Pharmacokinetics and toxicity of high-dose intravenous methotrexate in thetreatment of leptomeningeal carcinomatosis

Purpose: To evaluate the pharmacokinetics and toxicity of high-dose intrave nous (i.v.) methotrexate (MTX) with leucovorin in patients with meningeal c arcinomatosis. Methods: Of 16 eligible patients entered on this study, 13 w ith meningeal carcinomatosis from breast cancer, lung cancer, or osteosarco ma were treated with MTX at loading doses of 200-1500 mg/m(2), followed by a 23-h infusion of 800-6000 mg/m(2). Three patients without meningeal disea se were also treated and the cerebrospinal fluid (CSF) MTX concentrations w ere compared in patients with and without central nervous system (CNS) dise ase. Results: Patients without CNS disease had lower CSF MTX concentrations relative to the plasma MTX levels than those with CNS disease, who all had CSF MTX concentrations above the target cytotoxic concentration (1 mu M) T he CSF MTX concentrations correlated better with the free and the total pla sma MTX concentrations than with the doses. The mean half-life of CSF MTX w as 8.7 +/- 3.4 h. The mean plasma clearance of MTX was not significantly di fferent in patients with CNS disease (84 +/- 41 ml/min per m(2)) Versus wit hout CNS disease (59 +/- 38 ml/min per m(2)). All toxicities were grade 2 o r less except grade 3 hematologic toxicity. No patient had an objective res ponse in the CSF. Conclusion: potentially cytotoxic This trial demonstrates that CSF MTX concentrations (>1 mu M) are delivered safely by i.v. infusio n, a less invasive and better distributed CSF therapy compared with intrath ecal MTX. Because of the excellent pharmacokinetics and toxicity, high-dose i.v. MTX should be evaluated at a loading dose of 700 mg/m(2) and a 23-h i nfusion of 2800 mg/m(2) with leucovorin in less heavily pretreated patients with carcinomatous meningitis.