Integration of novel therapeutics into combined modality therapy of locally advanced non-small cell lung cancer.

Novel therapeutic agents (NTA) directed against a wide array of newly described molecular targets are now entering clinical investigation, many in the treatment of non-small cell lung cancer (NSCLC). The great majority of these clinical trials have been directed toward patients with advanced stage (metastatic) disease. More recently, study of NTAs has turned toward earlier-stage disease. Locally advanced, or stage III, NSCLC represents a large and heterogeneous group of patients and several clinically distinct substages. During the last 15 years, randomized clinical trials have shown improved survival with sequential chemoradiation compared with radiation alone and, more recently, the superiority of concurrent versus sequential chemoradiation. As NTAs have increasingly shown clinical activity against NSCLC, questions of how to incorporate them into clinical trials in stage III disease, whether they should be given together with radiotherapy, substituting for chemotherapy, or whether they should be added to current chemoradiation strategies, all remain as issues. Here, we describe conceptual issues, preclinical rationale, and ongoing or planned clinical trials incorporating NTAs into current treatment paradigms for unresectable stage III NSCLC.