Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: results of a randomized trial in patients with advanced colorectal cancer

J Clin Oncol. 1998 Feb;16(2):418-26. doi: 10.1200/JCO.1998.16.2.418.


Purpose: To determine whether high-dose infusional fluorouracil (FU) is effectively modulated by leucovorin (LV), interferon (IFN) alpha-2b, or both when given to patients with metastatic colorectal cancer.

Patients and methods: Patients (n = 236) with progressive, measurable disease were randomized to three groups and received FU 2,600 mg/m2 as a 24-hour continuous infusion (CI) weekly for 6 weeks with 2 weeks rest (FU24h) and LV 500 mg/m2 as a 2-hour infusion before FU or IFN 3 x 10(6) U subcutaneously 3 times weekly or both. Treatment continued until progressive disease or unacceptable toxicity was observed. Pairs of treatment arms were analyzed sequentially to detect equivalence or a 25% difference in response rates.

Results: The rate of objective remission in patients who received FU24h/LV (44%; 40 of 91) was significantly higher than in patients who received FU24h/IFN (18%; 16 of 90; P < .05). The response rates of patients who received FU24h/LV versus FU24h/LV/IFN (27%; 13 of 49) were statistically equivalent. Significant differences were observed for time to tumor progression (TTP) (FU24h/LV, 7.1 months; FU24h/IFN, 3.9 months; FU24h/LV/IFN, 6.3 months; global P value < .009) and survival (16.6 months, 12.7 months, 19.6 months, respectively; global P value < .04). Unpredictable and life-threatening toxicity in the FU24h/LV/IFN arm required dose reduction of FU to 2,000 mg/m2/day and early stoppage of this arm. Toxicity was manageable in patients who received both FU24h/LV (grade 3 to 4 diarrhea, 21%) and FU24h/IFN (grade 3 to 4 diarrhea, 15%).

Conclusion: Response rate, TTP, and overall survival were superior for LV-containing regimens compared with IFN modulation alone. The addition of IFN to high-dose infusional FU plus LV offers no advantage and may increase toxicity. The regimen of high-dose infusional FU24h/LV warrants further evaluation in patients with metastatic colorectal cancer.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / administration & dosage*
  • Antimetabolites, Antineoplastic / adverse effects
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Disease Progression
  • Drug Administration Schedule
  • Female
  • Fluorouracil / administration & dosage*
  • Fluorouracil / adverse effects
  • Humans
  • Immunologic Factors / administration & dosage*
  • Infusions, Intravenous
  • Interferon alpha-2
  • Interferon-alpha / administration & dosage
  • Leucovorin / administration & dosage*
  • Male
  • Middle Aged
  • Prospective Studies
  • Recombinant Proteins
  • Survival Rate


  • Antimetabolites, Antineoplastic
  • Immunologic Factors
  • Interferon alpha-2
  • Interferon-alpha
  • Recombinant Proteins
  • Leucovorin
  • Fluorouracil