Developing New, Rational Therapies for Recalcitrant Small Cell Lung Cancer

The Recalcitrant Cancer Research Congressional Act of 2012 (H.R.733) directs the National Cancer Institute (NCI) to utilize resources for research and treatment of recalcitrant cancers having five-year relative survival rates of less than 20% that have not seen substantial progress in diagnosis or treatment. The initial focus will be on pancreatic carcinoma and small cell cancer of the lung (SCLC). SCLC is strongly associated with tobacco exposure and is characterized by rapid growth, early metastasis, and a five-year survival rate of less than 7%. The basic therapeutic approach for SCLC has remained unchanged for three decades, and no effective targeted therapies exist to date ( 1 , 2 ). SCLC is a poster child for recalcitrant cancers as documented in subsequent NCI responses and workshop proceedings ( 3 , 4 ). Front-line therapy for SCLC is usually etoposide-platinum-based doublet chemotherapy for extensive-stage disease (∼75% of cases) ( 1 ) and often combined with thoracic irradiation for limited-stage disease (∼25% of cases) and prophylactic intracranial irradiation. While initial objective tumor response rates to chemotherapy and radiation therapy are very high, they are usually of short duration and recurrent tumors are nearly always resistant to further therapies. We do not understand the mechanisms underlying either the initial sensitivity or the subsequent omnipresent resistance to standard chemotherapy. Intense efforts of many clinical trials over the past 30 years have failed to find highly active new therapies for front-line or second-line therapy. Thus, the therapy and survival of SCLC patients have not changed in many decades. In addition, sophisticated efforts in molecular analyses have failed to translate to the clinic in a manner similar to those that have revolutionized our approach to non–small cell lung cancer (NSCLC) ( 5 ). In response, the NCI and multiple investigators have fast-tracked the comprehensive development of new diagnostic, prevention, and therapeutic approaches for SCLC, with reasons for optimism outlined below, in the NCI special reports and elsewhere ( 6 ).