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

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.

Keywords

• DPD
• therapeutic drug monitoring
• uracilemia
• UH₂/U ratio
• GI cancer
• 5-FU