A phase II evaluation of thiotepa in pediatric central nervous system malignancies

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Abstract
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 those in olasma. This provides a strong rationale for testing this agent against brain tumors. Methods. Sixty pediatric patients with recurrent primary brain tumors were treated on a multiinstitutional Phase II study of intravenous thiotepa at a dose of 5 mg/m2 administered every 3 weeks. This dose is the result of a prior pediatric Phase I trial and is significantly higher than those previously recommended. Results. Three of 13 assessable patients with medul‐oblastoma had partial responses lasting 22, 25, and 54 weeks. Although no objective responses were observed in 6 assessable patients with malignant gliomas and 14 with brain stem gliomas, 5 of 16 and 4 of 14 patients in elese respective strata had prolonged periods of stable isease (SD) lasting from 12 to more than 33 weeks. Nine ssessable patients with ependymoma had no objective esponse, but two had SD, both for more than 33 weeks. Myelosuppression was the principle toxic effect encoun‐ered and appeared to be more severe in patients who had received prior craniospinal radiation therapy or nitro‐urea therapy. Conclusions. By conventional Phase II criteria, thiotepa appears to have activity in medulloblastoma. Based on several patients with prolonged SD, it also may possess some limited 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 rescue may be associated with an improved response rate to this agent. Cancer 1993; 72:271–5.