doi:10.1016/j.ijrobp.2006.05.059 CLINICAL INVESTIGATION Head and Neck GEMCITABINE AND CISPLATIN IN A CONCOMITANT ALTERNATING CHEMORADIOTHERAPY PROGRAM FOR LOCALLY ADVANCED HEAD-AND-NECK CANCER: A PHARMACOLOGY-GUIDED SCHEDULE GIANMAURO NUMICO, M.D.,* ELVIO G. RUSSI, M.D., † RAFFELE VITIELLO, M.D., § RAFFAELE SORRENTINO, M.D.,  IDA COLANTONIO, M.D.,* MARCO CIPOLAT, M.D., ‡ RICCARDO VIGNA TAGLIANTI, M.D., † ANTONIO PELISSERO, M.D., † ELENA FEA, M.D.,* CRISTINA GRANETTO, M.D.,* GIANNA DI COSTANZO, M.D.,* MILENA GASCO, M.D.,* ORNELLA GARRONE, M.D.,* MARCELLA OCCELLI, M.D.,* AND MARCO MERLANO, M.D.* *Medical Oncology, S. Croce General Hospital, Cuneo, Italy; † Radiation Oncology Unit, S. Croce General Hospital, Cuneo, Italy; ‡ Clinical Nutrition Unit, S. Croce General Hospital, Cuneo, Italy; § Otolaringology Unit, S. Annunziata Hospital, Savigliano, Italy;  Otolaringology Unit, SS. Arrigo e Biagio Hospital, Alessandria, Italy Purpose: Administration of gemcitabine together with cisplatin at cytotoxic doses in a chemoradiotherapy regimen is hampered by a high degree of local toxicity. Using the pharmacologic properties of the drug we designed a modified schedule aimed at reducing toxicity while preserving activity. Methods and Materials: Patients with squamous cell carcinomas of the oral cavity, pharynx and larynx, bulky T4, and/or N2 to N3 were eligible. Gemcitabine was administered at a dose of 800 mg/m 2 on Days 1 and 12 and cisplatin at a dose of 20 mg/m 2 on Days 2 to 5, every 21 days for 3 courses. Radiotherapy, delivered with standard fractionation, was given on Days 8 to 12 and 15 to 19 and was repeated 3 times up to a total dose of >60 Gy. Results: A total of 28 patients were selected. Grade 3 to 4 stomatitis was recorded in 25 patients (89%). Thirteen patients (46%) experienced Grade 3 to 4 neutropenia. Febrile neutropenia occurred in 8 patients (29%) and in 2 was complicated by infection and death. The overall complete response rate was 79%. At a median follow up of 71 months, 11 patients had a locoregional relapse (3-year locoregional control, 64%); 6 patients had distant metastases, among whom only 2 were without locoregional recurrence. The 3-year progression-free survival is 39% and 3-year overall survival has been 43%. Conclusion: The schedule modification did not attenuate local toxicity. Moreover, infections and especially pneumonia, were a major problem. The high activity of gemcitabine when combined with radiotherapy would most likely be better exploited in the context of modified radiation schemes. © 2006 Elsevier Inc. Head-and-neck cancer, Chemoradiotherapy, gemcitabine. INTRODUCTION Concurrent administration of cisplatin-based chemotherapy and radiation is considered standard of care in the treatment of locally advanced, squamous cell head-and-neck cancer based on the results of a large meta-analysis and several recent randomized trials (1–5). However, long-term survival obtained with these regimens is less than 50%, mainly because of inadequate local control, and improvement in patient outcome is the object of current clinical research. Unfortunately, until now the attempts to intensify chemo- radiation through new regimens have yielded unsatisfactory results because of the increase of treatment related acute and late toxicity (6, 7). Alternating chemoradiotherapy regimens were developed as one of the possible ways of simulta- neously maximizing local control while sparing patients from severe local toxicities. In randomized trials this sched- ule has shown clear superiority compared with standard radiotherapy alone, as well as a favorable safety profile (8, 9). Gemcitabine, a deoxycytidine analogue with high radiosensitization properties (10, 11), was tested even in alternating chemoradiotherapy schedules, in trials aimed at improving outcome of advanced head-and-neck cancer pa- tients. In a feasibility trial, gemcitabine was administered at a dose of 800 mg/m 2 on Day 5 on Weeks 1 to 3 and Weeks 5 to 7 together with cisplatin at the daily dose of 20 mg/m 2 on Days 1 to 5 on Weeks 1 and 5. Radiotherapy was administered with standard fractionation on Weeks 2 to 4 and Weeks 6 to 8 up to a total dose of 60 Gy (12). After 14 patients had been treated, Grade 3 to 4 acute mucosal toxicity occurred in all patients, Grade 3 to 4 neutropenia in Reprint requests to: Gianmauro Numico, M.D., Medical On- cology, S. Croce General Hospital, Via M. Coppino 26, 12100, Cuneo, Italy. Tel: (+39) 0171-641309; Fax: (+39) 0171-616793; E-mail: gianmauro.numico@fastwebnet.it Received Feb 27, 2006, and in revised form April 3, 2006. Accepted for publication May 24, 2006. Int. J. Radiation Oncology Biol. Phys., Vol. 66, No. 3, pp. 731–737, 2006 Copyright © 2006 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/06/$–see front matter 731