SMALL-CELL LUNG-CANCER - ETIOLOGY, BIOLOGY, CLINICAL-FEATURES, STAGING, AND TREATMENT

Lung cancer is the leading cause of cancer death in the United States. Small cell lung cancer (SCLC) accounts for 20% to 25% of all bronchog enic carcinoma and is associated with the poorest 5-year survival of a ll histologic types. SCLC differs in its etiologic, pathologic, biolog ic, and clinical features from non-SCLC, and these differences have tr anslated to distinct approaches to its prevention and treatment. Compa red with other histologic types of lung cancer, exposures to tobacco s moke, ionizing radiation, and chloromethyl ethers pose a substantially greater risk for development of SCLC. The histologic classification o f SCLC has been revised to include three categories: (1) small cell ca rcinoma, (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 den se core vesicles or neurosecretory granules. These dense core vesicles are associated with a variety of secretory products, cell surface ant igens, and enzymes. The biology of SCLC is complex. The activation of a number of dominant proto-oncogenes and the inactivation of tumor sup pressor genes in SCLC have been described. Dominant proto-oncogenes th at have been found to be amplified or overexpressed in SCLC include th e myc family, c-myb, c-kit, c-jun, and c-src. Altered expression of tw o tumor suppressor genes in SCLC, p53 and the retinoblastoma gene prod uct, has been demonstrated. Cytogenetic and molecular evidence for chr omosomal 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 grow th factor 1, and transferrin have been identified as autocrine growth factors in SCLC, with a number of other peptides under active investig ation. Several mechanisms of drug resistance in SCLC have been describ ed, including gene amplification, the recently described overexpressio n of multi-drug resistance-related protein (MRP), and the expression o f P-glycoprotein. The classic SCLC staging system has been supplanted by a revised TNM staging system where limited disease and extensive di sease are equivalent to the TNM stages I through III and stage IV, res pectively. Therapeutically, recent strategies have attained small impr ovements in survival but significant reductions in the toxicities of c hemotherapeutic regimens. Presently, the overall 5-year survival for S CLC 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)-base d chemotherapy combined with concurrent or alternating radiotherapy. T here is no overwhelming evidence that alternating chemotherapeutic reg imens are superior to EP-based regimens. Maintenance chemotherapy is n ot recommended. It is reasonable to use a strategy of surgery followed by chemotherapy for the rare patient with stage I and II SCLC; howeve r, surgery remains an experimental option for those with stage III dis ease after chemotherapy. Chemotherapy without radiotherapy is the corn erstone of palliative therapy for diose patients with SCLC who have ex tensive disease. New therapies on the horizon for SCLC include the cam ptothecin derivatives, mitotic spindle poisons such as taxol, and anal ogues of the vinca alkaloids.