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Individual Fluorouracil Dose Adjustment Based on Pharmacokinetic Follow-Up Compared With Conventional Dosage: Results of a Multicenter Randomized Trial of Patients With Metastatic Colorectal Cancer

Erick Gamelin, Remy Delva, Jacques Jacob, Yacine Merrouche, Jean Luc Raoul, Denis Pezet, Etienne Dorval, Gilles Piot, Alain Morel, Michele Boisdron-Celle

From the Oncopharmacology and Pharmacogenetic Laboratory, L'Institut National de la Santé et de la Recherche Médicale; Medical Oncology Department; Anticancer Centre Paul Papin, Angers; Medical Oncology Department, Anticancer Centre François Baclesse, Caen; Medical Oncology Department, Institut de Cancerologie de la Loire, Saint Priest en Jarez; Medical Oncology Department, Anticancer Centre Eugene Marquis, Rennes and the European University of Brittany; Surgical Oncology Department, University Hospital, Clermont Ferrand; Gastroenterology Department, University Hospital, Tours; and Clinique, Le Havre, France

Corresponding author: Erick Gamelin, MD, PhD, Oncopharmacology and Pharmacogenetic Laboratory, L'Institut National de la Santé et de la Recherche Médicale, Centre Paul Papin, 2 rue Moll, 49933 Angers cedex 9, France; e-mail: e.gamelin{at}unimedia.fr

Purpose: A phase III, multicenter, randomized study compared conventional dosing of fluorouracil (FU) plus folinic acid with pharmacokinetically guided FU dose adjustment in terms of response, tolerability, and survival.

Patients and Methods: Two hundred eight patients with measurable metastatic colorectal cancer were randomly assigned to one of two arms: arm A (104 patients; 96 assessable), in which the FU dose was calculated based on body-surface area; and arm B (104 patients; 90 assessable), in which the FU dose was individually determined using pharmacokinetically guided adjustments. The initial regimen was 1,500 mg/m² FU plus 200 mg/m² folinic acid infusion during a continuous 8-hour period administered once weekly. FU doses were adjusted weekly in arm B based on a single-point measurement of FU plasma concentrations at steady state until the therapeutic range (targeted area under the curve 20-25 mg·h·L^–1) previously established in other studies was reached.

Results: An intent-to-treat analysis of the 208 patients showed the objective response rate was 18.3% in arm A and 33.7% in arm B (P = .004). Median overall survival was 16 months in arm A and 22 months in arm B (P = .08). The mean FU dose throughout treatment was 1,500 mg/m²/wk in arm A and 1,790 ± 386 mg/m²/wk (range, 900 to 3,300 mg/m²/wk) in arm B. Toxic adverse effects were significantly more frequent and severe in arm A compared with arm B (P = .003).

Conclusion: Individual FU dose adjustment based on pharmacokinetic monitoring resulted in significantly improved objective response rate, a trend to higher survival rate, and fewer grade 3/4 toxicities. These results support the value of pharmacokinetically guided management of FU dose in the treatment of metastatic colorectal patients.

Supported by the Comité Départemental du Maine et Loire de la Ligue Contre Le Cancer.

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

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