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.
OBJECTIVE
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.


METHODS
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/m(2)/d, for 5 days; paclitaxel, 100 mg/m(2) on Day 1; and concurrent 1.5 Gy twice-daily radiation for 5 days. Gemcitabine was dose escalated, 50-300 mg/m(2) on day 1. Cycles repeated every 14 days until the completion of chemoradiation. Dose-limiting toxicities (DLTs) included: neutropenic fever; grade > or =4 neutropenia or thrombocytopenia for >4 days; grade > or =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/m(2) during cycles 1-5 (1 of 7 patients with DLT) or 200 mg/m(2) 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.
Milano
Michael T
MT
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
Haraf
Daniel J
DJ
Stenson
Kerstin M
KM
Witt
Mary Ellyn
ME
Eng
Cathy
C
Mittal
Bharat B
BB
Argiris
Athanassios
A
Pelzer
Harold
H
Kozloff
Mark F
MF
Vokes
Everett E
EE
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000494:pharmacology; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage*; D011379:Prognosis; D011874:Radiometry; D013997:Time Factors; D016896:Treatment Outcome; D000093542:Gemcitabine
D003841:Deoxycytidine; D017239:Paclitaxel; D005472:Fluorouracil; D000093542:Gemcitabine