PHASE-I TRIAL OF RETINOIC ACID AND CISPLATINUM FOR ADVANCED SQUAMOUS-CELL CANCER OF THE HEAD AND NECK BASED ON EXPERIMENTAL-EVIDENCE OF DRUG SYNERGISM

OBJECTIVE: Cis-platinum and 13-cis-retinoic acid have received much at tention in the treatment of head and neck squamous cell cancer. Even t hough they have different mechanisms of action, little information is available on their interaction. This paper reviews experimental eviden ce for retinoic acid-cis-platinum synergy and presents toxicity data f rom patients with stage IV head and neck squamous cell cancer particip ating in a phase I trial combining 13-cis-retinoic acid and cis-platin um. METHODS: Patients were given 13-cis-retinoic acid orally daily for 7 days before and daily during high-dose (150 mg/m(2) per week for 4 weeks) intraarterial cis-platinum treatment with concurrent radiation, Toxicity was scored with use of the cancer and leukemia group B scale . RESULTS: In the phase I clinical trial, 15 patients were treated to determine a maximum tolerated dosage for 13-cis-retinoic acid of 20 mg /day. Grade 4 hematologic toxicity was dose limiting in 3 of 8 patient s treated with 40 mg/day and in 1 patient treated with 60 mg/day There were no deaths caused by toxicity; 12 of the 15 patients received all four weekly doses and the remaining 3 received three doses. Of 10 pat ients with fully evaluable data, all achieved a complete response at t he primary site and 9 had a complete response in the neck. One patient had persistent neck disease after chemoradiation, and this tumor was removed with neck dissection. CONCLUSIONS: 13-Cis-retinoic acid and ci s-platinum are strongly synergistic against head and neck squamous cel l cancer in vitro. Pretreatment with retinoic acid results in stronger synergy than concurrent drug exposure alone. Preliminary clinical exp erience with combined retinoic acid and cis-platinum in a design that parallels the in vitro study indicates that toxicity is acceptable wit h 13-cis-retinoic acid dosages of 20 mg/day in a high-dose-intensity i ntraarterial chemoradiation regimen.