5-fluorouracil and methotrexate administered simultaneously as a continuous infusion. A phase I study

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Abstract
Infusion delivery systems have been evaluated for administration of many individual chemotherapeutic agents including 5‐fluorouracil (5‐FU) and methotrexate (MTX). This study combined the two drugs as an admixture, and in a Phase I trial design established a useful dose schedule for each of the component drugs. 5‐FU at a fixed dose rate of 300 mg/M2/day was delivered with methotrexate (MTX) at four different dose rates (0.75, 1.0, 1.5, or 2.0 mg/M2/day, respectively). The drug solution was delivered via a subclavian venous access with a portable infusion pump in an ambulatory setting. Twenty‐nine patients received a total of 38 courses of the two‐drug infusion: 21 courses were delivered with the two agents admixed constanty throughout treatment (Schedule A) and 17 were administered the treatment with 5‐FU delivered continuously and MTX added to the 5‐FU for alternate 14‐day cycles (Schedule B). For the former schedule, dose‐rate‐limiting toxicity was related to MTX and included stomatitis developing at days 8 to 14 (median, day 8) with the higher dose rates (1.5‐2.0 mg/M2/day) and thrombocytopenia developing at days 11 to 56 (median, day 14) at the lowest dose rates (1.0 mg/M2/day). For Schedule B, dose‐rate‐limiting toxicity was similarly due to the MTX with thrombocytopenia and/or chemical hepatitis developing in six of seven courses of MTX at 1.0 mg/M2/day and in five of ten courses delivered at 0.75 mg/M2/day. On Schedule B the MTX‐associated toxicities were reversed when the MTX administration was interrupted and in the face of continued 5‐FU infusion. A reasonable dose rate and schedule for continuous infusion of 5‐FU combined with MTX is: 5‐FU 300 mg/M2/day × 28 days and MTX 0.75 mg/M2/day for days 1 to 14, with cycles administered consecutively each 28 days.