PHASE-I STUDY OF CONCOMITANT CHEMORADIOTHERAPY WITH PACLITAXEL, FLUOROURACIL, AND HYDROXYUREA WITH GRANULOCYTE-COLONY-STIMULATING FACTOR SUPPORT FOR PATIENTS WITH POOR-PROGNOSIS CANCER OF THE HEAD AND NECK

Purpose: We have previously demonstrated high locoregional control rat es in patients with poor prognosis head and neck cancer using fluorour acil (5-FU), hydroxyurea (HU), and concomitant radiotherapy (RT) (FHX) . In the trial reported here, we added paclitaxel to the FHX base and used hyperfractionated PT to determine the maximum-tolerated dose (MTD ), toxicities, and response rate in a poor-prognosis group of patients . Methods: Fifty-five patients who had either failed to respond to pri or RT (n = 25) or surgery, had a coexistent or prior second malignancy , or who had unresectable or metastatic disease and an expected 2-year survival rate less than 10%, were treated. Chemoradiotherapy consiste d of 2 Gy on days 2 to 6 (once-daily PT cohorts) or 1.5 Gy twice a day (hyperfractionated cohorts). Simultaneous HU (500 or 1,000 mg twice p er day for 11 doses) and infusional 5-FU (600-800 mg/m(2)/d for 5 days ) were given along with infusional paclitaxel at escalating doses of 5 to 25 mg/m(2)/d for 5 days. Granulocyte colony-stimulating factor (G- CSF) was administered on days 7 through 13 at 5 mu g/kg/d. Cycles were repeated every 14 days until completion of RT. Plasma paclitaxel leve ls were determined on day 4 of cycle 1. Results: Dose-limiting toxicit ies (DLTs) consisted of myelosuppression, mucositis, dermatitis, and d iarrhea. Plasma concentrations of paclitaxel greater than 10 nmol/L we re achieved in 65% of patients at the recommended phase II dose (RPTD) level of paclitaxel. Seventy percent of assessable patients achieved a complete response (CR) to therapy. Twenty patients were treated at t he RPTD of HU 500 mg orally twice daily for 11 doses, 5-FU 600 mg/m(2) /d by continuous infusion for 5 days; and paclitaxel 20 mg/m(2)/d by c ontinuous infusion for 5 days, with twice-daily RT. Conclusion: The ad dition of infusional paclitaxel and hyperfractionated PT to FHX is fea sible. Radiosensitizing levels of paclitaxel are achieved in most pati ents. The high locoregional control rate of this regimen justifies fur ther investigation in previously untreated patients. (C) 1998 by Ameri can Society of Clinical Oncology.