I. ETIOLOGY
Lung cancer is predominantly a disease of smokers. Eighty-five percent of lung cancer occurs in active or former smokers, and an additional 5% of cases are estimated to occur as a consequence of passive exposure to tobacco smoke. Tobacco smoke causes an increased incidence of all four histologic types of lung cancer, although adenocarcinoma (particularly the bronchioloalveolar variant) is also found in nonsmokers. Other risk factors for lung cancer include exposure to asbestos or radon. Familial factors such as polymorphisms in carcinogen-metabolizing hepatic enzyme systems may also play a role in determining an individual’s propensity to develop lung cancer.
II. MOLECULAR BIOLOGY
Numerous genetic changes have been associated with lung tumors. Most common among these include activation or overexpression of the myc family of oncogenes in SCLC and NSCLC and of the KRAS oncogene in NSCLC, particularly adenocarcinoma. Inactivation or deletion of the p53 and retinoblastoma tumor suppressor genes and a tumor suppressor gene on chromosome 3p (the FHIT gene) have been found in 50% to 90% of patients with SCLC. Abnormalities of p53 and 3p have been associated with 50% to 70% of cases of NSCLC. The KRAS mutation is more frequently found in smokers, those with adenocarcinoma, and those with poorly differentiated tumors. It is also associated with poor prognosis.
Recently, abnormalities in the epidermal growth factor receptor (EGFR) pathway have been identified, making EGFR an attractive molecular target for anticancer therapy. EGFR is expressed or overexpressed
in the majority of NSCLC tumors. Binding of ligand to the extracellular domain of EGFR causes receptor dimerization, which in turn activates an intracellular tyrosine kinase domain. Autophosphorylation of the receptor induces a cascade of signal transduction events leading to cell proliferation, inhibition of apoptosis, angiogenesis, and invasion, all resulting in tumor growth and spread. Agents targeting EGFR include tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, and anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab and panitumumab. Tumors harboring activating EGFR gene mutations, which render the cancer highly dependent on EGFR for proliferation and survival, often have dramatic and sustained responses to EGFR TKIs. KRAS and EGFR mutations are rarely found in the same tumor.
Still more recently, abnormalities in the anaplastic lymphoma kinase (ALK) gene have been identified in a subset of lung cancers. These molecular aberrations, which appear mutually exclusive with both EGFR and KRAS gene mutations, appear to render cancers highly responsive to ALK inhibitors in phase I studies. These agents are currently undergoing phase II and III testing.
III. SCREENING
Three U.S. randomized screening studies in the 1980s failed to detect an impact on mortality of screening high-risk patients with chest radiography or sputum cytology, although earlier-stage cancers were detected in the screened groups. Since then, however, low-dose spiral computed tomography (CT) has emerged as a possible new tool for lung cancer screening. Spiral CT is CT imaging in which only the pulmonary parenchyma is scanned, thus negating the use of intravenous contrast medium and the necessity of a physician having to be present. This type of scan can usually be done quickly (within one breath) and involves low doses of radiation. In a nonrandomized, controlled study from the Early Lung Cancer Action Project, low-dose CT was shown to be more sensitive than chest radiography in detecting lung nodules and lung cancer at early stages. However, despite these promising results, it is unclear whether screening with spiral CT will result in a reduction in lung cancer mortality. Potential methodologic issues pertaining to this and other screening studies include lead-time bias, length bias, and overdiagnosis. Overdiagnosis refers to the possibility that small tumors preferentially detected by screening would otherwise remain clinically silent until death from other causes. Furthermore, in some geographic regions, such as the midwestern United States, the incidence of benign nodules is relatively high, resulting in frequent follow-up biopsies that contribute to both the cost and morbidity of screening. To address these issues, the National Cancer Institute has recently completed a large randomized controlled trial (the Lung Screening Study) involving at least 15,000 participants over several years, and initial trial results found 20% fewer cancer deaths among the CT screened participants compared with those screened with chest radiographs.
IV. NSCLC
A. Histology
Until recently, the histologic subtype of NSCLC, while thought to influence the presentation and natural history of disease, did not affect patient management. Due to differences in both efficacy and safety, histologic designation now represents a primary consideration in treatment selection. For instance, bronchioloalveolar carcinoma, which has a predilection for younger, never-smoking women, is frequently associated with EGFR gene mutations and thus a high likelihood of response to EGFR inhibitors. Pemetrexed, a multitargeted antifolate, has greater efficacy for the treatment of nonsquamous tumors, presumably due to higher thymidylate synthase levels in squamous cell cancers. Bevacizumab, a MoAb directed against vascular endothelial growth factor (VEGF), is contraindicated in patients with squamous cell tumors due to unacceptably high rates of life-threatening hemoptysis in early phase clinical trials. These histology-dependent safety and efficacy distinctions have highlighted the importance of accurate pathologic classification.
B. Staging
The prognosis and treatment of NSCLCs are dependent primarily on stage of disease at the time of diagnosis. Major changes in the staging of lung cancer were adopted in 2009. These changes are based on an analysis of 68,463 patients with NSCLC worldwide; by contrast, the previous (1997 and 2002) editions of the TNM classification of lung cancer were based on data from 5,319 patients in North America. The 2009 TNM staging classification is shown in Tables 6.1 and 6.2; the changes are summarized in Table 6.3. Major changes include subclassification of T1 and T2 by tumor size, reclassification of additional nodule(s) in the same lobe or another ipsilateral lobe, and reclassification of malignant effusions as M1a. This reflects the similar prognosis and treatment (typically chemotherapy alone) of patients with malignant effusions and patients with distant disease. As before, a pleural or pericardial effusion is considered malignant if it has any of the following characteristics: positive cytology, exudative, or hemorrhagic. Survival based on the 2009 staging classification is shown in Table 6.4.
C. Pretreatment evaluation
The diagnosis of lung cancer is usually made by bronchial biopsy or percutaneous needle biopsy. A CT scan of the chest is necessary to evaluate the extent of the primary disease, mediastinal extension or lymphadenopathy, and the presence or absence of other parenchymal nodules in patients in whom surgical resection is a consideration. The upper abdomen is included to evaluate for hepatic or adrenal metastases. Bone scans should be obtained for the patient with bone pain or an elevated calcium or alkaline phosphatase level. Head CT or magnetic resonance imaging (MRI) is not routinely done in the absence of central nervous system (CNS) signs or symptoms. Because the presence of mediastinal nodal metastases is a key factor in determining tumor resectability, lymph node sampling by mediastinoscopy, Chamberlain procedure (which samples station 5 and 6 nodes not accessible by mediastinoscopy), and/or endobronchial ultrasound is recommended in most instances when there is not clear evidence of distant disease.
TABLE 6.1 TNM Definitions of NSCLC
Descriptors
Definitions
T
Primary Tumor
T0
No primary tumor
T1
Tumor ≤3 cm in the greatest dimension, surrounded by lung or visceral pleura, not more proximal than the lobar bronchus
T1a
Tumor ≤2 cm in the greatest dimension
T1b
Tumor >2 but ≤3 cm in the greatest dimension
T2
Tumor >3 but ≤7 cm in the greatest dimension or tumor with any of the following* : invades visceral pleura, involves main bronchus ≥ 2 cm distal to the carina, atelectasis/obstructive pneumonia extending to hilum but not involving the entire lung
T2a
Tumor >3 but ≤5 cm in the greatest dimension
T2b
Tumor >5 but ≤7 cm in the greatest dimension
T3
Tumor >7 cm; directly invading chest wall, diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium; tumor in the main bronchus <2 cm distal to the carina† ; atelectasis/obstructive pneumonitis of entire lung; or separate tumor nodules in the same lobe
T4
Tumor of any size with invasion of heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; or separate tumor nodules in a different ipsilateral lobe
N
Regional Lymph Nodes
N0
No regional node metastasis
N1
Metastasis in ipsilateral peribronchial and/or perihilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
N2
Metastasis in ipsilateral mediastinal and/or subcarinal lymph nodes
N3
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes
M
Distant Metastasis
M0
No distant metastasis
M1a
Separate tumor nodules in a contralateral lobe; or tumor with pleural nodules or malignant pleural dissemination‡
M1b
Distant metastasis
Special Situations
TX, NX, MX
T, N, or M status not able to be assessed
Tis
Focus of in situ cancer
T1†
Superficial spreading tumor of any size but confined to the wall of the trachea or mainstem bronchus
* T2 tumors with these features are classified as T2a if ≤5 cm.
† The uncommon superficial spreading tumor in central airways is classified as T1.
‡ Pleural effusions are excluded that are cytologically negative, nonbloody, transudative, and clinically judged not to be due to cancer.
Source: Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg. 2009;15:4-9.
TABLE 6.2 Stage Groupings by TNM Elements for NSCLC
Descriptors
Stage Groups
T
N
M
Ia
T1a,b
N0
M0
Ib
T2a
N0
M0
IIa
T1a,b
N1
M0
T2a
N1
M0
T2b
N0
M0
IIb
T2b
N1
M0
T3
N0
M0
IIIa
T1-3
N2
M0
T3
N1
M0
T4
N0, 1
M0
IIIb
T4
N2
M0
T1-4
N3
M0
IV
TAny
NAny
M1a,b
Source: Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg. 2009;15:4-9.
Positron emission tomography (PET), a metabolic imaging scan using fluorodeoxyglucose (FDG), has emerged as a useful staging modality. PET scans are more sensitive and specific than CT scans and could thus potentially save patients with advanced disease, either within or outside of the chest, from unnecessary invasive procedures. However, it is not yet clear as to whether PET scanning can replace mediastinal lymph node sampling, as the scan can be falsely positive in inflammatory processes and falsely negative in lung tumors with low metabolic activity such as bronchioloalveolar carcinoma or carcinoid tumors. Furthermore, due to high background FDG uptake in the brain, PET-CT scans are generally not sufficient to evaluate for brain metastases, and a head CT or MRI should be performed. PET scans are frequently performed in conjunction with CT imaging (PET-CT scans) to provide enhanced anatomic detail. Randomized clinical trials have demonstrated that use of PET-CT scans decreases the total number of thoracotomies and number of futile thoracotomies performed. Population-based studies suggest that increasing use of PET-CT scans may have resulted in stage shifting.
TABLE 6.3 2009 Major Changes to TNM Classification Stage Grouping of NSCLC
Component of Classification
Changes
T
Subclassify T1 according to tumor size:
T1a: ≤2 cm
T1b: >2 cm but ≤3 cm
Subclassify T2 according to tumor size:
T2a: >3 cm but ≤5 cm (or tumor with any other T2 descriptors, but ≤5 cm)
T2b: >5 cm but ≤7 cm
Reclassify T2 tumors >7 cm as T3
Reclassify T4 tumors by additional nodule(s) in the same lobe of the primary tumor as T3
Reclassify M1 tumors by additional nodule(s) in another ipsilateral lobe as T4
Reclassify T4 tumors by malignant pleural effusion as M1a
N
No changes
M
Subclassify M1:
M1a: separate tumor nodule(s) in contralateral lung; tumor with pleural nodules or malignant pleural (or pericardial) effusion
M1b: distant metastasis
Stage Grouping
Changes
Large T2 tumors (T2b) N0M0
Upstage from IB to IIA
Small T2 tumors (T2a) N1M0
Downstage from IIB to IIA
T4 tumors N0 or N1 M0
Downstage from IIIB to IIIA
Source: Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Sung. 2009;15:4-9.
TABLE 6.4 Five-year Survival Rates for New Clinical Stages of NSCLC
Clinical Stage
Five-year Survival
IA
50%
IB
47%
IIA
36%
IIB
26%
IIIA
19%
IIIB
7%
IV
2%
Source: Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg. 2009;15:4-9.
Pulmonary function testing is generally recommended before surgery and, if severe pulmonary disease is clinically apparent, before radiation therapy. Increased postoperative morbidity is associated with a predicted postoperative 1-second forced expiratory volume of less than 800 to 1000 mL, a preoperative maximum voluntary ventilation less than 35% of predicted, a carbon monoxide diffusing capacity less than 60% of predicted, and an arterial oxygen pressure of less than 60 mm Hg or a carbon dioxide pressure of more than 45 mm Hg.
D. Management of early stage NSCLC
1. Stage I disease. Surgical resection is the mainstay of treatment for stage I NSCLC, with cure rates of 60% to 80%. Lobectomy is considered superior to smaller procedures such as wedge resection. An exception may be bronchioloalveolar cancer, which spreads by lepidic (airway) growth rather than hematogenous or lymphatic spread and may be adequately treated with more focal excision. Clinical studies evaluating this approach are ongoing. If not performed preoperatively, it is recommended that mediastinal lymph nodes be sampled at the time of resection to complete staging.
In patients with medical contraindications to surgery but with adequate pulmonary function, conventional fractionated radiotherapy (e.g., 6000 cGy in 30 fractions of 200 cGy each) results in cure in about 20% of patients. Recently, advances in imaging and radiation delivery have led to the use of stereotactic radiation therapy for lung tumors. With this technology, radiation delivery to surrounding normal lung parenchyma is substantially less than that occurring with conventional radiation. Thus, it is possible to give much higher, “ablative” radiation doses over a small number of fractions (e.g., 20 Gyper fraction for three fractions). To date, outcomes with this technique appear promising, with 2-year local control rates in excess of 90%. Clinical trials of stereotactic radiation for early stage lung cancer in both medically operable and inoperable patients are ongoing.
The rationale for adjuvant chemotherapy in patients with early-stage lung cancer is based on the observation that distant metastases are the most common site of failure following potentially curative surgery. Interest in this treatment strategy grew after a 1995 meta-analysis of over 4300 patients, in which those who received cisplatin-based regimens had a survival benefit nearing statistical significance (p = 0.07). Since then, a number of randomized clinical trials have evaluated the role of adjuvant chemotherapy following resection of early-stage NSCLC (see Table 6.5). In a pooled analysis of five of these trials, the hazard ratio for death was 0.89 (95% confidence interval [CI], 0.82-0.96; p = 0.005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. Importantly, the benefit of chemotherapy varied considerably by stage. For stage IA NSCLC, adjuvant chemotherapy resulted in a trend toward worse survival (hazard ratio [HR] for death 1.40; 95% CI, 0.95-2.06). For stage IB disease, the HR was 0.93 (95% CI, 0.78-1.10). Similarly, in the CALGB 9633 trial of patients with stage IB disease randomized to surgery alone or surgery followed by carboplatin-paclitaxel, only those patients with tumors ≥4 cm demonstrated a significant survival difference in favor of adjuvant chemotherapy (HR, 0.69; 95% CI, 0.48-0.99; p = 0.04). Given these data, it seems reasonable to discuss the option of adjuvant platinum-based doublet chemotherapy with good performance status (PS) patients with completely resected stage IB disease, particularly those with tumors ≥4 cm. Additional studies are needed for stage IA disease before adjuvant therapy can be routinely recommended for this group of patients.
TABLE 6.5 Randomized Studies of Adjuvant Chemotherapy for Resected NSCLC
Trial
Patient Population (Stage)
Number of patients
Chemotherapy regimen
Absolute overall survival benefit
CALGB 9633 (2004)
IB
344
Carboplatin
AUC 6, on day 1
12% (4-year)
Paclitaxel
200 mg/m2 IV on day 1 every 3 weeks for four cycles
NCIC JBR10 (2005)
IB, II
482
Cisplatin
50 mg/m2 IV on days 1 and 8 every 4 weeks for four cycles
15% (5-year)
Vinorelbine
25 mg/m2 IV on days 1, 8, 15, and 22 every 4 weeks for four cycles
ANITA (2005)
IB, II, IIIA
840
Cisplatin
100 mg/m2 IV on day 1 every 4 weeks for four cycles
8% (5-year)
Vinorelbine
30 mg/m2/wk IV on days 1, 8, 15, and 22 every 4 weeks for four cycles
IALT (2004)
I, II, IIIA
1867
Cisplatin (options)
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Carcinoma of the Lung
Carcinoma of the Lung
David E. Gerber
Joan H. Schiller
Carcinoma of the lung is responsible for more than 165,000 deaths each year in the United States. This represents one-third of all deaths due to cancer and more than the number of deaths due to breast, colon, and prostate cancers combined. Because early-stage lung tumors are often asymptomatic and there has been no proven approach to radiographic screening, most patients are diagnosed with advanced stage disease. Approximately 85% of cases are histologically classified as non-small-cell lung cancer (NSCLC), of which adenocarcinoma, squamous cell carcinoma, and large cell carcinoma are the primary subtypes. Small-cell lung cancer (SCLC) accounts for the remaining 15% of cases. The biology, staging, and treatment of SCLC differ substantially from NSCLC. Thus, these two groups are addressed in two separate sections.
