5-fluorouracil pharmacokinetics predicts disease-free survival in patients administered adjuvant chemotherapy for colorectal cancer.

Abstract

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/m(2)/day and 5-FU 370 mg/m(2)/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.

• Authors: Antonello Di Paolo, Monica Lencioni, Federica Amatori, Samantha Di Donato, Guido Bocci, Cinzia Orlandini, Marianna Lastella, Francesca Federici, Mauro Iannopollo, Alfredo Falcone, Sergio Ricci, Mario Del Tacca, Romano Danesi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 9 Pg. 2749-55 (May 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18451241 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• 5-fluorodihydrouracil
• Leucovorin
• Fluorouracil

Topics

• Adult
• Aged
• Analysis of Variance
• Antimetabolites, Antineoplastic (administration & dosage, pharmacokinetics, therapeutic use)
• Chemotherapy, Adjuvant
• Colorectal Neoplasms (drug therapy)
• Disease-Free Survival
• Female
• Fluorouracil (administration & dosage, analogs & derivatives, pharmacokinetics, therapeutic use)
• Humans
• Leucovorin (administration & dosage, therapeutic use)
• Male
• Middle Aged
• Multivariate Analysis
• Retrospective Studies