GENERAL PRINCIPLES
Lung cancer is first divided into two broad groups: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), based on histology. Their clinical behavior and management are different and, therefore, discussed separately.
Epidemiology
Lung cancer is the leading cause of cancer-related mortality in the United States with an estimated 222,520 new cases and 157,300 deaths attributable to lung cancer in 2010.1 The incidence of lung cancer is continuing to decline in men. However, in women the rates appear to be plateauing after several years of rising incidence.2
Risk Factors
Tobacco smoke is the major risk factor for lung cancer. There is a clear, dose-dependent relationship between tobacco use and lung cancer. A major public health goal in reducing total mortality from lung cancer remains reducing the prevalence of smoking. Smoking reduction by 50% in heavy smokers significantly reduces the risk of lung cancer.3 Squamous cell lung cancers and SCLCs, in particular, are associated with tobacco smoking.
Other exposures have also been associated with lung cancer, including asbestos, radon, chromium, nickel, and arsenic compounds.4 Genetic predisposition is an important risk factor, and there are well-identified familial clusters of lung cancers. A major inheritable lung cancer susceptibility locus has been reported to be within 6q23–25.5 Genetic polymorphisms of enzymes regulating tobacco carcinogen metabolism, such as an exon 7 cytochrome p450 (CYP1A1) polymorphism, and GSTM1 null genotype are associated with increased risk of lung cancer.6–8 In addition, polymorphisms of genes regulating DNA repair (ERCC2 and XRCC1) and inflammation (COX-2, IL-6, and IL-8) have also been reported to be associated with increased risk of lung cancer.9
Prevention and Screening
Current and former smokers have a significant risk of lung cancer, and smoking cessation should be encouraged. Chemoprevention agents for lung cancer have not been established. The National Lung Screening Trial (NLST) is a randomized National Cancer Institute–sponsored trial comparing the effect of low-dose helical computed tomography (CT) and standard chest x-ray on lung cancer mortality in former and current smokers. According to the press release, 20% fewer lung cancer deaths were seen among trial participants screened with low-dose helical CT.10 The National Comprehensive Cancer Network (NCCN) does not currently recommend screening CT use.11
NON-SMALL-CELL LUNG CANCER
GENERAL PRINCIPLES
Non-small-cell lung cancer accounts for ~87% of lung cancers in the United States. NSCLC encompasses four pathologic subtypes:
Squamous cell lung cancer usually arises in proximal bronchi and can cause obstruction of the larger airways.
Adenocarcinoma is the most common subtype, representing 40% of lung cancers in North America. It usually arises in the lung periphery.
Bronchoalveolar carcinoma is a subtype of adenocarcinoma that grows along alveolar septa. It can present as a single nodule, as multiple nodules, or as a rapidly progressive multilobar disease that radiographically resembles pneumonia. It is not associated with tobacco smoking.
Large-cell carcinoma is the least common subtype.
DIAGNOSIS
Clinical Presentation
Presenting signs and symptoms of lung cancer depend on the size, location, and degree of spread of the tumor. Lung cancer can present as an asymptomatic lung nodule found incidentally on chest x-ray (CXR). Local symptoms can include cough, wheeze, hemoptysis, dyspnea, postobstructive pneumonia (due to tumors that occlude major bronchi), pain (particularly with pleural or chest wall involvement), dysphagia (due to esophageal compression by tumor or lymphadenopathy), and hoarseness (caused by laryngeal nerve involvement). Apical tumors that invade the lower brachial plexus can present with Pancoast syndrome, which is a brachial plexopathy, Horner syndrome, and shoulder pain. Mediastinal lymph-adenopathy that compresses the superior vena cava (SVC) can cause SVC syndrome, which most commonly presents with dyspnea and facial swelling. Systemic symptoms usually accompany disease that is more advanced and can include weight loss, fatigue, and loss of appetite. Metastatic disease may cause symptoms specific to the involved organs. For example, patients may have pain from bony metastases, dyspnea from pericardial or pleural effusions, or headache and neurologic deficits from brain metastases. Although adrenal and liver metastases are common, they are usually asymptomatic.
NSCLC has been associated with numerous paraneoplastic syndromes. Clubbing results from proliferation of connective tissue at the ends of the digits and usually improves with treatment of the tumor. Hypercalcemia may be due to ectopic parathyroid hormone production by the tumor. Pulmonary hypertrophic osteoarthropathy is a syndrome consisting of bone and joint pain, clubbing, and increased alkaline phosphatase. It can be diagnosed by plain films (which show periosteal inflammation) or bone scan (which shows increased uptake symmetrically in long bones).
Diagnostic Testing
The goal of the initial workup is to establish the diagnosis of malignancy and to determine accurately the clinical stage of the cancer so that candidates for potentially curable surgical resection are identified. Strategies for obtaining a pathologic diagnosis of a lung mass include sputum cytology (optimally from three early morning sputum collections), biopsy by percutaneous fine-needle aspiration, and bronchoscopy with biopsy.
Imaging
Once the diagnosis of NSCLC has been confirmed, recommended imaging studies include a chest x-ray and a chest CT scan, which can reveal the size of the tumor, extent of invasion of local structures, and presence of regional lymph node metastases. PET scan is also useful, as it has high accuracy in detecting disease metastatic to lymph nodes and distant sites, and it can aid in the differentiation of benign and malignant lung nodules.
Diagnostic Procedures
Potential lymph node metastases identified on imaging studies should be confirmed with direct biopsy. Mediastinoscopy is the most accurate means of staging mediastinal lymph nodes and should be performed when nodal involvement cannot be defined with chest CT. Pleural effusions should always be examined by thoracentesis, as a tumor associated with a malignant effusion is inoperable. The best way to identify the presence of distant metastases is with a thorough history and physical exam. Further imaging exams (i.e., head CT, abdominal CT, bone scan) should be directed by the patient’s symptoms and are not required in asymptomatic patients who have early-stage tumors.
Staging
If tissue sampling confirms the diagnosis of NSCLC, the stage of disease should be determined using the tumor, node, metastasis (TNM) staging. The 7th edition of TNM staging was developed by the International Association for the Study of Lung Cancer (IASLC), based on retrospective analysis of survival data from patients with NSCLC. It was approved by the American Joint Committee on Cancer (AJCC) for use starting January 1, 2010. See Table 19-1 for details regarding TNM staging. The major changes in this edition include reclassification of malignant pleural effusions as M1a rather than T4, downstaging of additional tumor nodules in a different lobe of the same lung to T4 rather than M1. T4 tumors with separate tumor nodules in the same lobe have been reclassified as T3. In addition, T1 and T2 tumors are divided into additional categories (a and b) based on size cutoffs. Finally, T2 tumors larger than 7 cm were reclassified as T3.12,13
TREATMENT
Stages I and II
Stage I and II tumors are considered resectable, as they have extended no further than adjacent resectable structures or first-level lymph nodes. The optimal treatment is surgical resection with lobectomy or pneumonectomy. Preoperative workup includes spirometry, arterial blood gases, and V/Q scan to establish both that the FEV1 will be > 1.2 L post-resection and that the patient does not have hypercapnia or cor pulmonale.
Patients who are not candidates for surgery because of poor lung function or comorbid conditions should be considered for radiation therapy (RT) administered with curative intent. Toxicities of RT include pneumonitis (shortness of breath, tachypnea, tachycardia, fever, nonproductive cough, and infiltrate on CXR 1 to 3 months after RT), pulmonary fibrosis, acute esophagitis, pericarditis, and Lhermitte’s phenomenon or radiation myelitis (transient electric sensation radiating down the spine or into the limbs with neck flexion). Adjuvant RT is indicated if the surgical margins are positive for tumor.
Several prospective studies have reported that the addition of adjuvant platinum-based chemotherapy to resected stage II patients with good performance status significantly improves survival. 14–16 In patients with stage I patients, there is currently not enough evidence to recommend adjuvant chemotherapy, although there is a suggestion that stage IB tumors >4 cm in size may benefit.17,18
Stage III
Treatment of patients with stage III disease requires a multidisciplinary approach, involving input from surgeons, medical oncologists, and radiation oncologists. In patients with surgically resectable stage IIIA disease (T3N1), the addition of adjuvant chemotherapy following surgical resection significantly improves survival. 19 Patients with N2 disease are generally considered to be unresectable. Concurrent chemotherapy and radiation has been shown to improve long-term survival compared with sequential chemotherapy followed by radiation in patients with unresectable IIIA and IIIB NSCLC.20 However, survival benefit was seen only in patients with good performance status. The addition of surgery after receiving chemoradiation in patients with stage IIIA disease (N2) has not shown a significant survival advantage; however, a subset analysis suggested a survival advantage in a subset of patients who underwent lobectomy, but not pneumonectomy.21 In patients with poor performance status, a palliative treatment approach is preferred.
Stage IV
Patients with stage IV disease are considered to be incurable. Recent advances in the treatment of stage IV NSCLC include the use of targeted agents, such as bevacizumab and erlotinib, factoring histology and genetic mutations into treatment decisions. Front-line platinum-based doublet chemotherapy provides modest improvement in survival.22 In patients with non-squamous histology, treatment options include front-line platinum and pemetrexed (a folate antagonist)doublet therapy or addition of bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, to platinum-based doublet chemotherapy.23,24 Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been studied in the front-line setting. Single-agent gefitinib, an oral EGFR-TKI, has been shown to improve progression-free survival over combination chemotherapy in patients with EGFR mutations, but not in patients with EGFR wild-type tumors.25 However, neither gefitinib nor erlotinib improved outcome when combined with cytotoxic chemotherapy.26,27
Front-line platinum-based chemotherapy is generally given for 4 to 6 cycles. Maintenance chemotherapy is an option for patients with good performance status who do not have disease progression after 4 cycles of front-line platinum-based doublet therapy. Agents approved for this indication include pemetrexed and erlotinib.28,29 Selection of agent is based on histology (pemetrexed for nonsquamous histology) and presence of EGFR mutation (erlotinib in patients with EGFR mutations). In patients who have had significant toxicities with first-line therapy, or those who desire a treatment break, waiting until disease progression to start second-line therapy is appropriate.
Single-agent docetaxel in the second-line setting has been shown to improve survival compared to best supportive care.30 In addition, pemetrexed is approved as a second-line agent for patients with non-squamous histology.31Second-line erlotinib is also approved for NSCLC.30
For patients with poor performance status, who may not benefit from chemo-therapy, treatment should focus on palliation of symptoms. A brief palliative course of RT may reduce disease bulk, relieving dyspnea, pain, or other symptoms. Targeted RT may also treat pain and complications from bony or brain metastases. Early palliative care in patients with metastatic NSCLC integrated with standard oncologic care improves quality of life.32
SPECIAL CONSIDERATIONS
Somatic activating mutations in EGFR are present in 10% of unselected NSCLC tumors. These mutations are further enriched in never smokers, with a frequency of ~50%. Exon 19 deletions and exon 21 L858R mutations account for 85% of EGFR mutations and are predictive for response to EGFR-TKIs, such as erlotinib and gefitinib. The most common mutations are exon 19 deletions and L858R mutations. Resistance to EGFR-TKI therapy in previously responsive patients is mediated by EGFRT90M mutations or MET amplification.
Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor under study in patients with advanced NSCLC carrying the EML4-ALK fusion gene.33 Patients carrying this fusion gene are typically nonsmokers and do not have the EGFR mutation. EML4-ALK fusion gene is seen in 3% to 5% of patients with NSCLC. There is currently no standard test for detecting the EML4-ALK fusion gene.
MONITORING/FOLLOW-UP
According to the NCCN guidelines, in patients with no evidence of disease, a careful history and physical exam and CT of the chest with contrast should be performed every 4 to 6 months for 2 years. After 2 years, history, physical exam and non-contrast CT of the chest should be performed annually.11 Patients should be counseled regarding smoking cessation. Further tests such as PET scan, abdominal CT, bone scan, and MRI of the brain are not part of routine surveillance and should be obtained only if signs or symptoms suggest recurrent disease. Blood tests and sputum cytology do not have a role in routine follow-up. Unfortunately, even with close follow-up, it is unlikely that recurrent disease will be resectable and curable.
OUTCOME/PROGNOSIS
Prognosis varies by stage. Recurrences may be local or distant and will occur in up to 30% of patients with stage I disease and 50% of patients with stage II disease over the subsequent 5 years. The 3-year survival in patients with stage III disease treated with chemoradiation is 25%.34 Patients with advanced stage disease treated with platinum-based doublets have a median survival of 8 to 10 months, with a 1-year survival of 30% to 40% and 2-year survival of 10% to 15%.22
SMALL-CELL LUNG CANCER
GENERAL PRINCIPLES
SCLC accounts for ~13% of lung cancers in the United States. As opposed to NSCLC, SCLC grows more rapidly, is more often associated with diverse paraneo-plastic syndromes, and is initially more chemosensitive.35
DIAGNOSIS
Clinical Presentation
The presenting signs and symptoms of SCLC are similar to those of NSCLC. SCLCs are often centrally located and symptoms result from obstruction of the airway lumen. Common symptoms are cough, dyspnea, hemoptysis, wheezing, and post-obstructive pneumonia. Ten percent of patients have SVC syndrome at presentation. Occasionally, SCLCs can present as asymptomatic lung nodules found on imaging studies.
Paraneoplastic syndromes associated with SCLC include syndrome of inappropriate secretion of antidiuretic hormone (SIADH), Cushing syndrome from ectopic adrenocorticotropic hormone production, and neurologic paraneoplastic syndromes, including peripheral neuropathy and encephalomyelitis, are thought to be due to the production of autoantibodies. Lambert–Eaton syndrome is caused by an autoantibody that impairs acetylcholine release at the neuromuscular junction, leading to proximal muscle weakness and hyporeflexia.
Diagnostic Testing
Initial workup should include a comprehensive history and physical exam. Initial studies include CBC and CMP. Tumor lysis syndrome may occur with bulky disease, so lactate dehydrogenase and uric acidshould also be checked. In addition to a baseline chest x-ray, CT scan of the chest and abdomen should be performed to define the extent of intrathoracic disease and to detect abdominal metastases. Further workup may include a head CT and bone scan. Once disease has been found outside of the thorax, workup for additional sites of metastasis is not necessary unless a metastasis requiring immediate intervention (e.g., to weight-bearing bone or CNS) is suspected.
Staging
The TNM (tumor, node, metastases) staging system is not widely used to classify SCLC, although the IASLC has proposed the use of TNM staging.36 Currently, SCLC is described either as limited stage, with disease confined to one hemithorax that is encompassed in a single radiation field, or as extensive stage, which describes all other patterns of disease.
TREATMENT
Chemotherapy is the primary modality used for the treatment of SCLC, as inferior results are obtained when RT is used alone. For patients with limited-stage disease, combined modality treatment with chemotherapy and RT to the chest is standard of care.37Extensive stage disease is treated with chemotherapy alone. The commonly used standard chemotherapy regimens for SCLC include combinations of carboplatin or cisplatin with etoposide. Irinotecan, topotecan, and epirubicin are acceptable alternatives to etoposide and have a lower incidence of myelosuppression. Overall response rate to chemotherapy is ~60%, but nearly all patients eventually have disease relapse.
Prophylactic cranial radiation (PCI) is recommended for patients with limited-stage SCLC who achieve complete response after initial chemoradiation to prevent intracranial metastases.38 It can also be considered in patients with extensive-stage SCLC with a complete response to treatment.39 However, it should not be administered to patients with poor performance status or impaired mental function.
Patients with poor performance status or significant comorbidities may not be able to tolerate aggressive chemotherapy. These patients may receive only RT or attenuated schedules of chemotherapy, with the goal of relieving symptoms.
MONITORING/FOLLOW-UP
Most patients treated for SCLC will relapse, usually in the first 2 years after diagnosis. Therefore, they should have close follow-up with a medical oncologist for the identification of symptoms, physical exam findings, or lab and CXR abnormalities that suggest recurrent disease. According to the NCCN guidelines, patients with no evidence of disease should have a follow-up visit every 2 to 3 months during year 1, every 3 to 4 months during years 2 to 3, and then every 4 to 6 months during years 4 to 5.40 After this, follow-up visits should be scheduled annually. At every visit, a careful history and physical exam, labs, and CXR should be performed. Patients should be counseled regarding smoking cessation.
OUTCOME/PROGNOSIS
Stage (limited vs. extensive), performance status, and markers of disease burden, such as serum lactate dehydrogenase, are the factors that most reliably correlate with outcome. The median survival of limited-stage disease treated with chemotherapy and RT is 15 to 26 months. However, long-term survival can be achieved in 20% to 40% of patients with limited-stage SCLC with chemoradiation. The median survival of extensive-stage disease treated with chemotherapy is 7 to 12 months. Only 5% of patients with extensive disease survive to 2 years.
OTHER MALIGNANT TUMORS OF THE LUNG
Malignant tumors of the lung, other than NSCLC and SCLC, are uncommon and include carcinoid tumors, mucoepidermoid carcinoma, and sarcomas. Carcinoid tumors account for 1% of lung malignancies and are derived from neuroendocrine cells. They arise in the bronchi and may cause bronchial obstruction and can produce a variety of systemically active substances that cause the carcinoid syndrome:flushing, diarrhea, and wheezing. Carcinoid tumors of the lung tend to grow slowly and are associated with a 5-year survival of 77% to 87%.
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