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J Clin Oncol. 2008 May 1;26(13):2099-105. doi: 10.1200/JCO.2007.13.3934.

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.

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  • 1Erick Gamelin, 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.gamelin@unimedia.fr

Erratum in

  • J Clin Oncol. 2013 Oct 1;31(28):3612.

Abstract

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/m(2) FU plus 200 mg/m(2) 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 x h x 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/m(2)/wk in arm A and 1,790 +/- 386 mg/m(2)/wk (range, 900 to 3,300 mg/m(2)/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.

PMID:
18445839
DOI:
10.1200/JCO.2007.13.3934
[PubMed - indexed for MEDLINE]
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