Phase II study of oral eniluracil, 5-fluorouracil, and leucovorin in patients with advanced colorectal carcinoma

BACKGROUND. The oral administration of 5-fluorouracil (5-FU) is hindered by erratic bioavailability due to catabolism of 5-FU by the enzyme dihydropyr imidine dehydrogenase (DPD) in the gastrointestinal tract. Eniluracil is a potent inactivator of DPD which results in 100% oral bioavailability of 5-F U. Leucovorin (LV) is another biochemical modulator of 5-FU that potentiate s inhibition of thymidylate synthase, the primary target of 5-FU. The goal of this study was to determine the antitumor activity and toxicity of an or al regimen containing eniluracil, 5-FU, and LV in patients with colorectal carcinoma. METHODS. Sixty eligible patients who had previously untreated, measurable, metastatic colorectal carcinoma were treated with oral eniluracil 50 mg on Days 1-7, 5-FU 20 mg/m(2) on Days 2-6, and LV 50 mg on Days 2-6. Cycles wer e repeated at 28-day intervals. RESULTS. The overall response rate was 13% (95% confidence interval [CI] = 6, 25%), with 1 complete response and 7 partial responses. Three additional patients had partial responses that were not confirmed at subsequent evalu ations. The median time to progression of disease was 4.4 months (95% CI = 3.45, 7.69) and the median survival time was 12.6 months (95% CI = 9.1, 14. 75). Grade 3-5 toxicity (1 toxic death) occurred in 51 patients (85%). Grad e 4 neutropenia occurred in 25 patients (42%), and 18 patients (30%) had Gr ade 3-4 diarrhea. Twenty-one patients (35%) were hospitalized for toxicity, and 12 (20%) had febrile neutropenia. Baseline creatinine clearance was as sociated inversely with severe toxicity (P = 0.001). CONCLUSIONS. Although antitumor activity was observed, the frequent occurre nce of severe toxicity with this regimen limited its clinical utility. Alte rnate schedules with a more favorable therapeutic index are undergoing clin ical testing and should pursued. The high level of toxicity observed with o rally administered low dose 5-FU underscored the potency of eniluracil as a biochemical modulator. (C) 2001 American Cancer Society.