PULMONARY BOARD REVIEW:
NON-SMALL CELL LUNG CARCINOMA
See Non-Small Cell Lung Cancer Guidelines, Chest, Jan 2003; 123: Supplements
A. CLINICAL:
1. Primary Disease: cough, dyspnea, hemoptysis, fever, sputum, chest pain
2. Local Extension: chest pain, dyspnea, cough, dysphagia, phrenic nerve paralysis
a. Pancoast’s Syndrome: tumor of apex  pain down arm, hoarseness (entrapment of left recurrent
laryngeal nerve), endopthalmitis
b. Horners syndrome: involvement of last cervical and first thoracic segment of sympathetic trunk
c. SVC syndrome, Tracheal obstruction, Pericardial effusion, Pleural effusion
3. Paraneoplastic: cachexia, wt loss, fever, clubbing, hypertrophic osteoarthropathy, Eaton Lambert,
peripheral neuropathy, polymyositis/dermatomyositis, migratory venous thrombophlebitis, marantic
endocarditis, DIC, acanthosis, GN or nephritic…
a. Hypercalcemia: PTH-RP, boney mets
b. SIADH
c. Cushings: via ectopic ACTH production
4. Extrathoracic Metastasis: cervical lymph nodes, brain, bone, adrenals, liver, epidural
B. CLASSIFICATION: is it NSCC vs. SCC?
1. Adenocarcinoma: 31%
a. peripheral/slow grower/early mets
b. gland formation with mucin production
c. Bronchoalveolar Carcinoma – variant that spreads along alveolar wall
2. Squamous Cell Carcinoma: 30%
a. central/slow grower/late mets
b. associated with smoking
c. central necrosis/cavitation, bulky with bronchial obstruction
3. Large Cell Carcinoma: 10%
a. rare, anaplastic cells, highly malignant, early mets
4. Small Cell Carcinoma: 18% - Oat Cell Carcinoma, Intermediate Cell Carcinoma
a. central/ rapid grower/ early mets
b. APUD – neurosecretory cyto granules  paraneoplastic
C. STAGING:
1.
Primary Tumor:
a. T1: <3 cm, peripheral coin lesion surrounded by lung tissue or visceral pleura, and invading no further
than lobar bronchus
b. T2:
(1) >3cm OR
(2) invades visceral pleura or involves main bronchus (>2cm from carina) OR
(3) associated with atelectasis or obstructive pneumonitis (POP) that extends to hilar region (not
whole lung)
c. T3:
(1) into thorax (chest wall), diaphragm, parietal pleura, pericardium OR
(2) main bronchus (<2 cm from carina, but not involving carina) OR
(3) atelectasis or POP of whole lung
d. T4:
(1) involvement of mediastinum = heart, great vessels, trachea, esophagus, vertebra, carina
(2) malignant pleural or pericardial effusion
(3) satellite tumor nodules within ipsilateral, primary tumor lobe
2.
Nodal Involvement:
a. N1: ipsilateral hilar or peri-bronchial lymph nodes = ipsi hilar (10), interlobar (11), lobar (12),
segmental (13), subsegmental (14)
b. N2: ipsilateral mediastinal or subcarinal = ipsi Sup Med  highest Med (1), Upper Paratracheal (2),
Prevascular and Retrotracheal (3), Lower Paratracheal (4); Aortic Nodes  Subaortic (5), ParaAortic
(6); Inf Med  subcarinal (7), ParaEsophageal (8), Pulmonary Ligament (9)
c. N3: contralateral LN or supraclavicular/scalene
3.
Staging: clinical (c) TNM vs. surgical/pathological (p) TNM
T1
clinical 5 yr surv = 65%
surg 5 yr surv = 70%
T2
clinical 5 yr surv = 30%
surg 5 yr surv = 50%
T3
clinical 5 yr surv = 20%
surg 5 yr surv = 30%
T4
clinical 5 yr surv = <10%
N0
N1
N2
N3
1A
(70%)
(70%)
1B
(40%)
(60%)
2A
(40%)
(60%)
2B
(30%)
(40%)
3A
(<20%)
(25%)
3B
(10%)
3A
3B
2B
3A
3A
3B
3B
3B
3B
3B
D. SCREENING:
1. when diagnosed as incidental finding in asymptomatic pt  survival is better
2. several studies of CXR screening in ‘60s showed no reduction in mortality
3. 70’s had 3 NCI trials: benefit of adding sputum cytology every 4 mths to yearly CXR and cytology and
CXR every 4 mths vs yearly  CXR detected significantly more lung cancers than cytology and together
had highest sensitivity, BUT neither improved mortality
4. CXR screening NOT recommended
5. Low dose Chest CT – the future???
E. IMAGING:
1. Evaluating Primary Tumor:
a. CT limited use in detection of chest wall and parietal pleural invasion
b. CT sensitivity of 62% for distinguishing T3/T4 from T1/T2 tumors
c. CT sensitivity of 60-75% in detection of central tumors and invasion of mediastinum  requires
contrast and thin sections
d. MRI not significantly better overall, except evaluation of superior sulcus tumors (evaluate Brachial
plexus, spinal canal, chest wall, and subclavian artery)
2. Evaluating Nodal Mets: CT recommended in all pts to evaluate Mediastinal LN
a. accuracy of CT in detecting Mediastinal LN = 79% sensitivity and 78% specificity  by 42 study
meta-analysis
b. N2 disease not apparent on CT after resection has 30% 5 yr survival
c. Canadian Lung Oncology Group:
(1) Mediastinoscopy in all pts vs. mediastinoscopy only in pts with LN >1cm on CT
(2) the use of CT was likely to produce same or fewer unnecessary thoracotomies and less expensive
d. CT has low specificity  enlarged LN must be biopsied b/c can have hyperplastic LN or granulomas
3. PET:
a. Most studies and meta-analyses have found that FDG-PET is superior to CT in detecting pathologic
mediastinal lymph nodes
b. FDG-PET has a good negative predictive value, but poor positive predictive value for detection of
malignant lymph node infiltration
c. If a patient has a normal PET but enlarged mediastinal lymph nodes on CT, mediastinal lymph node
sampling is warranted
d. Patients who have normal FDG-PET and no enlarged lymph nodes on CT can proceed directly to
thoracotomy
e. PET imaging may also detect otherwise occult distant metastases
F.
SEARCH FOR EXTRATHORACIC METASTASIS:
1. Clinical:
a. Symptoms elicited in history: wt loss, focal skeletal pain, chest pain, headache, syncope, seizure,
extremity weakness, change in MS
b. Signs on exam: LAN, hoarseness, SVC syndrome, bone tenderness, hepatomegaly, focal neurological
signs, soft tissue mass
c. Routine lab tests: complete blood count, serum electrolytes, calcium, alkaline phosphatase, albumin,
AST, ALT, total bilirubin, and creatinine, no utility for tumor markers
d. Patients with clinical Stage I or II and normal clinical evaluation – no further imaging for extrathoracic disease
e. Patients with Stage III or IV – routine imaging for extra-thoracic disease
2. Adrenal Mets: freq site of mets, must d/d from adenoma (in 2-10% population, typically homogenous and
< 3cm, low attenuation via fatty content, MRI may be helpful)
3. Liver Mets: most liver lesions are benign and contrast needed to d/d from hemangioma or cyst
4. Cranial Mets:
a. uncommon (found in no more than 3% who have negative clinical evaluation)
b. false positive of head CT = ~11%
c. solitary lesion may warrant Bx
d. Recommendations = head CT only in pts with clinical neurological findings or findings suggestive of
metastatic disease (weight loss, severe anemia)
5. Bone Mets: perform bone scan when  AP/Ca, bone pain, pathological fracture or evidence/suggestions of
met disease
G. ROLE OF BRONCHOSCOPY:
1. Role is in diagnosis and local staging
2. Central lesions: yield = 70% and >90% if visible lesion
3. additive yield of brush and biopsy (BAL does not increase yield)
4. TBNA for staging malignant LN disease (sensitivity = 50%, specificity = 96%) – less invasive than
mediastinoscopy but its sensitivity is 50 to 90 percent compared to mediastinoscopy
5. Peripheral lesions: yield of biopsy/brush/wash varies 40-80% (<2 cm = <30%, >2 cm = 60-70%, >4 cm =
80%)
H. ROLE OF TRANSTHORACIC NEEDLE ASPIRATION:
1. Procedure of choice for sampling peripheral lesions b/c accuracy = 80-95%
2. 20-30% of pts with non-diagnostic TTNA may still have malignant lesions
3.
4.
5.
only conclusive evidence of benign diagnosis can exclude malignancy
repeat TTNA is diagnostic in 35-65%
PTX = 25-30% with 5-10% require chest tube
I.
EVALUATION OF PLEURAL EFFUSION:
1. 1/3 have PE on presentation and frequently indicates pleural mets, BUT proof of malignancy is mandatory
2. Thoracentesis: cytology of 50-100cc of fluid will be positive in 65%, one study showed that cytology and
biopsy yield together was 60%
3. 2nd thoracentesis preferred over closed pleural biopsy b/c may provide positive specimen in as many as
30% more pts
4. Thoracoscopy: diagnosis confirmed in >95%, also may help stage LN or med invasion
J.
TREATMENT - STRATEGIES:
a. Resectable (Stage 1, 2):
(1) Operable candidate: surgery - if pulmonary function is adequate and medical comorbidity does not
preclude surgery  lobectomy
(2) Medically Inoperable: RT alone or combined with combo chemo if can tolerate
(3) Adjuvant chemo:
(a) recommend adjuvant chemotherapy with a platinum-containing doublet after complete
resection of stage IB and II disease
(b) No adjuvant chemo for 1A
b. N1 Stage 3A: surgery followed by adjuvant chemotherapy
c. N2 Stage 3A: controversial
(1) Not resected - concurrent chemoradiotherapy - combination of cisplatin and etoposide
(2) Resected and negative margins – adjuvant chemo – platinum based and no XRT
(3) Resected and surgical resection margins are positive or uncertain, recommend postoperative XRT
as well as adjuvant chemotherapy
(4) Neoadjuavnt??? – see discussion below on positive N2 disease
d. T4N0 - surgery for the subset of patients with satellite nodules in the same lobe
e. Non-resectable (Stage 3B and 4): Advanced NSCLC
(1) Palliative systemic chemotherapy is associated with increased survival and palliation of lung
cancer-related symptoms
(2) Confined to chest – concurrent chemoradiotherapy
(a) Good performance status patients with non-squamous NSCLC and without brain metastases
or a history of hemoptysis, recommend the combination of bevacimuzab (an anti-VEGF
monoclonal antibody), and the carboplatinum and paclitaxel doublet
(b) Combinations of the newer agents, such as gemcitabine and vinorelbine are associated with
fewer toxic effects compared to platinum-based regimens
(c) Poor performance status - chemotherapy may improve disease-related symptoms and prolong
survival compared to no treatment for some patients
(3) Extrathoracic – RT or chemo to symptomatic sites (bronchial obstruction, painful bony mets or
CNS mets) vs. palliative care
(4) Malignant effusions - carry the same prognosis as patients with stage IV disease - specific
treatment directed toward control of the malignant effusion, palliative RT to control symptoms
from the primary tumor if necessary, systemic chemotherapy to control symptoms and prolong
survival
f. Rule: postoperative XRT – always if surgical margins are positive or uncertain
g. Novel therapies: targeted therapies seek to differentiate between malignant and nonmalignant cells,
they lack many of the side effects associated with systemic chemotherapy
(1) TYROSINE KINASE - comprise the largest family of dominant oncogenes that are altered in
lung cancer
(a) Receptor TK - epidermal growth factor receptor (EGFR, also celled HER1 or erbB-1), erbB-2
(also called HER-2/neu), erbB-3 (HER-3) and erbB-4 (HER-4).
(i) EGFR - overexpressed in a variety of solid tumors, including NSCLC and EGFR
overexpression correlates with advanced disease stage and poor prognosis in many but
not all studies  gefitinib (Iressa) and erlotinib (Tarceva), have been approved for use in
NSCLC as salvage therapy  Monotherapy with erlotinib is well tolerated and can
prolong survival and improve quality of life as second-line treatment in a subset of
patients with NSCLC. Combining erlotinib with cytotoxic chemotherapy does not offer
any advantages over chemotherapy alone. Objective response rates are higher in women,
Asians, lifelong nonsmokers, and patients with adenocarcinoma (particularly the BAC
subtype), but the survival benefit associated with treatment may be present in other
groups as well. Gefitinib should be restricted to patients already on treatment with this
agent who are responding.
(ii) HER2/neu - 25 to 30 percent of NSCLC overexpress HER2/neu (predominantly
adenocarcinomas)  Trastuzumab (Herceptin)is a humanized MoAb that targets the
HER-2/neu receptor – disappointing phase II studies
(b) Non-Receptor TK – PKC, RAS, Raf kinase
(2) RETINOID SIGNALING PATHWAYS, CELL SURVIVAL PATHWAYS
(3) ANGIOGENESIS - The induction of angiogenesis (neovascularization) is an important mechanism
by which tumors promote their own continued growth and metastasis. The extent of tumor
angiogenesis, which is controlled by a variety of local factors with both proangiogenic and
antiangiogenic activity, correlates with an increased risk of metastases, local recurrence, and a
poor overall survival in several tumor types, including NSCLC
(a) BEVACIZUMAB - a recombinant humanized monoclonal antibody (MoAb) which binds
VEGF. Vascular endothelial growth factor (VEGF) is an endothelial-specific mitogen, and a
potent angiogenic factor that is expressed in a wide array of tumors. In NSCLC, as in other
tumors, high levels of VEGF expression are associated with a poor prognosis, suggesting that
interference in this pathway might be useful therapeutically. Concern regarding hemoptysis in
squamous cell or intracerebral hemorrhage in brain lesions.
(4) COX-2 INHIBITORS - Cyclooxygenase-2 (COX-2), an enzyme in the arachidonic acid cascade, is
upregulated and overexpressed in many tumors, including lung cancer. COX-2 expression can be
identified not only in tumor cells, but also in the newly formed blood vessels within tumors.
K. POSITIVE N2 DISEASE:
1. Positive Med LN found at Thoracotomy: 30% survival, give post op adjuvant chemo
2. Positive Med LN by Mediastinoscopy: 0-15% 5 year survival
3. PreOp Chemo = Neoadjuvant: b/c of undetectable micromets and local recurrence
a. Rationale:  size of tumor  downstage or ease resection, perform negative margin resection,
minimal seeding of tumor, treat micro-metastatic disease
b. Disadvantage: mortality secondary to chemo, delayed surgery, increase postop complications, tumor
may not respond
c. Conclusions: Increase post op complication and increase surgical technique, BUT increase
resectability rate and more complete resection – Unknown???
4. PreOp RT: does not increase long term survival, does sterilize tumor and decrease rate of local recurrence
L. SUPERIOR SULCUS TUMORS:
1. arises adjacent to superior pulmonary sulcus and invades by direct extension
2. Pancoasts = apical portion of chest wall
3. Symptoms: rib destruction, pain secondary C8 & T1/T2 invasion, horners syndrome, brachial plexus,
stellate ganglion, 1-3 ribs, vertebral body
4. CXR: apical mass, rib destruction
5. CT:
a. define anatomy and inoperablity (vertebral body or extensive invasion)
b. define Med LN:
(1) if > 1.5cm  Mediastinoscopy  if + LN  INOP, NO long term survivors
6. FOB: for histological confirmation and check for endobronchial lesion
7. Bone Scan: R/O mets, rib invasion does not indicate INOP
8. Tx:
a. PreOp Chemoradiotherapy (more recent data) of Cisplatinum and Etoposide  3-4 wks
b. Perform surgery after 3-4 wks after RT to wait for RT reaction to subside
c. Two additional postoperative courses of chemotherapy, identical to that administered
preoperatively
d. Can remove: upper lung, ribs, vertebral body portions, first thoracic nerve root, sometimes C8
(Ulnar N)
e. Unresectable disease should be considered for definitive chemoradiotherapy - 12-23% 5 yr survival
f. Contraindications to resection: brachial plexus, subclavian, vert body, positive Med LN
g. If peripheral to vertebral body  can do partial resection
h. Post Op Complication: neurological deficits, horners, CSF leak, anhidrosis
9. Px: 5 year survival = 44% with NO Med LN
M. CHEST WALL INVASION:
1. occurs in 5% of pts with primary bronchogenic carcinoma
2. rib destruction usually not identified on CXR, bone scan used to confirm
3.
4.
5.
6.
7.
8.
chest pain usually indicates invasion of parietal pleura and intercostal muscle and alerts physician need to
plan a chest wall resection
positive Med LN with chest wall involvement  consider neo-adjuvant b/c low cure, but at same time
gain of successful palliation of pain
Piehler: 66 pts with chest wall invasion – 5 year survival T3-N0 = 54% AND T3-N1/2 = 7.4% AND
factors affecting survival in T3-N0 included age and cell type
5 year post op survival: <60 yo = 85% and >60 yo = 28%
post op RT: only when resected margins are involved by microscopic cancer
chest wall invasion and negative Med LN represent favorable subset of St. 3 lung cancer and resection
can be accomplished with reasonable expectation of long term survival
Lung Cancer Epidemiology and Etiology
Epidemiology of Lung Cancer. Alberg and Samet. Chest. 2003;123:21S-49S.
Population Attributable Risk Estimates
Active smoking = 90%
Occupational exposure = 9-15%
Radon = 10%
Outdoor air pollution = 1-2%
1. Etiologies of lung cancer (memorize!): arsenic exposure, radon (decay of uranium), chromates,
polycyclic aromatic hydrocarbons, chloromethyl ethers, silica (?) and nickel.
2. Smoking:
a. 20-fold increase in lung cancer risk.
b. A tripling of the number of cigarettes smoked per day was estimated to triple the risk,
whereas a tripling of the duration of smoking was estimated to increase the lung cancer risk
100-fold  duration more important variable!
c. Cigarette smokers can benefit at any age by quitting smoking. As the period of abstinence
from smoking cigarettes increases, the risk of lung cancer decreases. However, even for
periods of abstinence of > 40 years, the risk of lung cancer among former smokers remains
elevated compared to never-smokers.
d. Lung cancer risks with cigar smoking are substantial, but less than cigarette smoking due to
differences in smoking frequency and depth of inhalation
3. Passive smokers:
a. The National Research Council reviewed the epidemiologic evidence and concluded that
nonsmoking spouses who were married to cigarette smokers were about 30% more likely to
develop lung cancer than nonsmoking spouses who were married to nonsmokers.
b. A 1997 meta-analysis by Law and colleagues found an approximately 20% increased risk
associated with marriage to a smoker!
c. Almost 1/4 of lung cancer cases among never-smokers were estimated to be attributed to
exposure to passive smoking.
4.
Air pollution:
a. descriptive evidence is consistent with role for air pollution - reasonable estimate that perhaps
1 to 2% of lung cancer cases are related to air pollution
b. indoor pollutants: passive smoking, radon
5. Diet:
a. People who eat more vegetables are at lower risk of lung cancer than persons who consume
fewer vegetables. The same may also apply to fruit consumption, but the evidence is less
clear-cut.
b. No evidence for high dietary retinol or circulating retinol concentrations.
c. The results for total carotenoids, ß-carotene, and vitamin C are more supportive of a reduction
in lung cancer risk.
d. However ß-carotene supplementation was associated with an increased risk of lung cancer
among the high-risk populations of heavy smokers in the alpha-Tocopherol ß-Carotene
Cancer Prevention Study.