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

Abstract

BACKGROUND:

The oral administration of 5-fluorouracil (5-FU) is hindered by erratic bioavailability due to catabolism of 5-FU by the enzyme dihydropyrimidine dehydrogenase (DPD) in the gastrointestinal tract. Eniluracil is a potent inactivator of DPD which results in 100% oral bioavailability of 5-FU. Leucovorin (LV) is another biochemical modulator of 5-FU that potentiates 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 oral 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 were 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 evaluations. 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%). Grade 4 neutropenia occurred in 25 patients (42%), and 18 patients (30%) had Grade 3-4 diarrhea. Twenty-one patients (35%) were hospitalized for toxicity, and 12 (20%) had febrile neutropenia. Baseline creatinine clearance was associated inversely with severe toxicity (P = 0.001).

CONCLUSIONS:

Although antitumor activity was observed, the frequent occurrence of severe toxicity with this regimen limited its clinical utility. Alternate schedules with a more favorable therapeutic index are undergoing clinical testing and should be pursued. The high level of toxicity observed with orally administered low dose 5-FU underscored the potency of eniluracil as a biochemical modulator.

• Authors: N J Meropol, D Niedzwiecki, D Hollis, R L Schilsky, R J Mayer, Cancer and Leukemia Group B
• Journal: Cancer (Cancer) Vol. 91 Issue 7 Pg. 1256-63 (Apr 01 2001) ISSN: 0008-543X [Print] United States
• PMID: 11283924 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2001 American Cancer Society.

Chemical References

• Antimetabolites, Antineoplastic
• Enzyme Inhibitors
• eniluracil
• Uracil
• Oxidoreductases
• Oxidoreductases Acting on CH-CH Group Donors
• Dihydrouracil Dehydrogenase (NAD+)
• Thymidylate Synthase
• Leucovorin
• Fluorouracil

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Antimetabolites, Antineoplastic (administration & dosage, adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Carcinoma (drug therapy, mortality, pathology)
• Colorectal Neoplasms (drug therapy, mortality, pathology)
• Dihydrouracil Dehydrogenase (NAD+)
• Disease Progression
• Enzyme Inhibitors (administration & dosage, adverse effects)
• Female
• Fluorouracil (administration & dosage, adverse effects)
• Humans
• Leucovorin (administration & dosage, adverse effects)
• Male
• Middle Aged
• Oxidoreductases (antagonists & inhibitors)
• Oxidoreductases Acting on CH-CH Group Donors
• Thymidylate Synthase (antagonists & inhibitors)
• Uracil (administration & dosage, adverse effects, analogs & derivatives, pharmacology)