Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial

J Natl Cancer Inst. 1994 Nov 2;86(21):1608-17. doi: 10.1093/jnci/86.21.1608.


Background: In a previous phase II trial, circadian (chronomodulated) delivery of fluorouracil (5-FU), folinic acid (FA; leucovorin), and oxaliplatin (1-OHP; a new platinum complex with no renal and minor hematologic toxic effects) produced an objective response rate of 58% in 93 patients with metastatic colorectal cancer.

Purpose: To determine whether chronomodulated drug delivery affects therapeutic activity, we again tested this regimen in another trial in patients with previously untreated metastatic colorectal cancer, this time comparing chronomodulated with constant-rate drug delivery.

Methods: Seven European centers participated in this trial. Ninety-two patients with metastatic colorectal cancer were enrolled and assigned to a treatment schedule by central randomization. Treatment courses consisted of the daily administration of 5-FU (600 mg/m2 per day), FA (300 mg/m2 per day), and 1-OHP (20 mg/m2 per day) for 5 days and were repeated every 21 days (16-day intermission) in ambulatory patients with the use of a programmable in-time pump. Drug delivery was kept constant over a 5-day period in schedule A (47 patients). It was chronomodulated in schedule B (maximum delivery of 5-FU and FA infusions at 0400 hours and maximum delivery of 1-OHP at 1600 hours; 45 patients). A risk of partial chemical inactivation of 1-OHP by its 2-hour exposure to the basic pH of the 5-FU solution in the catheter was documented in schedule A.

Results: Severe stomatitis (grade 3 or 4, World Health Organization [WHO] grading system), the dose-limiting toxic effect of 5-FU, occurred in five times as many patients on schedule A than on schedule B (89% versus 18%; chi 2 = 46; P < .001). The cumulative dose-limiting toxicity of schedule B was peripheral sensitive neuropathy (WHO grade 2). This side effect was reversible following 1-OHP withdrawal. Higher doses of 5-FU were administered in schedule B (median: 700 mg/m2 per day) compared with schedule A (median: 500 mg/m2 per day) (P < .0001; Mann-Whitney U test). On schedule B, 24 of 45 patients (53%; 95% confidence interval [CI] = 38%-68%) exhibited an objective response compared with 15 of 47 patients (32%; 95% CI = 18%-46%) on schedule A (chi 2 = 4.3; P = .038). The median progression-free survival was, respectively, 11 and 8 months (P = .19; logrank). The median survival was 19 months (95% CI = 14.8-23.2) on schedule B and 14.9 months (95% CI = 12.1-17.8) on schedule A (P = .03; logrank).

Conclusion: This ambulatory treatment modality was both more effective and less toxic if drug delivery was chronomodulated rather than constant over time.

Implication: The respective roles of 1-OHP dose and schedule and circadian peak time of drug delivery are being investigated with regard to the high activity of this three-drug, chronomodulated chemotherapeutic regimen.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Ambulatory Care
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Circadian Rhythm*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • Drug Administration Schedule
  • Female
  • Fluorouracil / administration & dosage
  • Humans
  • Leucovorin / administration & dosage
  • Male
  • Middle Aged
  • Organoplatinum Compounds / administration & dosage
  • Oxaliplatin
  • Survival Analysis
  • Treatment Outcome


  • Organoplatinum Compounds
  • Oxaliplatin
  • Leucovorin
  • Fluorouracil