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Prediction of severe toxicity in adult patients under treatment with 5-fluorouracil

a prospective cohort study

Vázquez, Carolinaa,c; Orlova, Maríac; Angriman, Federicoc,e; Minatta, José N.b; Scibona, Paulaa; Verzura, María A.b; Jáuregui, Esteban G.a; Díaz de Arce, Heidyd; Pallotta, María G.b; Belloso, Waldo H.a

doi: 10.1097/CAD.0000000000000546
CLINICAL REPORTS
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5-Fluorouracil (5-FU) has long been used for the treatment of gastrointestinal tumors harboring interindividual variability in both the pharmacokinetic and the pharmacogenetic profiles, which in turn may lead to life-threatening toxicities. We carried out a prospective cohort study of adult patients initiating treatment with 5-FU between 2013 and 2015. Primary exposures of interest were the methylenetetrahydrofolate reductase single nucleotide polymorphism in exons 4 and 7 and 5′-untranslated region-thymidylate synthase VNTR genotypes, in addition to baseline clinical and demographic variables. The primary outcome was the time to the occurrence of severe toxicity. We used a Cox regression model to evaluate patients’ survival and toxicity experience and its association with baseline characteristics and a priori determined genetic polymorphisms. A total of 197 patients were included, 40.1% developed severe toxicity during follow-up. Variables that were significantly associated with developing severe toxicity were the European Organization for Research and Treatment of Cancer functional score [hazard ratio (HR): 0.98; 95% confidence interval (CI): 0.97–0.99]; type of tumor [anus (HR: 2.50; 95% CI: 1.07–5.82), head and neck/esophagus/stomach (HR: 2.95; 95% CI: 1.64–5.33)] and 5-FU continuous infusion regimens over 4–5 days (HR: 9.35; 95% CI: 2.68–32.59). We found a significant association between baseline functional status, type of tumor and continuous infusion regimens and the occurrence of severe toxicity during the follow-up of patients receiving 5-FU. No association was found with the genotypic variants evaluated. Future validation and modeling of an everyday easy-to-use score to predict toxicity among these subgroup of patients remains warranted.

aClinical Pharmacology Section

bClinical Oncology Section, Internal Medicine Department

cInternal Medicine Section, Internal Medicine Department

dMolecular Biology Section, Central Laboratory, Hospital Italiano de Buenos Aires

ePharmacology Department, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina

Correspondence to Carolina Vázquez, MD, J.D. Perón 4190, Clinical Pharmacology Section, Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Buenos Aires C1181ACH, Argentina Tel/fax: +54 114 959 0866; e-mail: carolina.vazquez@hospitalitaliano.org.ar

Received December 28, 2016

Accepted June 29, 2017

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.