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Annals of Oncology Advance Access originally published online on September 12, 2006
Annals of Oncology 2006 17(11):1656-1660; doi:10.1093/annonc/mdl284
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© 2006 European Society for Medical Oncology

gastrointestinal tumors

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

M Gusella1,*, G Crepaldi1, C Barile1, A Bononi1, D Menon1, S Toso1, D Scapoli1, L Stievano1, E Ferrazzi1, F Grigoletto2, M Ferrari3 and R Padrini3

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

*Correspondence to: Dr M. Gusella, Oncology Division, Rovigo General Hospital, Viale Tre Martiri 149, 45100 Rovigo, Italy. Tel: +39-0425-394340; Fax +39-0425-393045; E-mail: milenagusella{at}libero.it

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.

Key words: area under the curve, colorectal cancer, toxicity, 5-fluorouracil


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