Impact of Guidelines Regarding Dihydropyrimidine Dehydrogenase (DPD) Deficiency Screening Using Uracil-Based Phenotyping on the Reduction of Severe Side Effect of 5-Fluorouracil-Based Chemotherapy: A Propension Score Analysis

Abstract

Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with severe fluoropyrimidines-induced toxicity. As of September 2018, French recommendations call for screening for DPD deficiency by plasma uracil quantification prior to all fluoropyrimidine-based chemotherapy. A dose reduction of fluoropyrimidine is recommended when uracil concentration is equal to or greater than 16 ng/mL. This matched retrospective study assessed the impact of DPD screening on the reduction of severe side effects and on the management of DPD-deficient patients. Using a propensity score, we balanced the factors influencing 5-Fluorouracil (5-FU) toxicity. Then, the severity scores (G3 and G4 severity as well as their frequency) of patients who did not benefit from DPD screening were compared with those of patients who benefited from DPD screening for each treatment cycle (from 1 to 4). Among 349 screened patients, 198 treated patients were included. Among them, 31 (15.7%) had DPD deficiency (median uracilemia 19.8 ng/mL (range: 16.1–172.3)). The median toxicity severity score was higher in the unscreened group for each treatment cycle (0 vs. 1, p < 0.001 at each cycle from 1 to 4) as well as the cumulative score during all courses of treatment (p = 0.028). DPD-deficient patients received a significantly lower dose of 5-FU (p < 0.001). This study suggests that pretherapeutic plasmatic uracil assessment, along with 5-FU dosage adjustment, may be beneficial in reducing 5-FU toxicity in real-life patients.

Renal impairment and abnormal liver function tests in pre-therapeutic phenotype-based DPD deficiency screening using uracilemia: a comprehensive population-based study in 1138 patients

“…This may also be a result of inter-laboratory variability, as observed in several previous studies. 29,37 To our knowledge, this study was also the first to describe several patients who underwent a second uracil concentration measurement. Intraindividual test reproducibility should be considered to evaluate its accuracy.…”

“…This may also be a result of inter-laboratory variability, as observed in several previous studies. 29,37…”

“…A recent matched retrospective study, using a propension score analysis in 198 patients, suggested that pretherapeutic plasmatic uracil assessment, along with 5-FU dosage adjustment, may be beneficial in reducing 5-FU toxicity in real-life patients. 37 However, the retrospective design limited the sensitivity to detect toxicities below grade 3, and further prospective studies are needed. Second, biological confounders were measured during a period up to 28 days before or after the uracil concentration measurement which could have impacted the results.…”

Complete DPYD genotyping combined with dihydropyrimidine dehydrogenase phenotyping to prevent fluoropyrimidine toxicity: A retrospective study

“…11 In the genotyping group, we found that 6% of our patients carried nonfunctional DPYD variants, which is in line of prior findings (4% in the report by Pallet et al 11 and about 8% in three other studies 1,8,14 ). In the phenotyping group, 2% of patients were poor metabolizers, a lower percentage than previously reported (e.g., 16% in the study by Laures et al 15 and 7% in Pallet et al 11 ). However, this percentage should be interpreted with caution, given the small size of this group (n = 41).…”

Impact of renal impairment on dihydropyrimidine dehydrogenase (DPD) phenotyping

“…The use of pre-therapeutic uracilemia and subsequent adaptive dosing should not be questioned as it allows a decrease in the rate of 5-FU toxicity. 26 However, DPD phenotyping using uracil concentrations might be misleading in patients with impaired renal function. If the patients are dialyzed, even if false-positive results could not be excluded, phenotyping of DPD deficiency should preferably be carried out with samples collected after dialysis.…”