Summary
A total of 27 patients with leptomeningeal neoplasia were treated with the water-soluble nitrosourea ACNU given intraventricularly or intrathecally in a phase I/II study. Patients were entered in the study if they showed evidence of either a positive CSF cytology or neurodiagnostic evidence of leptomeningeal disease, or both. Patients were evaluated for toxicity and efficacy; additionally, in 13 patients ACNU pharmacokinetic studies were carried out. A variety of tumor types were represented in the study group, including primary and metastatic CNS tumors. Toxicity was mild and included pain at the injection site (four patients), transient radicular symptoms at a short distance from the injection site (three patients), and nausea and vomiting (one patient). No myelotoxicity was seen. Of 21 patients who presented with positive cytology, 8 (38%) had a conversion from positive to negative cytology, with a range of response durations from 1 to 20+ months. Of the remaining six patients with negative cytology but other neurodiagnostic evidence of leptomeningeal disease, one patient showed an improvement seen on the myelogram and one underwent a brief reduction in CSF protein. ACNU elimination from the ventricular system is rapid, with a beta slope of 0.028 min-1 and a computed elimination constant, Ko, of 13 min. The mean clearance was 3.8 ml/min (range, 1.0–6.2 ml/min). Peak ACNU levels varied between 108 and 620 μg/ml, with the AUC being 1.4–14.7 mg·min/ml. The total dose of ACNU given was between 9 and 104 mg, and the single dose range was 4–16.5 mg. We conclude that ACNU can be given safely with minimal toxicity as intra-CSF therapy, that it demonstrates efficacy in some patients with leptomeningeal disease, and that further studies are warranted to evaluate more fully alternative dosing and drug delivery approaches.
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Levin, V.A., Chamberlain, M., Silver, P. et al. Phase I/II study of intraventricular and intrathecal ACNU for leptomeningeal neoplasia. Cancer Chemother. Pharmacol. 23, 301–307 (1989). https://doi.org/10.1007/BF00292408
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DOI: https://doi.org/10.1007/BF00292408