A phase I trial of 96-hour paclitaxel infusion plus accelerated radiotherapy for unresectable head and neck cancer

Purpose: To determine the maximum tolerated dose (MTD) of paclitaxel given as a 96-hour continuous infusion during Weeks 1 and 5 of an accelerated radiotherapy schedule for the definitive treatment of advanced (nonmetastatic) unresectable squamous cell carcinoma of the head and neck (SCCHN). Methods and Materials: Thirteen patients with Stage IV SCCHN were enrolled. Radiotherapy consisted of 70-72 Gy over 6 weeks, with a fractionation scheme of 2 Gy q.d. for 4 weeks followed by 1.6 Gy b.i.d, for 2 weeks, with no planned interruptions. Paclitaxel was administered over a 96- hour continuous infusion during Weeks 1 and 5 of radiotherapy at the following dose levels: Dose Level 1:40 mg/m²/96-hours (3 patients); Dose Level 2: 80 mg/m²/96-hrs (5 patients); Dose Level 3: 120 mg/m²/96-hours (2 patients); and Dose Level 2A: 100 mg/m²/96 hours (3 patients). Results: The MTD of Paclitaxel was 100 mg/m²/96-hours. All but one patient (who experienced progressive disease after receiving 61 Gy and both cycles of paclitaxel) completed therapy as planned. Dose-limiting toxicity occurred in both patients enrolled at Dose Level 3, with one patient experiencing Grade 4 diffuse moist desquamation and the other patient experiencing Grade 4 mucositis and febrile neutropenia. Thus, Dose Level 2A was opened and no dose limiting toxicity was noted. Grade 3 non-dose limiting mucositis and dermatitis occurred at all paclitaxel dose levels. There were no treatment- related deaths. All Grade 3 and 4 toxicities were reversible. Complete responses were seen in 8 of 13 patients, 4 patients achieved partial responses, and 1 patient had no response/progressive disease. Conclusions: Infusional paclitaxel over 96 hours during Weeks 1 and 5 of this accelerated radiotherapy schedule is feasible. The MTD of paclitaxel in this protocol was 100 mg/m²/96-hours. Dose-limiting toxicities were primarily enhanced epithelial reactions, but febrile neutropenia also occurred. All patients develop non-dose limiting Grade 3 skin and mucosal reactions, reflecting the high treatment intensity. This regimen merits further investigation.