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A Clinical and Pharmacological Study of High-Dose Methotrexate with Minimal Leucovorin Rescue¹

Department of Medicine, Roger Williams General Hospital, Brown University Program in Medicine, Providence, Rhode Island 02908

Forty patients with advanced neoplasms received 118 infusions of high-dose methotrexate (MTX) for 18 hr. The dosage of MTX was varied between 800 and 1350 mg/sq m in an effort to achieve a standard peak plasma concentration of 5 x 10^–5 M. Three doses of leucovorin were given i.v. at Hr 30, 36, and 42 following the start of the MTX infusion. Leucovorin dosages were individualized based upon each patient's plasma MTX clearance. Early (18- and 24-hr) plasma MTX determinations were used to project a 36-hr concentration; then, assuming that equivalent doses of MTX and leucovorin give rise to comparable peak plasma levels, the leucovorin dose was calculated so as to give a plasma concentration of reduced folate 10-fold higher than the projected 36-hr plasma MTX concentration. Late (30-, 36-, 42-, and 48-hr) plasma MTX levels were measured in order to confirm expected concentrations based upon 18- and 24-hr determinations. Three general patterns of MTX plasma clearance were noted. In 110 of 118 infusions, plasma MTX clearance was rapid (mean t_1/2, 2.2 hr), leucovorin doses were minimized (median dose, 8.0 mg/sq m), and the incidence of significant myelosuppression (WBC, 2,000 and/or platelets, 50,000) was 2.7%. In five infusions, plasma MTX clearance was delayed from the onset (mean t_1/2, 6.4 hr), calculated leucovorin doses were high (median dose, 220 mg/sq m), and myelosuppression was seen in one of five infusions despite the initiation of prolonged administration of "high-dose" leucovorin rescue (50 to 100 mg/sq m i.v. every 6 hr). In the remaining three infusions, late MTX levels, when measured experimentally, deviated from projected concentrations based upon actual early plasma MTX determinations. Again, "high-dose" leucovorin was begun following the usual three protocol leucovorin doses, and myelosuppression did not occur.

The clinical feasibility of limiting doses of leucovorin rescue based upon plasma MTX clearance, without resulting excessive toxicity, has been demonstrated. The majority of patients (seven of eight) with delayed clearance of antifol were rescued clinically with "high-dose" leucovorin. Minimization of leucovorin rescue doses in an attempt to improve the therapeutic effectiveness of "high-dose" MTX chemotherapy should be further tested in future clinical protocols.

¹ Supported by National Cancer Institute Grant 5P30 CA 13943, RR 05765.

² To whom requests for reprints should be addressed, at Department of Medicine, Roger Williams General Hospital, 825 Chalkstone Avenue, Providence, R. I. 02908.

Received 9/ 5/78. Accepted 12/ 1/78.