The current state of paclitaxel and radiation in the combined-modality therapy of non-small cell lung cancer.

The results of randomized trials have prompted an evolution in the treatment approach to inoperable locally advanced non-small cell lung cancer, from radiotherapy alone to sequential chemoradiotherapy and now to concurrent chemoradiotherapy. The improvement in outcome seen with a concurrent chemoradiotherapy approach may be because of spatial cooperation, enhanced radiosensitization, and/or enhanced cytotoxicity. The taxanes, specifically paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), delivered in combination with radiation have been extensively examined in both preclinical and clinical studies. Several mechanisms have been suggested to explain the enhanced tumor cell kill seen with paclitaxel and radiation, and phase II studies have examined this combination in the setting of inoperable stage III non-small cell lung cancer. This review will explore some of the studies with this treatment approach in locally advanced disease. We also will briefly discuss some of the ongoing trials that are attempting to refine the delivery of concurrent thoracic radiation and paclitaxel-based chemotherapy.

Weekly irinotecan and concurrent radiation therapy for stage III unresectable NSCLC.

In preclinical studies, the topoisomerase I inhibitor irinotecan (Camptosar, CPT-11) has demonstrated activity as a radiosensitizer, probably due to its ability to inhibit potentially lethal radiation damage repair. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of weekly irinotecan with concurrent thoracic radiation therapy for patients with unresectable stage III non-small-cell lung cancer. For this study, 13 patients received three dose escalations (from 30 to 40 to 50 mg/m2/wk). At the first dose level, one patient developed grade 5 esophagitis. Accrual was expanded to seven patients. None of the remaining six patients developed esophagitis. At the second dose level (40 mg/m2/wk), the worst toxicity, which developed in one patient, was grade 2 esophagitis. At the third dose level (50 mg/m2/wk), two of three patients developed grade 4 nausea and vomiting; grade 3 or 4 esophagitis also occurred in two patients. Of the 12 evaluable patients, seven achieved a partial response, for an overall response rate of 58%. In conclusion, nausea, vomiting, and esophagitis appear to be the principal DLTs of concurrent weekly irinotecan and thoracic radiation in the outpatient setting. The MTD of concurrent weekly irinotecan with thoracic radiation therapy appears to be 40 mg/m2 weekly for 6 weeks. To confirm the MTD of this combination, this study is still open to accrual at the second dose level (40 mg/m2) in combination with carboplatin.