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Clinical Trials and Pharmacokinetics of Intermittent High-Dose Methotrexate-"Leucovorin Rescue" for Children with Malignant Tumors¹

St. Jude Children's Research Hospital, Memphis, Tennessee 38101

Methotrexate, 50 to 500 mg/kg, was infused i.v. in 6 hr into children with metastatic neoplasms. three hr after termination of drug infusion, leucovorin (N⁵-formyltetrahydrofolate) administration was initiated and continued at 3-hr intervals throughout the following 24 hr. A total dose equivalent to 5 or 10% by weight of the methotrexate dosage was administered. At termination of drug infusion, serum levels ranged between 71 and 727 µg of methotrexate per ml with drug dosages of 100 and 500 mg per kg, respectively. The mean half-life ± 1 standard deviation of serum methotrexate was 157 ± 31 min. Urinary excretion during the 6 hr of drug infusion ranged between 35 and 53% of the administered dose. Ninety-five % of the drug was excreted in the first 30 hr after initiation of the drug infusion. Transient disappearance or reduction of tumor size was observed for 3 of 9 patients treated at 2- or 3-week intervals with a total of 31 infusions. Hematopoietic depression was minimal. Transient elevations of serum glutamic-oxaloacetic transaminase followed 18 infusions, and evidence of abnormal renal function was observed after 8 infusions. Therapeutic response in 1 patient with rhabdomyosarcoma and 1 patient with osteosarcoma indicates a need to screen the sensitivity of other childhood tumors to high-dose methotrexate therapy plus leucovorin rescue.

¹ Supported by USPHS Cancer Research Center Grant CA-08480, Research Project Grants CA-11148 and CA-12732 from the National Cancer Institute, and American Lebanese Syrian Associated Charities.

Received 11/ 5/73. Accepted 9/ 9/74.

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