Individualization of 5-Fluorouracil in the Treatment of Colorectal Cancer

Abstract

Chemotherapeutic agents are generally characterized by a large inter-individual pharmacokinetic variability. The balance of efficacy and toxicity is critical and the imbalance can have devastating effects on patients. Standard dosing methods are inadequate in optimizing systemic exposure .Therapeutic drug monitoring (TDM) has the potential to improve the clinical use of chemotherapy agents. TDM has been successfully applied to optimize a few anticancer treatments including carboplatin, methotrexate, and 6-mercaptopurine. 5-Flurouracil (5-FU) is considered the backbone in treatments of advanced CRC. Toxic side effects remain a significant problem despite increased safety of newer regimens. Molecular mechanisms that control DPD-activity are complex and have not been fully elucidated and cannot be used effectively to individualize Fluorouracil dosing as there is no established standard genetic test for DPD deficiency. Current phenotypic methods to measure DPD-activity are cumbersome. A reliable relationship between DPD genotype and 5-FU toxicity phenotype has not been established. Standard dosing of 5FU is by body surface area (BSA). Low correlation exists between exposure and BSA. A better predictor of total exposure is the area under the curve (AUC). Toxicity and efficacy have been correlated to AUC with target of 24-30 (mg.h/l). The therapeutic window is very narrow and difficult to attain by clinical follow-up alone. TDM has been shown effective in adjusting the dose based on AUC.