Papel do teste respiratório com uracil marcado com carbono-13 na predição de risco de toxicidade ao quimoterápico 5-fluorouracil em pacientes portadores de Câncer Gastrointestinal

Abstract

INTRODUCTION: There are no clinically available methods to predict toxicity to the chemotherapeutic drug 5- Fluorouracil (5FU). The breath test after 13C-Uracil (UraBT) consists of measuring 13CO2 inexhaled breath after ingestion of 13C-Uracil to evaluate uracil (and 5FU) catabolic pathway.OBJECTIVES: To evaluate UraBT to 1) discriminate individuals with grade 3-4 toxicity versus grade 0-1 toxicity; 2) discriminate individuals with proven dihydropyrimidine-dehydrogenase (DPD)deficiency (among those with grade 3-4 toxicity) from those without DPD deficiency (among those with grade 0-1 toxicity). To develop a high-performance liquid chromatography method to measure plasma uracil (U) and dihydrouracil (UH2). To find the most frequent mutations ingene DPYD that cause DPD-deficiency in Brazilian subjects.PATIENTS: 33 patients with gastrointestinal cancer previously exposed to 5FU from which 13 had grade3-4 toxicity and 20 grade 0-1 toxicity.METHODS: The following tests were developed and conducted: (1) sequencing DPYD gene in search for deleterious mutations; (2) determination of plasma ratio UH2/U, surrogate marker of DPDactivity; (3) UraBT in IRIS-2 infrared spectrometry.RESULTS: 4/13 patients with grade 3-4 toxicity proved to be DPD-deficient: three had deleterious mutations, and one had low UH2/U ratio. UraBT was significantly different between groupswith grade 3-4 and grade 0-1 toxicity (sensitivity 61.5%; specificity 85%) and between DPDdeficient patients and non DPD-deficient patients (sensitivity 75%; specificity 85%). CONCLUSION: UraBT has moderate accuracy in discriminating individuals with grade 0-1 toxicity from those with grade 3-4 toxicity, and DPD-deficients from non DPD-deficients.