191).
Overall, median PFS was significantly longer with

erlotinib than with placebo (12.3 vs 11.1 weeks, HR 0.71,
95% CI 0.620.82; p <0.0001).
Patients who had stable disease after first-line
chemotherapy seemed to have a more pronounced OS
benefit with maintenance erlotinib (median 11.9 vs 9.6
months, HR 0.72; p = 0.0019) than those who had a
previous response (median 12.5 vs 12.0 months, HR 0.94;
p = 0.618).
100
Progression-free survival (%)
Progression-free survival
Maintenance therapy with pemetrexed was generally well

tolerated. For patients with squamous histology, PFS was
not significantly different (p = 0.896).
Pemetrexed
Placebo
10
09
PFS probability
To test the hypothesis of switch maintenance, 663 patients

with stage IIIB or IV NSCLC who had not progressed
on 4 cycles of platinum-based chemotherapy received
pemetrexed (n=441) or placebo (n=222) until disease
progression.
Pemetrexed+BSC
Placebo+BSC
Median PFS (95% CI)
Pemetrexed 41 (3246)
Placebo 28 (2631)
Log-rank p<00001
HR=062 (95% CI 049079)
Wald p<00001
80
60
40
20
0
0
Number at risk
Pemetrexed+BSC 359
180
Placebo+BSC
12
15
132
52
57
15
21
5
4
0
0
0
18
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?
48
Second-line therapy
Patients with stage IIIB/IV NSCLC and progression after
platinum-based chemotherapy were randomised to
treatment with docetaxel 100 mg/m (49 patients) or
75 mg/m (55 patients) or best supportive care (BSC).
DOCETAXEL 75 mg/m2
(n=55)
BSC75 (n=49)
0.9
0.8
CUMULATIVE PROBABILITY
Time to progression was longer for docetaxel patients

overall than for BSC patients (10.6 vs 6.7 weeks,
respectively; p <0.001), as was median survival
(7.0 vs 4.6 months; log-rank test, p = 0.047).
1.0
No benefit in survival was seen for patients treated with

docetaxel 100 mg/m. Conclusively, the benefits of
docetaxel therapy at a dose of 75 mg/m outweigh
the risks.
0.7
Log-rank test, p=0.010
0.6
0.5
0.4
0.3
0.2
0.1
0.0

0 3 6 9 12
15 18
21
SURVIVAL TIME (MONTHS)
571 NSCLC patients with one prior chemotherapy

regimen were treated with pemetrexed 500 mg/m or
docetaxel 75 mg/m.
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 after treatment
with 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).
100
After progression on 1 or 2 prior chemotherapy regimens,

731 patients were randomly assigned in a 2:1 ratio to
receive oral erlotinib or placebo.
Patients (%)
80
For erlotinib and placebo, PFS was 2.2 months and

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).
In a retrospective analysis of 204 tumours, 34 (17%) had
EGFR exon 19 deletion or exon 21 L858R mutations. After
erlotinib therapy, response rates were higher in EGFR
mutant tumours (27% vs 7%; p = 0.03) but no significant
OS benefit was seen (wild-type EGFR HR 0.74; p = 0.09;
mutant EGFR HR 0.55; p = 0.12).
P<0.001 by stratified log-rank test

Hazard ratio, 0.70 (95% CI, 0.580.85)
60
40
20
12
18
24
30
9
23
0
4
0
0
No. at Risk
Placebo
Erlotinib
243
488
1. What are the treatment options for progressing NSCLC tumours after first-line therapy?
2. Is histology important for treatment selection of second-line therapy?
3. Is chemotherapy the first choice for second-line therapy?
Reinmuth & Reck
Months
REVISION QUESTIONS
49
Erlotinib
Placebo
107
255
50
145
Overall survival
Summary: Treatment of metastatic NSCLC

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 mutations and EML4ALK translocations
Chemotherapy: New cytotoxic agents display improved efficacy in defined patient subgroups
Patients harbouring activating EGFR mutations are characterised by improved prognosis and superior response
to EGFR TKI
In comparison to chemotherapy, patients with EML4ALK translocations show improved response and outcome
with ALK inhibitors
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
Further Reading
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; 22:15891597.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;
361:947957.
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; 27:12271234.
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;
355:25422550.
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; 26:35433551.
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; 346:9298.
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; 18:20952103.
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; 353:123132.
Stinchcombe TE, Socinski MA. Maintenance therapy in advanced non-small cell lung cancer: current status and future implications.
J Thorac Oncol 2011; 6:174182.
50
Treatment of small cell lung cancer:

chemotherapy and radiotherapy
General principles
80% of patients with small cell lung cancer (SCLC)
present with metastatic (stage IV) disease.
SCLC pT1 M0
100%
20% have stage IIII SCLC, which overlaps with the

former so-called limited stage.
N0
N1
N2
80%
Median
Deaths / N in Months
37 / 68
78
22 / 37
29
15 / 20
18
60%
Very rarely, SCLC presents as a solitary nodule, stage I.
40%
20%
0%
10
Survival, Years
Survival of patients with oat cell carcinoma treated

primarily by methods other than operation
Survival, yr.
<1
1-2
2-3
7+
Treatment
No. pt.
Radiation only
80
72
7
1
Radiation & radioisotopes

2
2
Chemotherapy only
30
28
2
Chemotherapy & radiation

95
82
6
6
1*
Early attempts to treat SCLC with surgery failed.

In early trials, radiotherapy was better than surgery,
but still palliative when used alone.
The survival improvement was observed when patients
were treated with cyclophosphamide.
*The patient is alive and well.

Review: Platinum versus non-platinum chemotherapy regimens for small cell lung cancer
Comparison: 1 Treatment Regimens
Outcome: 3 24-month survival
NonPlatinum
regime
Study or subgroup
Platinum regime
Risk Ratio
M-H,
Random, 95% CI
n/N
n/N
1 Undifferentiated
Farris 1993
Fukuoka 1991
Postmus 1992
Sculier 1990
Sculier 1993
Smith 1991
Souhami 1997
Urban 1999b
Veronesi 1994
White 2001
Subtotal (95% CI)
8/56
14/97
4/60
9/95
11/107
6/47
0/80
11/229
5/70
2/60
6/57
12/97
5/63
12/106
9/108
4/48
4/75
11/228
11/66
2/59
901
907
Weight
3.7
5.5
2.6
4.7
4.6
2.8
0.6
4.7
3.6
1.3
%
%
%
%
%
%
%
%
%
%
34.1%
Risk Ratio
M-H,
Random, 95% CI
1.36
1.17
0.84
0.84
1.23
1.53
0.10
1.00
0.43
0.98
[
[
[
[
[
[
[
[
[
[
0.50,
0.57,
0.24,
0.37,
0.53,
0.46,
0.01,
0.44,
0.16,
0.14,
3.66
2.39
2.98
1.90
2.86
5.08
1.90
2.25
1.17
6.75
]
]
]
]
]
]
]
]
]
]
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)
Systemic treatment has improved survival in

all SCLC stages and is the cornerstone
of the treatment.
2 Limited Disease
Eagan 1981
Fukuoka 1986
Goodman 1990
Havemann 1987
Jones 1993
Sundstrom 2002
Urban 1999a
Wolf 1987
Subtotal (95% CI)
Non-platinum combinations
(e.g. cyclophosphamide, doxorubicin,
etoposide) are efficacious but less used
than cisplatinetoposide.
In stage IIII SCLC, cisplatinetoposide is
combined with concurrent chest radiotherapy.
10/31
1/10
62/194
7/51
0/17
26/105
8/81
6/27
9/31
2/11
52/194
6/53
5/15
9/109
20/88
3/27
516
528
5.2
1.0
9.7
3.5
0.6
5.5
5.1
2.5
%
%
%
%
%
%
%
%
33.2%
1.11
0.55
1.19
1.21
0.08
3.00
0.43
2.00
[
[
[
[
[
[
[
[
0.52,
0.06,
0.87,
0.44,
0.00,
1.48,
0.20,
0.56,
2.35
5.18
1.63
3.36
1.35
6.09
0.93
7.19
1.11 [0.67,1.82]

Heterogeneity: Tau2 = 0.26; Chi2 = 17.90, df = 7 (P = 0.01); I2 =61%
3 Extensive Disease
Chahinian 1989
Fukuoka 1986
Gatzemeier 1994
Greco 2005
Havemann 1987
Jones 1993
Kanitz 1992
Lyss 2002
Postmus 1996
Roth 1992
Sundstrom 2002
Urban 1999a
Wampler 1991
Wolf 1987
2/105
3/25
24/171
5/60
6/99
0/37
0/59
0/12
5/70
12/148
5/113
4/110
13/85
3/46
4/103
2/23
24/173
9/60
3/99
1/35
14/52
2/13
5/73
6/146
4/109
0/115
3/85
4/41
Subtotal (95% CI)
1140
1127
1.6
1.6
7.3
3.5
2.3
0.5
0.6
0.6
2.8
3.9
2.5
0.6
2.7
2.1
%
%
%
%
%
%
%
%
%
%
%
%
%
%
0.49 [ 0.09, 2.62

1.38 [ 0.25, 7.53
1.01 [ 0.60, 1.71
0.56 [ 0.20, 1.56
2.00 [ 0.51, 7.77
0.32 [ 0.01, 7.50
0.03 [ 0.00, 0.50
0.22 [ 0.01, 4.08
1.04 [ 0.32, 3.45
1.97 [ 0.76, 5.12
1.21 [ 0.33, 4.37
9.41 [ 0.51, 172.68
4.33 [ 1.28, 14.66
0.67 [ 0.16, 2.81
Total (95% CI)
2557
2562

Heterogeneity: Tau2 = 0.12; Chi2 = 46.27, df = 31 (P = 0.04); I2 =33%
0.1 0.2
0.5 1
2
5 10
Favours Non-Platinum
Favours Platinum
REVISION QUESTIONS
1. What proportion of patients with newly diagnosed SCLC already have disseminated disease?
2. Has surgery a major role to play in the management of non-disseminated SCLC?
3. What is the cornerstone of treatment of SCLC?
De Ruysscher
]
]
]
]
]
]
]
]
]
]
]
]
]
]
32.7%
1.08 [0.68,1.71]
100.0%
1.06 [0.84,1.33]

Heterogeneity:2 Tau = 0.25; Chi2 = 20.83, df = 13 (P = 0.08); I2 =38%
51
]
]
]
]
]
]
]
]
Disseminated disease: first-line treatment

SCLC is in first line a very chemosensitive disease.
1.0
Rapid tumour responses are observed in over 80% of

patients.
0.8
Proportion surviving
Chemotherapy is also useful in patients with a poor

performance status, but at the cost of more toxicity.
0.9
1-year
2-year
0.6
CE 10.6 months 41%
MST
11%
0.5
SPE 9.9 months
12%
0.7
35%
0.4
0.3
P = 0.54
0.2
(one-sided, log-rank test)
0.1
0.0
Years after randomisation
CE, carboplatin plus etoposide; SPE, split doses of cisplatin plus etoposide
The first-choice treatment is 46 cycles of etoposide

and a platinum derivative (cisplatin or carboplatin).
1.0
0.9
Probability of survival
0.8
Other combinations may have similar activity, but this has

not been consistently demonstrated.
0.7
0.6
Cisplatin can probably safely be replaced by carboplatin

in order to decrease toxicity and to facilitate the delivery.
0.5
0.4
0.3
0.2
0.1
EP
CEV
0.0
0 12 24 36 48 60
Time (months)
CEV, cyclophosphamide, epirubicin, and vincristine; EP, etoposide and cisplatin
The combination of cisplatin and irinotecan was

superior for survival to cisplatin and etoposide, but only
in Asian populations.
European and US studies did not demonstrate a
beneficial effect of cisplatin and irinotecan over cisplatin
etoposide, the latter remaining first choice.
European and US patients experienced more toxicity
with irinotecan than Asians, possibly due to genetic
differences in topoisomerase I enzymes.
REVISION QUESTIONS
1. Is combination therapy acceptable in patients with a poor performance status?
2. Can cisplatin be substituted by carboplatin?
3. Which chemotherapy combination is first choice in European populations?
52
Treatment of small cell lung cancer: chemotherapy and radiotherapy
Disseminated disease: first-line treatment

Immediate whole-brain radiotherapy (WBRT) is indicated
in patients with brain metastases and intracranial
hypertension or neurological emergencies.
Asymptomatic brain metastases can be treated with
systemic therapy and WBRT deferred to symptomatic
relapse.
Directly after WBRT, systemic therapy can be given.
Time to progression inside the brain

%
100
90
80
70
60
50
40
30
20
10
N 0
60 55 CT
60 51 CT + WBRT
Logrank P = 0.005
(months)
0 2 4 6 8 10
Number of patients at risk:
60 24 11 3 2 CT
60 33 19 15 12 CT + WBRT
Because of the fast response to systemic treatment,

a superior vena cava syndrome can be treated with
chemotherapy 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 813 months and the 5-year
survival 5%.
Prophylactic cranial irradiation (PCI) given after

chemotherapy to patients showing any response and
with a reasonable performance status decreases the
incidence of symptomatic brain metastases.
100
90
Symptomatic brain metastases occur in nearly 50%

of patients, even in those without detectable brain
metastases at diagnosis.
80
70
60
50
40
P=0.003
30
20
Control
Irradiation
10
0
PCI also increases survival in these cases.
12
15
18
21
3
17
2
11
1
6
Months
No. at Risk
Control
Irradiation
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?
53
De Ruysscher
143
143
115
119
58
67
36
44
15
26
24
Disseminated disease: second-line treatment

Virtually all patients with disseminated disease will
relapse even after having achieved a remission with
first-line chemotherapy.
Progression free survival
100
Eligible patients who started treatment
90
Patients are classified as having a sensitive relapse when

the recurrence is seen 90 days or more after the end of
first-line treatment.
80
Median in Months (95% 2-sided CI)
70
Amrub:
5.2 (3.0, 7.5)
Amrub + Cisp: 6.9 (6.0, 7.5)
Cisp + Etop:
5.8 (5.3, 7.8)
60
50
40
30
A resistant relapse is defined as a recurrence within

90 days after the end of first-line chemotherapy.
20
10
0

0 3 6 9 12 15 18 21 24 27
O
27
28
28
(months)
Treatment
Amrub
Amrub + Cisp
Cisp + Etop
If disease progresses during initial chemotherapy, the

SCLC is called refractory.
1.0
Survival Probability

N
17
28
12 4 3 2 1 0 0
24
30
18 5 1 1 1 1 1
23
30
14 3 1 0 0 0 0
Median
<Median
0.8
Second-line treatment is useful only in those patients

in a good general condition and with adequate organ
function.
HR = 0.52
P = 0.025
0.6
In case of a sensitive relapse, the same chemotherapy as

initially given can be considered.
0.4
0.2
0.0
0
Median (n) 47
<Median (n) 42
3
31
19
12
15
17
11
7
2
1
1
0
0
Time (Months)
In case of a resistant relapse, second-line therapy results

in less than 10% remissions, with a few months of life
prolongation.
After platinum and etoposide, besides topotecan,

cyclophosphamide, doxorubicin, and vincristine are
often given.
Cumulative Proportion Alive
Topotecan is the only approved drug for resistant

relapse in second line.
1.0
0.8
Topotecan (n = 71)
Best supportive care (n = 70)
0.6
0.4
0.2
24
48
72
96
120
144
168
192
Time (weeks)
REVISION QUESTIONS
1. When is the same chemotherapy as in first line indicated at relapse?
2. What is a resistant relapse?
3. Which drug is approved for resistant relapse?
54
Localised disease
A rare subgroup of patients with very early stage SCLC,
i.e. T1-2N0M0, may be considered for primary surgery.
Even after complete resection, adjuvant chemotherapy is
standard, as well as PCI.
Pathological TNM Stage

100%
80%
60%
In most patients, radiotherapy is the standard local

treatment.
Median
Deaths / N in Months
78
37 / 68
31
55 / 91
29
22 / 37
33
26 / 34
14
67 / 76
17
27 / 33
13
9 / 10
IA
IB
IIA
IIB
IIIA
IIIB
IV
40%
20%
0%
0
6
Survival, Years
10
Old meta-analyses showed that the addition of thoracic

radiotherapy to chemotherapy improved survival over
chemotherapy alone.
Chemotherapy delivered concurrently with chest
radiotherapy is the first choice.
In frail patients, sequential chemotherapy and chest
radiotherapy may be considered.
The best results were achieved by combining 4 cycles of

cisplatin and etoposide with chest radiotherapy.
Overall survival
100
1-sided P = .90
HR = 1.43 (80% CI, 1.00 to 2.05)
Vandetanib
Placebo
New drug combinations have not improved survival.

There is no role for maintenance therapy after cisplatin
and etoposide and thoracic radiotherapy.
Probability (%)
80
60
40
20
12
18
24
8
7
1
2
Time (months)
No. at risk
Placebo
Vandetanib
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 radiotherapy be combined with chemotherapy?
55
De Ruysscher
54
53
42
30
15
14
Localised disease
Delivering chest radiotherapy in a short overall
treatment time leads to a better survival than giving the
same dose over a longer time.
Because of radiation-induced radiological changes, the

remission status cannot be assessed adequately, except
in the case of frank disease progression.
35
5-Year Survival (%)
Beginning chest radiotherapy as soon as possible after

the start of chemotherapy is associated with higher longterm survival.
40
30
25
20
15
10
0
20
40
60
80
100
120
140
160
180
SER (days)
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.
PCI may lead to slight neurocognitive impairment,

which may also be present at diagnosis and due to
chemotherapy.
LSMemory
p=0.17
60%
PCI is standard in all patients who show no disease

progression after chemotherapy and thoracic
radiotherapy and who are in a reasonable general
condition.
36-Gy group
40%
25-Gy group
20%
0%
60%
40%
PCI should be given within 4 weeks after the last

administration of chemotherapy.
20%
0%
0
REVISION QUESTIONS
1. How and when should thoracic irradiation be delivered?
2. Which patients should receive PCI?
3. When should PCI be given?
12
24
36
Proportion of patients
in the four classes of
unfavourable status [grade 1
(left), grade 2, grade 3 and
grade 4 (right)] in
each arm
56
Disseminated disease: experimental treatment

100
50
75
Placebo
Thalidomide
25
Thalidomide, a broad angiogenesis inhibitor, did not

show additional benefit over chemotherapy.
Percentage of patients alive (%)
Receptor tyrosine kinase inhibitors such as for EGFR,

c-Kit, and VEGFR have been studied in phase II trials,
with or without chemotherapy, but did not show
increased activity.
Targeted agents, unlike in adenocarcinomas, have not

been successful in SCLC.
12
18
24
30
36
42
48
Time since random assignment (months)

Placebo:
359 280 144
Thalidomide: 365 276 132
78
67
39
42
23
21
12
14
6
10
Matrix proteinase inhibitors did not increase survival and

were associated with decreased quality of life.
Vaccination against gangliosides was not beneficial.
Low-molecular-weight heparin is being investigated.
Amrubicin is one of the few new cytotoxic drugs that

show activity in SCLC.
Ipilimumab showed promising activity when combined
with chemotherapy in a randomised phase II trial.
There are currently no validated biomarkers to identify
individuals who may benefit from new treatments and
research in this area is needed.
REVISION QUESTIONS
1. What is the role of targeted agents in SCLC?
2. Is vaccination beneficial in SCLC?
3. What is a promising novel strategy?
57
De Ruysscher
Localised disease: radiotherapy details

Two phase III studies (USA and EORTC) compared the
current standard radiotherapy schedule (45 Gy/ 30 twicedaily fractions of 1.5 Gy) to 6670 Gy in 2 Gy per day,
5 days per week schedules.
Frequency and location of recurrences as assessed by CT

Patients (n)
Recurrence
In both arms of these studies, thoracic radiotherapy

began at day 1 of the second cycle of chemotherapy.
Elective nodal irradiation could be omitted provided the
radiotherapy volumes were defined by FDG-PET/CT
scans.
Acute oesophagitis grade 3 occurred in 30% of patients

treated with accelerated radiotherapy.
None
21 (35)
Local
In field
Out of field
Both in field and out of field
Isolated local
Local and distant/nodal
Nodal
In field
Out of field
Both in field and out of field
Isolated nodal
Nodal and distant/nodal
Distant
Isolated distant
Distant and local/nodal
Isolated brain
9 (15)
3 (5.0)
4 (6.7)
2 (3.3)
2 (3.3)
7 (11.7)
20 (33.3)
8 (13.3)
7 (11.7)
5 (8.0)
2 (3.3)
18 (30.0)
34 (56.7)
19 (31.7)
15 (25.0)
9 (15.0)
There is not a higher risk of radiation pneumonitis for

accelerated radiotherapy compared to conventional
radiotherapy.
Oesophagitis healed within 36 weeks after the end of

radiotherapy.
Effect of modified radiotherapy compared with conventional radiotherapy on toxicity events
Severe Toxicity
Acute oesophageal
Acute pulmonary
Acute cardiac
Haematological
Neutrophils
Platelets
Haemoglobin
Availability
No. of
No. of
Trials
Patients
2
2
2
2
2
2
2
667
675
670
674
643
666
673
Result
Toxicity Rate in
Control Arm (%)
Toxicity Rate in
Experimental Arm (%)
OR
95% CI
P Efficacy
I2 (%)
P Heterogeneity
12
5
1
83
84
38
18
25
6
3
86
87
30
19
2.41
1.32
2.96
1.22
1.31
0.70
1.06
1.62 to 3.59
0.69 to 2.51
1.13 to 7.73
0.81 to 1.86
0.84 to 2.04
0.50 to 0.98
0.71 to 1.59
< .001
.40
.03
.34
.23
.04
.76
0
0
0
0
0
36
0
.99
.33
.76
.36
.70
.21
.35
A higher dose of PCI was shown not to be beneficial.
Avoidance of the hippocampus to preserve

neurocognition is being evaluated in clinical studies.
80
Overall survival (%)
The standard PCI dose remains 25 Gy in 10 daily

fractions.
100
60
40
Standard dose
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
REVISION QUESTIONS
1. Which is the standard dose of chest radiotherapy?
2. What are the differences in late side effects of radiotherapy comparing accelerated radiotherapy to conventional fractionation?
3. What is the standard schedule of PCI?
58
Summary: Treatment of small cell lung cancer:

chemotherapy and radiotherapy
The first-choice treatment is 4-6 cycles of etoposide and a platinum derivative (cisplatin or carboplatin)
Directly after whole brain radiotherapy, systemic treatment can be administered
Prophylactic cranial irradiation improves survival in all stages
Second-line treatment is useful only in patients in a good general condition and with good organ function
Topotecan is the only approved drug for resistant relapse in second line
Thoracic radiotherapy improves survival relative to chemotherapy alone in non-disseminated disease
Delivering chest radiotherapy in a short overall treatment time leads to a better long-term survival than giving the same
radiotherapy 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, 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; 24:10571063.
Frh 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):vi99105.
Le Pchoux 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;
10:467474.
OBrien 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; 24:54415447.
Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992;
327:16181624.
Pijls-Johannesma M, De Ruysscher D, Vansteenkiste J, et al. Timing of chest radiotherapy in patients with limited stage small cell lung
cancer: a systematic review and meta-analysis of randomised controlled trials. Cancer Treat Rev 2007; 33:461473.
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; 357:664672.
Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated
concurrently with cisplatin and etoposide. N Engl J Med 1999; 340:265271.
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; 77:329336.
59
De Ruysscher
More advanced knowledge
10 Malignant pleural mesothelioma

Clinical presentation and pathology
Malignant pleural mesothelioma (MPM) is a rare
tumour arising from the mesothelial cell linings of the
pleural space.
Its incidence is increasing worldwide due to extensive
previous exposure to asbestos. At least in Europe and in
the USA, the disease is often diagnosed in the elderly.
Typical onset of symptoms of MPM include progressive
dyspnoea mainly due to pleural effusion, cough, and
thoracic pain.
Number of
new cases
Male/ Estimated
Period of
female future cases estimate
Country
Year
Australia
United
Kingdom
USA
2008 661
4:1
6500
20042060
2009 2560
4.9:1
65 000
20022050
2009
4.6:1
85 000
20082054
Italy
2004
2.6:1
800/year
20122024
Japan
2007 1068
3.5:1
66 000
20032050
Data derived
from national
registries
Most frequent symptoms/signs of MPM
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.
These three subtypes comprise about 5060%, 2535%,
and 1020% of all MPM, respectively.
Histology is a major prognostic factor in MPM,
with epithelioid tumours carrying the best prognosis,
while mixed and sarcomatoid MPMs have the
worst outcome.
Epithelioid type.
Both cytoplasmic and
nuclear calretinin positivity by
immunohistochemistry
The diagnosis should be referred to an experienced

pathologist. Suggested work-up: 2 mesothelial markers
and 2 non-mesothelial markers.
Epithelioid type
Calretinin
Sarcomatoid type
Biphasic type
The staging system of MPM is still under revision,

especially in non-surgical patients. Staging procedures
include chest and abdominal computed tomography (CT)
scan and video-assisted thoracoscopic surgery (VATS).
The role of F18-fluorodeoxyglucose positron emission
tomography (FDG-PET)/CT scanning is not well
defined, although it has been proposed mainly to detect
extrapleural disease and to assess treatment response.
REVISION QUESTIONS
1. What are the histological subtypes of MPM?
2. What are the suggested staging procedures?
3. What are the most frequent symptoms?
61
Ceresoli et al
Surgery and multimodality treatment

Only a minority of MPM patients are amenable to surgical
resection, due to the pattern of growth of the disease and
the often advanced age at presentation.
Surgery in MPM has always been proposed in the

context of a multimodality treatment (MMT) including
chemotherapy and radiotherapy.
EPP
No EPP
Overall survival (%)
0.25
20
40
60
Months
P/D n=278 MS16 months
EPP n=385 MS12 months
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.
With EPP, postoperative morbidity is frequent (up to
50%). Mortality is under 5%. Best results are achieved in
epithelioid cases with no lymph node involvement.
50
25
12
18
Time from randomisation (months)

Number of events/
at risk
EPP
No EPP
P<0.001
0.50
75
0.75
0.00
Retrospective
comparison of EPP vs P/D
in more than 600 patients
100
Proportion Surviving
The role of surgery is debated. The two proposed

interventions are extrapleural pneumonectomy (EPP)
and pleurectomy/decortication (P/D).
Survival by Procedure
1.00
0/24
0/26
8/16
3/24
3/12
4/20
3/8
5/11
In the only available randomised trial (the MARS

trial), EPP within MMT offered no survival benefit
and possibly harmed patients as compared with
chemotherapy alone.
Median OS of
14.4 months (EPP) vs
19.5 months (no EPP)
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.
In a randomised trial (the MesoVATS trial), P/D was
compared to talc pleurodesis. A better effusion control
but no survival benefit was achieved with P/D.
Intensity modulated radiotherapy (IMRT) improves
tumour coverage and normal tissue sparing; however,
lung toxicity is a major concern, mainly after P/D.
REVISION QUESTIONS
1. What is the role of surgery in MPM?
2. What are the proposed surgical interventions?
3. Is radiotherapy with IMRT a standard procedure?
62
Systemic treatment and molecular pathways
0.75
0.50
0.25
90
Pemetrexed/Cisplatin
Cisplatin
Log rank p value
0.75
MS
13.3 Months
10.0 Months
0.051
0.50
0.00
0
Pts at Risk
Pem/Cis 226
Cis
222
10
15
20
25
30
Survival Time (Months)

185
173
111
91
50
32
19
19
All patients
7
3
0
0
0
Pts at Risk
Pem/Cis 168
Cis
163
10
15
20
25
30
1
0
0
0
Survival Time (Months)

141
128
86
69
35
20
9
9
Patients supplemented with folic acid

and vitamin B12
In this phase III trial,

the combination of cisplatin
and pemetrexed proved superior
to cisplatin alone in terms of
response rate (RR), TTP, OS,
and symptom control
In patients with
progression-free survival (PFS)
after 1st line > 12 months,
rechallenge with pemetrexed
yielded a mPFS
of 5.5 months
100
B 1.00
0.25
0.00
There is no consensus on the optimal duration of

first-line treatment; usually 46 cycles are administered.
Maintenance strategies are being explored.
80
Survival probability %
MS
Pemetrexed/Cisplatin 12.1 Months
Cisplatin
9.3 Months
Log rank p value
0.020
Proportion Alive
Schedules with carboplatin have been implemented,

showing similar results in terms of disease control rate,
TTP, and OS, with a more favourable toxicity profile.
A 1.00
Proportion Alive
The combination of cisplatin and pemetrexed is the

standard first-line treatment, with a median time to
progression (TTP) of 5.7 months and a median overall
survival (OS) of 12.1 months.
Unfortunately, nearly all MPM patients progress during or

after first-line treatment. The role of second-line treatment
in MPM is still not definitively proven.
70
60
50
A number of phase II and III trials have exploited different

chemotherapeutic and targeted agents, but results have
been generally poor.
1st-line PFS >12 months
40
30
p = .004
20
10
0
Options: 1. Rechallenge with pemetrexed (if prolonged

first-line PFS); 2. Clinical trial enrolment; 3. Palliative
chemotherapy (gemcitabine- or vinorelbine-based).
1st-line PFS 12 months

0 3 6 9 12 15
Months
Promise?
Genetic alterations in MPM include: wild-type p53;

tumour suppressor gene mutations: p14/p16 locus
70%, NF2 40%; Hippo pathway mutations, BAP1.
Neoangiogenesis and tumour vascularisation: circulating
VEGF levels are high in MPM patients, and associated
with microvessel density and poor prognosis.
Other targets for treatment: PI3K/mTOR pathway,
HDACs, NFB pathway, mesothelin overexpression,
immune system.
Hippo pathway
mutations in MPM:
LATS2 (30%), SAV1 (5%),
YAP (70%)
REVISION QUESTIONS
1. What is the standard first-line treatment in MPM?
2. What are the options for second-line treatment?
3. What are the main targets that are being explored in the treatment of MPM?
63
Ceresoli et al
Summary: Malignant pleural mesothelioma

The incidence of MPM is increasing worldwide due to asbestos exposure
There are three main histological subtypes, with different outcomes
The role of surgery is debated, as well as its extent (EPP vs P/D)
Radiotherapy with IMRT has shown promising results, but it is still experimental
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 patients unfit to receive cisplatin
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
In patients with a prolonged PFS after first-line chemotherapy, re-challenge with pemetrexed is a valuable option
In the other cases, enrolment in clinical trials or palliative chemotherapy (with gemcitabine- or vinorelbine-based
regimens) should be considered
Improved knowledge of MPM biology has led to several clinical trials investigating targeted agents, but therapeutic
results have so far been generally poor
Further Reading
Cao C, Tian D, Park J, et al. A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma.
Lung Cancer 2014; 83:240-245.
Ceresoli GL, Zucali PA, De Vincenzo F, et al. Retreatment with pemetrexed-based chemotherapy in patients with malignant pleural
mesothelioma. Lung Cancer 2011; 72:73-77.
Ceresoli GL, Zucali PA, Gianoncelli L, et al. Second-line treatment for malignant pleural mesothelioma. Cancer Treat Rev 2010; 36:24-32.
Hassan R, Miller AC, Sharon E, et al. Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin
and immune suppression. Sci Transl Med 2013; 5:208ra147.
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; 137:647667.
Rosenzweig KE, Zauderer MG, Laser B, et al. Pleural intensity-modulated radiotherapy for malignant pleural mesothelioma. Int J Radiat
Oncol Biol Phys 2012; 83:12781283.
Santoro A, OBrien ME, Stahel RA, et al. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonave patients with
malignant pleural mesothelioma: results of the International Expanded Access Program. J Thorac Oncol 2008; 3:756763.
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; 12:763772.
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.
64
11 Thymic malignancies
Pathology, staging, and prognostic factors
Thymic malignancies are rare epithelial tumours arising in
the anterior mediastinum. The current histopathological
classification distinguishes thymomas from thymic
carcinomas. Neuroendocrine tumours may also occur.
Thymomas are further subdivided into different types
(so-called A, AB, B1, B2, and B3) based upon the
atypia of tumour cells, the relative proportion of the
associated non-tumoural lymphocytic component,
and resemblance to the normal thymic architecture.
Thymic carcinomas (Car) are similar to their extrathymic
counterpart, the most frequent subtype being
squamous cell carcinoma.
AB
B1
B2
B3
Car
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).
Stage
Masaoka-Koga, 1994 (ITMIG, 2011)
Stage I
Grossly and microscopically completely encapsulated tumour

(invasion into but not through the capsule)
Microscopic transcapular invasion
Stage IIa
Stage IIb
Stage III
Stage IVa
Stage IVb
Microscopic invasion into thymic or surrounding fatty tissue, or

grossly adherent to but not breaking through the mediastinal
pleura or pericardium
Macroscopic invasion into neighbouring organ (i.e. pericardium,
great vessel, or lung) (microscopically confirmed)
Pleural or pericardial metastasis
(microscopically confirmed separate nodules)
Lymphogenous or haematogenous metastasis
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
Patients at risk
0 12 24 36 48 60 72 84 96 108
120
443 421 401 380 362 330 245 176 110 50
213 203 189 183 169 155 116 77 42 19
175 158 152 137 123 112 78 43
31 10
67 56 49 43 36 29 24 16 7 4
26 19 18 16 13 13 9 7 4 1
5
5
1
0
0
survival
time
(month)
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?
65
Girard
The MasaokaKogaITMIG system is a clinical

pathological staging system that may be assessed only
after the tumour is surgically resected.
No clinical staging system has been proposed so far.
The MasaokaKoga stage represents the most
significant prognostic factor for survival.
The WHO classification is correlated with stage at
diagnosis, as 8090% of type A to B1 thymomas
present as stage III tumors, whereas 5060% of
type B2 and 6080% of type B3 thymomas and
carcinomas present with stage IIIIV extent. Thus
histology was also reported as a prognostic factor
in thymic epithelial tumours.
survival rate
stage I
stage II
stage III
stage IVA
stage IVB
Staging is based on the MasaokaKoga system,

which was recently refined by the International Thymic
Malignancy Interest Group (ITMIG).
Clinical features, diagnosis, and surgery

One third of patients are asymptomatic. Another one third
of patients present with local symptoms such as cough,
dyspnoea, or chest pain. The remaining third present
with parathymic 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.
Differential diagnoses of anterior mediastinal masses
include thymic hyperplasia, lymphoma, and benign
or malignant germ cell neoplasms; surgical biopsy is
frequently required.
The treatment strategy for thymic epithelial tumour 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 is administered, part of a curative-intent sequential strategy integrating
subsequent surgery or radiotherapy.
Surgical principles are the following:

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
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?
66
Thymic malignancies
Radiotherapy and chemotherapy; prognostic factors

Postoperative radiotherapy aims at decreasing the risk
of mediastinal recurrence. Proposed indications, based
on expert opinion, are summarised in the table.
Radiotherapy principles include: the use of conformal
techniques; a clinical target volume including the whole
thymic space, the tumour and its extensions, and the
anterior, superior, and middle mediastinum; a total dose
ranging from 40 to 60 Gy.
Definitive radiotherapy may be delivered for advanced
non-resectable thymic tumours, after induction
chemotherapy.
Regimen
Agents
Doses
ADOC
Doxorubicin
Cisplatin
Vincristine
Cyclophosphamide
Cisplatin
Doxorubicin
Cyclophosphamide
Cisplatin
Etoposide
Etoposide
Ifosfamide
Cisplatin
Carboplatin
Paclitaxel
40 mg/m2 / 3 w
50 mg/m2 / 3 w
0.6 mg/m2 / 3 w
700 mg/m2 / 3 w
50 mg/m2 / 3 w
50 mg/m2 / 3 w
500 mg/m2 / 3 w
60 mg/m2 / 3 w
120 mg/m2/ 3 / 3 w
75 mg/m2 4d / 3 w
1.2 g/m2 4d / 3 w
20 mg/m2 4d / 3 w
AUC 5 / 3 w
225 mg/m2 / 3 w
CAP
PE
VIP
Carbo-Px
AUC, area under the concentration versus time curve
Stage
Postoperative radiotherapy (RT)
Stage I
Complete resection: - Thymoma: no postoperative RT

- Thymic carcinoma: consider postoperative RT
Incomplete resection: Postoperative RT
Stage IIa
Complete resection: - Type A-B2 thymoma: no postoperative RT

- Type B3 thymomathymic carcinoma:
consider postoperative RT
Incomplete resection: Postoperative radiotherapy
Stage IIb
Complete resection: - Type A-B1 thymoma: no postoperative RT

- Type B2-B3 thymomathymic carcinoma:
consider postoperative RT
Incomplete resection: Postoperative radiotherapy
Stage III-IVa Postoperative RT, with boost on areas of concern
Primary chemotherapy refers to chemotherapy

delivered as first part of the multimodal curative-intent
treatment of locally advanced non-resectable thymic
tumours, and is subsequently combined with surgery
or radiotherapy. Major regimens are presented in the
table. There is currently no rationale to support the use
of postoperative chemotherapy in thymomas; this may
be discussed in thymic carcinoma.
Chemotherapy may be administered as the sole
treatment modality for metastatic, unresectable, recurrent
disease not eligible for radiotherapy. Regimens are similar
to those for primary chemotherapy (table).
Non-chemotherapy options for refractory tumours
include octreotide and KIT/VEGFR multi-kinase inhibitors.
Emerging targets of therapeutic interest are the mTOR
and the IGF-1R pathways.
Besides MasaokaKoga stage, complete resection of

the tumour is the most significant prognostic factor in
thymic tumours.
When interpreting prognostic data, one must take into
consideration that only 50% of patients overall actually
die from tumour progression; causes of death include
autoimmune diseases and non-related disorders
(25% of patients each).
REVISION QUESTIONS
1. Is postoperative radiotherapy delivered after complete resection of stage I thymoma?
2. What are the two major chemotherapy drugs delivered in thymic tumours?
3. What are the molecular pathways of therapeutic interest in thymic tumours?
67
Girard
Summary: Thymic malignancies

Thymic tumours are rare epithelial malignancies; the pathological classification distinguishes thymomas and thymic
carcinomas
Thymic tumours may be associated with autoimmune disorders, such as myasthenia gravis
Tumour stage is assessed using the MasaokaKogaITMIG system
Surgery is the mainstay of the treatment of thymic tumours. Upfront resection is the standard strategy for resectable
tumours
Postoperative radiotherapy may be delivered, depending on the completeness of surgical resection, tumour stage, and
histology
For unresectable locally advanced tumours, primary chemotherapy is the standard, aiming at allowing subsequent R0
surgical resection, or alternatively sequential radiotherapy
The main chemotherapy regimens include doxorubicin- and cisplatin-based protocols
Major prognostic factors include tumour stage, completeness of surgical resection, and histology
Further Reading
Detterbeck F, 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):S1710S1716.
Detterbeck F, Youssef S, Ruffini E, et al. A review of prognostic factors in thymic malignancies. J Thorac Oncol 2011;
6(7 Suppl 3):S1698S1704.
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):S1730S1738.
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; 76:440445.
Girard N, Mornex F, Van Houtte P, et al. Thymoma: a focus on current therapeutic management. J Thorac Oncol 2009; 4:119126.
Girard N. Chemotherapy and targeted agents for thymic malignancies. Expert Rev Anticancer Ther 2012; 12:685695.
Huang J, Detterbeck FC, Wang Z, et al. Standard outcome measures for thymic malignancies. J Thorac Oncol 2011; 6(7 Suppl
3):S1691S1697.
Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 2003;
76:878884.
Marchevsky A, Marx A, Strbel 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; 6:614623.
68
Thymic malignancies
12 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 48% of cases.
Typical symptoms of lung NETs include obstructive
pneumonia, atelectasis, and wheezing as a result of
central airway obstruction due to tumour mass.
Typical carcinoid (TC)
Atypical carcinoid (AC)
Although NETs of the lung arise from cells capable of

producing serotonin and adrenocorticotrophic hormones,
hypersecretion of bioactive amines is rare.
They include a wide range of tumours, from welldifferentiated to poorly differentiated small cell lung
cancer and large cell neuroendocrine carcinoma.
Large cell neuroendocrine carcinoma (LCNEC)
Small cell lung cancer (SCLC)
Histological subtype is the most important prognostic

factor, the survival of TC being higher than AC, while LCC
and SCLC have the worst outcome.
Nodal status is another important prognostic factor. Up
to 60% of patients with AC have lymph node metastases
and a 5-year survival of 6188%.
In contrast, lymph node metastases are present in
fewer than 15% of cases of typical carcinoid lung NETs,
and 5-year survival exceeds 90%.
REVISION QUESTIONS
1. How frequent are NETs among lung malignancies?
2. Which are the four types of lung NETs?
3. What are the most important prognostic factors for lung NETs?
69
Garassino et al
The WHO classification combines architectural growth

patterns (organoid growth versus small cell diffuse growth)
with the mitotic index and the presence of necrosis.
Histological type
Necrosis
Mitotic count
TC
AC
Absent
<2/10 HPF
Present focal
29/10 HPF
LCNEC
Present (extensive)
>9/10 HPF
SCLC
Present (extensive)
>50/10 HPF
Staging and local treatment

Staging with FDG-PET is
recommended only for LCNEC and
SCLC. Its role is not well defined for
carcinoids (high rate of false negatives)
due to low grade, low mitotic count,
and often small lesion
Biochemical evaluations: chromogranin A and

plasma NSE for well-differentiated lung NETs;
dU-5-hydroxyindoleacetic acid in patients with
carcinoid syndrome.
Computed tomography of the chest may indicate a
diagnosis of lung NETs. Bronchoscopy is the best
procedure to detect central bronchial NETs.
Gallium positron emission tomography (PET) and
somatostatin receptor scintigraphy when somatostatin
receptors are expressed can be informative.
68
Macroscopic
appearance of bronchial
carcinoid after surgical
resection
For more aggressive bronchial NETs such as LCNEC and

SCLC, a fluorodeoxyglucose (FDG) PET scan would be
more informative.
The main therapy for bronchial NETs is surgical
resection. The surgical approach depends on the size,
location, and tissue type.
The surgical techniques of choice are lobectomy or sleeve
resection. Pneumonectomy should be avoided except in
selected cases.
Systemic nodal dissection should be performed since

lymphonodal metastases may be present in up to 15%
of cases in TC and >50% 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 8790% in TC, 4478% in AC,
1557% in LCNEC, and 5% in SCLC.
Around 10% of
patients will have multifocal
lesions of bronchopulmonary
carcinoids
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 subtype of NETs has the best 5-year survival rate?
70
Neuroendocrine tumours of lung origin
Systemic treatment
Cytotoxic treatment combined with surgical resection,
when indicated, has been the standard for metastatic
lung NETs.
Available chemotherapy regimens for TC and
AC include a combination of streptozotocin plus
5-fluorouracil/doxorubicin.
Temozolomide alone, or in combination with
capecitabine and sometimes bevacizumab,
has demonstrated clinical benefit.
In RADIANT-2, 6.9% pts in
the experimental group and
2.3% pts in the control group were
diagnosed with lung NETs
RADIANT-2 Phase 3 Double-Blind, Placebo-Controlled Trial: Study Design
No randomised trial
evidence is present for
chemotherapy, and its role for
bronchopulmonary carcinoids
continues to be debated
Study/year
n: primaries
ORR
m duration
Moerdel/1991
CDDP+VP16
27: GI lung welldifferentiated NET
7%
46 months
Mitry/1999
CDDP+VP16
12: well-differentiated
lung/mid gut
Only 1, pt
1/12 (9%)
8 months
Fjallskog/2001
CDDP+VP16
32: lung/thymus,
pancreas/ileum
34%
9 months
Bajetta/2007
XELOX
GEP, 5 pts lung
3 pts PR (60%) 20 months

1 pt SD (20%)
1 pt PD (20%)
Ekeblad/2007
TEMOZOLOMIDE
Lung NETs
NETs, 13 bronchial
PR (31%)
NETs (10 TCs and 3 ACs), SD (31%)
7 thymic
7 months
For low proliferating tumours, treatment with somatostatin

analogues might be an option in functional tumours with
clinical symptoms.
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-2 has reported
results specific to lung NETs.
RADIANT-2 evaluated the impact of the oral mammalian

target of rapamycin (mTOR) inhibitor everolimus combined
with somatostatin analogue (octreotide LAR) vs octreotide
LAR plus placebo.
Treatment with everolimus combined with octreotide was
associated with longer progression-free survival: 16.4 vs
11.3 months (p = 0.026).
Patients with lung NETs showed a trend to improved
progression-free survival with everolimus plus
octreotide (p = 0.228) in the subgroup of RADIANT-2.
Progression-free survival in patients with primary lung neuroendocrine tumors (NETs). P value is obtained from the one-sided
log-rank test. HR is obtained from unadjusted Cox model. A, Central radiology review. B, Local investigator review.
E+O = everolimus plus octreotide; HR = hazard ratio; LAR = long-acting repeatable; P+O = placebo plus octreotide.
REVISION QUESTIONS
1. Which drug has demonstrated clinical benefit?
2. Which drug do you prescribe in functional tumours?
3. Which result has been shown by the RADIANT-2 trial?
71
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
TC and AC carcinoids 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
Further Reading
Bertino EM, Confer PD, Colonna JE, et al. Pulmonary neuroendocrine/carcinoid tumors: a review article. Cancer 2009; 115:44344441.
Ekeblad S, Sundin A, Janson ET, et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine
tumors. Clin Cancer Res 2007; 13:29862991.
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; 143:955962.
Pavel M, Hainsworth JD, Baudin E, et al. A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus +
octreotide LAR vs placebo + octreotide LAR in patients with advanced neuroendocrine tumors (NET) (RADIANT-2). Ann Oncol 2010;
21(suppl 8). Abstract LBA8.
Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med 2010; 134:16281638.
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; 17:977987.
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; 21:548555.
Travis WD. Advances in neuroendocrine lung tumors. Ann Oncol 2010; 21(Suppl 7):vii65vii71.
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.
Zatelli MC, Minoia M, Martini C, et al. Everolimus as a new potential antiproliferative agent in aggressive human bronchial carcinoids.
Endocr Relat Cancer 2010; 17:719729.
72
Neuroendocrine tumours of lung origin
13 Emerging targets and new agents in lung cancer

Emerging targets and new agents
Afatinib is a second-generation
tyrosine kinase inhibitor (TKI) with
potent activity against EGFR, HER2,
and HER4.
This second-generation TKI results in
irreversible binding, leading to sustained
target blockade and antitumour activity
against EGFRT790M mutated tumours.
EGFR
HER2
HER3
HER4
Third-generation EGFR mutationspecific inhibitors, such as AZD9291,

HM61713 and CO-1686, are in
development.
p85
PIP3
PIP2
PTEN
p110
PI3K
TORC2
mTOR
PDK1
Ras
rictor
Akt
Raf
MEK1/2
P70
S6K
S6K1
MAPK
mTOR
raptor
TORC1
Src and BCR-ABL are key drivers of lung cancer that may
be targeted with targeted agents, e.g. dasatinib, imatinib,
saracatinib, KX2-391, and XL228.
BCL-2 is an important target in small cell lung cancer,
and antitumour agents include navitoclax, AT101,
oblimersen, and obatoclax.
The BRAF V600E mutation is an emerging target of
non-small cell lung cancer (NSCLC), and new
agents include vemurafenib and dabrafenib
(against mutant BRAF).
EGFR
K-RAS mutations are present in 2030% of NSCLC and

occur commonly in adenocarcinoma histology and longterm smokers, but are less common in Asians.
Although there are currently no specific K-RAS inhibitors,
numerous MEK inhibitors have been developed, including
selumetinib and trametinib.
Combination strategies against Ras-Raf and PI3KAKT pathways are being investigated in K-RAS mutant
NSCLC, with preliminary signals of antitumour activity.
Ras
Raf
X
MEK
MAPK
PI3K
X
AKT
mTOR
S6RP
Cell growth,
differentiation,
and apoptosis.
REVISION QUESTIONS
1. Why are second- and third-generation TKIs required?
2. What target does the second-generation TKI afatinib inhibit?
3. What approaches are in development to target K-RAS mutant NSCLC?
73
Yap & Popat

Most ALK-positive patients treated with crizotinib
develop drug resistance, with different ALK mutations
reported, e.g. F1174L, L1196M, G1202R, and G1269A.
New second-generation ALK inhibitors active against
kinase mutant ALK-positive and crizotinib-resistant
NSCLC include AP26113, LDK378, and CH5424802.
ALK fusion is a HSP90 client protein, and HSP90
inhibitors are in clinical development. Other resistant
mechanisms include EGFR, K-RAS, and KIT mutations.
c-MET gene amplification is found in approximately 4%

of patients with lung adenocarcinoma, while 40% of
lung cancers overexpress c-MET.
c-MET amplification is a mechanism of resistance to
EGFR TKIs in patients with EGFR-mutant tumours and
may be seen in 520% of patients in this setting.
Both monoclonal antibodies (onartuzumab) and TKIs
against c-MET are currently in NSCLC clinical trials, in
combination with erlotinib.
Growth
Factor
Fibroblast growth factor receptor 1 (FGFR1)

amplification occurs in 2025% of squamous tumours
and is transforming in some squamous cell lung
cancers.
FGFR1-amplified lung cancer cell lines demonstrate high
sensitivity to FGFR inhibitors in vitro.
Several potent small molecule inhibitors of FGFR are
in clinical trials, including brivanib, AZD4547, dovitinib,
FP-1039, TSU-68, ponatinib, BGJ398, and LY2874455.
FGFR
dimer
SOS
GRB2
FRS
RAS
RAF
MEK
ERK
Proliferation
REVISION QUESTIONS
1. What strategies to combat crizotinib resistance are in development?
2. Why is the combination of EGFR and c-MET an attractive antitumour strategy?
3. What type of lung cancer is FGFR1 commonly found in?
74
Emerging targets & new agents

ROS1 aberrant fusions involving the ROS1 gene
constitute a distinct molecularly defined subset of NSCLC
that occurs in less than 2% of lung cancers.
Several human tyrosine kinases present with a
substantial level of homology. Therefore, several
drugs characterised by a multi-kinase inhibitor
spectrum are being tested and developed for
ROS-rearranged NSCLC.
HSP90 inhibitors, e.g. AUY922 and STA-9090, show
ROS1-inhibitory activity and are in clinical development
in NSCLC.
RET is a recently discovered novel fusion gene involving

KIF5B as a fusion partner.
RET is found in approximately 1% of lung
adenocarcinomas, and is typically found in non-smokers.
Although specific RET inhibitors have not been
developed, several broad-spectrum targeted agents
show anti-RET activity and are under clinical evaluation.
The development of immune checkpoint inhibitors has led

to drugs with promising therapeutic efficacy, minimised
toxicities, and sustained clinical benefit.
Immune activation can be promoted through inhibition of
co-inhibitory pathways, e.g. PD-1/PD-L1 and the CTLA-4
pathways.
New agents include monoclonal antibodies (mAb)
against PD-1/PD-L1 and CTLA-4, e.g. BMS 936558
(PD-1 mAb) and ipilimumab (CTLA-4 mAb).
REVISION QUESTIONS
1. Which drug may patients with ROS1-rearranged NSCLC respond to?
2. What is the percentage of lung adenocarcinomas that RET is found in?
3. What is the mechanism of action for the PD-1 inhibitor BMS 936558?
75
Yap & Popat
Summary: Emerging targets and new agents in lung cancer

Despite initial patient benefit, drug resistance to first-generation EGFR TKIs is inevitable, with nearly all patients with
EGFR-mutated lung adenocarcinoma eventually developing progressive disease
Second- and third-generation EGFR TKIs have been developed to counteract drug resistance to first-generation
EGFR TKIs
Src and BCR-ABL are key drivers of lung cancer that may be targeted with new agents e.g. dasatinib, imatinib,
saracatinib, KX2-391, and XL228
Although there are currently no specific K-RAS inhibitors available, other antitumour strategies against the Ras-Raf
pathway are currently being investigated in NSCLC, such as the combination of the AKT inhibitor MK-2206 and MEK1/2
inhibitor selumetinib
Most ALK-positive patients treated with crizotinib develop drug resistance, with different ALK mutations reported,
e.g. F1174L, L1196M, G1202R, and G1269A
Since c-MET amplification is also one the mechanisms of resistance to EGFR TKIs, a combined strategy to target
EGFR and c-MET is very attractive
FGFR1 amplification is found in squamous cell lung carcinoma at a frequency of 2025% and is associated with poor
survival and smoking intensity
Although specific inhibitors have not been developed yet, several broad-spectrum targeted agents show anti-RET
or anti-ROS activity and are under clinical evaluation
The association of PD-1 and either of its ligands leads to induction of T-cell anergy, and therefore inhibition of PD-1
can overcome immune resistance and mediate tumour regression
Further Reading
Alamgeer M, Ganju V, Watkins DN. Novel therapeutic targets in non-small cell lung cancer. Curr Opin Pharmacol 2013; 13:394401.
Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;
30:863870.
Califano R, Landi L, Cappuzzo F. Prognostic and predictive value of K-RAS mutations in non-small cell lung cancer. Drugs 2012;
72(Suppl 1):2836.
Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005; 5:341354.
Ju YS, Lee WC, Shin JY, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and
transcriptome sequencing. Genome Res 2012; 22:436445.
Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;
352:786792.
Kumar MS, Hancock DC, Molina-Arcas M, et al. The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell
lung cancer. Cell 2012; 149:642655.
Oxnard GR, Arcila ME, Chmielecki J, et al. New strategies in overcoming acquired resistance to epidermal growth factor receptor
tyrosine kinase inhibitors in lung cancer. Clin Cancer Res 2011; 17:55305537.
Pal SK, Williams S, Josephson DY, et al. Novel therapies for metastatic renal cell carcinoma: efforts to expand beyond the VEGF/mTOR
signaling paradigm. Mol Cancer Ther 2012; 11:526537.
Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 2010;
10:760774.
76
Emerging targets & new agents
Appendix 1: WHO Classification

Lung cancer
WHO 2004: MALIGNANT EPITHELIAL TUMOURS
WHO 2004: MESENCHYMAL TUMOURS

Papillary
Clear cell
Small cell
Basaloid
Small cell carcinoma
Combined small cell carcinoma
Adenocarcinoma
Adenocarcinoma, mixed subtype
Acinar adenocarcinoma
Papillary adenocarcinoma
Bronchioloalveolar carcinoma
Nonmucinous
Mucinous
Mixed nonmucinous and mucinous or indeterminate
Solid adenocarcinoma with mucin production
Fetal adenocarcinoma
Mucinous (colloid) carcinoma
Mucinous cystadenocarcinoma
Signet ring adenocarcinoma
Clear cell adenocarcinoma
Large cell carcinoma
Combined large cell neuroendocrine carcinoma
Basaloid carcinoma
Lymphoepithelioma-like carcinoma
Clear cell carcinoma
Large cell carcinoma with rhabdoid phenotype
Adenosquamous carcinoma
Sarcomatoid carcinoma
Pleomorphic carcinoma
Spindle cell carcinoma
Giant cell carcinoma
Carcinosarcoma
Pulmonary blastoma
Carcinoid tumour
Typical carcinoid
Atypical carcinoid
Salivary gland tumours
Mucoepidermoid carcinoma
Adenoid cystic carcinoma
Epithelial-myoepithelial carcinoma
Preinvasive lesions
Squamous carcinoma in situ
Atypical adenomatous hyperplasia
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
Epithelioid haemangioendothelioma
Angiosarcoma
Pleuropulmonary blastoma
Chondroma
Congenital peribronchial myofibroblastic tumour
Diffuse pulmonary lymphangiomatosis
Inflammatory myofibroblastic tumour
Lymphangioleiomyomatosis
Synovial sarcoma
Monophasic
Biphasic
Pulmonary artery sarcoma
Pulmonary vein sarcoma
WHO 2004: BENIGN EPITHELIAL TUMOURS

Papillomas
Squamous cell papilloma
Exophytic
Inverted
Glandular papilloma
Mixed squamous cell and glandular papilloma
Adenomas
Alveolar adenoma
Papillary adenoma
Adenomas of the salivary gland type
Mucous gland adenoma
Pleomorphic adenoma
Others
Mucinous cystadenoma
WHO 2004: LYMPHOPROLIFERATIVE TUMOURS

Marginal zone B-cell lymphoma of the MALT type

Diffuse large B-cell lymphoma
Lymphomatoid granulomatosis
Langerhans cell histiocytosis
WHO 2004: MISCELLANEOUS TUMOURS

Harmatoma
Sclerosing haemangioma
Clear cell tumour
Germ cell tumours
Teratoma, mature
Immature
Other germ cell tumours
Intrapulmonary thymoma
Melanoma
WHO 2004: METASTATIC TUMOURS
Tumours of the pleura

WHO 2004: MESOTHELIAL TUMOURS
WHO 2004: LYMPHOPROLIFERATIVE DISORDERS
Diffuse malignant mesothelioma

Epithelioid mesothelioma
Sarcomatoid mesothelioma
Desmoplastic mesothelioma
Biphasic mesothelioma
Localised malignant mesothelioma
Other tumours of mesothelial origin
Well-differentiated papillary mesothelioma
Adenomatoid tumour
Primary effusion lymphoma

Pyothorax-associated lymphoma
77
WHO 2004: MESENCHYMAL TUMOURS

Angiosarcoma
Synovial sarcoma
Monophasic
Biphasic
Solitary fibrous tumour
Calcifying tumour of the pleura
Desmoplastic round cell tumour
Tumours of the thymus

WHO 2004: EPITHELIAL TUMOURS
Thymoma
Type A (spindle cell; medullary)
Type AB (mixed)
Type B1 (lymphocyte-rich; lymphocytic; predominantly cortical; organoid)
Type B2 (cortical)
Type B3 (epithelial; atypical; squamoid; well-differentiated thymic carcinoma)
Micronodular thymoma
Metaplastic thymoma
Microscopic thymoma
Sclerosing thymoma
Lipofibroadenoma
Thymic carcinoma (including neuroendocrine epithelial tumours of the thymus)
Basaloid carcinoma
Mucoepidermoid carcinoma
Lymphoepithelioma-like carcinoma
Sarcomatoid carcinoma (carcinosarcoma)
Clear cell carcinoma
Adenocarcinoma
Papillary adenocarcinoma
Carcinoma with t(15;19) translocation
Well-differentiated neuroendocrine carcinomas (carcinoid tumours)
Typical carcinoid
Atypical carcinoid
Poorly differentiated neuroendocrine carcinomas
Small cell carcinoma, neuroendocrine type
Undifferentiated carcinoma
Combined thymic epithelial tumours, including neuroendocrine carcinomas
WHO 2004: GERM CELL TUMOURS (GCT) OF THE MEDIASTINUM

GCTs of one histological type (pure GCTs)
Seminoma
Embryonal carcinoma
Yolk sac tumour
Choriocarcinoma
Teratoma, mature
Teratoma, immature
GCTs of more than one histological type (mixed GCT)
Variant: Polyembryoma
GCTs with somatic-type malignancy
GCTs with associated haematological malignancy
WHO 2004: MEDIASTINAL LYMPHOMAS AND HAEMATOPOIETIC

NEOPLASMS
B-cell lymphoma
Primary mediastinal large B-cell lymphoma
Thymic extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid
tissue (MALT)
T-cell lymphoma
Precursor T-lymphoblastic lymphoma
Precursor T-lymphoblastic leukaemia
[Precursor T-cell acute lymphoblastic leukaemia
(ALL)/Precursor T-cell lymphoblastic lymphoma (LBL)]
Anaplastic large cell lymphoma and other rare mature
T- and NK-cell lymphomas of the mediastinum
Hodgkin lymphoma of the mediastinum
Grey zone between Hodgkin and non-Hodgkin lymphoma
Histiocytic and dendritic cell tumours
Langerhans cell histiocytosis
Langerhans cell sarcoma
Histiocytic sarcoma
Malignant histiocytosis
Follicular dendritic cell tumour
Follicular dendritic cell sarcoma
Interdigitating dendritic cell tumour
Interdigitating dendritic cell sarcoma
Myeloid sarcoma and extramedullary acute myeloid leukaemia
WHO 2004: MESENCHYMAL TUMOURS OF THE THYMUS

Thymolipoma
Lipoma of the mediastinum
Liposarcoma of the mediastinum
Synovial sarcoma
Vascular neoplasms
Rhabdomyosarcoma
Leiomyomatous tumours
Tumours of peripheral nerves
WHO 2004: RARE TUMOURS OF THE MEDIASTINUM

Ectopic tumours of the thymus
Ectopic thyroid tumours
Ectopic parathyroid tumours
WHO 2004: METASTASIS TO THYMUS AND ANTERIOR

MEDIASTINUM
Tumours of the heart

WHO 2004: BENIGN TUMOURS AND TUMOUR-LIKE LESIONS
WHO 2004: MALIGNANT TUMOURS
Rhabdomyoma
Histiocytoid cardiomyopathy
Hamartoma of mature cardiac myocytes
Adult cellular rhabdomyoma
Cardiac myxoma
Papillary fibroelastoma
Haemangioma
Cardiac fibroma
Inflammatory myofibroblastic tumour
Lipoma
Cystic tumour of the atrioventricular node
Angiosarcoma
Malignant pleomorphic fibrous histiocytoma
(MFH)/Undifferentiated pleomorphic sarcoma
Fibrosarcoma and myxoid fibrosarcoma
Rhabdomyosarcoma
Leiomyosarcoma
Synovial sarcoma
Liposarcoma
Cardiac lymphomas
Metastatic tumour
WHO 2004: PERICARDIAL TUMOURS

Malignant mesothelioma
Germ cell tumours
Metastatic pericardial tumours
78
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)
79
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: 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/m
i.v.
d1 + d15
q 28 d [1, 2, 3, 4, 5, 6]
Vinorelbine
25 mg/m
i.v.
d1 + d8 + d15 + d22
OR
Cisplatin
100 mg/m
i.v.
d1
q 28 d [1, 2, 3, 4, 5, 6]
Vinorelbine
30 mg/m
i.v.
d1 + d8 + d15 + d22
OR
Cisplatin
75-80 mg/m
i.v.
d1
q 21 d [1, 2, 3, 4, 5, 6]
Vinorelbine
25-30 mg/m
i.v.
d1 + d8
OR
Cisplatin
100 mg/m
i.v.
d1
q 28 d [1, 2, 3]
Etoposide
100 mg/m
i.v.
d1-3
OR
Cisplatin
75 mg/m
i.v.
d1
q 21 d [7]
Gemcitabine
1250 mg/m
i.v.
d1 + d8
OR
Cisplatin
75 mg/m
i.v.
d1
q 21 d [8]
Docetaxel
75 mg/m
i.v.
d1
OR
Cisplatin
75 mg/m
i.v.
d1
q 21 d [7] (for non-squamous histologies)
Pemetrexed
500 mg/m
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/m
i.v.
d1
NON-SMALL CELL LUNG CANCER: STAGE IV OR RECURRENT DISEASE: FIRST-LINE CHEMOTHERAPY

Examples of drug regimens, including platinum-based doublets
Cisplatin
75 mg/m
i.v.
d1
Paclitaxel
175 mg/m
i.v.
d1
OR
Cisplatin
100 mg/m
i.v.
d1
Gemcitabine
1000 mg/m
i.v.
d1 + d8 + d15
OR
Cisplatin
60 mg/m
i.v.
d1
Gemcitabine
1000 mg/m
i.v.
d1 + d8
OR
Cisplatin
75 mg/m
i.v.
d1
Docetaxel
75 mg/m
i.v.
d1
OR
Carboplatin
AUC 6
i.v.
d1
Paclitaxel
175-225 mg/m
i.v.
d1
OR
Carboplatin
AUC 6
i.v.
d1
Paclitaxel
90 mg/m
i.v.
d1 + d8 + d15
OR
Paclitaxel protein bound
100 mg/m
i.v.
d1 + d8 + d15
Carboplatin
AUC 6
i.v.
d1
OR
Carboplatin
AUC 6
i.v.
d1
Docetaxel
75 mg/m
i.v.
d1
OR
Carboplatin
AUC 5
i.v.
d1
Gemcitabine
1250 mg/m
i.v.
d1 + d8
OR
Cisplatin
100 mg/m
i.v.
d1
Vinorelbine
25 mg/m
i.v.
weekly
OR
Cisplatin
40 mg/m
i.v.
d1
Vinorelbine
25 mg/m
i.v.
d1 + d8
OR
Carboplatin
AUC 5
i.v.
d1
Vinorelbine
30 mg/m
i.v.
d1 + d8
q 21 d [11, 12]
q 28 d [12]
q 21 d [13, 14]
q 21 d [8, 12]
q 21 d [12, 15]
q 28 d [16, 17, 18]
q 21 d [19]
q 21 d [20]
q 21 d [21, 22, 23]
q 28 d [8]
q 21 d [13]
q 21 d [24]
80
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)
Carboplatin
AUC 6
i.v.
d1
q 21 d (continue bevacizumab every 21 d after 4-6 cycles
Paclitaxel
200 mg/m
i.v.
d1
are completed: continue until disease progression) [25]
Bevacizumab
15 mg/kg
i.v.
d1
OR
Cisplatin
80 mg/m
i.v.
d1
q 21 d (continue bevacizumab every 21 d after 4-6 cycles
Gemcitabine
1250 mg/m
i.v.
d1 + d8
are completed): continue until disease progression [25]
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 progression (remember folate and B12 supplements
Pemetrexed
500 mg/m
i.v.
d1
along with dexamethasone premeds for pemetrexed) [26]
Bevacizumab
15 mg/kg
i.v.
d1
Pemetrexed-based chemotherapy for patients who meet eligibility requirements (non-squamous histology)
Cisplatin
75 mg/m
i.v.
d1
q 21 d (remember folate and B12 supplements along with
dexamethasone premeds for pemetrexed) [27]
Pemetrexed
500 mg/m
i.v.
d1
OR
Carboplatin
AUC 5
i.v.
d1
q 21 d (remember folate and B12 supplements along with
dexamethasone premeds for pemetrexed) [23, 28, 29]
Pemetrexed
500 mg/m
i.v.
d1
Treatment recommendations for patients with contraindications to carboplatin or cisplatin
Gemcitabine
1100 mg/m
i.v.
d1 + d8
q 21 d [30, 31]
Docetaxel
100 mg/m
i.v.
d8
OR
Gemcitabine
1000-1200 mg/m
i.v.
d1 + d8
q 21 d [24, 32, 33, 34]
Vinorelbine
25-30 mg/m
i.v.
d1 + d8
NON-SMALL CELL LUNG CANCER: STAGE IV OR RECURRENT DISEASE: EXAMPLES OF SECOND-LINE CHEMOTHERAPY
Docetaxel
75 mg/m
i.v.
d1
q 21 d (goal 4-6 cycles) [35, 36, 37, 38, 39]
OR
Pemetrexed
500 mg/m
i.v.
d1 (non-squamous histology)
q 21 d (goal 4-6 cycles; remember folate and B12
supplements along with dexamethasone premeds for
pemetrexed) [39]
OR
Erlotinib
150 mg
PO
daily
for patients with EGFR mutation or gene amplification; given
until disease progression [7, 15, 40, 41, 42, 43, 44, 45, 46]
Erlotinib alone in second-line and third-line settings remains the standard of care.[65]
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, 15, 40, 41, 42, 43, 44, 45, 46]
NON-SMALL CELL LUNG CANCER: STAGE IV OR RECURRENT DISEASE: EXAMPLES OF SINGLE-AGENT THERAPY
Paclitaxel
200 mg/m
i.v.
d1
q 21 d [47,48]
OR
Docetaxel
35 mg/m
i.v.
weekly
for 3 wks q 4 wks [31, 35, 38, 49]
OR
Docetaxel
75 mg/m
i.v.
d1
q 21 d [35, 36, 37, 38]
OR
Gemcitabine
1000 mg/m
i.v.
d1 + d8 + d15
q 4 wks [50, 51]
OR
Gemcitabine
1250 mg/m
i.v.
d1 + d8
q 21 d [21, 32]
OR
[52, 53]
Vinorelbine
25 mg/m
i.v.
weekly
OR
Vinorelbine
30 mg/m
i.v.
d1 + d8
q 21 d [31, 54, 55]
OR
Pemetrexed
500 mg/m
i.v.
d1
q 21 d [39] (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]
81
SMALL CELL LUNG CANCER: EXAMPLES OF TREATMENT REGIMENS RECOMMENDED FOR LIMITED-STAGE SCLC
Concurrent chemotherapy recommendations with radiation for limited-stage disease
Cisplatin
60 mg/m
i.v.
d1
q 21 d for 4 cycles [1]
Etoposide
120 mg/m
i.v.
d1-3
OR
Cisplatin
25 mg/m
i.v.
d1-3
q 21 d for 4 cycles [1, 2, 3]
Etoposide
100 mg/m
i.v.
d1-3
OR
Cisplatin
80 mg/m
i.v.
d1
q 28 d for 4 cycles [4]
Etoposide
100 mg/m
i.v.
d1-3
OR
Carboplatin
AUC 5-6
i.v.
d1
q 21 d [5]
Etoposide
100 mg/m
i.v.
d1-3
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/m
i.v.
d1
Etoposide
80-120 mg/m
i.v.
d1-3
OR
Carboplatin
AUC 5-6
i.v.
d1
Etoposide
80-100 mg/m
i.v.
d1-3
OR
Cisplatin
60 mg/m
i.v.
d1
Irinotecan
60 mg/m
i.v.
d1 + d8 + d15
OR
Cisplatin
30 mg/m
i.v.
d1 + d8 (or 80 mg/m d1)
Irinotecan
65 mg/m
i.v.
d1 + d8
OR
Carboplatin
AUC 5
i.v.
d1
Irinotecan
50 mg/m
i.v.
d1 + d8 + d15
OR
Carboplatin
AUC 4-5
i.v.
d1
Irinotecan
150-200 mg/m
i.v.
d1
OR
Cyclophosphamide
800-1000 mg/m
i.v.
d1
Doxorubicin
40-50 mg/m
i.v.
d1
Vincristine
1-1.4 mg/m
i.v.
d1
q 21-28 d [6, 7, 8, 9, 10, 11, 12, 13]
q 28 d [13, 14, 15, 16]
q 28 d [8, 11, 12]
q 21 d [7, 9]
q 28 d [14, 16]
q 21 d [17, 18, 19]
q 21-28 d [20, 21, 22]
SMALL CELL LUNG CANCER: EXAMPLES OF SECOND-LINE CHEMOTHERAPY FOR RELAPSED OR REFRACTORY DISEASE
Stage IV disease
Etoposide
50 mg/m
PO
daily
for 3 wks q 4 wks [23]
OR
Topotecan
2.3 mg/m
PO
d1-5
q 21 d [24, 25, 26]
OR
Topotecan
1.5 mg/m
i.v.
d1-5
q 21 d [24, 25, 27]
OR
Carboplatin
AUC 5
i.v.
d1
q 28 d [14, 16]
Irinotecan
50 mg/m
i.v.
d1 + d8 + d15
OR
Carboplatin
AUC 4-5
i.v.
d1
q 21 d [17, 18, 19]
Irinotecan
150-200 mg/m
i.v.
d1
OR
Cisplatin
30 mg/m
i.v.
d1
q 28 d 28]
Irinotecan
60 mg/m
i.v.
d1 + d8 + d15
OR
Cisplatin
60 mg/m
i.v.
d1
q 28 d [8, 12]
Irinotecan
60 mg/m
i.v.
d1 + d8 + d15
OR
Cisplatin
30 mg/m
i.v.
d1 + d8 (or 80 mg/m d1)
q 21 d [7, 9]
Irinotecan
65 mg/m
i.v.
d1 + d8
OR
Paclitaxel
80 mg/m
i.v.
weekly
for 6 wks q 8 wks [29]
OR
Paclitaxel
175 mg/m
i.v.
d1
q 3 wks [30]
82
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Chapter 8
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J Clin Oncol 2008;26:3543-3551; 3. Soon YY, et al. J Clin Oncol 2009;27:32773283; 4. Pao W, et al. Lancet Oncol 2011;12:175-180; 5. Sharma SV, et al. Nat Rev
Cancer 2007;7:169-181; 6. Shaw AT, et al. N Engl J Med 2013;368:2385-2394;
7. Mok TS, et al. N Engl J Med 2009;361:947-957; 8. Rosell R, et al. Lancet Oncol
2012;13:239-246; 9. Yang JC, et al. J Clin Oncol 2012;30(Suppl); Abstract LBA7500;
10. Sandler A, et al. N Engl J Med 2006;355:2542-2550; 11. Reck M, et al. J Clin
Oncol 2009;27:1227-1234; 12. Reck M, et al. J Clin Oncol 2013;31(Suppl); Abstract
LBA8011; 13. Ciuleanu T, et al. Lancet 2009;374:1432-1440; 14. Cappuzzo F, et al.
Lancet Oncol 2010;11:521-529; 15. Paz-Ares L, et al. Lancet Oncol 2012;13:247-255;
16. Shepherd FA, et al. J Clin Oncol 2000;18:2095-2103; 17. Hanna N, et al. J Clin
Oncol 2004;22:1589-1597; 18. Shepherd FA, et al. N Engl J Med 2005;353:123-132.
Chapter 9
Figure 1. Vallires E, et al. J Thorac Oncol 2009;4:1049-1059; 2. Watson WL, et al.
Cancer 1962;15:759-768; 3. Amarasena IU, et al. Cochrane Database Syst Rev.
2008 Oct 8;(4):CD006849; 4. Okamoto H, et al. Br J Cancer 2007;97:162-169;
5. Sundstrm S, et al. J Clin Oncol 2002;20:4665-4672; 6. Shao N, et al. J Thorac
Oncol 2012;7:470-472; 7. Postmus PE, et al. J Clin Oncol 2000;18:3400-3408;
8. Fink TH, et al. J Thorac Oncol 2012;7:1432-1439; 9. Slotman B, et al. N Engl J
Med 2007;357:664-672; 10. OBrien ME, et al. Eur J Cancer 2011;47:2322-2330;
11. Reck M, et al. Lung Cancer 2012;78:276-281; 12. OBrien ME, et al. J Clin Oncol
2006;24:5441-5447; 13. Vallires E, et al. J Thorac Oncol 2009;4:1049-1059;
14. Pignon JP, et al. N Engl J Med 1992;327:1618-1624; 15. Arnold AM, et al. J Clin
Oncol 2007;25:4278-4284; 16. De Ruysscher D, et al. J Clin Oncol 2006;24:10571063; 17. Auprin A, et al. N Engl J Med 1999;341:476-484; 18. Le Pchoux C, et al.
Ann Oncol 2011;22:1154-1163; 19. Lee SM, et al. J Natl Cancer Inst 2009;101:
1049-1057; 20. Giaccone G, et al. J Clin Oncol 2005;23:6854-6864; 21. Reck M,
et al. Ann Oncol 2013;24:75-83; 22. van Loon J, et al. Int J Radiat Oncol Biol Phys
2010;77:329-336; 23. Mauguen A, et al. J Clin Oncol 2012;30:2788-2797;
24. Le Pchoux C, et al. Lancet Oncol 2009;10:467-474.
Chapter 10
Figure 1. Robinson BM. Ann Cardiothorac Surg 2012;1:491-496; 4. Flores RM,
et al. J Thorac Cardiovasc Surg 2008;135:620-626; 5. Treasure T, et al. Lancet Oncol
2011;12:763-772; 7. Vogelzang NJ, et al. J Clin Oncol 2003;21:26362644;
8. Ceresoli GL, et al. Lung Cancer 2011;72:73-77; 9. Sekido Y. Pathol Int 2011;61:
331-344.
Chapter 11
Figure 3. Kondo K, et al. Ann Thorac Surg 2003;76:878-884; 5. Detterbeck FC,
et al. J Thoracic Oncol 2011;6:S1730-1738; 8. Huang J, et al. J Thorac Oncol
2011;6:S1691-1697.
Chapter 12
Figure 1, 2, 4, 5, 6. Courtesy Fondazione IRCCS Istituto Nazionale Tumori;
3. Daddi N, et al. Eur J Cardiothorac Surg 2004;26:813-817; 8. Pavel M, et al.
ESMO 2010 Congress, Abstract LBA 8; 9. Fazio N, et al. Chest 2013;143:955-962.
Chapter 13
Figure 1. Yap TA, et al. J Clin Oncol 2013;31:1592-1605; 2. Bollag G, et al. Nature
Rev Drug Discov 2012;11:873-886; 4. Courtesy http://www.mycancergenome.org/;
5. Yap TA, et al. Curr Drug Targets 2011;12:2045-2058; 6. Courtesy: http://www.
mycancergenome.org/; 7. Bergethon K, et al. J Clin Oncol 2012;30:863-870;
8. Ju YS, et al. Genome Res 2012;22:436-445; 9. Pal SK, et al. Mol Cancer Ther
2012;11:526-537.
While every effort has been made to contact the copyright holders of all images, the publisher would be grateful for any additional information about any images where they
have been unable to trace or obtain permissions and will be glad to make amendments in future editions.
86
Image sources
Index
A
accelerated radiotherapy, 58
adenocarcinoma (ADC)
antiangiogenic therapy, 47
chemoprevention trials, 8
c-MET amplification, 74
EGFR inhibitors, 46
epidemiology, 3, 5
histopathology, 21
in situ, 8, 26
K-RAS mutations, 73
molecular testing, 23, 24, 45
RET fusion, 75
screening, 9
staging, 16
surgery, 26
adenosquamous carcinomas, 21
Adjuvant Lung Cancer Project Italy, 38
Adjuvant Navelbine International Trialist Association 01, 38
adjuvant/neoadjuvant therapy, 38-42, 55
ADOC regimen, 67
adrenal metastasis, 18, 30
adrenocorticotrophic hormones, 69
afatinib, 46, 73
airway epithelium, 4
AKT1 mutation, 23, 45
amplifications, 23, 24, 74
amrubicin, 57
anaplastic lymphoma kinase (ALK), 24
ALK inhibitors, 74, 75
ALK mutations, 74
ALK translocation, 24
anethole dithiolethione, 8
anterior mediastinal masses, 66
anterolateral thoracotomy, 26
anti-PD1 antibodies, 42
aromatic amines, 5
asbestos, 5, 61
Asian populations, 5, 40, 46, 52, 73
aspirin, 8
asymptomatic lesions, 15
AT101, 73
atelectasis, 69
atypical carcinoid (AC), 69
autofluorescence bronchoscopy, 16
AUY922, 75
AZD4547, 74
AZD9291, 73
Bajetta 2007 study, 71

BAP1, 63
BCL-2, 73
BCR-ABL, 73
benign disease, 11
best supportive care (BSC), 48, 49, 54
beta-carotene, 8
bevacizumab, 42, 47, 71
BGJ398, 74
Big Lung Trial, 38
bilobectomy, 26
biomarkers, 12, 20-23, 42
87
Index
biopsy techniques, 18, 20

biphasic malignant pleural mesothelioma, 61
BMS 936558, 75
BRAF mutation, 23, 45, 73
brain metastasis, 29, 30, 33, 53, 56
breast cancer, 1, 2, 38
brivanib, 74
bronchoalveolar carcinoma, 8
bronchopulmonary carcinoids, 70, 71
bronchoscopy, 16, 70
budesonide, 8
bupropion, 7
CALGB Stage IB Trial, 39

calretinin malignant pleural mesothelioma, 61
CAP regimen, 67
capecitabine, 71
carbon monoxide, 5, 7
carboplatin, 39, 41, 44, 46, 47, 52, 63, 67
Carbo-Px regimen, 67
carcinoid, 21
carcinogens, 4, 5, 61
asbestos, 5, 61
inhaled, 4, 5, 61
smoking and, 1, 3, 4, 5, 21
tobacco smoke, 5
carcinoma in situ (CIS), 8, 24
CD117, 65
CD5, 65
CD56, 22
celecoxib, 8
cervical mediastinoscopy, 18
checkpoint inhibitors, 42, 75
chemoprevention, 8
chemoradiotherapy, 28, 29, 34, 36, 51, 55
chemotherapy
adjuvant/neoadjuvant, 38-42
EGFR inhibitors, 46, 73, 74
lung NETS, 71
maintenance therapy, 48
mesothelioma, 62, 63
metastatic NSCLC, 44
new agents, 73-76
with radiation, 28, 29, 34, 36, 51, 55, 62
resistance, 42, 45, 73
SCLC, 51, 52, 54, 55, 57
second-line therapy, 49, 54
thymic epithelial tumour, 66, 67
chest pain, 14, 61, 66
chest X-ray screening, 9, 10
chromogenic in situ hybridisation (CISH), 24
chromogranin A, 22, 70
chromosomal rearrangements, 23, 24
chronic obstructive pulmonary disease (COPD), 7, 34, 35
cisplatin (CDDP), 34, 38, 44, 46-48, 51, 52, 55, 63, 67, 71
13-cis-retinoic acid, 8
clinical features, 3, 66
c-MET amplification, 74
CO-1686, 73
computed tomography (CT), 9, 10, 15, 16, 17, 26, 32, 35, 61, 70
concurrent radiotherapy/chemotherapy, 33, 34, 36, 51, 55
continuous maintenance, 48
coronary heart disease, 7
COSMOS risk model, 11
cough, 14, 61, 66
crizotinib, 45, 74
cryobiopsies, 18, 20
CTLA-4 pathway, 75
cyclophosphamide, 51, 54, 67
cytology, 20
dabrafenib, 73
dasatinib, 73
desmin, 65
diagnosis
clinical presentation, 14-15
histochemistry and immunohistochemistry, 22
histology, 18, 20-21
molecular, 23-24
overdiagnosis, 10
TNM staging, 15-17
diagnostic algorithms, 11, 15
distant disease failures, 34
distant metastasis, 3, 14
DNA adducts, 4
DNA polymerase, 23
docetaxel, 44, 45, 47, 49
dovitinib, 74
doxorubicin, 51, 54, 67, 71
driving mutations, 45
dU-5-hydroxyindoleacetic acid, 70
dyspnoea, 14, 61, 66
Ekeblad 2007 study, 71

elderly patients, 3, 35, 61
EML4ALK translocations, 45
en bloc resection, 62, 66
endobronchial ultrasound (EBUS), 17, 18
endocrine paraneoplastic syndromes, 14
endoscopic biopsy, 18
endosonography, 17, 18
epidemiology
Europe, 2
USA, 1
epidermal growth factor (EGFR), 23, 42
EGFR mutations, 23, 42, 45, 46, 49, 74
epithelioid malignant pleural mesothelioma, 61, 62
erlotinib, 42, 46, 48, 49, 74
ethnicity, 3
etoposide, 34, 51, 52, 54, 55, 67
etretinate, 8
Europe
epidemiology, 2
NELSON trial, 10, 11
everolimus, 71
EvG staining, 22
experimental treatments, 38, 57, 58
external beam radiotherapy, 32
extrapleural pneumonectomy (EPP), 62
F1174L, 73
fenretinide, 8
fibroblast growth factor receptor 1 (FGFR1), 24, 74
fine needle aspiration (FNA), 18
Fjallskog 2001 study, 71
fluorescence in situ hybridisation (FISH), 24
fluorodeoxyglucose positron emission tomography (FDG-PET), 16, 17, 28,
61, 70
5-fluorouracil, 71
fluticasone, 8
forceps biopsies, 20
FP-1039, 74
G1202R, 73
G1269A, 73
gangliosides, 57
gefitinib, 46
gemcitabine, 44, 47, 63
gender
adenocarcinoma, 3, 5
clinical features and, 3
Europe, 2
USA, 1
haemoptysis, 14, 47
HE staining, 20, 22
HER2 mutation, 23, 45, 73
HER4 mutation, 73
hereditary component, 4
high-risk populations, 10
Hippo pathway mutations, 63
histochemistry, 22
histological diagnosis, 18, 20-21
histone deacetylase (HDAC), 63
histopathology, 21
HM61713, 73
HSP90 inhibitors, 74, 75
I-ELCAP study, 9
ifosfamide, 38, 67
iloprost, 8
image-guided radiotherapy, 32
imatinib, 73
immune checkpoint inhibitors, 42, 75
immunohistochemistry (IHC), 20, 22, 61
immunotherapy, 42
in situ hybridisation (ISH), 24
incidence
adenocarcinoma, 3
Europe, 2
USA, 1
indeterminate nodules, 11
indolent cancers, 11
induction chemoradiotherapy, 28, 29
inhaled carcinogens, 4, 5, 61
insulin-like growth factor 1 receptor (IGF-1R), 67
intensity modulated radiotherapy (IMRT), 62
International Adjuvant Lung Trial, 38
88
Index
International Agency for Research on Cancer (IARC), 5

International Thymic Malignancy Interest Group (ITMIG), 65
intracranial hypertension, 53
ipilimumab, 57, 75
irinotecan, 52
JBR.10 trial, 38
KIF5B, 75
KIT mutations, 73
KIT/VEGFR multi-kinase inhibitors, 67
K-RAS mutations, 23, 45, 73, 74
KX2-391, 73
L1196M, 73
L858R mutations, 23, 45, 49
LACE (Lung Adjuvant Cisplatin Evaluation) pooled analysis, 38
large cell neuroendocrine carcinoma (LCNEC), 21, 69
LATS2, 63
lead-time bias, 10
linear accelerators (LINACs), 32, 35
lobectomy, 12, 26, 27
local invasion, 14
locoregional invasion, 14, 35
low-dose computed tomography (LDCT) screening, 9, 10-11
lung anatomy, 4
lung neuroendocrine tumours (NETs), 69-71
lung toxicity, 62
LY2874455, 74
lymph node metastasis, 21
MAGE-A3 antigen-specific vaccine, 42

malignant pleural effusion, 30
malignant pleural mesothelioma (MPM), 61-64
mammalian target of rapamycin (mTOR), 67, 71
MasaokaKogaITMIG system, 65, 67
matrix proteinase inhibitors, 57
Mayo Lung Project, 9
median sternotomy, 66
mediastinal lymphadenectomy, 26
mediastinoscopy, 16, 17
MEK inhibitors, 73
MesoVATS trial, 62
MET mutation, 45
metastasis
adjuvant therapy, 42
brain, 29, 30, 33, 53, 56
at diagnosis, 3
lymph node, 21
oligometastatic, 30, 33
SBM, 30
staging, 15-18
symptoms, 14
treatment, NSCLC, 44-50
microdissection, 23
mitotic index, 69
Mitry 1999 study, 71
89
Index
Moerdel 1991 study, 71

molecular markers, 12, 23-24
monoclonal antibodies, 22, 74, 75
morphological subtyping, 21
mortality rates
Europe, 2
screening and, 9, 10
USA, 1
multi-detector computed tomography, 9, 16
musculoskeletal paraneoplastic syndromes, 14
mutation analyses, 23
myasthenia gravis, 66
myo-inositol, 8
N2-positive NSCLC, 28
Napsin A, 22
National Comprehensive Cancer Network (NCCN) Guidelines, 10
National Lung Screening Trial (NLST), 10
navitoclax, 73
needle core biopsies, 18, 20
NELSON trial, 10, 11
neoadjuvant therapy, 38-42
neuroendocrine tumours (NETS), 65, 69-71
neurological symptoms, 14, 53
never-smokers, 3, 5
new agents, 73-76
next generation sequencing, 23
NF2, 63
NF-B pathway, 63
nicotine replacement therapy (NRT), 7
nintedanib, 47
nodule management algorithm, 11
non-small cell lung cancer (NSCLC)
adjuvant chemotherapy, 38-42, 55
BRAF V600E mutation, 73
histopathology, 21
metastatic, 44-49
molecular testing, 23, 24, 45
PORT, 41, 67
radiotherapy, 33, 34, 35
ROS1 fusions, 75
second-line therapy, 49
SST, 29
surgery, 26, 27, 28, 30
NRAS mutations, 23
NSCLC see non-small cell lung cancer
NVP-TAE684, 75
oat cell carcinoma, 51

obatoclax, 73
oblimersen, 73
octreotide, 67, 71
oesophagitis, 34, 58
oligometastatic disease, 30, 33
onartuzumab, 74
Ontario adjuvant therapy database, 41
open thoracotomy, 12
over-diagnosis, 10
p14/p16 locus, 63
p53 mutation, 63
paclitaxel, 39, 41, 44, 46, 47, 67
palliation
radiotherapy, 33
surgery, 30
Pancoast tumours, 14, 29
pancytokeratin, 65
paraneoplastic syndromes, 14
parasternotomy, 18
parathymic autoimmune disorders, 66
parenchyma-sparing resections, 27
PAS staining, 20, 22
pathogenesis, 4
pathology, 20, 21
PD-1/PD-L1 pathway, 75
PE regimen, 67
pemetrexed, 44, 45, 46, 48, 49, 63
PET-CT, 11, 16, 17, 61
PI3KCA mutations, 23, 45
PI3K/mTOR pathway, 63, 73
platelet-derived growth factor receptor (PDGFR), 47
platinum-based chemotherapy, 34, 36, 40, 44, 46, 48, 51, 52, 54
pleurectomy/decortication (P/D), 62
pleurodesis, 30
pneumonectomy, 26-28, 70
pneumonia, 69
pneumonitis, 34
polyclonal antibodies, 22
polycyclic aromatic hydrocarbons (PAHs), 5
polymerase chain reaction (PCR), 22, 23, 42, 46
ponatinib, 74
postoperative radiotherapy (PORT), 41, 67
preoperative chemotherapy, 40, 41
prevalence of lung cancers, 3, 5
prevention
chemoprevention, 8
smoking cessation, 7, 10
prognosis, 1, 15, 21
PROMID trial, 71
prophylactic cranial irradiation (PCI), 36, 53, 56, 58
psychosocial counselling, 7
pyrosequencing, 23
race, 3
RADIANT trials, 42, 71
radiation pneumonitis, 34, 58
radiography, 9, 14
radiotherapy
accelerated, 58
distant disease failures, 34
dose-fractionation schemes, 33
in locally advanced NSCLC, 34
postoperative, 41, 67
principles, 32
prophylactic cranial (PCI), 36, 53, 56, 58
in SCLC, 33, 36, 51, 55-56
stereotactic, 12, 33, 35
in thymic epithelial tumour, 67
toxicities, 34, 58
whole-brain, 53
radon exposure, 5
rapamycin, 71
Ras-Raf pathway, 73
recurrence, 35
relapse, 54
resistance, 42, 45, 54, 73
respiration-correlated CT, 32
RET, 75
RET mutation, 23
retinyl palmitate, 8
risk factors, 5, 11
robotic surgery, 12
ROS1 fusion/translocation, 24, 75
ROS1 mutation, 23
salivary gland tumour, 21

salvage resections, 30
Sanger sequencing, 23
saracatinib, 73
sarcomatoid carcinoma, 21
sarcomatoid malignant pleural mesothelioma, 61
SAV1, 63
SCLC see small cell lung cancer
screening, 9-12
second-line therapy, 49, 54
selenium, 8
selumetinib, 73
sensitive relapse, 54
sequencing, 23
serotonin, 69
serum microRNAs, 12
sleeve lobectomy, 27
small cell lung cancer (SCLC)
disseminated, 51-54, 57
experimental treatment, 57
histopathology, 21
localised, 51, 55-56, 58
NETs, 69
overview, 51
PCI, 36
radiotherapy, 33, 36, 51, 55-56
surgery, 55
treatment, 51-58
smoking, 1, 4, 5, 21
smoking cessation, 7, 10, 36
solitary brain metastasis (SBM), 30
solitary pulmonary nodules (SPN), 15
sorafenib, 75
spiral multi-detector computed tomography, 9, 16
sputum screening, 9
squamous cell carcinoma, 3, 8, 21, 47, 74
squamous metaplasia, 21
Src, 73
STA-9090, 75
staging, 15-17, 61
stains for histology, 20, 22
stereotactic radiotherapy, 12, 33, 35
sternotomy, 18, 66
streptozotocin, 71
stroke, 7
sublobar resection, 12, 26
superior sulcus tumours (SST), 29
90
Index
superior vena cava syndrome, 14, 53

surgery
biopsy, 18
complications, 26
in lung NETS, 70
in MPM, 62
in NSCLC stage I and II, 26
in NSCLC stage II, 28
in NSCLC stage IV/palliative, 30
postoperative radiotherapy, 41, 67
preoperative chemotherapy, 40, 41
principles, 26
in SCLC, 55
in SST, 29
techniques, 12
in thymic epithelial tumour, 66
survival rates
adjuvant/neoadjuvant therapy and, 38, 40, 42
chemoradiotherapy and, 34
lung NETs, 69-71
metastatic NSCLC, 44-49
MPM, 62, 63
oligometastatic disease, 30
overview, 3, 6
PCI and, 36, 53, 58
SCLC, 51-56, 58
screening and, 9, 10
SST, 29
stereotactic radiotherapy and, 35
surgical technique and, 26-28
thymic tumours, 65
switch maintenance, 48
symptoms, 14
Synaptophysin, 22
T3N1, 28
T4N0-1, 28
T790M mutations, 46
TdT, 65
tegafururacil (UFT), 40
temozolomide, 71
thalidomide, 57
thymic malignancies, 65-67
thyroid transcription factor 1 (TTF1), 22
tissue processing, 20
TNM (tumour-node-metastasis) staging, 15-17
tobacco smoke carcinogens, 5
topoisomerase I enzymes, 52
topotecan, 54
trametinib, 73
transbronchial needle biopsy (TBNA), 18
TSU-68, 74
tunnelled pleural catheters (TPC), 30
typical carcinoid (TC), 69
tyrosine kinase inhibitors (TKIs), 23, 42, 45, 46, 47, 57, 73, 74
USA
epidemiology, 1
National Lung Screening Trial, 10
91
Index
vaccination, 57
vandetanib, 75
varenicline, 7
vascular endothelial growth factor (VEGF), 42, 63
vascular endothelial growth factor receptor (VEGFR), 47, 57, 67
vemurafenib, 73
video-assisted thoracoscopic surgery (VATS), 12, 17, 18, 27, 61
videobronchoscopy, 16
vincristine, 54, 67
vinorelbine, 34, 38, 63
VIP regimen, 67
vitamin B12/folate, 8
volume doubling time (VDT), 9, 11
wheezing, 14, 69
whole-brain radiotherapy (WBRT), 53
wild-type p53, 63
World Health Organisation (WHO), 2, 65, 69
XL228, 73
YAP, 63
www.esmo.org
www.esmo.org
Rolf A. Stahel Solange Peters Marina Garassino
THORACIC TUMOURS
Rolf A. Stahel
Solange Peters
Series Editor
Central compartment
Large bronchus
Ciliated cell
Mucous cell
Primary
bronchus
Neuro-endocrine
cell
Basal cell
Secondary
bronchus
Tertiary
bronchus
Basement membrane
>
Bronchiole
Terminal
bronchiole
Alveoli
Alveolus
Clara cell
Respiratory
bronchiole
Ciliated cell
Basement
membrane
Interstitium
Alveolar
duct
Alveolus
Alveolus
Type I
pneumocyte
Type II
pneumocyte
Alveolus
ISBN 978-88-906359-4-6
9 788890 635946
ESMO Press
CM 28 ESMO Essentials Thoracic sponsored cover v03.indd 1
ESMO Press ISBN 978-88-906359-4-6
Michele Ghielmini
ESMO Press
Rolf A. Stahel
Solange Peters
Marina Garassino
THORACIC TUMOURS
E S S E N T I A L S fo r C L I N I C I A N S
Thoracic tumours include cancers ranging from some

of the most common - such as non-small cell lung cancer to the most rare, such as extragonadal germ cell tumours.
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 should know. Other interested readers
will include more advanced doctors or students, who may have
never dealt with this topic and who wish to understand the
core concepts of management of these tumours.
It 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.
In addition to the essentials, this volume also gives
an introduction to more advanced knowledge for those
who wish to explore the topic further.
Marina Garassino
THORACIC TUMOURS
edited by
edited by
ESMO Press
31/08/2014 17:52

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www.esmo.

Rolf A. Stahel Solange Peters Marina Garassino

CM 28 ESMO Essentials Thoracic sponsored cover v03.indd 1

ESMO Press ISBN 978-88-906359-4-6

Thoracic tumours include cancers ranging from some

Marina Chiara Garassino

First published in 2014 by ESMO Press

2014 European Society for Medical Oncology

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

2. Prevention and screening of lung cancer

3. Diagnosing lung cancer

4. Histopathological and molecular characterisation of lung cancer

5. Principles of surgery of non-small cell lung cancer

6. Principles of radiotherapy of thoracic tumours

7. Adjuvant and neoadjuvant therapy

8. Treatment of metastatic non-small cell lung cancer

9. Treatment of small cell lung cancer: chemotherapy and radiotherapy

B. More advanced knowledge

11. Thymic malignancies

12. Neuroendocrine tumours of lung origin

13. Emerging targets and new agents in lung cancer

3. Selected treatment schedules

What every oncologist should know

Epidemiology, pathogenesis, and risk factors

US Incidence and mortality

Lung cancer US incidence rates in both genders have

US lung cancer death rates rose for most of the 20th

Central & Eastern Europe

1970 1980 1990 2000 2010 2020

On the contrary, the incidence rate for women was

For both sexes combined, the lowest rates were seen in

An evaluation performed in 2012 revealed that the lung

Deaths per 100 000 population

European mortality for lung cancer peaked in the late

Deaths per 100 000 population

Lung cancer is the primary cause of cancer-related

Agestandardized incidence (E) per 100,000

The lung cancer rate in underdeveloped countries is lower

Clinical features and survival expectancy

Five-year survival rate for all lung cancer stages combined

In a large percentage of cases, lung cancer is diagnosed

Lung cancer in both sexes is predominantly diagnosed

Adenocarcinoma accounts for 38.5% of all lung cancer

Pathogenesis of lung cancer

The putative stem cells of the bronchus are the basal

Lung cancer may arise from all these differentiated

The interaction between inhaled carcinogens and the

Studies on familial aggregation have supported the

The addition of smoking to this genetic inheritance is

Common risk factors for lung cancer

Non-smoking-related risk factors include occupational

(was used in the gas chambers)

(used as rocket fuel)

(found in exhaust fumes)

(used in plastic materials)

The relative risk of lung cancer in long-term smokers has

Cancers arising in never-smokers predominantly target

1. What is the definition of never-smokers?

Capelletto & Novello

An estimated 1025% of lung cancers worldwide occur in

Proportion of lung cancer cases (%)

Summary: Epidemiology, pathogenesis, and risk factors

Prevention and screening of lung cancer

2-FA-PET imaging of nAChR occupancy from cigarette smoke exposure

4. Histopathological and molecular characterisation of lung cancer