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A case report of a severe fluoropyrimidine-related toxicity due to an uncommon DPYD variant.
Medicine (Baltimore) 2019; 98(21):e15759M

Abstract

INTRODUCTION

Fluoropyrimidines such as 5-fluorouracil (5-FU) and its orally active prodrug, capecitabine, are widely used in the treatment of gastrointestinal cancer, including colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) plays an important role in the 5-FU metabolism. Dihydropyrimidine dehydrogenase gene (DPYD) is a highly polymorphic gene with several hundreds of reported genetic variants and DPD activity levels vary considerably among individuals, with different 5-FU-related efficacy and toxicity. About 5% of the population is deficient in DPD enzyme activity. The most well studied DPYD variant is the IVS14+1G>A, also known as DPYD *2A. In this report, we present a case of a patient with a double heterozygote DPYD variant (DPYD activity score: 0,5 according to Clinical Pharmacogenetics Implementation Consortium) who experienced a severe fluoropyrimidine-related toxicity resolved without any consequence.

PATIENT CONCERNS

A 46-years-old Caucasian man with diagnosis of left colon adenocarcinoma underwent left hemicolectomy on July 2017: pT3 G3 N1c M0. According to the disease stage, he started an adjuvant therapy with XELOX using capecitabine at 50% of total dose, because of his DPYD IVS14+1G>A variant, detected before the treatment.

DIAGNOSIS

After few days, despite of this dose reduction, he experienced life-threatening adverse events such as mucositis G3, diarrhea G3, neutropenia G4, thrombocytopenia G4, and hyperbilirubinemia G3 according to Common Terminology Criteria for Adverse Events v 5.0.

INTERVENTIONS

As first, we set up an intensive rehydration therapy, antibiotic and antifungal prophylaxis, Granulocyte-Colony Stimulating Factors, and supportive blood transfusions. Additional genetic tests revealed a double heterozygote variant of DPYD gene (DPYD IVS14+1G>A and 2846A>T) which is a very rare situation and only 3 cases are described in literature, all of them concluded with patient's death.

OUTCOMES

After 3 weeks of intensive therapy, the patient was fully recovered. Furthermore, all the whole-body CT scans performed since discharge from the hospital until now, have confirmed no evidence of disease.

CONCLUSIONS

Recent studies demonstrated that screening strategy for the most common DPYD variants allowed for avoiding toxicities and saving money. This report underlines the importance of genotyping DPYD before treatment and emphasizes the role of genotype-guided dose individualization.

Authors+Show Affiliations

Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli.Laboratorio di Biologia Molecolare, Ospedale Riuniti, Foggia, Italia.Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.Malattie Infettive, Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, Università degli Studi della Campania Luigi Vanvitelli.UOC di Chirurgia Generale ed Oncologica, Università degli Studi della Campania Luigi Vanvitelli.Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli.Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli.Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli.Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli.UOC Patologia clinica e molecolare, Dipartimento di Medicina di Precisione, DAI dei Sevizi di laboratorio e Sanità pubblica, Università degli Studi della Campania Luigi Vanvitelli, Complesso di S. Andrea delle Dame, Napoli, Italia.Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli.Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli.Laboratorio di Biologia Molecolare, Ospedale Riuniti, Foggia, Italia.Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli.Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli.Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli.

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

31124962

Citation

De Falco, Vincenzo, et al. "A Case Report of a Severe Fluoropyrimidine-related Toxicity Due to an Uncommon DPYD Variant." Medicine, vol. 98, no. 21, 2019, pp. e15759.
De Falco V, Natalicchio MI, Napolitano S, et al. A case report of a severe fluoropyrimidine-related toxicity due to an uncommon DPYD variant. Medicine (Baltimore). 2019;98(21):e15759.
De Falco, V., Natalicchio, M. I., Napolitano, S., Coppola, N., Conzo, G., Martinelli, E., ... Troiani, T. (2019). A case report of a severe fluoropyrimidine-related toxicity due to an uncommon DPYD variant. Medicine, 98(21), pp. e15759. doi:10.1097/MD.0000000000015759.
De Falco V, et al. A Case Report of a Severe Fluoropyrimidine-related Toxicity Due to an Uncommon DPYD Variant. Medicine (Baltimore). 2019;98(21):e15759. PubMed PMID: 31124962.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A case report of a severe fluoropyrimidine-related toxicity due to an uncommon DPYD variant. AU - De Falco,Vincenzo, AU - Natalicchio,Maria Iole, AU - Napolitano,Stefania, AU - Coppola,Nicola, AU - Conzo,Giovanni, AU - Martinelli,Erika, AU - Zanaletti,Nicoletta, AU - Vitale,Pasquale, AU - Giunta,Emilio Francesco, AU - Vietri,Maria Teresa, AU - Vitiello,Pietro Paolo, AU - Ciardiello,Davide, AU - Marinaccio,Anna, AU - De Vita,Ferdinando, AU - Ciardiello,Fortunato, AU - Troiani,Teresa, PY - 2019/5/25/entrez PY - 2019/5/28/pubmed PY - 2019/6/14/medline SP - e15759 EP - e15759 JF - Medicine JO - Medicine (Baltimore) VL - 98 IS - 21 N2 - INTRODUCTION: Fluoropyrimidines such as 5-fluorouracil (5-FU) and its orally active prodrug, capecitabine, are widely used in the treatment of gastrointestinal cancer, including colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) plays an important role in the 5-FU metabolism. Dihydropyrimidine dehydrogenase gene (DPYD) is a highly polymorphic gene with several hundreds of reported genetic variants and DPD activity levels vary considerably among individuals, with different 5-FU-related efficacy and toxicity. About 5% of the population is deficient in DPD enzyme activity. The most well studied DPYD variant is the IVS14+1G>A, also known as DPYD *2A. In this report, we present a case of a patient with a double heterozygote DPYD variant (DPYD activity score: 0,5 according to Clinical Pharmacogenetics Implementation Consortium) who experienced a severe fluoropyrimidine-related toxicity resolved without any consequence. PATIENT CONCERNS: A 46-years-old Caucasian man with diagnosis of left colon adenocarcinoma underwent left hemicolectomy on July 2017: pT3 G3 N1c M0. According to the disease stage, he started an adjuvant therapy with XELOX using capecitabine at 50% of total dose, because of his DPYD IVS14+1G>A variant, detected before the treatment. DIAGNOSIS: After few days, despite of this dose reduction, he experienced life-threatening adverse events such as mucositis G3, diarrhea G3, neutropenia G4, thrombocytopenia G4, and hyperbilirubinemia G3 according to Common Terminology Criteria for Adverse Events v 5.0. INTERVENTIONS: As first, we set up an intensive rehydration therapy, antibiotic and antifungal prophylaxis, Granulocyte-Colony Stimulating Factors, and supportive blood transfusions. Additional genetic tests revealed a double heterozygote variant of DPYD gene (DPYD IVS14+1G>A and 2846A>T) which is a very rare situation and only 3 cases are described in literature, all of them concluded with patient's death. OUTCOMES: After 3 weeks of intensive therapy, the patient was fully recovered. Furthermore, all the whole-body CT scans performed since discharge from the hospital until now, have confirmed no evidence of disease. CONCLUSIONS: Recent studies demonstrated that screening strategy for the most common DPYD variants allowed for avoiding toxicities and saving money. This report underlines the importance of genotyping DPYD before treatment and emphasizes the role of genotype-guided dose individualization. SN - 1536-5964 UR - https://www.unboundmedicine.com/medline/citation/31124962/A_case_report_of_a_severe_fluoropyrimidine_related_toxicity_due_to_an_uncommon_DPYD_variant_ L2 - http://Insights.ovid.com/pubmed?pmid=31124962 DB - PRIME DP - Unbound Medicine ER -