Dose-individualisation of fluoropyrimidines based on pre-treatment serum uracil levels: the Alpe2U study

Jonathan E. Knikman; Mirjam de With; Niels Heersche; Marta Lopez-Yurda; Arnold Baars; Geert Jan Creemers; Helga J. Droogendijk; Edward Fiets; Alexander L.T. Imholz; Liselot Valkenburg van Iersel; Caroline M.P.W. Mandigers; Alina J. van de Vendel; Frank J.F. Jeurissen; Peter Nieboer; Maarten J. Deenen; Marlène H.W. van de Poel; Machteld N.M. Wymenga; Ron H.N. van Schaik; Bianca J.C. van den Bosch; Esther Oomen de Hoop; Hilde Rosing; Jesse J. Swen; Hans Gelderblom; Jan H.M. Schellens; Jos H. Beijnen; Ron H.J. Mathijssen; Henk Jan Guchelaar; Annemieke Cats

doi:10.1016/j.ejca.2025.115483

Dose-individualisation of fluoropyrimidines based on pre-treatment serum uracil levels: the Alpe2U study

Jonathan E. Knikman
, Mirjam de With
, Niels Heersche
, Marta Lopez-Yurda
, Arnold Baars
, Geert Jan Creemers
, Helga J. Droogendijk
, Edward Fiets
, Alexander L.T. Imholz
, Liselot Valkenburg van Iersel
, Caroline M.P.W. Mandigers
, Alina J. van de Vendel
, Frank J.F. Jeurissen
, Peter Nieboer
, Maarten J. Deenen
, Marlène H.W. van de Poel
, Machteld N.M. Wymenga
, Ron H.N. van Schaik
, Bianca J.C. van den Bosch
, Esther Oomen de Hoop

Hilde Rosing, Jesse J. Swen, Hans Gelderblom, Jan H.M. Schellens, Jos H. Beijnen, Ron H.J. Mathijssen, Henk Jan Guchelaar, Annemieke Cats^*

^*Corresponding author for this work

Netherlands Cancer Institute
Erasmus University Rotterdam
Gelderland Valley Hospital
Catharina Hospital
Bravis Hospital
Medical Centre Leeuwarden
Deventer Ziekenhuis
Maastricht UMC+
Canisius Wilhelmina Hospital
Maasstad Ziekenhuis MCH - Bronovo
Wilhelmina Ziekenhuis
Leiden University
Laurentius Hospital
Medisch Spectrum Twente
Maastricht University

Research output: Contribution to journal › Article › Academic › peer-review

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 (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.

Original language	English
Article number	115483
Journal	European Journal of Cancer
Volume	224
Early online date	30 Apr 2025
DOIs	https://doi.org/10.1016/j.ejca.2025.115483
Publication status	Published - 25 Jun 2025

Bibliographical note

Publisher Copyright:
© 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Dose-individualisation
Fluoropyrimidines
Genotyping
Phenotyping
Toxicity

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10.1016/j.ejca.2025.115483

Dose-individualisation of fluoropyrimidines based on pre-treatment serum uracil levels: the Alpe2U studyFinal published version, 941 KBLicence: Taverne

Cite this

Knikman, J. E., de With, M., Heersche, N., Lopez-Yurda, M., Baars, A., Creemers, G. J., Droogendijk, H. J., Fiets, E., Imholz, A. L. T., Iersel, L. V. V., Mandigers, C. M. P. W., van de Vendel, A. J., Jeurissen, F. J. F., Nieboer, P., Deenen, M. J., van de Poel, M. H. W., Wymenga, M. N. M., van Schaik, R. H. N., van den Bosch, B. J. C., ... Cats, A. (2025). Dose-individualisation of fluoropyrimidines based on pre-treatment serum uracil levels: the Alpe2U study. European Journal of Cancer, 224, Article 115483. https://doi.org/10.1016/j.ejca.2025.115483

@article{e4437f0c64a24285b97751284d88fe3c,

title = "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 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.",

keywords = "Dose-individualisation, Fluoropyrimidines, Genotyping, Phenotyping, Toxicity",

author = "Knikman, \{Jonathan E.\} and \{de With\}, Mirjam and Niels Heersche and Marta Lopez-Yurda and Arnold Baars and Creemers, \{Geert Jan\} and Droogendijk, \{Helga J.\} and Edward Fiets and Imholz, \{Alexander L.T.\} and Iersel, \{Liselot Valkenburg van\} and Mandigers, \{Caroline M.P.W.\} and \{van de Vendel\}, \{Alina J.\} and Jeurissen, \{Frank J.F.\} and Peter Nieboer and Deenen, \{Maarten J.\} and \{van de Poel\}, \{Marl{\`e}ne H.W.\} and Wymenga, \{Machteld N.M.\} and \{van Schaik\}, \{Ron H.N.\} and \{van den Bosch\}, \{Bianca J.C.\} and Hoop, \{Esther Oomen de\} and Hilde Rosing and Swen, \{Jesse J.\} and Hans Gelderblom and Schellens, \{Jan H.M.\} and Beijnen, \{Jos H.\} and Mathijssen, \{Ron H.J.\} and Guchelaar, \{Henk Jan\} and Annemieke Cats",

note = "Publisher Copyright: {\textcopyright} 2025",

year = "2025",

month = jun,

day = "25",

doi = "10.1016/j.ejca.2025.115483",

language = "English",

volume = "224",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "Elsevier Ltd",

}

Knikman, JE, de With, M, Heersche, N, Lopez-Yurda, M, Baars, A, Creemers, GJ, Droogendijk, HJ, Fiets, E, Imholz, ALT, Iersel, LVV, 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, EOD, Rosing, H, Swen, JJ, Gelderblom, H, Schellens, JHM, Beijnen, JH, Mathijssen, RHJ, Guchelaar, HJ & Cats, A 2025, 'Dose-individualisation of fluoropyrimidines based on pre-treatment serum uracil levels: the Alpe2U study', European Journal of Cancer, vol. 224, 115483. https://doi.org/10.1016/j.ejca.2025.115483

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

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 (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.

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 (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.

KW - Dose-individualisation

KW - Fluoropyrimidines

KW - Genotyping

KW - Phenotyping

KW - Toxicity

UR - https://www.scopus.com/pages/publications/105007085803

U2 - 10.1016/j.ejca.2025.115483

DO - 10.1016/j.ejca.2025.115483

M3 - Article

AN - SCOPUS:105007085803

SN - 0959-8049

VL - 224

JO - European Journal of Cancer

JF - European Journal of Cancer

M1 - 115483

ER -

Dose-individualisation of fluoropyrimidines based on pre-treatment serum uracil levels: the Alpe2U study

Abstract

Bibliographical note

UN SDGs

Keywords

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