Continuous intrathecal administration of 5-fluoro-2'-deoxyuridine for the treatment of neoplastic meningitis.

OBJECTIVE: Previously, we reported a good clinical treatment effect of intrathecal chemotherapy by repeated bolus administration of 5-fluoro-2'-deoxyuridine (FdUrd) for neoplastic meningitis (NM). Moreover, we detected no side effects or neurotoxicity despite the long-term repetition of intrathecal administration. On the basis of these findings, continuous intrathecal chemotherapy (CIC) with FdUrd for patients with NM was attempted using a simple pump system. We evaluated the usefulness of CIC with FdUrd for the treatment of NM. METHODS: A total of 25 patients were enrolled in this study. FdUrd (1.0 mg/d) was administered using a balloon pump system. CIC was continued as long as possible. Eight patients received whole-brain irradiation (3 Gy x 10) simultaneously with CIC. The effects of the treatment were analyzed in terms of improvement in neurological signs and symptoms and the findings of ventricular and lumbar cerebrospinal fluid analysis 2 and 4 weeks after CIC was initiated and on magnetic resonance imaging scans 2 months after CIC began. RESULTS: No apparent toxicity has been observed to date. Evidence of a cerebrospinal fluid response was observed in 13 patients. Headache and nausea were improved in all patients, and cranial nerve impairment was improved in 12 patients. A magnetic resonance imaging response was observed in only 5 patients. Overall response was observed in 15 patients when cases of stable disease were excluded from the responding cases. Survival time from the commencement of CIC (mean +/- standard error of the mean) was 255 +/- 30 days in 25 patients. CONCLUSION: This therapy may be useful, especially as a maintenance therapy for NM.

Passage of 5'-dFUrd and its metabolites 5-FU and 5-FUH2 to CSF in a clinical phase 1 study.

Lumbar puncture was performed on eight patients in a clinical Phase 1 study of doxifluridine (5'-dFDrd). 5'-dFUrd, 5'FU, and 5-FUH2 were shown to cross the blood-brain barrier to CSF. The maximal concentrations of 5'-dFUrd and 5-FUH2 were about 1-3% of the maximal concentrations in plasma, and were reached within 1-4 h after the end of iv infusion of 5'-dFUrd. 5-FUH2 showed a marked increase in CSF between 3 and 4 h to about 40-60% of the maximal plasma concentration in 5 of the patients, indicating a possible further increase after 4 h. The relationship between the concentrations of 5'-dFUrd and its metabolites in the CSF, and CNS toxicity is discussed.