Original ArticleA Rapid and Inexpensive Method for Anticipating Severe Toxicity to Fluorouracil and Fluorouracil-based ChemotherapyCiccolini, Joseph PharmD, PhD*; Mercier, Cédric MD, PhD†; Evrard, Alexandre PharmD, PhD‡; Dahan, Laetitia MD§; Boyer, Jean-Christophe PharmD, PhD‡; Duffaud, Florence MD, PhD†; Richard, Karine MD§; Blanquicett, Carmelo PhD¶; Milano, Gérard PhD‖; Blesius, Aurore MD†; Durand, Alain PharmD, PhD*; Seitz, Jean-François MD, PhD§; Favre, Roger MD, PhD†; Lacarelle, Bruno PharmD, PhD* Author Information From the *Clinical Pharmacokinetics Department, La Timone University Hospital, Marseille, France; †Medical Oncology Department, La Timone University Hospital, Marseille, France; ‡Medical Biochemistry, Caremeau General Hospital, Nîmes, France; §Gastroenterology Department, La Timone University Hospital, Marseille, France; ¶Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, Wallace Tumor Institute, Birmingham, AL, USA; and ‖Oncopharmacology Unit, Centre Antoine Lacassagne, Nice, France. Joseph Ciccolini and Cédric Mercier contributed equally to this work. This study was partly presented at the AACR 96th Meeting, Anaheim, CA, April 16-20, 2005. Reprints: Cédric Mercier, MD, PhD, EA3286, School of Pharmacy of Marseille F-13385 Marseilles, France (e-mail: [email protected]). Therapeutic Drug Monitoring: October 2006 - Volume 28 - Issue 5 - p 678-685 doi: 10.1097/01.ftd.0000245771.82720.c7 Buy Metrics 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. © 2006 Lippincott Williams & Wilkins, Inc.