How may anticancer chemotherapy with fluorouracil be individualised?

Area of Science:

• Pharmacology
• Oncology
• Clinical Chemistry

Background:

• Fluorouracil (5-FU) is a critical chemotherapy agent for solid tumors.
• Significant inter-individual variability exists in 5-FU pharmacokinetics and toxicity.
• Current dosing strategies often fail to optimize 5-FU exposure due to complex factors like narrow therapeutic index and metabolic variations.

Purpose of the Study:

• To explore methods for individualizing fluorouracil (5-FU) dosing to improve efficacy and reduce toxicity.
• To assess the utility of dihydropyrimidine dehydrogenase (DPD) activity testing for predicting 5-FU outcomes.
• To define optimal 5-FU exposure ranges for therapeutic benefit without severe adverse events.

Main Methods:

• Review of existing methods for assessing DPD activity, including genotyping and phenotyping.
• Analysis of fluorouracil exposure (AUC) thresholds associated with toxicity (leukopenia, mucositis, hand-foot syndrome) and therapeutic response.
• Discussion of a priori (pre-treatment) and a posteriori (post-treatment) dose adaptation strategies.

Main Results:

• DPD enzyme activity, responsible for ~80% of 5-FU elimination, varies significantly due to genetic polymorphism.
• Complete or partial DPD deficiency in Caucasians (0.1-3.5%) leads to higher 5-FU exposure and toxicity.
• An AUC threshold of 25-30 mg.h/L for continuous 5-day infusions correlated with increased toxicity, while optimal tumor response occurred around 30 mg.h/L, highlighting a narrow therapeutic window.

Conclusions:

• Individualized fluorouracil dosing is essential but challenging.
• DPD activity assessment (genotyping and phenotyping) shows promise for predicting 5-FU toxicity.
• Further randomized clinical studies are needed to validate a priori and a posteriori dose adaptation strategies for fluorouracil therapy.