A PHASE-II EVALUATION OF THIOTEPA IN PEDIATRIC CENTRAL-NERVOUS-SYSTEMMALIGNANCIES

Background. Both thiotepa and its active metabolite, tepa, efficiently cross the blood-brain barrier. After intravenous administration, the cerebrospinal fluid concentrations achieved are nearly identical to th ose in plasma. This provides a strong rationale for testing this agent against brain tumors. Methods. Sixty pediatric patients with recurren t primary brain tumors were treated on a multiinstitutional Phase II s tudy of intravenous thiotepa at a dose of 65 mg/m2 administered every 3 weeks. This dose is the result of a prior pediatric Phase I trial an d is significantly higher than those previously recommended. Results. Three of 13 assessable patients with medulloblastoma had partial respo nses lasting 22, 25, and 54 weeks. Although no objective responses wer e observed in 16 assessable patients with malignant gliomas and 14 wit h brain stem gliomas, 5 of 16 and 4 of 14 patients in these respective strata had prolonged periods of stable disease (SD) lasting from 12 t o more than 33 weeks. Nine assessable patients with ependymoma had no objective response, but two had SD, both for more than 33 weeks. Myelo suppression was the principle toxic effect encountered and appeared to be more severe in patients who had received prior craniospinal radiat ion therapy or nitrosourea therapy. Conclusions. By conventional Phase II criteria, thiotepa appears to have activity in medulloblastoma. Ba sed on several patients with prolonged SD, it also may possess some li mited activity in brain stem and malignant gliomas. The steep in vitro dose-response curve of thiotepa and the long durations of response or SD observed with the dose reported here suggest that moderate-dose to high-dose thiotepa with cytokine support or autologous bone marrow re scue may be associated with an improved response rate to this agent.