PHASE-I STUDY OF ETANIDAZOLE AND RADIOTHERAPY IN MALIGNANT GLIOMA

Purpose: To determine the maximum tolerable total dose (MTD) of etanid azole (ETA) when administered with external beam radiotherapy (XRT) an d as a continuous infusion during stereotactic brachytherapy for patie nts with malignant glioma (anaplastic astrocytoma or glioblastoma mult iforme or mixed cell tumors). Methods and Materials: Seventy previousl y untreated patients were entered in a Phase I study. Prior to initiat ion of treatment, patients were stratified according to whether or not they were candidates for interstitial implantation. The implant patie nts (IMP, n = 17 pt) received accelerated fractionation XRT 20 Gy BID (6 h apart) to 40 Gy in 2 weeks with ETA 2 gm/m(2) X 6 doses, a 2 week break and then interstitial implant to 50 Gy (4-7 days) with a contin uous infusion of ETA over 90-96 h. The two sequentially conducted noni mplant arms started with accelerated fractionation XRT 2 Gy BID (6 h a part) to 40 Gy in 2 weeks with ETA 2 gm/m(2) X 4-5 doses/week. NonIMP 1 arm (n = 38) received a 2-week break before standard fractionated bo ost XRT of 20 Gy/day for 2 weeks to a total dose of 60 Gy with ETA. No nIR4P 2 arm (n = 14) did not have the 2-week break. All patients had p lasma pharmacokinetic monitoring of ETA. Results: The dose-limiting to xicity (DLT) in the IMP group was the cramping/arthralgia syndrome (4) and the cumulative MTD was 26 gm/m(2). For both nonIMP 1 and 2 the DL Ts were peripheral neuropathy and the cramping-arthralgia syndrome. Th e MTD for nonIMP 1 was 34 gm/m(2) and nonTMP 2, 30 gm/m(2). Conclusion : The clinical efficacy and radiation-related toxicity of these regime ns are being evaluated. The doses of ETA that can be used with acceler ated fractionation and with external beam irradiation plus brachythera py have been established.