Small cell lung cancer: will recent progress lead to improved outcomes?

Abstract

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with a unique natural history characterized by a short doubling time, high growth fraction, and early development of widespread metastases. Although a chemotherapy- and radiation-sensitive disease, SCLC typically recurs rapidly after primary treatment, with only 6% of patients surviving 5 years from diagnosis. This disease has been notable for the absence of major improvements in its treatment: Nearly four decades after the introduction of a platinum-etoposide doublet, therapeutic options have remained virtually unchanged, with correspondingly little improvement in survival rates. Here, we summarize specific barriers and challenges inherent to SCLC research and care that have limited progress in novel therapeutic development to date. We discuss recent progress in basic and translational research, especially in the development of mouse models, which will provide insights into the patterns of metastasis and resistance in SCLC. Opportunities in clinical research aimed at exploiting SCLC biology are reviewed, with an emphasis on ongoing trials. SCLC has been described as a recalcitrant cancer, for which there is an urgent need for accelerated progress. The NCI convened a panel of laboratory and clinical investigators interested in SCLC with a goal of defining consensus recommendations to accelerate progress in the treatment of SCLC, which we summarize here.

Figure 1

Chemoresistance and potential for research and change in treatment. A, SCLC is very sensitive to first-line chemotherapy, with 60-80% response rate. However, there is almost uniform relapse or progression of disease.Such relapse likely is due to the behavior of the chemoresistant cell population, which may also have enhanced tumorigenic potential (blue-colored cells). B, Opportunities for research and drug development.Patients with newly diagnosed advanced SCLC could be enrolled onto tissue acquisition protocols and their tumors biopsied prior to initiating treatment, facilitating comprehensive molecular studies, including but not limited to genome, transcriptome, proteomic and methylome profiling. Further, these samples can be available for creation of patient derived xenografts (not shown).At the time of progressive or recurrent disease, patients could be approached to undergo repeat biopsy. Evaluation and comparisons of molecular features of paired samples from the same patient could identify pathways of resistance to standard first line therapy, define new biomarkers, and provide opportunities for targeted drug development. Pathways of interest can be evaluated further in genetically engineered mice models (not shown). C,Once agents are found to be of benefit against chemoresistant cells, these can be incorporated into clinical trials and potentially lead to responses and importantly, more durable outcomes. EP, etoposide/platinum.