Oral topotecan in children with recurrent or progressive high-grade glioma: A Phase I/II study by the German Society for pediatric oncology and hematology

BACKGROUND Continuous oral treatment with topotecan may be more effective than the typical 1-day and 5-day treatment schedules. In previous studies of continuous treatment with topotecan, increased intestinal side effects were reported in adult patients; however, the experience in pediatric patients and patients with high-grade glioma is quite limited. METHODS Thirty-two pediatric patients with recurrent high-grade glioma (16 females and 16 males; median age, 9.5 years) were enrolled in the current Phase I/II study. Tumor locations included the cerebral cortex (n = 5), pons (n = 18), and other sites (n = 9). An injectable formulation of topotecan was administered orally, in ice-cold orange juice, once daily. The starting dose of 0.4 mg/m2 per day was escalated on a patient-by-patient basis. At each patient's maximum dose, blood samples were obtained for the determination of plasma hydroxytopotecan and topotecan lactone concentrations and for the calculation of pharmacokinetic quantities. RESULTS The toxicity criteria for a maximum tolerated topotecan dose were met in only 19 patients. The primary toxicity type was hematologic. The median maximum tolerated dose was 0.9 mg/m2 per day (n = 19). The calculated maximum total plasma topotecan concentration was 3.8 ng/mL (n = 7), with an area under the concentration-time curve of 38.4 ng · hours/mL and a half-life of 4.1 hours, which would result in the complete disappearance of topotecan from the plasma after 12 hours. Objective responses were observed in 2 of 13 evaluable patients and lasted for 2.5 and 9 months, respectively (continuous clinical remission, 1 of 14 patients; partial response, 2 of 14 patients; stable disease, 7 of 14 patients; progressive disease, 4 of 14 patients). CONCLUSIONS Oral topotecan (median dose, 0.9 mg/m2 per day) administered once daily was well tolerated and somewhat effective in children with recurrent high-grade glioma. A schedule in which the daily dose is split so that dosing is performed twice daily may be superior to the current schedule. Cancer 2004. © 2004 American Cancer Society.