Association of 5-FU Therapeutic Drug Monitoring to DPD Phenotype Assessment May Reduce 5-FU Under-Exposure.

Marine Dolat,Françoise Goirand,Pauline Macaire,Antonin Schmitt,Rémi Palmier,Bernard Royer,François Ghiringhelli,Audrey Hennequin,Leïla Bengrine-Lefevre,Julie Vincent

doi:10.3390/ph13110416

Abstract

In order to limit 5-fluorouracil (5-FU) toxicity, some health agencies recommend evaluating dihydropyrimidine dehydrogenase (DPD) deficiency before any 5-FU treatment introduction. In our study, we investigated relationships between 5-FU clearance and markers of DPD activity such as uracilemia (U), dihydrouracilemia (UH2)/U ratio, or genotype of the gene encoding DPD (DPYD). All patients with gastrointestinal cancers who received 5-FU-based regimens form March 2018 to June 2020 were included in our study. They routinely benefited of a pre-therapeutic DPYD genotyping and phenotyping. During 5-FU infusion, blood samples were collected to measure 5-FU steady-state concentration in order to adapt 5-FU doses at the following cycles. A total of 169 patients were included. Median age was 68 (40–88) years and main primary tumor sites were colorectal (40.8%) and pancreas (31.4%), metastatic in 76.3%. 5-FU was given as part of FOLFIRINOX (44.4%), simplified FOLFOX-6 (26.6%), or docetaxel/FOLFOX-4 (10.6%). Regarding DPD activity, median U and UH2/U were, respectively, 10.8 ng/mL and 10.1, and almost 15% harbored a heterozygous mutation. On the range of measured U and UH2/U, no correlation was observed with 5-FU clearance. Moreover, in patients with U < 16 ng/mL, 5-FU exposure was higher than in other patients, and most of them benefited of dose increase following 5-FU therapeutic drug monitoring (TDM). If recent guidelines recommend decreasing 5-FU dose in patients harboring U ≥ 16 ng/mL, our study highlights that those patients are at risk of under-exposure and that 5-FU TDM should be conducted in order to avoid loss of efficacy.

Highlights

The most well-known cause of 5-FU intolerance is deficiency of dihydropyrimidine dehydrogenase (DPD) activity—the key enzyme responsible for its metabolism [6]
Initial dose reduction of at least 50% is proposed in patients heterozygous for DPYD*2A, DPYD*13, and c.2846A>T who are considered to have intermediate or partial DPD enzyme activity, while a choice of alternative drug is strongly recommended for patients with complete DPD deficiency [11]
If over-exposure is an important concern for oncologists, several papers have shown that almost 50% of patients treated with 5-FU are at risk of under-exposure, leading to sub-optimal efficacy [17,18,19,20,21,22]. 5-FU therapeutic drug monitoring (TDM) has been suggested as an option to ensure a correct exposition in all patients

Summary

Introduction

The most well-known cause of 5-FU intolerance is deficiency of dihydropyrimidine dehydrogenase (DPD) activity—the key enzyme responsible for its metabolism [6]. Initial dose reduction of at least 50% is proposed in patients heterozygous for DPYD*2A, DPYD*13, and c.2846A>T who are considered to have intermediate or partial DPD enzyme activity, while a choice of alternative drug is strongly recommended for patients with complete DPD deficiency [11]. DPD activity is regulated at the level of DPYD gene, and at the transcriptional and the post-transcriptional levels [4] This highlights the significant limitation of the proposed algorithm. Given the evidence for DPD deficiency testing and 5-FU TDM efficacy, we conducted this retrospective study to investigate the relationship between DPD “activity” (by means of U, UH2/U, or DPYD genotyping) and 5-FU clearance in patients with gastrointestinal cancer receiving 5-FU-based regimens

Methods

Results

Discussion

Conclusion