Fluorouracil modulation in colorectal cancer: Lack of improvement with N-phosphonoacetyl-l-aspartic acid or oral leucovorin or interferon, but enhanced therapeutic index with weekly 24-hour infusion schedule an Eastern Cooperative Oncology Group/Cancer and leukemia group B study

P. J. O'Dwyer*, J. Manola, F. H. Valone, L. M. Ryan, J. D. Hines, S. Wadler, D. G. Haller, S. G. Arbuck, L. M. Weiner, R. J. Mayer, Al B. Benson

*Corresponding author for this work

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Purpose: To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer. Patients and Methods: Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m2 by 24-hour infusion, weekly; arm B, N-phosphonoacetylI-aspartic acid 250 mg/m2 day I, 5-FU 2,600 mg/m2 by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m2 with oral leucovorin (LV) 125 mg/m2 hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m2 with intravenous (IV) LV 600 mg/m2, weekly; arm E, 5-FU 750 mg/m2/d IV by continuous infusion for 5 days, then 750 mg/m2 weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years. Results: Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of ali the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P < .001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly. Conclusion: We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.

Original languageEnglish (US)
Pages (from-to)2413-2421
Number of pages9
JournalJournal of Clinical Oncology
Volume19
Issue number9
DOIs
StatePublished - May 1 2001

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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