DPD deficiency

Capecitabine is used for the treatment of colorectal and breast cancers. It is contraindicated in patients with known hypersensitivity to capecitabine or any of its components or to 5-fluorouracil and in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. The use of capecitabine is restricted in patients with severe renal impairment. The drag can induce diarrhea, sometimes severe. Other side effects include anemia, hand-foot syndrome, hyperbilirubinemia, nausea, stomatitis, pyrexia, edema, constipation, dyspnea, neutropenia, back pain, and headache. Cardiotoxicity has been observed with capecitabine. A clinically important drag interaction between capecitabine and warfarin has been demonstrated. Care should be exercised when the drag is co-administered with CYP2X9 substrates. 

Fig. 14.4 Heritability of DPD deficient phenotype. DPD activity was measured in peripheral blood mononuclear cells from a proband, her family members, and healthy volunteers (controls).

The complexity of the genetic basis of DPD deficiency implies that the identification of patients at high risk of 5-FU toxicity is mostly based on phenotypic procedures. These methods are not suitable for general use and concomitant drags, dietary intake and other environmental factors could reduce their predictive power in cases of partial DPD deficit. 

Collie-Duguid ES, Etienne MC, Milano G et al. Known variant DPYD alleles do not explain DPD deficiency in cancer patients. Pharmacogenetics 2000 10 217-223. 

FU Pharmacokinetics and Disposition DPD, THE Metabolic Gate-Keeper DPD Deficiency and Treatment-Related Toxicities Upon 5-FU Administration Tumoral DPD Expression and Treatment Efficacy... 

Recent studies have demonstrated that 5-FU clearance fell from 65 down to half-life increase from 0.7 to >5 hr in a subset of patients displaying profound alterations in DPD function (16). Separate studies have also consistently shown that patients with DPD deficiency exhibited 5-FU plasma levels... 

DPD DEFICIENCY AND TREATMENT-RELATED TOXICITIES UPON 5-FU ADMINISTRATION... 

Recent studies have shown that 5-FU therapy leads to approximately 6%-15% of early grade-3/4 toxicities, with l%-4% risk of fatal outcome depending on the age of the patients (20,21,22). Forty-seventy percent of the severe toxicities encountered with 5-FU can be linked with some kind of DPD deficiency (20,23,24). 

Besides the direct, dramatic incidence of acute toxicities on the patient s well-being, these side effects impact as well on the overall survival, because the forthcoming drug cycles have to be postponed or cancelled to allow proper recovery, with a subsequent loss of chance of treatment for the patients. Although the clinical consequences of DPD deficiency upon 5-FU therapy are well characterized now, its impact on capecitabine treatment remains unclear. 

The evidence for the role of DPD deficiency in capecitabine-induced toxicities has been demonstrated by some recent clinical reports (20, 29, 38), and has been finally confirmed by the first report of a toxic-death in a patient with DPYD gene polymorphism and severe enzyme deficiency treated in a capecitabine-containing protocol (28). Overall, numerous clinical reports have shown a link between the level of enzyme deficiency and the severity/lethality of the observed toxicities upon fiuoropyrimidines administration (35,39), thus warranting the need for early detection of patients at risk. 

Genetic mutations are a major cause of DPD impairment (24,58). Polymorphism of the DPYD gene has been well characterized as an autosomal recessive disease, with 0.5% and 3%-5% of the Caucasian population being subsequently affected by total and partial deficiencies, respectively (7,59,60). Thymine uraciluria is a condition caused by inherited total DPD deficiency that can be either associated with neurological disorders or be asymptomatic (61,62,63). 

Due to the critical role of the DPD status in 5-FU disposition and clinical outcome in cancer patients eligible for 5-FU-based chemotherapy, numerous methods have been proposed to identify DPD-deficient patients. A first strategy consists of describing... 

Ciccolini J, Mercier C, Dahan L et al. Implication of DPD deficiency in severe or lethal toxicities after 5-fluorouracil and capecitabine-based chemotherapies. AACR Annual Meeting Proceedings 2004 46. Ciccolini J, Mercier C, Dahan L et al. Toxic death-case after capecitabine + oxaliplatin (XELOX) administration probable implication of dihydropyrimidine deshydrogenase deficiency. Cancer Chemother Pharmacol 2006 58 272-275. 

Johnson MR, Yan J, Shao L et al. Semi-automated radioassay for determination of dihydropyrimidine dehydrogenase (DPD) activity screening cancer patients for DPD deficiency, a condition associated with 5-fluorouracil ioxieity. J Chromatogr B BiomedSci Appl 1997 696 183-191. 

Maring JG DPD phenotyping in human volunteers and a DPD-deficient patient by assessing uracil pharmacokinetics after an oral oral uracil test dose a preliminary report. In New Insight of Pyrimidine Antagonists Chemotherapy, Chapter 5, pp. 102-111, Thesis, University of Gronigen, NL, 2005. 

Mercier C, Ciccolini J, Dupuis C et al. Prospective phenotypic screening for DPD deficiency in patients upon fluoropyrimidines administration Impact on the reduction of drug-induced toxicities. Asco Annual Meeting Proceedings. J Clin Oncol. 2007 25. 

Saif MW, Ezzeldin H, Vance K et al. DPYD 2A mutation the most common mutation associated with DPD deficiency. Cancer Chemother Pharmacol 2007 60 503-507. 

Van Kuilenburg AB, Muller EW, Haasjes J, et al. Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil frequency of the common IVS14+1G> A mutation causing DPD deficiency. Clin Cancer Res 2001 7(5) 1149-53. 

Some patients unable to metabolize pyrimidine drugs (-8 % of population) may have dihydrr yrimidine dehydrogenase (DPD) deficiency... 

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