A Rapid and Inexpensive Method for Anticipating Severe Toxicity to Fluorouracil and Fluorouracil-based Chemotherapy

Abstract

Dihydropyrimidine dehydrogenase (DPD) deficiency leads to dramatic overexposure to fluorouracil (5-FU), resulting in a potentially lethal outcome in patients treated with standard doses. The aim of this study was to validate, in a routine clinical setting, a simple and rapid method to determine the DPD status in a subset of cancer patients, all presenting with life-threatening toxicities following 5-FU or capecitabine intake. In this study, 80 out of 615 patients (13%) suffered severe toxicities, including 5 lethal ones (0.8%), during or after chemotherapy with a fluoropyrimidine drug. Patients with severe toxicities were treated with 5-FU (76 patients) or capecitabine-containing protocols (4 patients). Simplified uracil to di-hydrouracil (U/UH2) ratio determination in plasma was retrospectively performed in these 80 patients, as a surrogate marker of DPD activity. When possible, 5-FU Css determination was performed, and screenings for the canonical IVS14+1G>A mutation were systematically carried out. Comparison of the U/UH2 ratios with a reference, non-toxic population, showed abnormal values suggesting impaired DPD activity in 57 out of the 80 toxic patients (71%) included in this study, and in 4 out of 5 patients (80%) with a fatal outcome. Similarly, drug exposures up to 15 times higher than the range observed in the non-toxic population were also observed. Importantly, no IVS14+1G>A mutation was found in these patients, including those displaying the most severe or lethal toxicities. These data warrant systematic detection of DPD-deficient patients prior to fluoropyrimidine administration, including when oral capecitabine (Xeloda) is scheduled. Finally, the simplified methodology presented here proved to be a low cost and rapid way to identify routinely patients at risk of toxicity with 5-FU or capecitabine.

5-FU-induced neurotoxicity in cancer patients with profound DPD deficiency syndrome: a report of two cases

“…ratio HPLC method in plasma. Both patients were found to be profoundly DPDdeficient with regard to our reference population [5]. …”

“…Using this methodology, we found that this patient was profoundly DPD-deficient (Figure 1), with a U/UH2 ratio value of 3.6, i.e. more than 3-time higher than the mean values usually recorded in our reference population [5]. Owing to the severity of her DPD deficiency, treatment was definitively stopped.…”

“…Here, we based our DPD evaluation on a simple and rapid functional testing which clinical relevance had already been demonstrated [5,13]. Several other functional approaches (e.g., uracil breath test, uracil challenge test, to name but a few) to establish the DPD status in patients had been proposed in the literature, with similar benefit compared to genotypic-based techniques [2,14].…”

“…Retrospective studies have demonstrated that 70% of the severe toxicities and 80% of the toxic deaths could be related to functional DPD deficiency, and therefore could be prevented by prospective screening and development of DPD-based dose tailoring strategies [5]. Beside haematological toxicities, some drug-induced neurotoxicities have been described with 5-FU, although this latter are by far less frequent and usually are not dose limiting [6].…”

Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy

“…Since eighties, the numerous methods based on determination of DPD status were advised to predict serious 5-FU-related toxicity. The function tests have been used for measurement of DPD enzyme activity by 2-[ 13 C]-uracil breath test, or determining uracil/dihydrouracil or [ 14 C]-thymine/dihydrothymine plasma ratio [32][33][34]. Substantial drawbacks of function tests are a need for specialized technology approaches or the use of radiolabeled chemicals not available worldwide [34].…”