Individualized Dosing of Fluoropyrimidine-Based Chemotherapy to Prevent Severe Fluoropyrimidine-Related Toxicity: What Are the Options?

Jonathan E Knikman, Hans Gelderblom, Jos H Beijnen, Annemieke Cats, Henk-Jan Guchelaar, Linda M Henricks, Jonathan E Knikman, Hans Gelderblom, Jos H Beijnen, Annemieke Cats, Henk-Jan Guchelaar, Linda M Henricks

Abstract

Fluoropyrimidines are widely used in the treatment of several types of solid tumors. Although most often well tolerated, severe toxicity is encountered in ~ 20-30% of the patients. Individualized dosing for these patients can reduce the incidence of severe fluoropyrimidine-related toxicity. However, no consensus has been achieved on which dosing strategy is preferred. The most established strategy for individualized dosing of fluoropyrimidines is upfront genotyping of the DPYD gene. Prospective research has shown that DPYD-guided dose-individualization significantly reduces the incidence of severe toxicity and can be easily applied in routine daily practice. Furthermore, the measurement of the dihydropyrimidine dehydrogenase (DPD) enzyme activity has shown to accurately detect patients with a DPD deficiency. Yet, because this assay is time-consuming and expensive, it is not widely implemented in routine clinical care. Other methods include the measurement of pretreatment endogenous serum uracil concentrations, the uracil/dihydrouracil-ratio, and the 5-fluorouracil (5-FU) degradation rate. These methods have shown mixed results. Next to these methods to detect DPD deficiency, pharmacokinetically guided follow-up of 5-FU could potentially be used as an addition to dosing strategies to further improve the safety of fluoropyrimidines. Furthermore, baseline characteristics, such as sex, age, body composition, and renal function have shown to have a relationship with the development of severe toxicity. Therefore, these baseline characteristics should be considered as a dose-individualization strategy. We present an overview of the current dose-individualization strategies and provide perspectives for a future multiparametric approach.

Trial registration: ClinicalTrials.gov NCT04194957.

Conflict of interest statement

The authors declared no competing interests for this work.

© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Metabolism of fluoropyrimidines. 5′‐dFCR, 5′‐deoxy‐5‐fluorocytidine; 5′‐dFUR, 5′‐deoxy‐5‐fluorouridine; 5‐FU, 5‐fluorouracil; 5‐FUH2, 5,6‐dihydro‐5‐fluorouracil; B‐AL, β‐ alanine; B‐UP, β‐ureidopropionate; DHU, Dihydrouracil; FBAL, α‐fluoro‐β‐alanine; FdUDP, 5‐fluoro‐2′‐deoxyuridine 5′‐diphosphate; FdUMP, 5‐fluoro‐2′‐deoxyuridine 5′‐monophosphate; FdUrd, 5‐fluoro‐2'‐deoxyuridine; FdUTP, 5‐fluoro‐2′‐deoxyuridine 5‐’triphosphate; FUDP, 5‐fluorouridine 5′‐diphosphate; FUMP, 5‐fluorouridine 5′‐monophosphate; FUPA, α‐fluoro‐β‐ureidopropionic acid; FUrd, 5‐fluorouridine; FUTP, 5‐fluorouridine 5′‐triphosphate. [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 2
Figure 2
Overview of the current dosing strategy and a suggestion for a potential future dosing strategy. (a) Current dosing strategy. (b) Potential future dosing strategy in which upfront screening is performed which includesDPYD‐genotyping, DPD‐phenotyping and screening of baseline characteristics and PK‐guided follow‐up. 5‐FU, 5‐fluorouracil; DPD, dihydropyrimidine dehydrogenase; PK, pharmacokinetic. [Colour figure can be viewed at wileyonlinelibrary.com]

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