Dose-individualisation of fluoropyrimidines based on pre-treatment serum uracil levels: the Alpe2U study
Abstract
BACKGROUND
DPYD-guided dosing enhances safety of fluoropyrimidine-based chemotherapy. However, approximately 23 % of patients still experience severe toxicity unexplained by the four commonly tested DPYD-variant alleles. Elevated pre-treatment uracil levels have been proposed as a surrogate marker for reduced DPD activity and an independent predictor of toxicity. This prospective study evaluated whether uracil-guided dose individualisation can reduce severe fluoropyrimidine-induced toxicity in DPYD wild-type patients.
METHODS
Pre-treatment plasma uracil levels were quantified in patients scheduled to receive fluoropyrimidine-based therapy. DPYD wild-type individuals with uracil concentrations > 16 ng/mL (DPYDwt/Uhigh) received a 50 % dose reduction, in accordance with French RNPGx guidelines. The incidence of grade ≥ 3 fluoropyrimidine-related toxicity was compared between dose-reduced DPYDwt/Uhigh patients, DPYDwt patients with uracil ≤ 16 ng/mL (DPYDwt/Unormal), and a historical cohort of DPYDwt/Uhigh patients treated at full dose. Pharmacokinetic data were compared to a second historical cohort.
RESULTS
Among 612 evaluable patients, 22 were DPYDwt/Uhigh. The incidence of severe toxicity in the dose-reduced group was significantly lower than in historical full-dose DPYDwt/Uhigh patients (20 % vs 43 %, P = 0.03) and comparable during the first 2 treatment cycles to DPYDwt/Unormal patients (10 % vs 11 %). However, 5-fluorouracil exposure was markedly reduced in nineteen…
How strong is the evidence?
Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 612 participants or records.
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