Optimal Therapy for Unresectable Stage III Non–Small-Cell Lung Cancer

The treatment of patients with unresectable regionally advanced non–small-cell lung cancer (NSCLC) has continued to evolve over the last two decades. In the 1980s, radiotherapy alone led to a median survival of less than 10 months and 3-year survival rates below 10%. The identification of drugs with single-agent activity in stage IV NSCLC allowed for subsequent investigations in the curative intent treatment setting. Combined-modality therapy initially focused on a sequential approach, using induction chemotherapy. Randomized phase III studies demonstrated an increase in median survival from 10 months to approximately 13 months with the addition of two cycles of cisplatin-based chemotherapy administered before radiotherapy. 1-3 Since locoregional control is infrequently achieved with radiotherapy alone, and most agents with single-agent systemic activity are also radiation sensitizers, the concomitant administration of both modalities has also been explored. Most studies evaluating single-agent cisplatin had negative results, but concomitant chemoradiotherapy using two drugs was shown to be superior to radiotherapy alone. 4-6 Thus, sequential and concomitant combined-modality strategies were each established to be superior to radiotherapy alone, although their effects might be mediated by different mechanism because concomitant chemoradiotherapy appears to prolong survival mainly by increasing locoregional control, whereas induction chemotherapy improves systemic control. The next generation of randomized trials directly compared induction chemotherapy with concomitant chemoradiotherapy in an effort to determine the most effective approach. Several randomized phase II and III studies have been presented that suggest that the concomitant approach results in a higher median survival of approximately 16 to 17 months, although in-field toxicity, in particular esophagitis, is also increased (grade 3 or 4 in approximately 25%). 7-9