The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: results of a phase III trial. Swiss Group for Clinical Cancer Research (SAKK)

Ann Oncol. 1998 May;9(5):535-41. doi: 10.1023/a:1008270916325.


Purpose: A wide variety of fluorouracil (FU)-plus-leucovorin (LV) dose schedules are in clinical use for the treatment of advanced colorectal cancer. Only the monthly low-dose LV-plus-FU regimen, as used by the North Central Cancer Treatment Group, has demonstrated a lasting survival benefit as opposed to FU alone (J Clin Oncol 1989; 7: 1407-1417). The Swiss Cancer Group adopted this regimen for a confirmatory phase III trial but used the same dose-intensity of fluorouracil in both treatment arms.

Patients and methods: Patients with inoperable or metastatic colorectal cancer were randomized to receive monthly FU 400 mg/m2/day plus LV 20 mg/m2/day as intravenous push daily for five days, or FU alone.

Results: Three hundred nine of the 310 patients randomized were eligible and included in the analysis. The objective response rate for patients with measurable disease was 9% with FU alone and 22% with FU-plus-LV (P = 0.0001). The median progression-free survival was 3.9 versus 6.2 months (P = 0.003) and the overall survival 10 versus 12.4 months (P = 0.02). The major prognostic factors for survival were performance status, weight loss, and disease symptoms. WHO > 2 toxicity, consisting of stomatitis (P = 0.001), diarrhea (P = 0.001), and nausea (P = 0.001), was more pronounced for FU-plus-LV, without fatal events.

Conclusions: This is the largest published randomized trial to compare FU-plus-LV to FU alone in advanced colorectal cancer. It confirms the survival benefit obtained from biomodulating monthly FU with low-dose LV. The toxic effects of FU-plus-LV were acceptable to most patients, and they responded well to FU dose reductions. In the absence of an ideal dose-intense FU monotherapy regimen, monthly FU with low-dose LV provides a simple and economical means by which to achieve adequate FU efficacy in the treatment of advanced colorectal cancer.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase III
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma / drug therapy*
  • Carcinoma / pathology
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • Drug Interactions
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / therapeutic use*
  • Humans
  • Leucovorin / administration & dosage
  • Male
  • Middle Aged
  • Survival Analysis


  • Leucovorin
  • Fluorouracil

Supplementary concepts

  • Fu-CF protocol