Non-Small Cell Lung Cancer

EPIDEMIOLOGY

• Lung cancer, broadly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), is the leading cause of cancer death in both men and women in the United States.
• An estimated 213,380 new cases of lung and bronchus cancer (114,760 in men and 98,620 in women) were diagnosed in 2007, resulting in 160,390 deaths (89,510 in men, 70,880 in women).
• More than 70% of patients are diagnosed with advanced disease that is not amenable to curative therapy.
• The 5-year relative survival rate for lung cancer is approximately 15%, reflecting a slow but steady improvement from 12.5% in the 1970s.
• Stage at diagnosis accounts for the most marked variation in prognosis; patient characteristics associated with poorer prognosis include older age, male gender, and African American heritage.
• In the United States, as many women now die from lung cancer as die from breast, uterine, and cervical cancers combined. The increase in lung cancer risk among women reflects changes in smoking habits during the twentieth century. By 1987, lung cancer had surpassed breast cancer as the leading cause of cancer death in women as a result of an increase in the prevalence of female smokers.
• Rates of cigarette smoking have declined in the United States in the last 10 years, but developing nations are now seeing an alarming increase in smoking rates.

ETIOLOGY AND RISK FACTORS

• The vast majority of lung cancer deaths are directly attributable to cigarette smoking.
• Tobacco smoke contains a highly complex mixture of carcinogens that have the potential to damage DNA. Polycyclic aromatic hydrocarbons, aromatic amines, and tobacco-specific nitrosamines have been implicated as the major mutagenic carcinogens responsible for DNA adduct formation. The number of DNA adducts formed is directly related to the number of cigarettes consumed; in heavy smokers they can be responsible for as many as 100 mutations per cell genome.
• Compared to those who have never smoked, smokers have an approximate 20-fold increase in lung cancer risk. The likelihood of developing lung cancer decreases among those who quit smoking compared to those who continue to smoke.
• Estimates indicate that passive smoking accounts for approximately 3,000 lung cancer deaths per year in the United States.
• Radon, a radioactive gas produced by the decay of radium 226, is the second leading cause of lung cancer in the United States, accounting for 6,000 to 36,000 cases of lung cancer each year. The decay of radium 226 produces substances that emit alpha particles, which may cause cell damage. Residential exposure has been associated with an increased risk of developing lung cancer.
• Occupational exposure to carcinogens such as asbestos, arsenic, chromates, chloromethyl ethers, nickel, polycyclic aromatic hydrocarbons, and other agents is estimated to cause approximately 9% to 15% of lung cancers. Asbestos exposure in smokers is associated with a synergistic risk of developing lung cancer. Cigarette smoking impairs bronchial clearance and thereby prolongs the presence of asbestos in the pulmonary epithelium.
• The contribution of hereditary factors to the development of lung cancer is less well understood than for any of the common forms of solid tumors in human. Proof that the familial occurrence of lung cancer has a genetic basis is complicated by the central role of cigarette smoking in the etiology of lung cancer.
• Large randomized, double-blind, placebo-controlled chemoprevention trials reported in the 1990s provided no evidence that specific dietary constituents confer protection against lung cancer.

PATHOLOGY

• NSCLC can be divided into three major subtypes (Table 2.1):
  • Adenocarcinoma
  • Squamous cell carcinoma
  • Large cell carcinoma
• Adenocarcinoma is the most frequently diagnosed form of NSCLC in both men and women in the United States and constitutes 54% of all cases of NSCLC. Tumors are classically peripheral and arise from surface epithelium or bronchial mucosal glands. Histologic examination reveals gland formation, papillary structures, or mucin production. The histologic characteristics of lung cancer in several developed countries, including the United States, have changed in the past few decades, demonstrating that the frequency of adenocarcinoma has risen while the frequency of squamous cell carcinoma has declined.
• Bronchioloalveolar carcinoma, a noninvasive subtype of adenocarcinoma, occurs more frequently in women and nonsmokers, and is associated with bilateral, multifocal pulmonary involvement, a lesser tendency for extrathoracic metastases, and a better survival rate than similar-stage NSCLC.
• Squamous cell carcinoma accounts for 35% of NSCLC and has the strongest association with cigarette smoking. This tumor arises most frequently in the central proximal bronchi and can lead to bronchial obstruction, with resultant atelectasis or pneumonia. Histologic examination reveals visible keratinization, with prominent desmosomes and intercellular bridges.
• Large cell carcinoma is the least common subtype of lung cancer, accounting for approximately 11% of all NSCLCs.

TABLE 2.1. Modified WHO classification of non-small cell lung cancer (1999)

1. Squamous cell carcinoma Variants: papillary, clear cell, small cell, basaloid 2. Adenocarcinoma Acinar Papillary Bronchioloalveolar Nonmucinous (Clara cell/type II pneumocyte type) Mucinous (goblet cell type) Mixed mucinous and nonmucinous (Clara cell/type II) pneumocyte and goblet cell type or indeterminate Solid adenocarcinoma with mucin formation Mixed Variants: well-differentiated fetal adenocarcinoma, mucinous (“colloid”), mucinous cystadenocarcinoma, signet ring, clear cell 3. Large cell carcinoma Variants: large cell neuroendocrine carcinoma, combined large cell neuroendocrine carcinoma, basaloid carcinoma, lymphoepithelioma-like carcinoma, clear cell carcinoma, large cell carcinoma with rhabdoid phenotype 4. Adenosquamous carcinoma WHO: Word Health Organization.

TABLE 2.2. Genetic mutations in NSCLC
Description Percentage Tumor suppressor genes Rb mutations (13q14) 15% p16/CDKN2 mutations (9p21) 60% p53 mutations (17p13) 50% 3p deletions 50% Dominant oncogene abnormalities K-ras mutations 30% Her-2/neu overexpression 25% Myc family amplification 10% BCL-2 overexpression 25%

BIOLOGY

• Lung cancer evolves through a multistep process from normal bronchial epithelium to dysplasia to carcinoma in situ and finally to invasive cancer. These changes include activation of oncogenes, inactivation of tumor suppressor genes, and loss of genomic stability. Changes can be both genetic (via deletions or mutations) or epigenetic (methylation), leading to altered cell proliferation, differentiation, and apoptosis. Mutations in multiple tumor suppressor genes and oncogenes have been associated with the development of NSCLC (Table 2.2).
• Cytogenetic studies have revealed a large number of chromosomal abnormalities in lung cancer, such as allelic loss leading to loss of tumor suppressor genes. Two of the most studied tumor suppressor genes are p53 and retinoblastoma (RB).
  • p53 is involved in DNA repair, cell division, apoptosis, and growth regulation. In normal conditions, p53 production increases when DNA damage occurs. Increased amounts of p53 induce cell cycle arrest in the G1 phase, allowing DNA repair. If a p53 deletion or mutation exists, G1 arrest is not achieved and the abnormal cell proceeds to S phase, further dividing and propagating genetic damage. Mutations in p53 are found in 50% of NSCLC.
  • The RB gene also regulates G1 growth arrest. Hypermethylation of the CpG-rich island at the 5′ end of the RB gene is thought to lead to silencing of the RB gene and tumor progression. RB gene mutations occur in 15% of NSCLC.
• K-ras is a member of the ras family of oncogenes and codes for a 21-kDa guanine-binding protein that mediates signal transduction pathways from cell surface receptors to intracellular molecules. The ras oncogene can be activated either by a point mutation or by overexpression. To function in signal transduction, ras requires a specific posttranslational modification called farnesylation. K-ras is a critical downstream effector of the epidermal growth factor receptor (EGFR) pathway. K-ras has been found to be mutated in approximately 15% to 30% of lung adenocarcinomas and is associated with exposure to tobacco smoke.
• EGFR is highly expressed in NSCLC. Following binding of a ligand to its extracellular receptor, dimerization occurs, leading to activation of tyrosine kinases and a subsequent increase in downstream signaling pathways including Ras-Raf and Akt protein kinases. Recently, it has been shown that point mutations within the tyrosine kinase domain greatly affect tumor sensitivity to EGFR inhibitors (erlotinib, gefitinib). Sensitizing mutations in exons 19, 21, and 18 can increase the efficacy of erlotinib. Other mutations are responsible for poor disease response to tyrosine kinase inhibitors such as T790M mutation. K-ras mutations are also associated with intrinsic tyrosine kinase inhibitor resistance. EGFR and K-ras mutations are mutually exclusive in patients with lung cancer.

CLINICAL PRESENTATION

• A minority of patients present with an asymptomatic lesion discovered incidentally on chest radiograph. No set of signs or symptoms are pathognomonic of lung cancer, so diagnosis is usually delayed.
• Clinical signs and symptoms of lung cancer are outlined in Table 2.3.

TABLE 2.3. Clinical signs and symptoms of lung cancer

Primary disease Central or endobronchial tumor growth Cough Sputum production Hemoptysis Dyspnea Wheeze (usually unilateral) Stridor Pneumonitis with fever and productive cough (secondary to obstruction) Peripheral tumor growth Pain from pleural or chest wall involvement Cough Dyspnea Pneumonitis Regional involvement (either direct or metastatic spread) Hoarseness (recurrent laryngeal nerve paralysis) Dysphagia (esophageal compression) Dyspnea (pleural effusion, tracheal/bronchial obstruction, pericardial effusion, phrenic nerve palsy, lymphatic infiltration, superior vena cava obstruction) Horner’s syndrome (sympathetic nerve palsy) Metastatic involvement (common sites) Bone (pain exacerbated by movement or weight bearing, often worse at night; fracture) Liver (right hypochondrial pain, icterus, altered mental status) Brain (altered mental status, seizures, motor and sensory deficits) Paraneoplastic syndromes Hypertrophic pulmonary osteoarthropathy Hypercalcemia Dermatomyositis (Eaton-Lambert syndrome) Hypercoagulable state Gynecomastia

CLINICAL EVALUATION

Single Pulmonary Nodule (SPN)

• Definition: solitary mass, often found incidentally, surrounded by lung tissue, well circumscribed, measures <3 cm without mediastinal or hilar adenopathy.
• Benign inflammatory vascular abnormalities or infectious lesions can mimic more sinister lesions. Review of previous chest x-rays is a crucial first step. A stable lesion over a 2-year period suggests a benign condition.
• Computed tomography (CT) of the chest is required to assess for other nodules, adenopathy, or chest wall invasion.
• FDG-PET (18F-fluorodeoxyglucose-positron emission tomography) is used to evaluate SPNs. False-positive PET scans may occur in conditions such as tuberculosis or histoplasmosis. Falsenegative results have been reported for small lesions (<1 cm) and neoplasms with low metabolic activity, such as in some cases of bronchioloalveolar carcinoma. Mean sensitivity of FDG-PET is 96%; mean specificity is 75%. The negative and positive predictive value of PET for pulmonary nodules is approximately 90%.
• A growing SPN needs a pathologic diagnosis. Tissue can be obtained by fine needle aspiration (FNA), transbronchial biopsy, or surgical resection. Flexible fiber optic bronchoscopy is appropriate for central lesions and can lead to a diagnosis in 97% of cases via biopsies, bronchial washings, and brushings.
• Observation may be reasonable in a low-risk patient (<40 years old and has never smoked) with a negative FDG-PET and a stable lesion measuring <2 cm. Reimaging with regular CT scans and follow-up clinic appointments are recommended.

Suspected Lung Cancer

• Full history and physical examination are recommended, followed by complete blood count and chemistry tests, chest x-ray, and CT of the chest and abdomen (including adrenal glands).
• Sputum analysis may be helpful in cases of central lesions.
• Bone scans and plain films of affected areas are warranted where bone pain exists, but routine imaging of the brain in asymptomatic patients is controversial.
• Peripheral lesions may require percutaneous transthoracic FNA, which can be performed under CT or fluoroscopic guidance.
• Mediastinoscopy, a more invasive method, may be needed to obtain a histologic diagnosis in difficultto-reach primary tumors. Mediastinoscopy can reveal unsuspected tumors in mediastinal lymph nodes—a negative implication for survival. Evaluation of the mediastinum is recommended before surgery in suspected mediastinal disease and intraoperatively prior to any planned resections.
• An accurate pathologic diagnosis and staging of disease is essential in the management of lung cancer. Stage of disease determines whether surgical resection is warranted. Clinical staging often underestimates the true extent of the disease. The combination of PET evaluation and mediastinoscopy is routinely used to complete staging. In patients who undergo surgical resection, surgical/pathologic staging should be used to predict recurrence and to evaluate the need for adjuvant therapy.
• Preresection forced expiratory volume/1 second (FEV1) should be ≥2 L for pneumonectomy, 1 L for lobectomy, or 0.6 L for segmentectomy.
• Preresection forced vital capacity should be ≥1.7 L.

STAGING

• The tumor-node-metastasis (TNM) staging system bases patient prognoses on tumor size, lymph node involvement, and metastasis.
• The seventh edition of the TNM Classification of Malignant Tumours (UICC) has recently been published. Revisions of the TNM system (Table 2.4) raise important questions about treatment options. The most important change is the shift of node-negative patients with large tumors from stage IB, where adjuvant chemotherapy is often not recommended, to stage IIA or IIB, where chemotherapy is standard treatment after surgical resection. Under the revised system, node-negative patients with tumors >5 cm will be categorized as IIA and those with tumors >7 cm as IIB. Previously, these patients would have been categorized as IB.
• Another change involves the staging of disease in patients with malignant nodules. Currently, ipsilateral malignant nodules in the same lobe as the primary tumor are classified as stage IIIB. Under the
  

  P.40

  
  
  new system, same lobe nodules will be stage IIB if there is no lymph node involvement (N0) and IIIA if lymph node disease is limited (N1 or N2). This down-staging could mean that more patients with ipsilateral nodules will be considered surgical candidates.
• Staging changes will also occur in patients with an ipsilateral nodule in a different lobe. These will move from stage IV to stage IIIA (N0 or N1) or IIIB (N2 or N3). Extensive tumors with pleural or pericardial effusions will move from stage IIIB to stage IV, where they will be grouped with other nonresectable tumors. These so-called wet IIIBs have always been treated as stage IV, so this is perhaps the most obvious change required.
• A major change with no treatment implications at present is the division of metastases into two subgroups: M1a for metastases in the other lung and M1b for distant metastases. Both remain stage IV.

TABLE 2.4. Revisions of the TNM staging in the seventh edition of the TNM classification of malignant tumors

TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy T0 No evidence of primary tumor Tis Carcinoma in situ T1 Primary tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus) T1a Tumor ≤2 cm in greatest dimension T1b Tumor >2 cm but ≤3 cm in greatest dimension T2 Tumor >3 cm but ≤7 cm or tumor with any of the following features: (T2 tumors with these features are classified T2a if ≤5 cm in greatest dimension) Involves main bronchus, ≥2 cm distal to the carina Invades the visceral pleura Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung T2a Tumor >3 cm but ≤5 cm in greatest dimension T2b Tumor >5 cm but ≤7 cm in greatest dimension T3 Tumor >7 cm or that directly invades any of the following: Chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, or tumor in the main bronchus <2 cm distal to the carina but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe T4 Tumor of any size that directly invades any of the following: Mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in a different ipsilateral lobe, esophagus, vertebral body, heart, great vessels, malignant pleural/pericardial effusion, satellite tumor within the ipsilateral primary tumor lobe of the lung NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension of the primary N2 Metastasis in ipsilateral, mediastinal, and/or subcarinal lymph node(s) N3 Metastasis in contralateral, mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) MX Presence of distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural (or pericardial) effusion M1b Distant metastases

TREATMENT

Stages I and II

• Stage I and stage II NSCLC are considered early-stage disease. These two stages combined account for 25% to 30% of all lung cancers.
• Five-year survival rates are 60% to 80% for stage I and 40% to 50% for stage II.
• Surgical resection is the recommended treatment for patients with stage I and stage II NSCLC. In patients who are medically fit for conventional surgical resection, lobectomy or greater resection is recommended rather than sublobar resections (wedge or segmentectomy).
• Video-assisted thorascopic surgery (VATS) is an acceptable alternative to open thoracotomy.
• Intraoperative systematic mediastinal lymph node sampling or dissection is recommended for accurate pathologic staging.
• Even with complete resection, many patients with stage I and stage II NSCLC experience recurrence. Most of these relapses are distant metastases.
• For completely resected stage IA NSCLC, postoperative chemotherapy is not recommended, and most studies have found no statistically significant benefit for the subset of patients with stage IB NSCLC.
• Data on the use of adjuvant cisplatin-based chemotherapy in stage II NSCLC are convincing. The International Adjuvant Lung Trial (IALT), National Cancer Institute of Canada JBR.10, and Adjuvant
  

  P.41

  
  
  Navelbine International Trialists Association (ANITA) studies all found significant survival benefit in the use of adjuvant chemotherapy. The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis found a 27% reduction in the risk of death (hazard ratio, 0.83; 95% CI, 0.73-0.95) in stage II patients.
• Current evidence suggests that postoperative radiotherapy is associated with decreased survival for patients with stage I (N0) and stage II (N1) NSCLC. However, most meta-analyses include several older studies that used radiotherapy methods that are inferior to current methods.
• If surgery is contraindicated in early-stage NSCLC, radiotherapy can be an effective means of local control. In clinical studies, accelerated radiotherapy (54 Gy in 12 days) was associated with better 4-year survival than conventional radiotherapy (60 Gy in 6 weeks).

Stage IIIA

• Stage IIIA (N2) NSCLC is a therapeutically challenging and controversial subset of lung cancer, with a 5-year survival rate of only 23%.
• Recent randomized trials strongly suggest a combined modality approach in stage IIIA disease. Conflicting data, however, have led to difficulties in proposing specific management guidelines.
• For patients with incidental (occult) N2 disease found at surgical resection, complete tumor resection and mediastinal lymphadenectomy is recommended, if technically possible. However, if metastatic disease is found in the N2 nodes at mediastinoscopy before thoracotomy, then further surgery at that time should be avoided based on the poor results of primary resection for stage IIIA disease.
• Postoperative radiation therapy (PORT) in completely resected stage IIIA disease is not recommended, based on the lack of evidence of improved survival.
  • The PORT meta-analysis (Meta-Analysis Trialist Group) of 2,128 patients treated in nine randomized trials of PORT concluded that this treatment was associated with a highly significant increase in risk of death (overall risk ratio 1:21; P = 0.001). The authors concluded that postoperative radiotherapy, as used in these studies, was detrimental and should not be used. Advocates of radiotherapy have emphasized that there are several differences between the treatment administered in several trials included in this meta-analysis and current practices in the United States.
  • Practice guidelines on postoperative radiotherapy in stage II and IIIA NSCLC were developed and published in 2004 by the Lung Cancer Disease Site Group of Cancer Care Ontario Program of Evidence-Based Care. After reviewing the literature they too concluded that no survival benefit was found with postoperative radiotherapy in completely resected stage IIIA disease and that the data for improved local control were conflicting.
• Postoperative chemotherapy in completely resected stage IIIA disease is recommended. The International Adjuvant Lung Cancer Trial of 1,867 patients with stages IB to IIIA (39% stage IIIA) randomized patients to three to four cycles of postoperative cisplatin-based chemotherapy versus surgery alone, with adjuvant 60 Gy radiotherapy given to both arms of stage IIIA patients (the use of radiotherapy was left to investigator’s choice). After a median 56-month follow-up, the overall survival rate was significantly higher in the chemotherapy group (hazard ratio, 0.86), with a 5-year survival rate of 44.5% in the chemotherapy group versus 40.4% in the control arm, with the strongest benefit in patients with stage III disease.
  • The ANITA study randomized 840 completely resected patients with stages I to IIIA (35% stage IIIA) to four postoperative cycles of cisplatin and navelbine versus observation (radiotherapy as per preference of participating center). After a median follow-up of >70 months, long-term 5-year survival of stage IIIA patients in the chemotherapy arm was significantly greater at 42% versus 26% in the observation arm (P = 0.013). Adjuvant chemotherapy showed a benefit in stage II but not stage I patients.
• To date, evidence has yet to be established substantiating the benefit of adding adjuvant radiotherapy to adjuvant chemotherapy in fully resected stage IIIA patients.
• Poor survival rates with surgery alone in N2 disease, even with postoperative chemotherapy or radiotherapy, have led to the use of radiotherapy and/or chemotherapy in the neoadjuvant setting, with
  

  P.42

  
  
  the aim of making an unresectable tumor resectable and improving long-term survival. Theoretically, advantages include shrinking the tumor to allow for easier resection and nodal clearance, decreased surgical seeding, in vivo chemosensitivity testing of the chemotherapy regimen, and increased patient acceptance and compliance.
• Disadvantages of neoadjuvant therapy may include delayed tumor resection and increased surgical morbidity and mortality. A 2005 meta-analysis by Berghmans et al. evaluating neoadjuvant chemotherapy found only a marginal benefit in favor of induction chemotherapy.
• Two clinical trials (European Organization for Research and Treatment of Cancer 08941 and North American Intergroup 0196) showed no significant difference in overall survival between patients with stage IIIA NSCLC treated with neoadjuvant chemotherapy then surgery versus definitive chemoradiation alone (no surgery). Induction chemotherapy followed by surgery in stage IIIA disease is feasible; however, published data do not support this treatment as the standard of care.
• The use of concurrent chemotherapy/radiotherapy versus sequential treatment has been addressed in numerous trials. At present, for patients with bulky NSCLC with N2 disease, the data recommend treatment with concurrent over sequential chemotherapy/radiotherapy.
• Concurrent chemotherapy/radiotherapy followed by consolidation chemotherapy is currently not recommended as the standard of care.

Stage IIIB With No Malignant Pleural Effusion

• This stage includes patients with T4 lesions or N3 involvement. Anticipated 5-year survival for most patients with stage IIIB disease is 3% to 7%.
• Optimal treatment depends on extent of disease, age of patient, co-morbid risk factors, performance status (PS), and weight loss.
• Stage IIIB lung cancers are not amenable to curative surgical resection unless they are highly selected. Patients with clinical T4N0-1 as a result of satellite tumor nodule(s) in the same lobe, carinal involvement, or superior vena cava invasion may be considered operable based on a multidisciplinary evaluation.
• For patients with stage IIIB disease with no malignant pleural effusions, PS of 0 to 1, and minimal weight loss (<5%), platinum-based combination chemoradiotherapy is recommended.
• The most common chemotherapeutic agents used concurrently with radiotherapy have been vinorelbine, vinblastine, and etoposide in conjunction with cisplatin or weekly paclitaxel and carboplatin. No randomized phase 3 trials of concurrent chemoradiotherapy have shown the superiority of one chemotherapy regimen over another.
• Studies have shown that induction chemotherapy followed by concurrent chemoradiotherapy is not superior to initial treatment with concurrent therapy. It is uncertain how many cycles of chemotherapy are optimal in the treatment of patients with stage IIIB disease. The American Society of Clinical Oncology (ASCO) guidelines recommend two to four cycles of platinum-based chemotherapy, two of which should be administered concurrently with thoracic radiotherapy.

Stage IIIB With Malignant Pleural Effusion and Stage IV

• Prognosis for patients with advanced-stage (IIIB with malignant pleural effusions, and IV) NSCLC is extremely poor. Best supportive care produces median survival rates of 16 to 17 weeks and 1-year survival rates of 10% to 15%.
• Subsets of patients with stage IIIB disease who are treated as though they had stage IV disease include those with malignant pleural or pericardial effusions, those with advanced ipsilateral supraclavicular adenopathy, and those whose intrathoracic disease is not amenable to combined treatment modalities. For these patients, therapy options include systemic chemotherapy or supportive therapy alone if the patient’s general condition is not suitable for systemic chemotherapy.
• In patients with stage IV NSCLC and good PS, chemotherapy clearly improves survival and palliates disease-related symptoms. Chemotherapeutic regimens can be divided into first-line, second-line, and third-line settings.

P.43

First-Line Therapy

• Platinum-based doublets are the standard of care for patients with stage IV NSCLC and good PS.
• There is no clearly superior regimen for first-line chemotherapy, which should not exceed four cycles, unless continuing response is seen, in which case a maximum of six cycles is recommended.
• Two chemotherapeutic agents produce superior response and survival rates compared to single agents.
• There is general agreement that either cisplatin or carboplatin combined with a taxane (paclitaxel or docetaxel), gemcitabine, vinorelbine, or irinotecan can be used as first-line treatment of patients with advanced NSCLC and good PS. Addition of a third chemotherapeutic agent to existing doublets has failed to show a superior survival benefit; response rates improved only at the cost of substantially increased toxicity.
• Clinical trials have shown evidence of survival benefit with bevacizumab in NSCLC. For example, the Eastern Cooperative Oncology Group (ECOG) E4599 trial studied patients with stage IIIB/IV disease and an ECOG performance status of 0 to 1 who were therapy naïve. Patients with squamous cell histology, hemoptysis, or brain metastases were excluded. The addition of bevacizumab to chemotherapy reduced the risk of death by 20% versus chemotherapy alone. Median survival was 12.3 months in the bevacizumab arm and 10.3 months in the control arm (P = 0.003). In the AVAIL (Avastin in Lung) trial bevacizumab in combination with gemcitabine/cisplatin was compared to gemcitabine/cisplatin alone. Median progression-free survival was 6.1 months in the chemotherapy-alone arm versus 6.7 months in the group receiving bevacizumab at the lower dose of 7.5 mg/kg. However, this study did not show an increase in overall survival.
• The addition of bevacizumab in eligible patients (no hemoptysis, no brain metastasis, and nonsquamous histology) may be considered in combination with carboplatin-paclitaxel.

Second-Line Therapy

• Second-line therapy has an impact on survival and quality of life in advanced NSCLC; therefore, patients with a PS of 0 to 2 should be offered further treatment following progression.
• Approved agents include docetaxel, pemetrexed, and erlotinib.
• The BR-21 trial showed an improvement in median overall survival of 6.7 versus 4.7 months in patients who received erlotinib following failure of first-line or second-line chemotherapy, compared to placebo.
• Current recommendations do not support the combination of cytotoxic chemotherapy and a tyrosine kinase inhibitor outside of a clinical trial.

Third-Line Therapy

• Erlotinib is also an approved agent in the third-line setting. If disease progression occurs after second-line or third-line chemotherapy, it is recommended that patients with a PS of 0 to 2 be enrolled in a clinical trial or treated with best supportive care.