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Annals of Oncology Advance Access published online on September 12, 2006
Annals of Oncology, doi:10.1093/annonc/mdl284
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© 2006 European Society for Medical Oncology
Received May 26, 2006
Revised June 30, 2006
Accepted July 3, 2006

original article

Pharmacokinetic and demographic markers of 5-fluorouracil toxicity in 181 patients on adjuvant therapy for colorectal cancer

M. Gusella 1 *, G. Crepaldi 1, C. Barile 1, A. Bononi 1, D. Menon 1, S. Toso 1, D. Scapoli 1, L. Stievano 1, E. Ferrazzi 1, F. Grigoletto 2, M. Ferrari 3, and R. Padrini 3

1 Oncology Division, Rovigo General Hospital, Rovigo, Italy
2 Department of Environmental Medicine and Public Health, University of Padova, Padova, Italy
3 Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy

* To whom correspondence should be addressed.
M. Gusella, E-mail: milenagusella{at}libero.it


  Abstract

Background: The relationship between 5-fluorouracil (5-FU) pharmacokinetics and toxicity following i.v. bolus administration has not been extensively studied.

Patients and methods: One hundred and eighty-one patients on adjuvant therapy with 5-FU plus leucovorin for colorectal cancer were the study population. 5-FU pharmacokinetics was determined on day 2 of the first, third, and fifth cycles; type and the grade of adverse reactions were recorded on the next cycle.

Results: The 5-FU area under the curve (AUC) measured at the first cycle ranged between 146 and 1236 mg x min/l and was significantly correlated with drug dose, patients' body weight (BW) and gender, females having higher AUCs. These covariates explained only 23% of AUC variability. AUC and age were the only covariates which discriminated between toxic (grade ≥2) and nontoxic cycles (grade <2), with an optimal AUC cut-off value of 596 mg x min/l. Such a correlation was lost during the next cycles following dose reduction because of toxicity in 80 patients.

Conclusions: A method for calculating the initial 5-FU dose is proposed which takes into account patient BW, gender and a target AUC of 596 mg x min/l. Nevertheless, it appears that a substantial part of 5-FU toxicity is not linked to pharmacokinetic factors and dose adjustments must still be on the basis of careful clinical surveillance.

Keywords: area under the curve; colorectal cancer; toxicity; 5-fluorouracil.
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