Concomitant radiotherapy and metronomic temozolomide in pediatric high-risk brain tumors

Temozolomide, an oral alkylating agent has a significant activity in preclinical testing and in clinical trials in adults and children as well. Penetration across the blood brain barrier has been documented. In adult and pediatric phase I and II trials a five-day every 28 days schedule was first approved for clinical use. With respect to temozolomide proximal mechanism of resistance, and further to increase dose intensity, new schedules are proposed to use more prolonged drug exposure. Higher doses of metronomic temozolomide were piloted. Eight children with poor prognosis brain tumors were eligible. Treatment consisted from concomitant radiotherapy given 1x170 cGy, 5d/wk, for total dose 55/56 Gy, together with temozolomide 90 mg/m2/day for 42 days. No further dose escalation has been planned for this group of patients. Myelosuppression was the primary toxicity, occurring around day 21. Nonhematologic toxicities were infrequent and in no case dose limiting toxicity (DLT) occurred. The most common nonhematologic toxicity was vomiting, effectively managed with antiemetics. Six responses were documented. The best responses (CR) were seen in 2 patients with high-risk medulloblastomas, who have progressed early after neurosurgery. Furthermore, one more patient had CR and 3 patients PR at the end of temozolomide treatment. We have piloted novel dose schedule of temozolomide and evaluated clinical toxicities in a cohort of 8 children. This is the first study to report feasibility and tolerability of 90 mg/m2/day of temozolomide treatment in metronomic fashion. In addition, we have documented encouraging responses in children with medulloblastomas, progressing early after their initial surgery.