PTCT-05CHEMOTHERAPY ADMINISTRATION DIRECTLY INTO THE FOURTH VENTRICLE IN CHILDREN WITH MALIGNANT FOURTH VENTRICULAR BRAIN TUMORS: A PILOT CLINICAL TRIAL

Abstract

BACKGROUND: We hypothesize that chemotherapy can be safely and repeatedly administered directly into the fourth ventricle to treat recurrent malignant brain tumors in children. METHODS: For the first time in humans, methotrexate was infused into the fourth ventricle in children with recurrent, malignant brain tumors. A catheter was surgically placed into the fourth ventricle under direct visualization and attached to a ventricular access device. Cerebrospinal fluid (CSF) flow was confirmed by CINE MRI postoperatively. Each cycle consisted of 4 consecutive daily methotrexate infusions (2 milligrams). Disease response was monitored with serial MRI scans and CSF cytologic analysis. Trough CSF methotrexate levels were sampled. RESULTS: Five patients (3 with medulloblastoma and 2 with ependymoma) received 18, 18, 12, 9, and 3 cycles, respectively. There were no serious adverse events or new neurological deficits attributed to methotrexate. Two additional enrolled patients were withdrawn prior to planned infusions due to rapid disease progression. Median serum methotrexate level four hours after infusion was 0.04 micromoles per liter (µmol/L). Range was 0.02–0.13 µmol/L. Median trough CSF methotrexate level 24 hours after infusion was 3.18 µmol/L (range 0.53 - 212.36 µmol/L). All three patients with medulloblastoma had partial response or stable disease until one patient had progressive disease after cycle 18. Both patients with ependymoma had progressive disease after 9 and 3 cycles, respectively. CONCLUSIONS: These data establish the safety of neurosurgical implantation of a catheter into the fourth ventricle and direct infusion of low-dose methotrexate into the fourth ventricle. Some patients with recurrent medulloblastoma experience a beneficial anti-tumor effect both within the fourth ventricle and at distant sites. These results support future clinical trials of direct infusion of chemotherapy and novel agents into the fourth ventricle for children with malignant posterior fossa tumors.