Issues and limitations of available biomarkers for fluoropyrimidine-based chemotherapy toxicity, a narrative review of the literature

Abstract

Fluoropyrimidine-based chemotherapies are widely used to treat gastrointestinal tract, head and neck, and breast carcinomas. Severe toxicities mostly impact rapidly dividing cell lines and can occur due to the partial or complete deficiency in dihydropyrimidine dehydrogenase (DPD) catabolism. Since April 2020, the European Medicines Agency (EMA) recommends DPD testing before any fluoropyrimidine-based treatment. Currently, different assays are used to predict DPD deficiency; the two main approaches consist of either phenotyping the enzyme activity (directly or indirectly) or genotyping the four main deficiency-related polymorphisms associated with 5-fluorouracil (5-FU) toxicity. In this review, we focused on the advantages and limitations of these diagnostic methods: direct phenotyping by evaluation of peripheral mononuclear cell DPD activity (PBMC-DPD activity), indirect phenotyping assessed by uracil levels or UH2/U ratio, and genotyping DPD of four variants directly associated with 5-FU toxicity. The risk of 5-FU toxicity increases with uracil concentration. Having a pyrimidine-related structure, 5-FU is catabolised by the same physiological pathway. By assessing uracil concentration in plasma, indirect phenotyping of DPD is then measured. With this approach, in France, a decreased 5-FU dose is systematically recommended at a uracil concentration of 16 ng/ml, which may lead to chemotherapy under-exposure as uracil concentration is a continuous variable and the association between uracil levels and DPD activity is not clear. We aim herein to describe the different available strategies developed to improve fluoropyrimidine-based chemotherapy safety, how they are implemented in routine clinical practice, and the possible relationship with inefficacy mechanisms.

A narrative review of genetic factors affecting fluoropyrimidine toxicity

“…However, this approach, while rapid and reliable, requires use of either radioactive isotopes or mass spectrometry ( 70 ), and thus may have less potential for widespread implementation. The French cancer institute and French health authority recommend measurement of uracil blood level and implementation of alternative regimens for cancer patients with elevated levels ( 71 ).…”

Concordance of Blood-Based and Normal Tissue-Based Dihydropyrimidine Dehydrogenase (DPYD) Genotyping

“…Since 2018, international guidelines recommend DPYD screening before fluorouracil-treatment start, with reduction of the dosage in case of impaired drug catabolism. 3 Genotyping the main 4 polymorphisms on germline DNA isolated from peripheral blood cells as well as phenotyping enzyme activity by measurement of uracil blood levels are both European Medicines Agency and Food and Drug Administration approved methods. 3-5 However, some national recommendations, such as those from the Italian Association of Medical Oncology and the Society of Pharmacology (AIOM-SIF), indicate that only the use of blood-based germline testing should be taken into account.…”

“… 3 Genotyping the main 4 polymorphisms on germline DNA isolated from peripheral blood cells as well as phenotyping enzyme activity by measurement of uracil blood levels are both European Medicines Agency and Food and Drug Administration approved methods. 3-5 However, some national recommendations, such as those from the Italian Association of Medical Oncology and the Society of Pharmacology (AIOM-SIF), indicate that only the use of blood-based germline testing should be taken into account. 6 The widespread application of testing remains an issue and, where the testing is available, an additional blood draw for genotyping is needed.…”

Effect of Ketorolac on Pharmacokinetics and Pharmacodynamics of 5-Fluorouracil: In Vivo and In Vitro Study

“…The pharmacokinetics of 5-FU are significantly influenced by various factors such as high serum alkaline phosphatase level, drug infusion duration, and DPD level [ 19 , 24 ]. DPD is an effective enzyme in the first step of reduction and the rate-limiting step in the degradation of pyrimidine nucleic acids and their analogues.…”