Small cell lung cancer (SCLC) is an aggressive bronchogenic carcinoma diagnosed in 14% of all patients with lung cancer, accounting for approximately 30,000 new cases annually in the United States (1). It is distinguished from non–small cell lung cancer (NSCLC) by its rapid doubling time, high proliferative fraction, and early development of metastases. Regional lymph node involvement or distant metastasis is present in 90% or more of patients at diagnosis. Historically, SCLC has been staged as limited disease (LD), which is confined to the ipsilateral thorax of origin and regional nodes, versus extensive disease (ED). The recent International Association for the Study of Lung Cancer (IASLC) staging project and American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) seventh edition suggest use of the tumor, node, metastasis (TNM) system for the staging of SCLC (2). Clinically, the limited- and extensive-stage classification is practical given that most patients present with advanced disease (stages III-IV) and are only rarely candidates for resection.
Standard treatment for LD (stages I-IIIB) includes both chemotherapy and radiation; chemotherapy is the mainstay of treatment for ED (stage IV). Although a dramatic response to initial therapy is usually observed, greater than 95% of patients with ED and 80% to 90% of those with LD eventually suffer relapse and die of their disease.
Despite extensive research, no substantive advances in the systemic treatment of SCLC have been made for decades. Molecular profiling and preclinical models of SCLC have increased our understanding of the biology and genomic changes in the pathogenesis of SCLC. Translation of preclinical research to the clinical arena has resulted in recent promising data with targeted therapies, providing hope that improved outcomes for patients is on the horizon.
Small cell lung cancer is uncommon in never smokers, who constitute only 3% to 5% of cases, and is commonly associated with intense tobacco exposure (3). However, transformation to SCLC has been recently documented in never smokers with epidermal growth factor receptor (EGFR)–mutation positive adenocarcinoma of the lung, in the setting of resistance to tyrosine kinase inhibitors (4). The original EGFR mutation is maintained in the SCLC, supporting the notion that the tumor evolved from transformation and is not a second primary cancer.
The incidence of SCLC has steadily declined, as illustrated by an analysis of the Surveillance, Epidemiology, and End Results (SEER) database (1), in which the proportion of SCLCs decreased from 17% in 1986 to 13% in 2002. However, this decrease was accompanied by an increase in SCLC cases arising in women (28% in 1973 vs 50% in 2002), attributed to increasing tobacco use among women starting in the 1960s. The reduced incidence may be related, in part, to changes in the pathologic criteria leading to the classification of cases as large cell neuroendocrine carcinoma (LCNEC) that would have been ...