Small cell lung cancer: strategies to optimize chemotherapy response

During the past two decades, a major focus of clinical research in small cell lung cancer (SCLC) has been the manipulation of the dose and schedule of the available active cytotoxic agents. Approaches tested include alternating cyclic combination chemotherapy, increasing the dose intensity of chemotherapy with or without the support of either cytokines or stem cells, and increasing the dose density by delivering treatment at shorter intervals. Overall, the results of clinical trials testing these approaches have been disappointing. One of the difficulties in intensifying treatment for SCLC is that the patients tend to be elderly and have smoking-related pulmonary and cardiovascular comorbidities. In fact, as treatment regimens have become more intensive, several multicenter groups have identified a dramatic increase in early-treatment-related mortality rates. Yet, toxicity associated with dose-intensification may obscure a potential therapeutic advantage in unselected patients. Therefore, some of these groups have performed retrospective analyses to identify factors that predict excessive treatment-related toxicity that can be used for patient stratification in clinical trials. This article reviews the data regarding the role of dose-intensified therapy in the treatment of SCLC. We propose that delivery of the currently available chemotherapy drugs at greater dose intensity, if excessive toxicity is avoided, may offer a meaningful improvement in survival, and that clinical trials that appropriately test this hypothesis are warranted.