The Emerging Role of Gemcitabine in Combination with Radiation in Locally Advanced, Unresectable Non–Small-Cell Lung Cancer

Abstract

The median survival for patients with locally advanced non–small-cell lung cancer (NSCLC) remains 18 months, at best, in cooperative group efforts. Integrating new agents into the standard combined modality treatment paradigm is a daunting challenge. Gemcitabine has activity in advanced NSCLC and is a potent radiosensitizer, but preclinical trials did not delineate an optimal dose or schedule, and early attempts to graft full-dose gemcitabine (1000 mg/m2/week) onto standard radical thoracic radiation therapy (RT) were marked by significant grade 4 and 5 toxicity. More recent trials, however, have shown that attenuated doses of 150-300 mg/m2/week during radiation (XRT) are safer and potentially efficacious. Higher doses produce dose-limiting esophageal and pulmonary toxicities. Using a twice-weekly schedule, the maximum tolerated dose is 35 mg/m2. The use of 3 dimensional conformal RT may enable significant dose escalations while substantially reducing esophageal exposure and minimizing toxicity. The cooperative oncology groups are just beginning to evaluate gemcitabine in this setting. Cancer and Leukemia Group B, in a randomized phase II study, assessed combination gemcitabine and cisplatin in both the induction and radiosensitizing setting. During the induction phase, gemcitabine was given 1250 mg/m2 on days 1 and 8 every 3 weeks for 2 cycles in combination with cisplatin 80 mg/m2 every 3 weeks, and then reduced to 600 mg/m2 days 1 and 8 every 3 weeks during XRT. The overall response rate was 63% with median survival of 18.3 months and 1-year and 3-year survival rates of 68% and 28%, respectively. Radiation Therapy Oncology Group is currently spearheading a phase I study of concurrent radiation and weekly gemcitabine in combination with either weekly carboplatin or paclitaxel. Ongoing efforts will also evaluate the role of gemcitabine either alone or in combination with docetaxel in the consolidation setting after definitive chemoradiation has been completed. Whether gemcitabine in combination with radiation, with or without other agents, will ultimately prove superior to standard chemoradiation regimens remains to be determined.