European journal of cancer (Oxford, England : 1990), Volume 224, 30 5 2025, Pages 115483 Dose-individualisation of fluoropyrimidines based on pre-treatment serum uracil levels: the Alpe2U study. Knikman JE, de With M, Heersche N, Lopez-Yurda M, Baars A, Creemers GJ, Droogendijk HJ, Fiets E, Imholz ALT, Iersel LV, Mandigers CMPW, van de Vendel AJ, Jeurissen FJF, Nieboer P, Deenen MJ, van de Poel MHW, Wymenga MNM, van Schaik RHN, van den Bosch BJC, Hoop EO, Rosing H, Swen JJ, Gelderblom H, Schellens JHM, Beijnen JH, Mathijssen RHJ, Guchelaar HJ, Cats A
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 dose-reduced DPYDwt/Uhigh patients (177 vs 381 ng*h/mL), while five subsequently treated fully dosed DPYDwt/Uhigh patients exhibited comparable exposure to historical wild-type controls (456 vs 381 ng*h/mL). No correlation was found between uracil levels and DPD enzyme activity (R=-0.006, P = 0.98).
Conclusion
Uracil-guided dosing of fluoropyrimidines may reduce toxicity risk but leads to subtherapeutic 5-fluorouracil exposure in DPYD wild-type patients. This indicates that these patients are treated sub-optimally and that uracil is not a reliable predictor of DPD deficiency in DPYD wild-type patients.
