Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis.
OBJECTIVE
To evaluate the pharmacokinetics and toxicity of high-dose intravenous (i.v.) methotrexate (MTX) with leucovorin in patients with meningeal carcinomatosis.


METHODS
Of 16 eligible patients entered on this study, 13 with meningeal carcinomatosis from breast cancer, lung cancer, or osteosarcoma were treated with MTX at loading doses of 200-1500 mg/m2, followed by a 23-h infusion of 800-6000 mg/m2. Three patients without meningeal disease were also treated and the cerebrospinal fluid (CSF) MTX concentrations were compared in patients with and without central nervous system (CNS) disease.


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 microM). The CSF MTX concentrations correlated better with the free and the total plasma MTX concentrations than with the doses. The mean half-life of CSF MTX was 8.7 +/- 3.4 h. The mean plasma clearance of MTX was not significantly different in patients with CNS disease (84 +/- 41 ml/min per m2) versus without CNS disease (59 +/- 38 ml/min per m2). All toxicities were grade 2 or less except grade 3 hematologic toxicity. No patient had an objective response in the CSF.


CONCLUSIONS
This trial demonstrates that potentially cytotoxic CSF MTX concentrations (> 1 microM) are delivered safely by i.v. infusion, a less invasive and better distributed CSF therapy compared with intrathecal MTX. Because of the excellent pharmacokinetics and toxicity, high-dose i.v. MTX should be evaluated at a loading dose of 700 mg/m2 and a 23-h infusion of 2800 mg/m2 with leucovorin in less heavily pretreated patients with carcinomatous meningitis.
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
M L
ML
Tetef
K A
KA
Margolin
J H
JH
Doroshow
S
S
Akman
L A
LA
Leong
R J
RJ
Morgan
J W
JW
Raschko
N
N
Slatkin
G
G
Somlo
J A
JA
Longmate
M I
MI
Carroll
E M
EM
Newman
D000328:Adult; D001943:Breast Neoplasms / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000473:pathology; D008297:Male; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000473:pathology
D002955:Leucovorin; D008727:Methotrexate