A rapid and inexpensive method for anticipating severe toxicity to fluorouracil and fluorouracil-based chemotherapy

• Published in: Therapeutic drug monitoring Vol. 28; no. 5; p. 678
• Main Authors: Ciccolini, Joseph, Mercier, Cédric, Evrard, Alexandre, Dahan, Laetitia, Boyer, Jean-Christophe, Duffaud, Florence, Richard, Karine, Blanquicett, Carmelo, Milano, Gérard, Blesius, Aurore, Durand, Alain, Seitz, Jean-François, Favre, Roger, Lacarelle, Bruno
• Format: Journal Article
• Language: English
• Published: United States 01.10.2006
• Subjects: Adult; Aged; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - therapeutic use; Chromatography, High Pressure Liquid; Dihydropyrimidine Dehydrogenase Deficiency; Dihydrouracil Dehydrogenase (NADP) - genetics; Drug Monitoring - methods; Female; Fluorouracil - adverse effects; Fluorouracil - blood; Fluorouracil - therapeutic use; Humans; Male; Middle Aged; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - mortality; Phenotype; Retrospective Studies
• ISSN: 0163-4356; 1536-3694
• DOI: 10.1097/01.ftd.0000245771.82720.c7

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.