1.1 Lung Cancer
Worldwide, lung cancer is the most common cause of major cancer incidence and mortality in men,
whereas in women it is the third most common cause of cancer incidence and the second most
common cause of cancer mortality. Even if there was some improvement in survival during the past
decades, the survival advances that were realized in other diseases have yet to be achieved in lung
cancer, considering that the majority of individuals have advanced-stage disease at presentation and
only 20% of patients present potentially resectable early-stage disease. The 5-year survival rate re-
mains at approximately 16%, and even with targeted therapy, treatment options have improved sur-
vival of only a small percentage of patients, which present mutations in genes that can be currently
targeted, like EGFR or ALK. The median age at diagnosis for cancer of the lung and bronchus is 71
years; no cases are diagnosed in patients younger than 20 years (Fig. 1)
1
.
pipes, tobacco became widely available in ciga-
retteformafterthedevelopmentofcigarettewrap-
ping machinery in the mid-1800s. Before World
War I, cigarette use in the United States was
modest. Wynder and Graham estimated that the
average adult smoked fewer than 100 cigarettes
per year in 1900.
10
Fifty years later, this number
rose to approximately 3500 cigarettes per person
peryearandreachedamaximumofapproximately
4400 cigarettes per person per year in the mid-
1960s (Fig. 8).
11
In 1964, the US Public Health
Service published a landmark report from the
Surgeon General on smoking and its effects on
health.
12
That seminal report stated the following
important principal findings. (1) Cigarette smoking
was associated with a 70% increase in the
62
19.4
336
75.2
21.6
446.2
52.3
17.4
293.8
0
50
100
150
200
250
300
350
400
450
500
All ages < 65 ≥ 65
ALL RACES
Both Sexes
Males
Females
Incidence Rate per 100,000
0
100
200
300
400
500
600
Lung Cancer Incidence
Rates per 100,000
Age at Diagnosis of Lung Cancer
Both Sexes
Males
Females
1-4
<1
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85+
AB
Fig. 5. US age-adjusted lung cancer incidence by gender, age, and race. (A) Separated by age <65 years and
age 65 years. (B) Separated by age from <1 to 851 years. Rates are per 100,000 and are age-adjusted to the
2000 US standard population. (Data from Howlader N, Noone AM, Krapcho M, et al, editors. SEER Cancer Statis-
tics Review, 1975–2008. Bethesda (MD): National Cancer Institute; 2010. Available at: http://seer.cancer.gov/csr/
1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011.)
Fig. 6. Stage distribution and 5-year relative survival by stage at time of diagnosis for 2001 to 2007. (A) Stage
distribution and (B) 5-year relative survival based on stage at diagnosis of lung cancer. Localized disease defined
by confinementto primarysite.Regionalrefersto spreadto regionallymph nodes.Distant refersto whencancer
has metastasized. Unknown includes unstaged cancers. Stage distribution is based on summary stage 2000 docu-
mentations. (Data from Howlader N, Noone AM, Krapcho M, et al, editors. SEER Cancer Statistics Review, 1975–
2008.Bethesda(MD):NationalCancerInstitute;2010.Availableat:http://seer.cancer.gov/csr/1975_2008/,basedon
November 2010 SEER data submission, posted to the SEER web site, 2011.)
Lung Cancer Epidemiology 609
Figure 1: Age-adjusted lung cancer incidence by gender and age. Taken from
1
Lung cancer incidence and mortality rates are higher in the developed countries, while in under-
developed geographic areas, including Central America and most of Africa, are lower, even if the
rates are slowly increasing. The World Health Organization estimates that lung cancer deaths will
continue to rise, because of an increase in global tobacco use, especially in Asia. So, despite the
efforts to curb tobacco smoking, the availability of new diagnostic and genetic technologies, ad-
vancements in surgical techniques and the development of new biologic treatments, the overall
situation will continue to worsen, unless people change their habits
1
.
Introduction
2
1.1.1 Etiology
Tobacco use is the principal risk factor for this disease, and 75% of all pulmonary carcinomas are
attributed to smoking. Cigarette smoke is a complex aerosol composed of gaseous and particulate
compounds and consists of mainstream smoke and sidestream smoke components; the former is
produced by inhalation of air through the cigarette and is the primary source of smoke exposure for
the smoker, while the latter is produced from smoldering of the cigarette and is the major source of
environmental tobacco smoke. Mainstream smoke contains a lot of potential carcinogens, such as
aromatic amines, N-nitrosamines, benzene and arsenic. The International Agency for Research on
Cancer (IARC) has identified at least 50 carcinogens in tobacco smoke to date and the agents that
seem to have a particulate involvement in lung carcinoma are the tobacco-specific N-nitrosamines
(TSNAs) formed by nitrosation of nicotine during tobacco processing and during smoking. These
carcinogens can bind to DNA and create DNA adducts, that lead to the intervention of repair proc-
esses that may remove these adducts and restore normal DNA; but, if there is a failure of the normal
DNA repair mechanisms, cells could acquire permanent mutations that can ultimately result in un-
controlled cellular proliferation and tumorigenesis. Nowadays, despite different campaigns in order
to stop smoking, it is estimated that 20.6% of all adults over age 18 years continue to smoke and
that the cumulative lung cancer risk among heavy smokers can be as high as 30% compared with a
lifetime risk of less than 1% in non-smokers.
Despite the high percentage of lung cancer in smokers, this disease also appears in persons that be-
long to the group of never smokers, a term used to indicate persons who have smoked fewer than
100 cigarettes in their lifetime. The overall global statistics estimate that never smokers account for
25% of all lung cancer cases worldwide; if lung cancer in never smokers was considered separately,
it would rank as the seventh most common cause of cancer death worldwide, before cervical, pan-
creatic, and prostate cancer. The incidence of lung cancer in never smokers seems to have a geo-
graphic and gender variation, because it was seen that women are more frequently affected than
men and it is more prevalent in certain parts of the world, such as Asia. Although all histologic
types of lung cancer are associated with cigarette smoking, in smokers the association is stronger
for SCLC and squamous cell carcinoma. In contrast, adenocarcinoma of the lung is more common
in never smokers compared with smokers (however, it is becoming more common even among
Introduction
3
smokers). The survival rate for never smokers is better than for smokers, independently of disease
stage, treatment received, and presence of comorbidities, and there are epidemiologic, clinicopatho-
logic, and molecular differences between lung cancer in the two groups. These differences have lead
some investigators to think that lung cancer in never smokers could be a different disease
1
.
However, considering that 15% of all lung cancers in men and up to 53% in women are not attribut-
able to smoking, with never smokers accounting for 25% of all lung cancer cases worldwide, there
could be other important causes of lung cancer, like: diet, that seems to be responsible for approxi-
mately 30% of all cancers occurring in developed countries, environmental tobacco smoke (ETS),
that consists of both mainstream smoke and sidestream smoke and can contribute to an increase risk
for lung cancer with a dose-dependent relationship between the degree of exposure and the relative
risk, genetic factors, like genes known to be involved in the absorption, metabolism, and accumula-
tion of tobacco or other carcinogens in lung tissue and genes involved in DNA repair mechanisms,
gender, considering that women seem to be more susceptible than men to the carcinogenic effects of
cigarette smoke (maybe because of differences in nicotine metabolism and in metabolic activation
or detoxification of lung carcinogens), and radon, a naturally occurring decay product of radium
226, that itself decays into a series of radioisotopes, which emit alpha particles, that could damage
cells and genetic material leading to induction of cancer
2-3
.
1.1.2 Diagnosis
The main symptom of lung cancer is a cough that persists over time, or does not go away with
treatment; other local symptoms that can be caused by lung cancer include:
- coughing up blood (hemoptysis)
- difficulty breathing, due to decreased airflow by a tumor obstructing the large airways or
spread through lungs
- wheezing, caused by the interference of airflow through an airway obstructed by a tumor
- pain in the chest, back, shoulder, and arm, due to a lung tumor presses on nerves
- repeated lung infections such as pneumonia or bronchitis
It must be underlined, however, that roughly 25% of cases are asymptomatic. These tumors are usu-
ally found when a chest x-ray is done for another reason or when a smoker or former smoker has a
Introduction
4
procedure to screen for lung cancer. Despite the efforts, current clinical management of patients
with lung cancer too often begins at the time of symptomatic presentation, when the disease is in
advance stage. Currently, radiology has a central role in all aspects of managing patients with lung
cancer, because it is essential for localizing abnormalities, suggesting the diagnosis, providing clini-
cal staging, following response to treatment, and permitting surveillance of patients after therapy is
complete. Despite that, there are still a lot of limitations: not all radiographic abnormalities that ap-
pear to be lung cancer are cancer, clinical staging is not uniformly accurate, and response criteria do
not consistently correlate with survival
4
. All these limitations make necessary to find novel diagnos-
tics and screening tests in order to improve patients survival. Nowadays, the most sensitive and cur-
rently used imaging modality for detecting pulmonary nodules is low-dose spiral computed tomo-
graphy (LDSCT)
5
. Several observational studies have shown that LDSCT of the lung detects more
nodules and lung cancers, including early-stage cancers, than chest radiography does. Therefore, the
National Cancer Institute (NCI) funded the National Lung Screening Trial (NLST), a randomized
trial to determine whether screening with LDSCT, compared with chest radiography, would reduce
mortality from lung cancer among high-risk persons. The NSLT was initiated in 2002 and the data
published in October 2010 showed that there was a 20% decrease in lung cancer mortality with
LDSCT compared to radiography of chest (Fig. 2)
6
.
Reduced Lung-Cancer Mortality with Low-Dose CT Screening
n engl j med 365;5 nejm.org august 4, 2011 405
lung cancer. The decrease in the rate of death from
any cause with the use of low-dose CT screening
suggests that such screening is not, on the whole,
deleterious.
A high rate of adherence to the screening, low
rates of lung-cancer screening outside the NLST,
and thorough ascertainment of lung cancers and
deaths contributed to the success of the NLST.
Moreover, because there was no mandated diag-
nostic evaluation algorithm, the follow-up of posi-
tive screening tests reflected the practice patterns
at the participating medical centers. A multidis-
ciplinary team ensured that all aspects of the
NLST were conducted rigorously.
There are several limitations of the NLST. First,
as is possible in any clinical study, the findings
may be affected by the “healthy-volunteer” effect,
which can bias results such that they are more
favorable than those that will be observed when
the intervention is implemented in the commu-
nity.
24
The role of this bias in our results cannot
be ascertained at this time. Second, the scanners
that are currently used are technologically more
advanced than those that were used in the trial.
This difference may mean that screening with
today’s scanners will result in a larger reduction
in the rate of death from lung cancer than was
observed in the NLST; however, the ability to de-
tect more abnormalities may result only in higher
rates of false positive results.
25
Third, the NLST
was conducted at a variety of medical institutions,
many of which are recognized for their expertise
in radiology and in the diagnosis and treatment
of cancer. It is possible that community facilities
will be less prepared to undertake screening pro-
grams and the medical care that must be asso-
ciated with them. For example, one of the most
important factors determining the success of
screening will be the mortality associated with
surgical resection, which was much lower in the
NLST than has been reported previously in the
general U.S. population (1% vs. 4%).
26
Finally, the
reduction in the rate of death from lung cancer
associated with an ongoing low-dose CT screen-
ing program was not estimated in the NLST and
may be larger than the 20% reduction observed
with only three rounds of screening.
Radiographic screening rather than community
care (care that a participant usually receives) was
chosen as the comparator in the NLST because
radiographic screening was being evaluated in the
PLCO trial at the time the NLST was designed.
11
The designers of the NLST reasoned that if the
PLCO trial were to show a reduction in lung-cancer
mortality with radiographic screening, a trial of
low-dose CT screening in which a community-
care group was the control would be of less val-
ue, since the standard of care would have become
screening with chest radiography. Nevertheless,
the choice of radiography precludes a direct com-
parison of low-dose CT with community care.
Analysis of the subgroup of PLCO participants
who met the NLST criteria for age and smoking
history indicated that radiography, as compared
with community care, does not reduce mortality
from lung cancer.
27
Therefore, a similar reduction
Cumulative No. of Lung Cancers
1100
800
1000
900
700
600
400
300
100
500
200
0
0 1 2 3 4 5 6 7 8
B Death from Lung Cancer
A Lung Cancer
Years since Randomization
Cumulative No. of Lung-Cancer Deaths
500
400
300
100
200
0
0 1 2 3 4 5 6 7 8
Years since Randomization
Low-dose CT
Low-dose CT
Chest radiography
Chest radiography
Figure 1. Cumulative Numbers of Lung Cancers and of Deaths from Lung Cancer.
The number of lung cancers (Panel A) includes lung cancers that were di-
agnosed from the date of randomization through December 31, 2009. The
number of deaths from lung cancer (Panel B) includes deaths that occurred
from the date of randomization through January 15, 2009.
The New England Journal of Medicine
Downloaded from nejm.org on April 14, 2013. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
Reduced Lung-Cancer Mortality with Low-Dose CT Screening
n engl j med 365;5 nejm.org august 4, 2011 405
lung cancer. The decrease in the rate of death from
any cause with the use of low-dose CT screening
suggests that such screening is not, on the whole,
deleterious.
A high rate of adherence to the screening, low
rates of lung-cancer screening outside the NLST,
and thorough ascertainment of lung cancers and
deaths contributed to the success of the NLST.
Moreover, because there was no mandated diag-
nostic evaluation algorithm, the follow-up of posi-
tive screening tests reflected the practice patterns
at the participating medical centers. A multidis-
ciplinary team ensured that all aspects of the
NLST were conducted rigorously.
There are several limitations of the NLST. First,
as is possible in any clinical study, the findings
may be affected by the “healthy-volunteer” effect,
which can bias results such that they are more
favorable than those that will be observed when
the intervention is implemented in the commu-
nity.
24
The role of this bias in our results cannot
be ascertained at this time. Second, the scanners
that are currently used are technologically more
advanced than those that were used in the trial.
This difference may mean that screening with
today’s scanners will result in a larger reduction
in the rate of death from lung cancer than was
observed in the NLST; however, the ability to de-
tect more abnormalities may result only in higher
rates of false positive results.
25
Third, the NLST
was conducted at a variety of medical institutions,
many of which are recognized for their expertise
in radiology and in the diagnosis and treatment
of cancer. It is possible that community facilities
will be less prepared to undertake screening pro-
grams and the medical care that must be asso-
ciated with them. For example, one of the most
important factors determining the success of
screening will be the mortality associated with
surgical resection, which was much lower in the
NLST than has been reported previously in the
general U.S. population (1% vs. 4%).
26
Finally, the
reduction in the rate of death from lung cancer
associated with an ongoing low-dose CT screen-
ing program was not estimated in the NLST and
may be larger than the 20% reduction observed
with only three rounds of screening.
Radiographic screening rather than community
care (care that a participant usually receives) was
chosen as the comparator in the NLST because
radiographic screening was being evaluated in the
PLCO trial at the time the NLST was designed.
11
The designers of the NLST reasoned that if the
PLCO trial were to show a reduction in lung-cancer
mortality with radiographic screening, a trial of
low-dose CT screening in which a community-
care group was the control would be of less val-
ue, since the standard of care would have become
screening with chest radiography. Nevertheless,
the choice of radiography precludes a direct com-
parison of low-dose CT with community care.
Analysis of the subgroup of PLCO participants
who met the NLST criteria for age and smoking
history indicated that radiography, as compared
with community care, does not reduce mortality
from lung cancer.
27
Therefore, a similar reduction
Cumulative No. of Lung Cancers
1100
800
1000
900
700
600
400
300
100
500
200
0
0 1 2 3 4 5 6 7 8
B Death from Lung Cancer
A Lung Cancer
Years since Randomization
Cumulative No. of Lung-Cancer Deaths
500
400
300
100
200
0
0 1 2 3 4 5 6 7 8
Years since Randomization
Low-dose CT
Low-dose CT
Chest radiography
Chest radiography
Figure 1. Cumulative Numbers of Lung Cancers and of Deaths from Lung Cancer.
The number of lung cancers (Panel A) includes lung cancers that were di-
agnosed from the date of randomization through December 31, 2009. The
number of deaths from lung cancer (Panel B) includes deaths that occurred
from the date of randomization through January 15, 2009.
The New England Journal of Medicine
Downloaded from nejm.org on April 14, 2013. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
Figure 2: Cumulative numbers of lung cancers and of deaths from lung cancer with chest radiography and LDSCT.
Adapted from
6
Other diagnosis methods that may be used for patients affected by lung cancer are positron emission
tomography (PET), that helps to differentiate benign from malignant nodules and guides patient
management, and magnetic resonance (MR), which is reserved for the assessment of cases in which
Introduction
5
local invasion is suspected and it is useful to differentiate malignant nodules from inflammatory
ones. However, despite the availability of different diagnostic solutions, diagnosis and screening of
lung cancer is currently a public problem, because it is difficult to obtain information regarding cur-
rent or future biological behavior of an identified lesion. Therefore, novel strategies are needed to
improve both diagnosis and prognostic ability, like the development of specific biomarkers that, in
conjunction with imaging, could help to understand which patients have lung cancer and which
ones require further evaluation. In conclusion, no test has currently proven efficacy for an early de-
tection of lung cancer, so the only way to reduce its incidence and mortality is prevention, that can
be mainly reached by smoking avoidance and cessation; indeed, prevention of smoking initiation
avoids the sequence of events leading to cancer, so it is fundamental to continue campaigns and
programs to let people know about risks associated with smoking, in particular because an increas-
ing number of persons worldwide continue to smoke. Indeed, it has been demonstrated that smokers
who quit for more than 15 years have an 80% to 90% reduction in their risk for lung cancer com-
pared with persons who continue to smoke
1
.
1.1.3 Classification
The two main types of lung cancer, non-small cell lung cancer (NSCLC), representing 80-85% of
cases, and small cell lung cancer (SCLC), representing 15-20% of cases, are identified for histo-
logic, clinical, molecular, and neuroendocrine characteristics. NSCLC can be further divided in:
- Squamous cell carcinoma: this type of lung cancer accounts for approximately 20% of all
cases. Historically, two-thirds of squamous cell carcinomas presented as central lung tumors,
while the others were peripheral; however, recent reports have shown an increasing percent-
age in carcinoma found in the periphery. The morphologic features that identify squamous
differentiation include intercellular bridging, squamous pearl formation, and individual cell
keratinization (Fig. 3). Molecular characteristics of this tumor type include: high mutation
frequency of p53 (60-70%), inactivation of inhibitor of cyclin-dependent kinases p16 in 65%
of cases, and overexpression of EGFR in 80% of cases (even if this gene is rarely mutated)
7
.
- Adenocarcinoma: more present in women and never smokers, adenocarcinomas represent
38% of all lung cancers
7
. They commonly occur as peripheral solitary masses, but they can
also arise in the central airways or present as lobar consolidation, diffuse bilateral disease, or
Introduction
6
rarely pleural thickening mimicking malignant mesothelioma (Fig. 3). The main growth pat-
terns are acinar, papillary, bronchioloalveolar, and solid with mucin, even if most lung adeno-
carcinomas show a mixture of these patterns
8
. Molecular characteristics of this tumor type
include: highest presence of K-ras gene mutations, mutation in p53, RB1, and p16 with the
same frequency of squamous cell carcinoma, and amplification and mutation in EGFR gene.
- Large cell carcinoma: these tumors, that represent 3% of all lung cancer cases, are mostly
found in the lung periphery, although they could also be centrally located. By gross examina-
tion, they frequently appear as large necrotic tumors and they histologically consist of sheets
and nests of large polygonal cells with prominent nucleoli (Fig. 3). Large cell carcinoma is
normally a diagnosis of exclusion, which is made when the presence of squamous cell or
glandular differentiation is excluded by light microscopy
7
.
SCLC comprises 15-20% of lung cancers (high frequency in smokers) and have a distinctive histo-
logic appearance (Fig. 3), because cells are small and have a round to fusiform shape, finely granu-
lar nuclear chromatin, and absent nucleoli (after chemotherapy, mixtures of large cell, squamous,
giant cell, or adenocarcinoma may be seen in 15% to 45% of SCLC). Approximately two-thirds of
SCLC are situated in a peribronchial location with infiltration of the bronchial submucosa and peri-
bronchial tissue. This type of lung tumor has distinctive clinical properties, with an aggressive clini-
cal course, frequent wide-spread metastases at presentation, common paraneoplastic syndromes,
and responsiveness to chemotherapy. With combination of chemotherapy and chest radiotherapy, for
patients with early disease, the median survival time is 15 months and 5-year survival is 10%. Mo-
lecular characteristics of SCLC include: frequent mutation of onco-suppressor gene p53 and RB1
(90% of cases), and high levels of anti-apoptotic protein BCL2 (75-90% of cases)
7
.
Introduction
7
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