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5-Fluorouracil Pharmacokinetics Predicts Disease-free Survival in Patients Administered Adjuvant Chemotherapy for Colorectal Cancer

Authors' Affiliations: ¹ Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa; ² Division of Medical Oncology, University Hospital, Pisa, Italy; and ³ Division of Medical Oncology, Civil Hospital, Livorno, Italy

Requests for reprints: Antonello Di Paolo, Division of Pharmacology and Chemotherapy, Department of Internal Medicine, Via Roma 55, 56126 Pisa, Italy. Phone: 39-050830148; Fax: 39-050562020; E-mail: a.dipaolo{at}ao-pisa.toscana.it.

Purpose: To evaluate 5-fluorouracil (5-FU) and 5-fluoro-5,6-dihydrouracil (5-FDHU) pharmacokinetics and disease-free survival (DFS) in colorectal cancer patients given 5-FU–based adjuvant chemotherapy within a nonrandomized, retrospective, pharmacokinetic study.

Experimental Design: One hundred fifteen patients including 72 men (median age, 63 years; range, 36-79 years) and 43 women (median age, 60 years; range, 36-73 years) received 6 cycles of L-leucovorin 100 mg/m²/day and 5-FU 370 mg/m²/day i.v. boluses (5 days every 4 weeks). Individual plasma concentrations of 5-FU and 5-FDHU were determined on day 1 of the first cycle with a validated high performance liquid chromatography method, and the main pharmacokinetic variables were determined. Follow-up of all patients was extended up to 5 years after the end of adjuvant chemotherapy, and DFS was recorded. Univariate and multivariate analyses were conducted to evaluate any correlation among 5-FU pharmacokinetics, clinical and pathologic variables, and DFS.

Results: The area under the time/concentration curve (AUC) of 5-FU was significantly lower in 58 subjects who recurred (7.5 ± 2.9 h x mg/L) with respect to other patients (9.3 ± 4.1 h x mg/L). Furthermore, AUC values lower than 8.4 h x mg/L together with lymph node involvement and the interruption of treatment or reduction of doses were identified as risk factors at univariate analysis. The completion of 6 cycles of adjuvant treatment without dosage modifications was the only independent risk factor at multivariate analysis, despite a trend toward significance for 5-FU AUC values (cutoff value, 8.4 hxmg/L) was observed (P = 0.06).

Conclusions: Pharmacokinetics of 5-FU should be regarded as an important factor for predicting disease recurrence in colorectal cancers.