The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group

J Clin Oncol. 1989 Oct;7(10):1419-26. doi: 10.1200/JCO.1989.7.10.1419.


A total of 343 patients with previously untreated metastatic measurable colorectal carcinoma were studied to evaluate the impact on toxicity, response, and survival of leucovorin-modulated fluorouracil (5-FU). A maximally tolerated intravenous bolus loading course regimen of 5-FU alone (500 mg/m2 x 5 days every 4 weeks with 25 mg/m2 escalation) was compared with a high-dose leucovorin regimen (600 mg/m2 of 5-FU with 500 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest) and with a similar low-dose leucovorin regimen (600 mg/m2 of 5-FU with 25 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest). The dose-limiting toxicity for the two 5-FU and leucovorin regimens was gastrointestinal, specifically diarrhea; severe diarrhea was seen frequently, and treatment-related toxicity was implicated in the demise of 11 of the patients (5%). Significant improvements in response rates were observed with a response rate of 33 of 109 (30.3%) on the high-dose leucovorin regimen (P less than .01 v control); 13 of 107 (12.1%) on the 5-FU control; and 21 of 112 (18.8%) on the low-dose leucovorin regimen. A trend toward longer survival in the 5-FU plus high-dose leucovorin regimen was observed. In this study, leucovorin was shown to significantly enhance the therapeutic effect of 5-FU in metastatic colorectal carcinoma.

Publication types

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

MeSH terms

  • Aged
  • Clinical Trials as Topic
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / mortality
  • Drug Administration Schedule
  • Drug Interactions
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / metabolism
  • Fluorouracil / therapeutic use*
  • Humans
  • Leucovorin / administration & dosage
  • Leucovorin / metabolism
  • Leucovorin / therapeutic use*
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / secondary*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / secondary*
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local / drug therapy
  • Prospective Studies
  • Random Allocation


  • Leucovorin
  • Fluorouracil