Dépistage du déficit en dihydropyrimidine déshydrogénase (DPD) et sécurisation des chimiothérapies à base de fluoropyrimidines : mise au point et recommandations nationales du GPCO-Unicancer et du RNPGx

Loriot, Marie‐Anne; Ciccolini, Joseph; Thomas, Fabienne; Guellec, Chantal Barin‐Le; Royer, Bernard; Milano, Gérard; Picard, Nicolas; Becquemont, Laurent; Verstuyft, Céline; Narjoz, Céline; Schmitt, Antonin; Bobin‐Dubigeon, Christine; Harlé, Alexandre; Paci, Angélo; Poinsignon, Vianney; Quaranta, Sylvie; Evrard, Alexandre; Hennart, Benjamin; Broly, Franck; Fonrose, Xavier; Lafay-Chebassier, Claire; Wozny, Anne-Sophie; Masskouri, Fadil; Boyer, Jean-Christophe; Étienne-Grimaldi, Marie-Christine

doi:10.1016/j.bulcan.2018.02.001

Cited by 91 publications

(37 citation statements)

References 37 publications

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“…In patients who need treatment with fluoropyrimidine, DPD status should be determined before the start of the treatment to prevent the potential toxicity. At this moment, clinical validity is well known for four variants (DPYD*2A, DPYD*9B, DPYD*13, and c.1236G > A/Haplotype B3), but there are no official recommendations for genotyping before the treatment and also to adjust the dose based on these findings [ 40 ]. Also others characteristics such as age, gender, hepatic and renal function may increase the toxicity risk [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…The French National Network of Pharmacogenetics recommend that if genotyping has found a partial deficiency for DPYD*2A, DPYD*9B or DPYD*13 variants, the dose should be reduced by 50% for the first cycle of chemotherapy [ 40 ]. If a complete deficiency is found by genotyping, fluoropyrimidines are contraindicated and another therapy should be administrated.…”

Section: Discussionmentioning

confidence: 99%

“…If the deficiency is demonstrated by phenotyping methods, the dose can be reduced in correlation with the degree of deficiency, by 25% to 75%. Also, if tolerance is observed after the first cycle of chemotherapy, the dose can be increased [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

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A systematic review on the importance of genotyping and phenotyping in fluoropyrimidine treatment

Deac¹,

Burz²,

Bocşe³

et al. 2020

Medicine and Pharmacy Reports

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Fluoropyrimidines, after more than 50 years of their discovery, are still the treatment of many types of cancer, and annually is estimated that two million patients use fluoropyrimidine treatment. The toxicity associated with fluoropyrimidines affects 30-40% of patients and some adverse effects can be lethal. Dihydroypyrimidine dehydrogenase is the main enzyme in the catabolism of 5-FU and DPD activity deficiency can cause important toxicity. There is an important reason for determinate DPD activity in order to improve patient safety and to limit potential life-threating toxicity. Now, are available multiple phenotypic and genotypic methods to determinate DPD activity, some of this methods have proven their usefulness in practice, but yet there are not routinely recommended in clinical practice. This review is another statement of the importance of determination DPD status, the phenotypic and genotypic methods that are available and can be used.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A systematic review on the importance of genotyping and phenotyping in fluoropyrimidine treatment

Deac¹,

Burz²,

Bocşe³

et al. 2020

Medicine and Pharmacy Reports

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“…Pre-emptive screening of DPD deficiency before administrating fluoropyrimidine-based chemotherapy has been a standard practice in some European Countries: France ( 14 ), Italy and Netherlands 4 . Majority of our current knowledge on DPYD is derived from studies on Caucasian population.…”

Section: Discussionmentioning

confidence: 99%

A Novel DPYD Variant Associated With Severe Toxicity of Fluoropyrimidines: Role of Pre-emptive DPYD Genotype Screening

Tong

Lam

et al. 2018

Front. Oncol.

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Background: The fluoropyrimidine anticancer drug, especially 5- fluorouracil (5-FU) and its prodrug capecitabine are still being the backbone of chemotherapeutic regimens for colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) is the crucial enzyme in the catabolism of 5-FU. Over the past 30 years, there is substantial clinical evidence showing that DPD deficiency is strongly associated with severe and fatal fluoropyrimidine-induced toxicity.Patients and methods: A 49-year-old lady with resected stage III carcinoma of sigmoid colon was scheduled to have a course of 5-FU based adjuvant chemotherapy. She developed unexpected acute severe (grade 4) toxicity after the first cycle of chemotherapy. Genomic DNA was isolated from 3 ml peripheral blood cells for full sequencing of DPYD (the gene encoding DPD).Results: Exome sequencing confirmed that she is heterozygous for NM_000110.3: c.321+2T>C of the DPYD gene. To the best of our knowledge, this variant is a novel pathogenic splicing variant of the DPYD gene resulting in a non-functional allele. As she has a heterozygous genotype and considered having decreased DPD activity, we followed the international recommendation and restart chemotherapy with at least 50% reduction for 5-FU dose. We then titrated the 5-FU dose, and she tolerated the subsequent cycles of chemotherapy and completed the whole course of adjuvant chemotherapy.Conclusions: With a pre-emptive test on DPD deficiency before the administration of the fluoropyrimidine drugs, the aforementioned patient's life-threatening event could be avoided. This clinical utility has been confirmed by two recent large-scale studies and called for a drug label update.

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“…Figure 1 summarises the recommendations for a diagnostic and therapeutic algorithm. They are based on the recommendations of the Clinical Pharmacogenetics Implementation Consortium (CPIC), Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update [11], Dutch Pharmacogenetics Working Group Guideline [24], and the recommendations of GPCOUnicancer and RNPGx from France [46].…”

Section: Diagnostic and Therapeutic Algorithmmentioning

confidence: 99%

Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper

et al. 2020

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Background: 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2–1.0%. Summary: Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. Key Messages: (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitoring.

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Dépistage du déficit en dihydropyrimidine déshydrogénase (DPD) et sécurisation des chimiothérapies à base de fluoropyrimidines : mise au point et recommandations nationales du GPCO-Unicancer et du RNPGx

Cited by 91 publications

References 37 publications

A systematic review on the importance of genotyping and phenotyping in fluoropyrimidine treatment

A systematic review on the importance of genotyping and phenotyping in fluoropyrimidine treatment

A Novel DPYD Variant Associated With Severe Toxicity of Fluoropyrimidines: Role of Pre-emptive DPYD Genotype Screening

Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper

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