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Lung Neoplasms, Primary

BASIC INFORMATION

DEFINITION
A primary lung neoplasm is a malignancy arising
from lung tissue. The World Health Organization
distinguishes 12 types of pulmonary neoplasms.
The major types are squamous cell carcinoma,
adenocarcinoma, small cell carcinoma, and
large cell carcinoma. However, the crucial difference in the diagnosis of lung cancer is between
small cell lung cancer (SCLC) and nonsmall
cell lung cancer (NSCLC) because the prognosis
and therapeutic approach are different.
ADENOCARCINOMA: Represents 35% to 40%
of lung carcinomas; frequently located in midlung and periphery; initial metastases are to
lymphatics; frequently associated with peripheral scars; adenocarcinoma is described as
preinvasive, minimally invasive, or invasive
SQUAMOUS CELL (EPIDERMOID): 20% to 30%
of lung cancers; central location; metastasis by
local invasion; frequent cavitation and obstructive phenomena
SMALL CELL (OAT CELL): 20% of lung carcinomas; central location; metastasis through
lymphatics; associated with lesion of the short
arm of chromosome 3; high cavitation rate
LARGE CELL: 10% to 15% of lung carcinomas;
frequently located in the periphery; metastasis
to central nervous system and mediastinum;
rapid growth rate with early metastasis
LEPIDIC-PREDOMINANT PATTERN (BRON
CHOALVEOLAR): 5% of lung carcinomas; frequently located in the periphery; may be bilateral;
initial metastasis through lymphatic, hematogenous, and local invasion; no correlation with
cigarette smoking; cavitation rare
SYNONYMS
Lung cancer
ICD-9CM CODES
162.9Malignant neoplasm of bronchus and
lung, unspecified
ICD-10CM CODES
C34.90Malignant neoplasm of unspecified
part of unspecified bronchus or lung

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EPIDEMIOLOGY &
DEMOGRAPHICS


Lung cancer is responsible for >30% of
cancer deaths in males and >25% of cancer
deaths in females. It has been the most common cancer in the world since 1985 and is
the leading cause of cancer-related death.
Tobacco smoking is implicated in 90% of
cases; second-hand smoke is responsible for
approximately 20% of cases.
There are >200,000 new cases of lung cancer yearly in the U.S., most occurring at age
>50 yr (<4% in patients <40 yr).


Among women there has been a 600%
increase in incidence of lung cancer during
the past 80 years. The rates of death among
women with lung cancer in the U.S. are the
highest in the world.
PHYSICAL FINDINGS & CLINICAL
PRESENTATION
Weight loss, fatigue, fever, anorexia, dysphagia
Cough, hemoptysis, dyspnea, wheezing
Chest, shoulder, and bone pain
Paraneoplastic syndromes (see Table 1-309):
C Lambert-Eaton myasthenic syndrome:
myopathy involving proximal muscle
groups
C Endocrine manifestations: hypercalcemia,
ectopic adrenocorticotropic hormone, syndrome of inappropriate excretion of adrenocorticotropic hormone
C 
Neurologic: subacute cerebellar degeneration, peripheral neuropathy, cortical
degeneration
C 
Musculoskeletal: polymyositis, clubbing,
hypertrophic pulmonary osteoarthropathy
C Hematologic or vascular: migratory thrombophlebitis, marantic thrombosis, anemia,
thrombocytosis, or thrombocytopenia
C Cutaneous: acanthosis nigricans, dermatomyositis


Pleural effusion (10% of patients), recurrent pneumonias (from obstruction), localized
wheezing
Superior vena cava syndrome:
C Obstruction of venous return of the superior vena cava is most commonly caused

by bronchogenic carcinoma or metastasis

to paratracheal nodes.
C The patient usually reports headache, nausea, dizziness, visual changes, syncope,
and respiratory distress.
C Physical examination reveals distention of
thoracic and neck veins, edema of face
and upper extremities, facial plethora, and
cyanosis.
Horners syndrome: constricted pupil, ptosis, facial anhidrosis caused by spinal cord
damage between C8 and T1 as a result of a
superior sulcus tumor (bronchogenic carcinoma of the extreme lung apex)
Pancoast tumor: a superior sulcus tumor
associated with ipsilateral Horners syndrome and shoulder pain

ETIOLOGY


Tobacco abuse; the chance of developing
lung cancer for a 40-pack-year persistent
smoker is 20 times that of someone who
never smoked
Environmental agents (e.g., radon) and industrial agents (e.g., ionizing radiation, asbestos,
nickel, uranium, vinyl chloride, chromium,
arsenic, coal dust)
Lung cancer susceptibility and risk increased
in inherited cancer syndromes caused by
germ-line mutations in p53, retinoblastoma,
and germ-line mutation in the epidermal
growth factor receptor (EGFR) gene; also an
association between single-nucleotide polymorphism variation at 15q24-15q25.1 and
susceptibility to lung cancer

Dx DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
Pneumonia
Tuberculosis (TB)
Metastatic carcinoma to the lung
Lung abscess
Granulomatous disease
Carcinoid tumor
Mycobacterial and fungal diseases
Sarcoidosis
Viral pneumonitis

TABLE 1-309 Paraneoplastic Syndromes Associated with Bronchogenic Carcinoma

Syndrome

Cell Type

Mechanism

Hypertrophic pulmonary osteoarthropathy and clubbing

Hyponatremia
Hypercalcemia

All except small cell

Unknown

Small cell most common; may be any type

Usually squamous cell

Cushings syndrome
Lambert-Eaton myasthenic syndrome

Usually small cell

Usually small cell

Other neuromyopathic disorders

Thrombophlebitis

Small cell most common; may be any type

All types

SIADH, ectopic antidiuretic hormone production by tumor

Bone metastases, osteoclast-activating factor, parathyroid hormonelike hormone,
prostaglandins
Ectopic ACTH production
Voltage-sensitive calcium channel antibodies in >75%; affects presynaptic neuronal calcium channel activity
Antineuronal nuclear antibodies, also known as anti-Hu; others unknown
Unknown

ACTH, Adrenocorticotropic hormone; SIADH, syndrome of inappropriate secretion of antidiuretic hormone.

From Andreoli TE etal: Andreoli and Carpenters Cecil essentials of medicine, ed 8, Philadelphia, 2010, Saunders.

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WORKUP
Workup generally includes chest radiograph, CT
scan of chest, positron-emission tomographic
(PET) scan, and tissue biopsy. Lab tests should
include CBC, serum calcium, and liver chemistry
studies. Diagnosis and staging of lung cancer
should be performed simultaneously to minimize invasive testing.
LABORATORY TESTS
Obtain tissue diagnosis. Various modalities are
available:
Biopsy of any suspicious lymph nodes (e.g.,
supraclavicular node)
Flexible fiberoptic bronchoscopy: brush and
biopsy specimens are obtained from any
visualized endobronchial lesions
Transbronchial needle aspiration: done with
a special needle passed through the bronchoscope; this technique is useful to sample
mediastinal masses or paratracheal lymph
nodes
Transthoracic fine-needle aspiration biopsy
with fluoroscopic or CT scan guidance to
evaluate peripheral pulmonary nodules
Mediastinoscopy and anteromedial sternotomy in suspected tumor involvement of the
mediastinum
Pleural biopsy in patients with pleural effusion
Thoracentesis of pleural effusion and cytologic evaluation of the obtained fluid: may
confirm diagnosis
IMAGING STUDIES


Chest radiograph (Fig. 1-566): The radiographic presentation often varies with the
cell type. Pleural effusion, lobar atelectasis,
and mediastinal adenopathy can accompany
any cell types.
CT scan of chest (Fig. 1-567) is performed to
evaluate mediastinal and pleural extension
of suspected lung neoplasms. The chest CT
should include liver and adrenal glands (common sites of metastases). CT or MRI of brain
should be considered in a patient presenting
with neurologic symptoms (e.g., headaches,
vision disturbances).
PET with 18F-fluorodeoxyglucose (18FDGPET), a metabolic marker of malignant tissue,
is superior to CT scan in detecting medias-

tinal and distant metastases in NSCLC. It is

useful for preoperative staging of NSCLC.
The use of PET-CT for preoperative staging
of NSCLC reduces both the total number
of thoracotomies and the number of futile
thoracotomies but does not affect overall
mortality.


T he combination of endoluminal ultrasound (EUS) and endobronchial ultrasound
(EBUS) with fine-needle aspiration has
been reported to have a 93% sensitivity
and 97% specificity for establishing the
presence of mediastinal disease in lung
cancer patients.

STAGING
After confirmation of diagnosis, patients should
undergo staging:
1. The international staging system is the most
widely accepted staging system for NSCLC. In
this system, stage I (N0 [no lymph node involvement]) and stage II (N1 [spread to ipsilateral bronchopulmonary or hilar lymph nodes])
include localized tumors for which surgical
resection is the preferred treatment. Stage III
is subdivided into IIIA (potentially resectable)
and IIIB. The surgical management of stage
IIIA disease (N2 [involvement of ipsilateral
mediastinal nodes]) is controversial. Only 20%
of N2 disease is considered minimal disease

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Diseases
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Benign lesions that simulate thoracic malignancy:

C Lobar atelectasis: pneumonia, TB, chronic
inflammatory disease, allergic bronchopulmonary aspergillosis
C Multiple pulmonary nodules: septic emboli,
Wegeners granulomatosis, sarcoidosis,
rheumatoid nodules, fungal disease, multiple pulmonary atrioventricular fistulas
C Mediastinal adenopathy: sarcoidosis, lymphoma, primary TB, fungal disease, silicosis, pneumoconiosis, drug-induced (e.g.,
phenytoin, trimethadione)
C Pleural effusion: congestive heart failure,
pneumonia with parapneumonic effusion,
TB, viral pneumonitis, ascites, pancreatitis,
collagen-vascular disease

Lung Neoplasms, Primary

I
Right lower
lobe density

Right lower
lobe density

FIGURE 1-566 Lung neoplasm, primary. Lung mass presenting with hemoptysis. A, Posterior-anterior (PA)
chest x-ray. B, Lateral chest x-ray. This 83-year-old female presented with hemoptysis of a quarter-sized clot.
Her posterior-anterior chest x-ray shows a rounded right lower lobe density. On the lateral view, this is visible in
the retrocardiac space. This density measures 7.6 cm in diameter. Pneumonia, neoplasm, or abscess could have
this appearance on chest x-ray. Computed tomography was performed to further delineate the pathology (see
Fig. 1-567). (From Broder JS: Diagnostic imaging for the emergency physician, Philadelphia, 2011, Saunders.)

Major
fissure

Solid mass consistent

with neoplasm

FIGURE 1-567 Lung neoplasm, primary. Lung mass presenting with hemoptysis. Same patient as in Fig.
1-566. Noncontrast computed tomography was performed (contrast was withheld as a consequence of the
patients renal dysfunction) and shows a 6 by 6 cm round lesion abutting the oblique fissure (also called the
major fissure) and lateral chest wall. A, Soft tissue windows. B, Lung windows. On soft tissue windows, the
center appears slightly darker, indicating lower density that may represent central necrosis. If IV contrast
had been given, an area of necrosis would have failed to enhance. Infection or infarction is technically possible, but a pulmonary neoplasm is the most likely explanation for this lesion. Biopsy showed this to be a
moderately differentiated squamous cell carcinoma. (From Broder JS: Diagnostic imaging for the emergency
physician, Philadelphia, 2011, Saunders.)

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Lung Neoplasms, Primary

(involvement of only one node) and technically
resectable. Stage IV indicates metastatic disease. The pathologic staging system uses a
tumor/nodal involvement/metastasis system.
2. In patients with SCLC, a more practical accepted staging system is the one developed
by the Veterans Administration Lung Cancer
Study Group. This system contains two stages:
a. 
Limited-stage disease: confined to the
regional lymph nodes and to one hemithorax (excluding pleural surfaces)
b. Extensive-stage disease: spread beyond
the confines of limited-stage disease

3. 
Pretreatment staging procedures for lung
cancer patients, in addition to complete history and physical examination, generally include the following tests:
a. 
Chest radiograph (posteroanterior and
lateral), ECG
b. 
Laboratory evaluation: complete blood
count, complete metabolic panel, arterial blood gases, pulse oximetry. The
identification of molecular signatures
of lung cancer to predict prognosis with
data from microarray and/or reversetranscription polymerase chain reaction
analysis has been validated in recent trials. A five-gene signature (DUSP6, MMD,
STAT1, ERBB3, and LCK) is closely associated with relapse-free and overall survival among patients with NSCLC. Anaplastic
lymphoma kinase (ALK) translocation is
found in about 4% to 5% of lung cancers. Detection of mutations in epidermal
growth factor receptor (EGFR) in circulating tumor cells from the blood of patients
with lung cancer offers the possibility of
monitoring changes in epithelial tumor
genotypes during the course of treatment
c. Pulmonary function studies
d. CT scan of chest and PET scan: a recent
Dutch trial revealed a 51% relative reduction in futile thoracotomies for patients
with suspected NSCLC who underwent
preoperative assessment with PET with
the tracer 18FDG-PET in addition to conventional workup
e. 
Mediastinoscopy or anterior mediastinotomy in patients being considered for
possible curative lung resection
f. Biopsy of any accessible suspect lesions
g. CT scan of liver and brain; radionuclide
scans of bone in all patients with small
cell carcinoma of the lung and patients
with NSCLC neoplasms suspected of involving these organs
h. Bone marrow aspiration and biopsy only
in selected patients with small cell carcinoma of the lung. In the absence of an
increased lactate dehydrogenase or cytopenia, routine bone marrow examination
not recommended
i. Newer technologies in preoperative staging include endoscopic bronchial ultrasonography and esophageal ultrasonography
to guide biopsies; however, cervical mediastinoscopy is standard criterion in preoperative nodal staging (sensitivity >93%,
specificity >95%)

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Rx TREATMENT
NONPHARMACOLOGIC THERAPY
Nutritional support
Avoidance of tobacco and other substances
toxic to the lungs
Supplemental O2 prn
ACUTE GENERAL Rx
NONSMALL CELL CARCINOMA:
Surgical resection is the best hope for cure
in patients with operable NSCLC (stage I or
II when the patient is a surgical candidate).
Lobectomy is the best standard surgical
approach. Lesser resections may be necessary in patients with marginal pulmonary
reserve. Video-assisted thoracic surgery
(VATS) is helpful in decreasing morbidity and
shortening hospital stay.
1. Surgical resection is indicated in patients
with limited disease (not involving mediastinal nodes, ribs, pleura, or distant
sites). This represents approximately 15%
to 30% of diagnosed cases.
2. 
Preoperative evaluation includes review
of cardiac status (e.g., recent myocardial
infarction, major arrhythmias) and evaluation of pulmonary function (to determine
if the patient can tolerate any loss of
lung tissue). Pneumonectomy is possible
if the patient has a preoperative FEV1
= 2 L or if the maximal voluntary ventilation is >50% of predicted capacity.
Individuals with FEV1 >1.5 L are suitable
for lobectomy without further evaluation
unless there is evidence of interstitial lung
disease or undue dyspnea on exertion.
In that case, carbon dioxide diffusion in
the lung (DLCO) should be measured. If
the DLCO is <80% predicted normal, the
individual is not clearly operable.
3. 
Preoperative chemotherapy should
be considered in patients with more
advanced disease (stage IIIA) who are
being considered for surgery because
it increases the median survival time in
patients with NSCLC compared with the
use of surgery alone. Gene expression
profiles that predict the risk of recurrence
in patients with early stage (IA) NSCLC
have been identified. These patients are
at high risk of recurrence and may also
benefit from adjuvant chemotherapy.
4. 
Postoperative adjuvant chemotherapy
(chemotherapy given after surgical resection of an apparently localized tumor to
eradicate occult metastases) with vinorelbine plus cisplatin significantly increases
5-yr survival (69% vs. 54%) in patients
with completely resected stage IB or
stage II NSCLC and good performance
status. Adjuvant chemotherapy is generally indicated for patients with resected
stages IIA through IIIA.
Treatment of unresectable NSCLC:
1. 
Radiotherapy can be used alone or in
combination with chemotherapy; it is

used primarily for treatment of central

nervous system and skeletal metastases, superior vena cava syndrome, and
obstructive atelectasis. Although thoracic
radiotherapy is generally considered standard therapy for stage 3 disease, it has
limited effect on survival. Palliative radiotherapy should be delayed until symptoms occur because immediate therapy
offers no advantage over delayed therapy
and results in more adverse events from
the radiotherapy. Conventional radiotherapy fails to durably control the primary lung
tumor in nearly 70% of patients and 2-yr
survival is less than 40%. Stereotactic
body radiation (SBRT) uses several highly
focused radiation beams to deliver high
doses in 15 treatments and appears to be
more effective than conventional radiotherapy, with a survival rate of 55.8% at 3
yr for inoperable early stage lung cancer.
2. Chemotherapy remains the mainstay of
treatment for advanced stage IIIB and
stage IV NSCLC. (stage I or II when
the patient is a surgical candidate).
Lobectomy is the best standard surgical approach. Lesser resections may be
necessary in patients with marginal pulmonary reserve. Video-assisted thoracic
surgery (VATS) is helpful in decreasing
morbidity and shortening hospital stay..
A platinum-based treatment is recommended for fit patients, and single agents
can be offered in elderly patients and
in those with poor performance status.
Various combination regimens are available. Current drugs of choice are paclitaxel plus either carboplatin or cisplatin,
cisplatin plus vinorelbine, gemcitabine
plus cisplatin, and carboplatin or cisplatin plus docetaxel. The overall results are
disappointing, and none of the standard
regimens for NSCLC is clearly superior to
the others. The addition of bevacizumab
to paclitaxel plus carboplatin results in
significant survival benefit but carries an
increased risk of treatment-related death.
Gefitinib and erlotinib are oral inhibitors
of EGFR tyrosine kinase. Activating mutations in the EGFR gene confer hypersensitivity to these medications. Sensitivity of
lung neoplasms to these agents is seen
primarily in tumors with somatic mutations in the tyrosine kinase domain (more
common in adenocarcinomas found in
patients who never smoked and in Asian
patients). Recent trials revealed that gefitinib is superior to carboplatin-paclitaxel
as an initial treatment for pulmonary
adenocarcinoma among nonsmokers or
former smokers in East Asia. In these
patients the presence in the tumor of
a mutation of the EGFR gene was a
strong predictor of a better outcome with
gefitinib. The National Comprehensive
Cancer Network (NCCN) recognizes erlotinib as an option for second- or thirdline therapy in patients with advanced
NSCLC who have a performance status

PTG

1Shaw

AT et al: Crizotinib versus chemotherapy

in advanced ALK-positive lung cancer, N Engl J Med
368:2385-2394, 2013.

survival, and less use of aggressive endof-life care.

SMALL CELL LUNG CANCER:
Limited-stage disease: standard treatments
include thoracic radiotherapy and chemotherapy (cisplatin and etoposide).


Extensive-stage disease: standard treatments include combination chemotherapy
(cisplatin or carboplatin plus etoposide or
combination of irinotecan and cisplatin).
Prophylactic cranial irradiation for patients in
complete remission to decrease the risk of
central nervous system metastasis.


Despite high initial response rates, most
patients eventually relapse. Topotecan may
be an option for these patients.

DISPOSITION


The 5-yr survival of patients with NSCLC
when the disease is resectable is approximately 30%.
Median survival time in patients with limitedstage disease and SCLC is 15 mo; in patients
with extensive stage disease, it is 9 mo.
Among patients with metastatic NSCLC, early
palliative care results in longer survival and
significant improvements in both quality of
life and mood.
Methylation of the promoter region of certain
genes (P16, CDH13, APC, and RASSF1A) in a
resected NSCLC specimen is associated with
recurrence of the tumor.

PEARLS &
CONSIDERATIONS

COMMENTS
CT screening with use of low-dose computed
tomography (LDCT) for detection of lung
cancer among persons with a heavy history
of smoking increases the percentage of lung

cancer cases that are diagnosed in stage

1 and reduces mortality from lung cancer.
The National Lung Screening Trial (NLST)
showed that lung cancer screening with
LDCT resulted in a 20% reduction in mortality
from lung cancer. New guidelines from the
American College of Chest Physicians, the
American Society of Clinical Oncology, and
the National Comprehensive Cancer Network
recommend annual LDCT for those who are
current or former smokers aged 55-74. The
U.S. Preventive Services Task Force (USPSTF)
recommends annual screening for lung cancer with LDCT in adults aged 55 to 80 years
who have a 30 pack-year smoking history
and currently smoke or have quit within the
past 15 years. Screening should be discontinued once a person has not smoked for 15
years or develops a health problem that substantially limits life expectancy or the ability
or willingness to have curative lung surgery.2
Quitting smoking is the most effective method to reduce risk for lung cancer. Following
smoking cessation, the risk of lung cancer
remains higher than normal based on duration and quantity of smoking but does not
increase further as in a continuing smoker.

SUGGESTED READINGS
available at www.expertconsult.com
RELATED CONTENT
Lung Cancer Diagnosis
Lung Cancer Screening (Patient Information)
AUTHOR: FRED F. FERRI, M.D.

2Moyer VA on behalf of U.S. Preventive Services

Task Force: Screening for lung cancer: U.S. Preventive
Services Task Force recommendation statement, Ann
Intern Med 160:330-338, 2014.

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Diseases
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of 0 to 3. It also recommends erlotinib

monotherapy as first line for patients
with an EGFR mutation. Erlotinib can also
be used as a salvage treatment in this
subgroup and as a maintenance agent for
patients with stable or responsive disease
after first-line platinum-based chemotherapy.Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma
kinase (ALK) are present in a subgroup
of NSCLCs, representing 4% to 5% of
such tumors. The inhibition of ALK in lung
tumors with crizotinib, an orally available
small-molecule inhibitor of the ALK tyrosine kinase, has resulted in tumor shrinkage and significant prolonged progression-free survival. Crizotinib was recently
approved by the FDA for locally advanced
or metastatic NSCLC with ALK translocation, which is found in about 5% of lung
cancers. Recent trials1 have shown that
crizotinib is superior to standard chemotherapy in patients with previously treated
advanced nonsmall-cell cancer with ALK
rearrangement.
3. The addition of chemotherapy to radiotherapy improves survival in patients with
locally advanced, unresectable NSCLC.
The absolute benefit is relatively small,
however, and should be balanced against
the increased toxicity associated with the
addition of chemotherapy.
4. Early initiation of palliative care focusing
on management of symptoms, psychosocial support, and assistance with decision
making in patients with metastatic NSCLC
leads to improved quality of life, longer

Lung Neoplasms, Primary

Lung Neoplasms, Primary

SUGGESTED READINGS
Brock MV etal: DNA methylation markers and early recurrence in stage I lung
cancer, N Engl J Med 358:1118-1128, 2008.
Cataldo VD etal: Treatment of non-small cell lung cancer with erlotinib and gefitinib, N Engl J Med 364:947-955, 2011.
Fisher B etal: Preoperative staging of lung cancer with combined PET-CT, N Engl
J Med 361:32-39, 2009.
Goldstraw P etal: Nonsmall-cell lung cancer, Lancet 378:1727-1740, 2011.
Henschke CI etal: Definition of a positive test result in computed tomography
screening for lung cancer, Ann Intern Med 185:246-252, 2013.
Herbst RS etal: Lung cancer, N Engl J Med 359:1367-1380, 2008.
Iannettoni MD: Staging strategies for lung cancer, JAMA 304:2296, 2010.
Kwak E etal: Anaplastic lymphoma kinase inhibition in nonsmall-cell lung cancer, N Engl J Med 363:1693, 2010.
Maemondo M etal: Gefitinib or chemotherapy for non-small cell lung cancer with
mutated EGFR, N Engl J Med 362:2380-2388, 2010.
Maheswaran S etal: Detection of mutations in EGFR in circulating lung cancer
cells, N Engl J Med 359:366, 2008.
Mok TS etal: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma,
N Engl J Med 361:947-957, 2009.
Molina JR etal: Non-small cell lung cancer: epidemiology, risk factors, treatment,
and survivorship, Mayo Clin Proc 83(5):584-594, 2008.
Mostertz W etal: Age- and sex-specific genomic profiles in non-small cell lung
cancer, JAMA 303(6):535-543, 2010.
Shert DY etal: Small cell lung cancer, Mayo Clin Proc 83(3):355-367, 2008.
Silvestri GA: Screening for lung cancer: it works, but does it really work? Ann Intern
Med 155:537-539, 2011.
Tammemagi MC etal: Selection criteria for lung cancer screening, N Engl J Med
368:728-736, 2013.
Temel JS etal: Early palliative care for patients with metastatic non-small cell
lung cancer, N Engl J Med 363:733-742, 2010.
The National Lung Screening Trial research team: Reduced lung-cancer mortality
with low-dose computed tomographic screening, N Engl J Med 365:395-409,
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Timmerman R etal: Stereotactic body radiation therapy for inoperable early stage
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