Dpd Deficiency And Treatmentrelated Toxicities Upon 5fu Administration

Recent studies have shown that 5-FU therapy leads to approximately 6%-15% of early grade-3/4 toxicities, with 1%-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).

Because there is a growing number of patients likely to be given a fluoropyrimi-dine drug, the clinical incidence of DPD impairment is a rising concern in oncology. Several studies have investigated the clinical consequences of 5-FU and capecitabine, administration in patients with impaired DPD activity (25,26,27,28,29). Fatal outcome has been associated with total DPD deficiency (30), although some data showed that partial deficiencies can result in toxic death as well upon 5-FU administration (31). When not directly lethal, the most frequent side effects reported in DPD-deficient patients treated with standard dosage of 5-FU are digestive and haematological toxicities (26,27,32,33,34,35).

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.

As an oral, triple pro-drug, capecitabine has been designed to deliver specifically 5-FU in tumor cells, and as such its pharmacokinetics profile should not be strongly affected by erratic DPD activity in the liver (36). Nevertheless, because the enzymes supporting final activation of capecitabine can be expressed in hepatocytes too, early synthesis of 5-FU may occur in the liver, thus leading eventually to plasma overexposure, as confirmed by a physiologically-based PK model (37).

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 fluoropyrimidines administration (35,39), thus warranting the need for early detection of patients at risk.

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