These pilot trials clearly demonstrate the feasibility of administering neoadjuvant chemotherapy to patients with stage III NSCLC. Response rates in most of these trials reach or exceed 50%, indicating increased activity of chemotherapy in NSCLC when used at an earlier time in the natural history of the disease, as has been shown in other diseases. In addition, histologic confirmation of complete response can occasionally be achieved. Most of the studies reviewed here have included patients with unresectable disease, who would now frequently be classified as stage IIIB. For these patient cohorts the survival data reported are frequently disappointing, suggesting that the high response rates to neoadjuvant chemotherapy do not necessarily translate into improved survival of the patients. On the other hand, where patients with stage IIIA disease were treated and surgery was included in the overall treatment plan, the survival data are more encouraging. Although most chemotherapy regimens have included cisplatin, it is not clear which combination of drugs and which schedules are superior. Clinical research, therefore, clearly needs to continue to focus on the development of innovative drug combinations and the evaluation of new drugs in NSCLC in an attempt to further increase overall and complete response rates to neoadjuvant chemotherapy. At the same time, randomized studies are needed to unequivocally establish whether the addition of neoadjuvant chemotherapy to standard therapy improves survival for stage IIIA and/or stage IIIB NSCLC as compared with standard therapy alone. Results from one such randomized study, which was conducted by the Cancer and Leukemia Group B (CALGB), have recently been reported. One-hundred and eighty patients with unresectable NSCLC were randomized to receive radiotherapy alone or two cycles of cisplatin and vinblastine followed by radiotherapy. One-hundred and fifty-five eligible patients were analyzed for response. Of 77 patients receiving radiotherapy alone, 43% responded, including 16% with a complete response. Of 78 patients receiving neoadjuvant chemotherapy, 56% responded to both treatment modalities, including 19% with complete response. With a median follow-up of 19 months, the median survival was 16.5 months for patients receiving combined modality therapy and 8.5 months for patients receiving radiotherapy alone. The pattern of relapse was identical in both study arms, showing a predominance of local recurrence or of combined local and distant recurrence, whereas few patients experienced distant disease progression alone.(ABSTRACT TRUNCATED AT 400 WORDS)