Thiotepa and etoposide treatment of recurrent malignant gliomas : phase I study

To determine: (1) the maximum tolerable dose (MTD) of thiotepa (TT) that can be administered with etoposide without stem cell support; (2) whether this regimen is active against recurrent malignant gliomas. Although several chemotherapeutic agents show minor activity against recurrent brain tumors, there is no consensus about the most effective regimen. The alkylating agent TT has excellent central nervous system (CNS) penetration and is synergistic with the topoisomerase II inhibitor etoposide. Fifteen patients with recurrent malignant gliomas (14 glioblastomas, 1 anaplastic astrocytoma) received intravenous etoposide 100 mg/m2 on days 1, 2, and 3, and intravenous TT (40, 50, 60, or 70 mg/m2) on day 2. All had received irradiation, and eight BCNU. Chemotherapy was repeated every 3-4 weeks, with stepwise TT dose increments of 10 mg/m2, provided toxicity was less than grade III. The major toxicity was dose-limiting leukopenia. The MTD of TT in cycle 1 was 60 mg/m2. All patients died of progressive disease and none died of chemotherapy-related complications. The MTD of TT in this regimen for recurrent malignant gliomas is 60 mg/m2. Higher doses of TT would require colony-stimulating factors or stem cell support.