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Phase I Study of Concomitant Chemoradiotherapy with Paclitaxel, Fluorouracil, Gemcitabine, and Twice-Daily Radiation in Patients with Poor-Prognosis Cancer of the Head and Neck

¹ Department of Radiation and Cellular Oncology, and ² Department of Surgery, University of Chicago, Chicago, Illinois; ³ Department of Medical Oncology, M. D. Anderson Cancer Center, Houston Texas; ⁴ Departments of Radiation Oncology ⁵ Medicine, and ⁶ Otolaryngology, Northwestern University, Chicago; ⁷ Department of Medicine, Michael Reese Hospital, University of Chicago, and ⁸ Department of Medicine, and ⁹ Cancer Research Center, University of Chicago, Chicago, Illinois

ABSTRACT

Purpose: We previously demonstrated high locoregional control, in patients with poor-prognosis head and neck cancer (HNC), using paclitaxel, 5-fluorouracil, hydroxyurea, and concomitant hyperfractionated radiotherapy. In the present phase I trial, gemcitabine, a novel antimetabolite with strong radiation-enhancing activity, replaces hydroxyurea. We sought to determine the recommended phase II dose and clinical efficacy in poor-prognosis HNC patients.

Experimental Design: Seventy-two patients enrolled. Eligibility criteria included recurrent or second primary HNC, metastases or expected 2-year survival <20%. Chemoradiotherapy consisted of 5-fluorouracil, 600 mg/m²/d, for 5 days; paclitaxel, 100 mg/m² on Day 1; and concurrent 1.5 Gy twice-daily radiation for 5 days. Gemcitabine was dose escalated, 50–300 mg/m² on day 1. Cycles repeated every 14 days until the completion of chemoradiation. Dose-limiting toxicities (DLTs) included: neutropenic fever; grade 4 neutropenia or thrombocytopenia for >4 days; grade 4 mucositis or dermatitis for >7 days; or grade 3 toxicity necessitating chemotherapy dose reductions. Non-DLT dose reductions in 5-fluorouracil and/or paclitaxel were allowed.

Results: Seventy-nine percent of assessable patients experienced a clinical response. Five-year actuarial survival is 33.0%, and locoregional control is 61.4%. The recommended phase II dose of gemcitabine in this regimen is 100 mg/m² during cycles 1–5 (1 of 7 patients with DLT) or 200 mg/m² delivered only during cycles 3–5 (3 of 19 with DLT). Grades 3 and 4 mucositis (56 and 21%, respectively) and dermatitis (25 and 21%, respectively) were common.

Conclusions: Gemcitabine, 5-fluorouracil, paclitaxel, and twice-daily radiation, delivered on alternating weeks, is active in patients with poor-prognosis HNC, although severe mucositis limits the clinical applicability of this regimen. Refinements in radiotherapy, including intensity-modulated radiation therapy, may improve the tolerance for this regimen.

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