Toxicity Associated with Capecitabine in Patients Suffering from Dihydropyrimidine Dehydrogenase Deficiency

Abstract

Dihydropyrimidine dehydrogenase (DPD) is a metabolic enzyme that is crucial in 5-fluorouracil (5-FU) degradation. A deficiency in it is associated with the occurrence of adverse events following fluoropyrimidine-based therapies. We describe a case of toxicity grade 5 after the administration of capecitabine and oxaliplatin in a patient with stage III colorectal cancer and DPD congenital deficiency, which was identified later. Several polymorphisms have been associated with the global toxicity of 5-FU; however, genetic tests are low in sensitivity and therefore they cannot as yet be used as prescreening techniques in clinical practice.

Dihydropyrimidine Dehydrogenase Levels in Colorectal Cancer Cells Treated with a Combination of Heat Shock Protein 90 Inhibitor and Oxaliplatin or Capecitabine

“…DPD dysregulation has been shown to be involved in occurrence of the adverse events of fluoropyrimidine- and oxaliplatin treatments. 24,25 In this study, the DPD levels was evaluated after treatments with capecitabine and oxaliplatin in combination with 17-AAG in CRC cells.…”

“…17,35,36 DPD is an important enzyme in the biochemical functions of the antimetabolite drugs whose altered expression is related to adverse events following fluoropyrimidine- and oxaliplatin-based treatments. 24,25 In two panels of CRC cell lines, double chemotherapy with capecitabine, oxaliplatin, and 17-AAG was superior to single chemotherapy in terms of efficacy. 17 The elevated levels of cytotoxicity in more effective combinations could be related to different mechanisms apart from DPD mediating effects in double combinations.…”

“…24 Indeed, DPD dysregulation has been shown to be associated with the toxicity of these drugs. 20,24,25…”

Fluoropyrimidine-Associated Toxicity in Two Gastrointestinal Cancer Patients: Potential Role of Common DPYD Polymorphisms

“…As rightly underlined by Deenen and Meulendijks [6], screening for DPYD variants may not eliminate all fluoropyrimidine-associated toxicities; however, the evidence regarding the clinical utility of DPYD genotype-guided dosing of fluoropyrimidines is such that it should be considered in international clinical practice guidelines. Until now, pretherapeutic DPYD pharmacogenetic testing to prevent fluoropyrimidine-related toxicities has not been a very common practice in medical oncology; however, the evidence of the clinical validity and specificity of the DPYD *2A, DPYD *13, and DPYD rs67376798 genotyping test to prevent fluoropryrimidine-related toxicity and to preserve treatment compliance could change the habits in medical oncology [7,8]. The more common deep intronic variant c.1129- 5923C>G has been significantly linked to severe 5-FU toxicity [9,10].…”