Small cell lung cancer: Etiology, biology, clinical features, staging, and treatment

Abstract

Lung cancer is the leading cause of cancer death in the United States. Small cell lung cancer (SCLC) accounts for 20% to 2516 of all bronchogenic carcinoma and is associated with the poorest 5-year survival of all histologic types. SCLC differs in its etiologic, pathologic, biologic, and clinical features from non-SCLC, and these differences have translated to distinct approaches to its prevention and treatment. Compared with other histologic types of lung cancer, exposures to tobacco smoke, ionizing radiation, and chloromethyl ethers pose a substantially greater risk for development of SCLC. The histologic classification of SCLC has been revised to include three categories: (1) small cell carcinoma, (2) mixed small cell/large cell, and (3) combined small cell carcinoma. Ultrastructurally, SCLC displays a number of neuroendocrine features in common with pulmonary neuroendocrine cells, including dense core vesicles or neurosecretory granules. These dense core vesicles are associated with a variety of secretory products, cell surface antigens, and enzymes. The biology of SCLC is complex. The activation of a number of dominant proto-oncogenes and the inactivation of tumor suppressor genes in SCLC have been described. Dominant proto-oncogenes that have been found to be amplified or overexpressed in SCLC include the myc family, c- myb, c- kit, c- jun, and c- src. Altered expression of two tumor suppressor genes in SCLC, p53 and the retinoblastoma gene product, has been demonstrated. Cytogenetic and molecular evidence for chromosomal loss of 3p, 5q, 9p, 11p, 13q, and 17p in SCLC has intensified the search for other tumor suppressor genes with potential import in this malignancy. Bombesin/gastrin-releasing peptide, insulin-like growth factor I, and transferrin have been identified as autocrine growth factors in SCLC, with a number of other peptides under active investigation. Several mechanisms of drug resistance in SCLC have been described, including gene amplification, the recently described overexpression of multi-drug resistance-related protein (MRP), and the expression of P-glycoprotein. The classic SCLC staging system has been supplanted by a revised TNM staging system where limited disease and extensive disease are equivalent to the TNM stages I through III and stage IV, respectively. Therapeutically, recent strategies have attained small improvements in survival but significant reductions in the toxicities of chemotherapeutic regimens. Presently, the overall 5-year survival for SCLC is 5% to 10%, with limited disease associated with a significantly higher survival rate. The present preferred therapeutic strategy for limited disease is four to six cycles of etoposide-cisplatin (EP)-based chemotherapy combined with concurrent or alternating radiotherapy. There is no overwhelming evidence that alternating chemotherapeutic regimens are superior to EP-based regimens. Maintenance chemotherapy is not recommended. It is reasonable to use a strategy of surgery followed by chemotherapy for the rare patient with stage I and II SCLC; however, surgery remains an experimental option for those with stage III disease after chemotherapy. Chemotherapy without radiotherapy is the cornerstone of palliative therapy for those patients with SCLC who have extensive disease. New therapies on the horizon for SCLC include the camptothecin derivatives, mitotic spindle poisons such as taxol, and analogues of the vinca alkaloids.