Prospective DPYD genotyping prevents severe fluoropyrimidine-induced toxicity by decreasing initial dosages in DPYD variant allele carriers. However, fluoropyrimidine dosages in chemoradiation therapy are already lower compared to other fluoropyrimidine-containing regimens. It is unknown if recommended dose reductions of pharmacogenetic guidelines are valid for DPYD variant allele carriers receiving fluoropyrimidines in chemoradiation therapy. The aim of this study was to investigate severe toxicity in DPYD variant allele carriers receiving chemoradiation therapy.
Three databases were used, containing data on patients who received fluoropyrimidine-based chemoradiation therapy. Frequencies of severe (grade ≥3) toxicity in DPYD variant allele carriers (DPYD*2A, DPYD*13, c.2846A>T or c.1236G>A) receiving upfront fluoropyrimidine dose reductions according to current pharmacogenetic dosing guidelines (50 or 75% depending on the variant), and DPYD variant allele carriers receiving full-dose were compared to DPYD wild-type patients receiving standard dose fluoropyrimidines in chemoradiation therapy.
DPYD variant allele carriers treated with standard dosages (N = 34) showed an increased risk of severe gastrointestinal (adjusted OR = 2.58, 95% CI = 1.02-6.53, P = 0.045) or severe haematological (adjusted OR = 4.19, 95% CI = 1.32-13.25, P = 0.015) toxicity compared to wild-type patients (N = 771). DPYD variant allele carriers who received dose reductions (N = 22) showed a comparable frequency of severe gastrointestinal toxicity, but a higher frequency of severe haematological toxicity, compared to wild-type patients. The mean duration of hospitalisation was significantly shorter in DPYD variant allele carriers who received dose reductions compared to DPYD variant allele carriers treated with standard dosages (4 versus 23 days, P = 0.010).
Standard fluoropyrimidine dosages in chemoradiation therapy resulted in an increased risk of severe toxicity in DPYD variant allele carriers. Fluoropyrimidine dose reductions for DPYD variant allele carriers should also be applied in patients receiving chemoradiation therapy.
Clinical trial identification
Legal entity responsible for the study
Leiden University Medical Centre.
Has not received any funding.
C.A.T.C. Lunenburg: Previously supported by an unrestricted grant from Roche Pharmaceuticals. All other authors have declared no conflicts of interest.