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.

Preliminary observations indicate variable patterns of plasma 5-fluorouracil (5-FU) levels during dose optimization of infusional 5-FU in colorectal cancer patients

“…28 Continuous infusion (CI) of 5-FU has been shown to have advantages possibly due to the short half-life of 5-FU and its cell cycle-dependent effect on thymidylate synthase. 29 Currently, the combination of short-term infusional 5-FU/ LV and oxaliplatin (FOLFOX) is considered a standard first-line therapy for mCRC. At least seven modifications of this combination exist based on a difference in the dose intensity of 5-FU/ LV and oxaliplatin.…”

Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic–pharmacodynamic model in gastrointestinal cancer patients

“…Continuous infusions exhibit lower myelosuppression with greater efficacy and are considered superior over the bolus administrations [19]. Furthermore, 5FU has a narrow therapeutic index with severe toxicities tending to occur with AUC values > 25 mg h/L during continuous venous infusion [20]. Therefore, therapeutic drug monitoring is considered valuable to achieve optimal 5FU exposure with minimal serious toxicity [21].…”

Modeling the 5-Fluorouracil Area Under the Curve Versus Dose Relationship to Develop a Pharmacokinetic Dosing Algorithm for Colorectal Cancer Patients Receiving FOLFOX6

“…Like other chemotherapeutic drugs, 5-FU is generally characterized by a narrow therapeutic index and a large interindividual PK variability that has a direct effect on both toxicity and efficacy [4,5]. Regardless of the regimen and schedule in which 5-FU is used, the method of dosing 5-FU in standard practice has not changed for decades and is based on the traditional use of body surface area (BSA).…”

“…Thus, fine tuning of chemotherapy needs to consider the generally wide interindividual pharmacokinetic (PK) variability of such drugs and the finding that general toxicity and effi-cacy are more related to systemic exposure than to dose and dose intensity [1][2][3]. 5-fluorouracil (5-FU), which has been used in the treatment of a variety of solid tumors, is a prime example of this concept [4,5]. 5-FU has been the cornerstone of colorectal cancer (CRC) therapy since the 1960s, with regimens having undergone a series of modifications in order to enhance the benefits to pa-tients, ranging from enhanced monotherapy to multiagent polychemotherapy including irinotecan and oxaliplatin, and more recently, the addition of the targeted agents bevacizumab and anti-epidermal growth factor receptor antibodies.…”