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

F. A. Levi, R. Zidani, J. M. Vannetzel, B. Perpoint, C. Focan, R. Faggiuolo, P. Chollet, C. Garufi, M. Itzhaki, L. Dogliotti, S. Iacobelli, R. Adam, F. Kunstlinger, J. Gastiaburu, H. Bismuth, C. Jasmin, J. L. Misset

Research output: Contribution to journalArticle

Abstract

Background: In a previous phase II trial, circadian (chronomodulated) delivery of fluorouracil (5-FU), folinic acid (FA; leucovorin), and oxaliplatin (I-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 l-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 l-OHP at 1600 hours; 45 patients). A risk of partial chemical inactivation of l-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%; χ2 = 46; P2 per day) compared with schedule A (median: 500 mg/m2 per day) (P2 = 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 l-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.

Original languageEnglish
Pages (from-to)1608-1617
Number of pages10
JournalJournal of the National Cancer Institute
Volume86
Issue number21
Publication statusPublished - 1994

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Radiology Nuclear Medicine and imaging

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this

    Levi, F. A., Zidani, R., Vannetzel, J. M., Perpoint, B., Focan, C., Faggiuolo, R., Chollet, P., Garufi, C., Itzhaki, M., Dogliotti, L., Iacobelli, S., Adam, R., Kunstlinger, F., Gastiaburu, J., Bismuth, H., Jasmin, C., & Misset, J. L. (1994). 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. Journal of the National Cancer Institute, 86(21), 1608-1617.