Potential added value of combined DPYD/DPD genotyping and phenotyping to prevent severe toxicity in patients with a DPYD variant and decreased dihydropyrimidine dehydrogenase enzyme activity.

Charlotte W Ockeloen,Annelieke Ecab Willemsen,Manon Hijmans-Van Der Vegt,Bianca Jc Van Den Bosch,Aron Raaijmakers,Judith De Vos-Geelen,Marieke Jh Coenen,Jörgen Bierau

doi:10.1177/10781552211049144

Abstract

To investigate if dihydropyrimidine dehydrogenase phenotyping has added value when combined with DPYD genotyping in predicting fluoropyrimidine-related toxicity. Retrospective cohort study in which treatment and toxicity data were collected of 228 patients genotyped for four DPYD variants and phenotyped using an ex vivo peripheral blood mononuclear cell assay. Severe toxicity occurred in 25% of patients with a variant and normal dihydropyrimidine dehydrogenase activity, in 21% of patients without a variant and with decreased dihydropyrimidine dehydrogenase activity, and in 29% of patients without a variant and with normal dihydropyrimidine dehydrogenase activity (controls). The majority of patients with a variant or a decreased dihydropyrimidine dehydrogenase activity received an initial dose reduction (68% and 53% vs 19% in controls) and had a lower mean dose intensity (75% and 81% vs 91% in controls). Fifty percent of patients with a variant and decreased enzyme activity experienced severe toxicity, despite the lowest initial dose and whole treatment dose intensity. They also experienced more grade 4/5 toxicities. Our results indicate that a combined genotype-phenotype approach could be useful to identify patients at increased risk for fluoropyrimidine-associated toxicity (e.g. patients with a variant and decreased dihydropyrimidine dehydrogenase activity). Because the group sizes are too small to demonstrate statistically significant differences, this warrants further research in a prospective study in a larger cohort.

Highlights

Fluoropyrimidines (fluorouracil (5-FU) and its prodrug capecitabine) are commonly used in the treatment of several types of malignancies.[1,2,3] Previous studies have shown that nonindividualized fluoropyrimidine treatment causes severe toxicity in 6–34% of patients (grade ≥3, based on the CommonTerminology Criteria for Adverse Effects (CTCAE) gradingsystem).[4,5,6,7] Toxic effects of fluoropyrimidines mainly include stomatitis, mucositis, myelosuppression, and hand-foot syndrome
There are very few studies investigating toxicity in patients who are genotyped and phenotyped for dihydropyrimidine dehydrogenase (DPD) prior to fluoropyrimidine treatment. The results of this retrospective cohort study suggest that patients carrying a DPYD variant who have a decreased DPD enzyme activity, might have a high risk of toxicity even with a reduced fluoropyrimidine dose intensity
Our results indicate that in patients with a known DPYD variant, the risk of severe toxicity could be even higher when the DPD enzyme activity is low

Summary

Introduction

Fluoropyrimidines (fluorouracil (5-FU) and its prodrug capecitabine) are commonly used in the treatment of several types of malignancies.[1,2,3] Previous studies have shown that nonindividualized fluoropyrimidine treatment causes severe toxicity in 6–34% of patients (grade ≥3, based on the CommonTerminology Criteria for Adverse Effects (CTCAE) gradingsystem).[4,5,6,7] Toxic effects of fluoropyrimidines mainly include stomatitis, mucositis, myelosuppression, and hand-foot syndrome. Fluoropyrimidines (fluorouracil (5-FU) and its prodrug capecitabine) are commonly used in the treatment of several types of malignancies.[1,2,3] Previous studies have shown that nonindividualized fluoropyrimidine treatment causes severe toxicity in 6–34% of patients Over 80% of the active 5-fluorouracil (5-FU) is metabolized in the liver.[10] The most important enzyme in the metabolism of fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD).[11] At least 3–5% of the Caucasian population has a decreased or absent DPD enzyme activity.[12,13] As these findings strongly depend on methods used to measure DPD activity, considerably higher numbers of patients with decreased DPD activity have been reported.[14] Several studies have shown a link between a decreased DPD enzyme activity and severe fluoropyrimidine toxicity. Between 36 and 59% of the patients who experience severe fluoropyrimidine toxicity (grade ≥3) have a decreased DPD enzyme activity.[15,16,17]

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