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Phase III Trial Comparing 4-Day Chronomodulated Therapy Versus 2-Day Conventional Delivery of Fluorouracil, Leucovorin, and Oxaliplatin As First-Line Chemotherapy of Metastatic Colorectal Cancer: The European Organisation for Research and Treatment of Cancer Chronotherapy Group

Sylvie Giacchetti, Georg Bjarnason, Carlo Garufi, Dominique Genet, Stefano Iacobelli, Marco Tampellini, Rune Smaaland, Christian Focan, Bruno Coudert, Yves Humblet, Jean Luc Canon, Antoine Adenis, Giovanni Lo Re, Carlos Carvalho, Johannes Schueller, Nicole Anciaux, Marie-Ange Lentz, Benoît Baron, Thierry Gorlia, Francis Lévi

From the Hopital Paul Brousse and INSERM, Villejuif; Centre Hospitalier Universitaire Dupuytren, Limoges; Centre Georges-François Leclerc, Dijon; Centre Oscar Lambret, Lille, France; Toronto-Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada; Istituto Regina Elena, Roma; Universita G. d'Annunzio di Chieti, Chieti; Ospedale San Luigi Gonzaga, Orbassano-Torino; S.M. Angeli, Pordenone, Italy; Haukeland University Hospital, University of Bergen, Norway; CHC-Les Cliniques Saint-Joseph, Liège Cliniques Universitaires St Luc; European Organisation for Research and Treatment of Cancer Data Center, Brussels; Clinique Notre Dame, Charleroi; Clinique Ste Elisabeth, Namur, Belgium; Hopital F. Fonseca, Amadora, Portugal; and Krankenanstalt Rudolfstiftung, Vienna, Austria

Address reprint requests to Francis Lévi, MD, PhD, INSERM E0354 "Cancer Chronotherapeutics," Paul Brousse Hospital, 14-16 avenue Paul-Vaillant-Couturier, 94807 Villejuif Cedex, France; e-mail: levi-m{at}vjf.inserm.fr

PURPOSE: In two previous randomized trials, the adjustment of chemotherapy delivery to circadian rhythms improved tolerability and anticancer activity compared with constant-rate infusion during 5 days in patients with metastatic colorectal cancer.

PATIENTS AND METHODS: For this multicenter randomized trial, it was hypothesized that a chronomodulated infusion of fluorouracil, leucovorin, and oxaliplatin for 4 days (chronoFLO4) would improve survival by 10% compared with conventional 2-day delivery of the same drugs (FOLFOX2). Patients were treated every 2 weeks with intrapatient dose escalation.

RESULTS: Baseline characteristics were similar in both arms for the 564 patients (36 institutions, 10 countries). Median survival was 19.6 months (95% confidence limit [CL] = 18.2, 21.2) with chronoFLO4 and 18.7 months with FOLFOX2 (95% CL = 17.7, 21.0; P = .55). The main dose-limiting toxicities were diarrhea for chronoFLO4 and neutropenia for FOLFOX2. The analysis of survival predictors showed that sex was the single most important factor (P = .001). In women, the risk of an earlier death with chronoFLO4 was increased by 38% compared with FOLFOX2, with median survival times of 16.3 and 19.1 months (P = .03), respectively. In men, the risk of death was decreased by 25% with chronoFLO4 compared with FOLFOX2, with median survival times of 21.4 and 18.3 months (P = .02), respectively.

CONCLUSION: Both regimens achieved similar median survival times more than 18 months with an acceptable toxicity. The chronomodulated schedule produced a survival advantage over FOLFOX in men. The strong sex dependency of optimal scheduling of fluorouracil, leucovorin, and oxaliplatin calls for translational investigations of determinants related to the patient's molecular clock.

Supported in part by a grant from Sanofi Pharma, which also provided oxaliplatin for patients until approval of the drug. Supported by Association pour la Recherche sur le temps Biologique et la Chronotherapie (ARTBC) Internationale and Cephyten.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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