PILOT-STUDY OF LOCAL HYPERTHERMIA, RADIATION-THERAPY, ETANIDAZOLE, AND CISPLATIN FOR ADVANCED SUPERFICIAL TUMORS

Five patients (six hyperthermia sites) with advanced superficial tumou rs were treated with combined etanidazole, cisplatin, local hypertherm ia, and radiation therapy as part of a Phase I pilot study. Treatment was given once weekly and consisted of etanidazole 3 gm/m(2) IV bolus, cisplatin 50 mg/m(2) IV bolus, hyperthermia for 60 min with a target temperature of 43 degrees C, and radiation therapy 500 cGy/fraction (m edian total dose 3000 cGy) for a total of six weeks. Blood levels of e tanidazole were taken during treatment at week 1 and week 4. Etanidazo le drug exposure was calculated using the trapezoidal rule and express ed as the area under the curve (AUG) of plasma concentration X time. F ive of six treatment sites had received prior irradiation. Prior chemo therapy had been given in three patients and tamoxifen therapy given i n the other two patients. The median follow-up time is 34 months; 3/5 patients have died of disease. The most significant toxicity was grade I or II nausea and vomiting associated with 19/32 treatments (59%) an d a second degree burn in 2/6 fields. None of the five patients experi enced peripheral neuropathy, skin ulceration, or needed surgical repai r. In addition, there was mild renal toxicity; pharmacokinetic analysi s showed a 28-75% increase in the week 1 to week 4 AUC in three patien ts, all of whom had a decrease in creatinine clearance over the same t ime of 15-47%. This pilot study suggests this combined modality therap y can be delivered without major complications and that renal function , determined by creatinine clearance, affects clearance of etanidazole and alters the AUG. Therefore, monitoring renal function is important in patients receiving etanidazole in addition to other nephrotoxic ag ents such as cisplatin. The impact of etanidazole on the therapeutic i ndex of hyperthermia, radiation therapy and cisplatin may be worthy of study, especially since a positive interaction between these modaliti es is found in laboratory models.