How can we best monitor 5-FU administration to maximize benefit to risk ratio?

ABSTRACT

Introduction: 5-Fluorouracil (5-FU) is currently used as a chemotherapy in several cancers such as head-and-neck (H&N) and colorectal cancers. 5-FU dosing is traditionally based on body surface area (BSA), but this strategy is usually associated with severe toxicities. 5-FU is mainly catabolized by dihydropyrimidine dehydrogenase (DPD), and 5-FU dosage adaptation according to DPD status at the first cycle of treatment is now recommended. To further optimize 5-FU-based chemotherapy, a body of evidences justifies therapeutic drug monitoring (TDM).

Areas covered: 5-FU pharmacokinetics, relationships between pharmacokinetics and efficacy or toxicity of 5-FU, proofs of interest of 5-FU TDM and its practical considerations are discussed.

Expert opinion: BSA-adjusted 5-FU administration is associated with a large inter-individual variability, and according to this strategy, many patients experience under- or overexposure. Moreover, relationships between 5-FU area under the curve (AUC) and its toxicity or efficacy have been demonstrated, at least in patients with colorectal or H&N cancers. 5-FU therapeutic index has been validated and algorithms of 5-FU dosage adaptation according to its AUC are now available. Advances in pre-analytical and analytical steps of 5-FU TDM make its use feasible in clinical practice. Thus, there are consistent evidences to recommend 5-FU TDM in patients with advanced colorectal or H&N cancers.

KEYWORDS:

• 5-fluorouracil
• colorectal cancer
• head and neck (H&N) cancer
• pharmacokinetics
• therapeutic drug monitoring (TDM)

Article highlights

• 5-Fluorouracil (5-FU) pharmacokinetic is characterized by a large inter-individual variability, the main covariates explaining this variability being sex and dihydropyrimidine dehydrogenase status. Body surface area -based dosing methods for 5-FU lead to under- or overexposure in patients.

• 5-FU exposure has been correlated to its efficacy and toxicity. In colorectal or head-and-neck cancers, most of the studies describe an optimization of the response when the area under the curve (AUC) is within the range of 20–30 mg·h/L.

• Use of 5-FU therapeutic drug monitoring (TDM) to achieve 5-FU exposure within the target AUC improves response rate of chemotherapy and reduces the risk of overall grade 3–4 toxicities.

• Dose-adjustment algorithms have been published and represent useful tools to longitudinally modify 5-FU dosage in a same patient.

• A recommendation of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology strongly supports TDM for the management of 5-FU therapy in patients with colorectal or head-and-neck cancer receiving common 5-FU regimens.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.