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5-Fluorouracil degradation rate could predict toxicity in stages II–III colorectal cancer patients undergoing adjuvant FOLFOX

Onesti, Concetta E.; Botticelli, Andrea; La Torre, Marco; Borro, Marina; Gentile, Giovanna; Romiti, Adriana; Lionetto, Luana; Petremolo, Antonella; Occhipinti, Mario; Roberto, Michela; Falcone, Rosa; Simmaco, Maurizio; Marchetti, Paolo; Mazzuca, Federica

doi: 10.1097/CAD.0000000000000453

5-Fluorouracil is commonly used for gastrointestinal cancer treatment in an adjuvant setting; however, the toxicity can lead to a reduction, delay, or discontinuation of treatment. We retrospectively investigated the association between the 5-fluorouracil degradation rate (5-FUDR) and genetic polymorphisms of TSER, DPYD, and MHTFR with toxicity in colorectal cancer patients treated with adjuvant FOLFOX. Pretreatment 5-FUDR and MTHFR A1298T or C677T, TSER, and DPYD gene polymorphisms were characterized in stages II–III colorectal cancer patients. Patients were classified into three metabolic classes according to the 5-FUDR value. Association with toxicities was evaluated retrospectively using logistic regression analysis. Overall, 126 patients were selected (35 women, 91 men). Seven patients were poor metabolizers, 116 patients were normal metabolizers and three patients were ultra-rapid metabolizers. The median 5-FUDR was 1.53 ng/ml/106 cells/min (range: 0.42–2.57 ng/ml/106 cells/min). Severe, rate-limiting toxicities (grades 3–4) were encountered in 22.2% of patients. No associations between MTHFR or TSER polymorphisms and toxicity were detected, whereas 5-FUDR showed a statistically significant association with toxicity (P=0.0047). The DPYD heterozygous mutation was detected in only one patient, who showed grade 4 hematological toxicity and a lower 5-FUDR value. The 5-FUDR value seems not to be affected by MTHFR and TSER polymorphisms. Compared with the available pharmacogenomics tests, the pretreatment evaluation of 5-FUDR increases the proportion of identified colorectal patients at high risk for severe toxicity. Thus, it appears to be a suitable pretreatment toxicity biomarker in a subgroup of patients in whom dose-intensity maintenance is the key factor.

Departments of aClinical and Molecular Medicine

bNeurosciences, Mental Health and Sensory Organs (NESMOS), ‘Sapienza’ University of Rome

Departments of cMedical Oncology

dGeneral Surgery, Sant’Andrea Hospital

eIstituto Dermopatico dell’Immacolata-IRCCS, Rome, Italy

Correspondence to Andrea Botticelli, MD, Department of Clinical and Molecular Medicine, ‘Sapienza’ University of Rome, Rome 00189, Italy Tel: +39 06 33775699; fax: +39 06 33776629; e-mail:

Received September 10, 2016

Accepted October 19, 2016

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