Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper

Abstract

<b><i>Background:</i></b> 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2–1.0%. <b><i>Summary:</i></b> Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (<i>DPYD</i>). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. <b><i>Key Messages:</i></b> (i) Patients should be tested for the 4 most common genetic <i>DPYD</i> variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitoring.

Capecitabine-Induced Terminal Ileitis: Case Report and Literature Review

“…The majority of 5-FU is catabolized by DPD, which is encoded by the highly polymorphic DPYD gene [ 18 ]. Deficiency of DPD is reported in approximately 5-9% of patients, and administering fluoropyrimidines in the context of depressed enzyme activity can be fatal [ 4 , 19 ].…”

“…Curiously, the patient described by Mokrim et al only developed symptoms of ileitis after completing an entire cycle of capecitabine despite having diminished DPD activity [ 10 ]. Recommendations are in place advocating for routing screening for four most common DPD variants before initiating treatment with capecitabine, especially in regions with accentuated prevalence [ 19 ]. A recent genome-wide association study identified three novel SNPs, which can be used as germline genetic predictors of capecitabine-associated diarrhea and, potentially, ileitis [ 20 ].…”

Metastatic colorectal cancer: Advances in the folate-fluoropyrimidine chemotherapy backbone

“…In April 2020, the EMA recommended testing for DPD-deficiency prior to initiation of fluoropyrimidine treatment [92]. There are a number of laboratory tests for identifying patients with a DPD deficiency: measurement of uracil in plasma; measurement of DPD/thymidylate synthase activity in mononuclear cells; measurement of the physiological dihydrouracil/uracil ratio (UH2/U) in blood, urine, or saliva; or measurement of UH2/U following a test dose of uracil [93].…”

Overcoming barriers to implementing precision dosing with 5‐fluorouracil and capecitabine

“…The European Medicines Agency now recommends testing for DPD activity for patients receiving 5FU and capecitabine 48 and some countries are moving to make testing mandatory 49 . The increased push for mandatory screening should provide impetus for other countries to invest in and develop resources to make DPD testing part of routine care in patients receiving 5FU or capecitabine, for example by adding a requirement for TDM in the product label.…”

“…The European Medicines Agency now recommends testing for DPD activity for patients receiving 5FU and capecitabine 48 and some countries are moving to make testing mandatory. 49 Published cost analysis data showing upfront DPYD genotype-guided dose individualisation results in cost saving or in worst case cost neutral outcomes could be used to support the implementation of testing in a healthcare setting.…”