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Phase I and Pharmacokinetic Trial of Weekly Oral Fluorouracil Given With Eniluracil and Low-Dose Leucovorin to Patients With Solid Tumors

From the Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Naval Medical Center; Hematology/Oncology Section, Department of Internal Medicine, National Naval Medical Center; and Department of Radiology, National Naval Medical Center, Bethesda, MD.

Address reprint requests to Jean Grem, MD, National Cancer Institute–Medicine Branch, National Naval Medical Center, 8901 Wisconsin Ave, Bldg 8, Rm 5101, Bethesda, MD 20889; email jgrem{at}helix.nih.gov

PURPOSE: Fluorouracil (5-FU) given as a weekly, high-dose 24-hour infusion is active and tolerable. We evaluated an oral regimen of eniluracil (which inactivates dihydropyrimidine dehydrogenase [DPD]), 5-FU, and leucovorin to simulate this schedule.

PATIENTS AND METHODS: Patients received a single 24-hour infusion of 5-FU (2,300 mg/m² on day 2) with leucovorin (15 mg orally [PO] bid on days 1 through 3) to provide reference pharmacokinetic data. Two weeks later, patients began treatment with eniluracil (20 mg) and leucovorin (15 mg) (PO bid on days 1 through 3) and 5-FU (10 to 15 mg/m² PO bid on day 2).

RESULTS: Dose-limiting toxicity (diarrhea, neutropenia, and fatigue) was seen with 5-FU 15 mg/m² PO bid on day 2 given weekly for either 6 of 8 weeks or 3 of 4 weeks, whereas five of seven patients tolerated 5-FU 10 mg/m² PO bid given weekly for 3 of 4 weeks. Eniluracil led to a 35-fold reduction in 5-FU clearance. Fluoro-beta-alanine, a 5-FU catabolite, was not detected in plasma during oral 5-FU–eniluracil therapy. DPD activity was markedly suppressed in all patients during eniluracil therapy; the inactivation persisted after the last eniluracil dose; percentages of baseline values were 1.8% on day 5, 4.5% on day 12, and 23.6% on day 19.

CONCLUSION: The recommended oral dosage of 5-FU (10 mg/m² PO bid) given with eniluracil and leucovorin is approximately 115-fold lower than the reference dosage for 24-hour infusional 5-FU. This difference is greater than expected given the reduction in 5-FU clearance. DPD inactivation persisted for several weeks after completion of eniluracil therapy.

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