Porfiromycin as an adjunct to radiation therapy in squamous cell carcinoma of the head and neck

Purpose: Two previous randomized trials demonstrated a statistically significant improvement in local-regional control and disease free survival with the concomitant use of mitomycin C and radiation therapy in the management of squamous cell carcinoma of the head and neck. Porfiromyin (methyl mitomycin C) has been shown in laboratory studies to have increased selective cytotoxicity to hypoxic cells and therefore may provide enhanced therapeutic efficacy over mitomycin C when used in combination with radiation therapy. The purpose of the two clinical studies reported here is to evaluate the concomitant use of porfiromycin with radiation therapy in the management of squamous cell carcinoma of the head and neck. Methods and Materials: Between (10(89)) and (7(92)), 21 patients presenting with locally advanced stage III/IV squamous cell carcinoma of the head and neck were entered into a phase I toxicity trial evaluating porfiromycin as an adjunct to radiation therapy. Patients were eligible if they had biopsy documented squamous cell carcinoma of the head and neck with a low probability of cure by conventional means. Patients were treated with standard fractionated daily radiation therapy to a total median dose of 63 Gy, as either primary treatment (n = 10) or postoperatively (n = 11). Porfiromycin was scheduled to be administered on days 5 and 47 of the course of radiation therapy. Based on laboratory studies and prior clinical data in other malignancies, a dose of 50 mg/M2 was chosen as an appropriate starting dose, which should theoretically result in normal tissue toxicity roughly equivalent to 15 mg/M2 mitomycin C, but have significantly greater cytotoxicity to hypoxic cells. Final outcome of these 21 patients, now with a median follow-up of nearly five years, is reported here. Upon completion of this phase I trial, a phase III trial was initiated in (11(92)) randomizing patients with squamous cell carcinoma of the head and neck to radiation therapy with mitomycin C vs. radiation therapy with porfiromycin. There is no radiation only arm in this current trial. To date, 75 patients have been entered on this trial and acute toxicity data is available on 71 patients (37-porfiromycin, 34-mitomycin C), who have completed their entire course of treatment. Results: As of (12(95)), median follow-up of the 21 patients enrolled in the phase I porfiromycin trial is 58.5 months. Of the 21 patients, five were treated at a dose of 50 mg/M2, four at 45 mg/M2 and the final 12 at 40 mg/M2 which appeared to result in acceptable acute hematological and nonhematological toxicities. Of the 10 patients treated with radical radiation therapy, five had complete responses, one had a near complete response and four had partial responses (two of the four with partial responses did not complete the prescribed course of radiation). Of the 16 patients evaluable for relapse, three experienced a local relapse, two experienced regional relapse and two experienced distant relapse. As of (12(95)), 14 of the 21 patients have died with disease and seven remain alive and free of disease resulting in a 5-year actuarial survival of 32%. Of the 71 patients enrolled to date in the phase III randomized trial of mitomycin C vs. porfiromycin, there have been no statistically significant differences between the two arms with respect to WBC, platelet or hemoglobin nadirs. Acute non-hematological toxicities including mucositis, epidermitis, odynophagia, and nausea have also been comparable. Two patients in this current randomized trial expired during treatment, apparently of nondrug-related causes. Conclusions: The bioreductive alkylating agent porfiromycin has demonstrated an acceptable toxicity profile to date. Final analysis of the phase I trial, which revealed a 5-year NED survival rate of 32% in patients with locally advanced disease and a low probability of cure by conventional radiation therapy with or without surgery, appears encouraging. We anticipate completion of the current ongoing trial comparing mitomycin C to porfiromycin in the next two years. Further investigations, including large scale multi-institutional trials employing bioreductive alkylating agents or other hypoxic cell cytotoxins as adjuncts to radiation therapy, are warranted