Margaret L. Seager

Intrathecal cytosine arabinoside for the treatment of meningeal metastases from malignant brain tumors and systemic tumors

SummaryThirty-two patients with primary or metastatic neoplasms in the ventricular system or subarachnoid space were treated with intrathecal Ara-C. Twenty patients (group I) were treated with single twice-weekly doses; the mean number of doses was 9.7, and the mean total dosage was 165 mg. Six patients received intrathecal Ara-C alone and 14 received concurrent chemotherapy. All four symptomatic patients showed clinical improvement. Malignant cells disappeared from the spinal fluid of six of the 12 patients with positive pretherapy cerebrospinal fluid (CSF) cytology. Two patients were alive with no evidence of recurrence 8 and 16 weeks after beginning therapy, two patients died without demonstrating evidence of recurrence 8 weeks and 9 weeks after starting therapy, 12 patients had recurrences an average of 13 weeks after beginning treatment, and four patients refused further investigation or treatment and died of disease after 6–52 weeks.Pharmacokinetic studies were performed in eight patients. For five patients who received 12 mg Ara-C by injection into an SC-implanted reservior connected to the ventricular system, the CSF disappearance curve was biphasic with half-times of 30 min and 3.5 h.Based on the results of the pharmacokinetic study, an additional 12 patients (group II) were treated on three consecutive days weekly. The mean number of doses was 9.7 and the mean total dosage was 189 mg. Three patients received intrathecal Ara-C alone and nine received concurrent chemotherapy. One of the five symptomatic patients showed clinical improvement. Malignant cells disappeared from the spinal fluid of two of the four patients with positive pretherapy CSF cytology. Four patients were alive with no evidence of recurrence 3–26 weeks after beginning therapy, two patients died within 10 days of beginning treatment without formal re-evaluation, four patients demonstrated progression of tumor an average of 7 weeks after beginning treatment, and two patients changed to another form of therapy because of persistent CSF abnormalities, although there was no radiographic evidence of tumor progression.There were no clear differences in response between group I and group II; however, the groups were not comparable with respect to pathological diagnosis.Intrathecal Ara-C is a promising and relatively safe treatment for malignant disease in the subarachnoid space. Further studies are needed to determine the optimum dose and administration schedule in combination with other intrathecal therapies that may be more active against noncycling G0 cells.

Improvement in survival produced by sequential therapies in the treatment of recurrent medulloblastoma

Thirty‐six patients with recurrent medulloblastoma were treated with various combination chemotherapy protocols after initial treatment (usually irradiation) failed. Use of systemic chemotherapy was limited by depressed bone marrow reserves secondary to previous craniospinal irradiation. Intraventricular and intrathecal therapies included cytosine arabinoside (Ara‐C), methotrexate, and thio‐tepa given as single agents. Major systemic agents used alone or in combination included CCNU, procarbazine, vincristine, and the hexitol epoxides. Patients were reirradiated with or without misonidazole when there was definite tumor progression after all other therapies failed and/or because myelosuppression was so severe that further chemotherapy was not possible. Sequential systemic or intrathecal chemotherapy and reirradiation produced median survivals of two years and 25% quartile survivals of 2.9 years. The prognosis for patients harboring recurrent medulloblastoma has improved considerably over the years because of the therapeutic approaches reported here.

Intrathecal Chemotherapy for Leptomeningeal Dissemination of Medulloblastoma

Cerebrospinal fluid dissemination of medulloblastoma occurs despite adequate systemic chemotherapy, and unless it is present at the time of initial diagnosis, occurs late in the course of the disease. Intrathecal chemotherapy with an implanted Ommaya reservoir can produce short-term benefit. We report here our protocol for and the results of intrathecal chemotherapy for leptomeningeal dissemination of medulloblastoma.