Clinical and Pharmacological Studies of Methotrexate-Minimal Leucovorin Rescue plus Fluorouracil1

The sequential combination of methotrexate (MTX) followed by 5-fluorouracil (5-FUra) was evaluated. We treated 26 pa tients with 101 courses of high-dose MTX and minimal leucovorin rescue plus 5-FUra. MTX, 1.0 g/sq m, was administered as an 18-hr infusion. Three doses of leucovorin were given i.v. at Hours 30, 36, and 42 following the start of the MTX infusion. Leucovorin dosages were individualized based upon the plasma MTX clearance of each patient. 5-FUra, 600 mg/sq m, was given as a rapid i.v. bolus at Hour 9 after the start of the MTX infusion. The 5-FUra administration time was later changed to Hour 20, 2 hr following the completion of the MTX infusion, in order to more closely approximate effective preclinical sequencing schedules. The 5-FUra was escalated to 1000 mg/sq m but was subsequently reduced to 800 mg/sq m because of unacceptable toxicity at the highest dose. The addition of 5-FUra to this high-dose MTX regimen did not alter MTX pharmacokinetics or leucovorin requirements. Median values for peak plasma MTX concentration, plasma MTX half-life, and leucovorin dose did not differ significantly for each 5-FUra schedule. Ninety-four (93%) infusions were associated with rapid clearance, and seven (7.0%) were as sociated with delayed MTX clearance. The incidence and severity of toxicity, particularly myelosuppression, were best related to the 5-FUra dose rather than to MTX pharmacokinetics. Seven (58.3%) infusions at a 5-FUra dose of 1000 mg/sq m resulted in severe toxicity. When the 5FUra dose was decreased to 800 mg/sq m, severe toxicity occurred with only 2 of 11 infusions (18.1%). One complete response and one partial response were ob served. There were two treatment-related deaths. The clinical feasibility of incorporating 5-FUra in doses <800 mg/sq m into a sequential regimen with high-dose MTX and minimal leucovorin rescue has been demonstrated. Further clinical trials to determine the optimum MTX dose and timing of 5-FUra administration are warranted.