TY - JOUR
T1 - Dose-individualisation of fluoropyrimidines based on pre-treatment serum uracil levels
T2 - the Alpe2U study
AU - Knikman, Jonathan E
AU - de With, Mirjam
AU - Heersche, Niels
AU - Lopez-Yurda, Marta
AU - Baars, Arnold
AU - Creemers, Geert-Jan
AU - Droogendijk, Helga J
AU - Fiets, Edward
AU - Imholz, Alexander L T
AU - Iersel, Liselot Valkenburg-van
AU - Mandigers, Caroline M P W
AU - van de Vendel, Alina J
AU - Jeurissen, Frank J F
AU - Nieboer, Peter
AU - Deenen, Maarten J
AU - van de Poel, Marlène H W
AU - Wymenga, Machteld N M
AU - van Schaik, Ron H N
AU - van den Bosch, Bianca J C
AU - Hoop, Esther Oomen-de
AU - Rosing, Hilde
AU - Swen, Jesse J
AU - Gelderblom, Hans
AU - Schellens, Jan H M
AU - Beijnen, Jos H
AU - Mathijssen, Ron H J
AU - Guchelaar, Henk-Jan
AU - Cats, Annemieke
N1 - Publisher Copyright:
© 2025
PY - 2025/6/25
Y1 - 2025/6/25
N2 - 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 (DPYD
wt/U
high) received a 50 % dose reduction, in accordance with French RNPGx guidelines. The incidence of grade ≥ 3 fluoropyrimidine-related toxicity was compared between dose-reduced DPYD
wt/U
high patients, DPYD
wt patients with uracil ≤ 16 ng/mL (DPYD
wt/U
normal), and a historical cohort of DPYD
wt/U
high patients treated at full dose. Pharmacokinetic data were compared to a second historical cohort.
RESULTS: Among 612 evaluable patients, 22 were DPYD
wt/U
high. The incidence of severe toxicity in the dose-reduced group was significantly lower than in historical full-dose DPYD
wt/U
high patients (20 % vs 43 %, P = 0.03) and comparable during the first 2 treatment cycles to DPYD
wt/U
normal patients (10 % vs 11 %). However, 5-fluorouracil exposure was markedly reduced in nineteen dose-reduced DPYD
wt/U
high patients (177 vs 381 ng*h/mL), while five subsequently treated fully dosed DPYD
wt/U
high 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.
AB - 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 (DPYD
wt/U
high) received a 50 % dose reduction, in accordance with French RNPGx guidelines. The incidence of grade ≥ 3 fluoropyrimidine-related toxicity was compared between dose-reduced DPYD
wt/U
high patients, DPYD
wt patients with uracil ≤ 16 ng/mL (DPYD
wt/U
normal), and a historical cohort of DPYD
wt/U
high patients treated at full dose. Pharmacokinetic data were compared to a second historical cohort.
RESULTS: Among 612 evaluable patients, 22 were DPYD
wt/U
high. The incidence of severe toxicity in the dose-reduced group was significantly lower than in historical full-dose DPYD
wt/U
high patients (20 % vs 43 %, P = 0.03) and comparable during the first 2 treatment cycles to DPYD
wt/U
normal patients (10 % vs 11 %). However, 5-fluorouracil exposure was markedly reduced in nineteen dose-reduced DPYD
wt/U
high patients (177 vs 381 ng*h/mL), while five subsequently treated fully dosed DPYD
wt/U
high 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.
U2 - 10.1016/j.ejca.2025.115483
DO - 10.1016/j.ejca.2025.115483
M3 - Article
C2 - 40466468
SN - 0959-8049
VL - 224
JO - European Journal of Cancer
JF - European Journal of Cancer
M1 - 115483
ER -