A systematic review and meta-analysis of toxicity and treatment outcomes with pharmacogenetic-guided dosing compared to standard of care BSA-based fluoropyrimidine dosing (original) (raw)
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New advances in DPYD genotype and risk of severe toxicity under capecitabine
PloS one, 2017
Deficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency screening, including DPYD genotyping and phenotyping. The goal of this prospective observational study was to perform exhaustive exome DPYD sequencing and to examine relationships between DPYD variants and toxicity in advanced breast cancer patients receiving capecitabine. Two-hundred forty-three patients were analysed (88.5% capecitabine monotherapy). Grade 3 and grade 4 capecitabine-related digestive and/or neurologic and/or hemato-toxicities were observed in 10.3% and 2.1% of patients, respectively. DPYD exome, along with flanking intronic regions 3'UTR and 5'UTR, were sequenced on MiSeq Illumina. DPD phenotype was assessed by pre-treatment plasma uracil (U) and dihydrouracil (UH2) measurement. Among the 48 SNPs identified, 19 were located in coding regions, including 3 novel variatio...
A case report of a severe fluoropyrimidine-related toxicity due to an uncommon DPYD variant
Medicine, 2019
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. Abbreviations: 5,10-MTHF = 5,10-Methylenetetrahydrofolate, 5-FU = 5-fluorouracil, AEs = Adverse events, CDA = cytidinedeaminase, CES = carboxylesterase, CPIC = Clinical Pharmacogenetics Implementation Consortium, CRC = colorectal cancer, CT = computed tomography, CTCAE = Common Terminology Criteria for Adverse Events, DPD = dihydropyrimidine dehydrogenase, DPYD = dihydropyrimidine dehydrogenase gene, DPYD-AS = DPYD activity score, ECOG = Eastern Cooperative Oncology Group, EDTA = ethylenediaminetetraacetic acid, FdUMP = 5-fluoro-2 0-deoxyuridine-5 0-monophosphate, HFS = handfoot syndrome, HGB = hemoglobin, INB = incremental net benefit, INR = International Normalized Ratio, mCRC = metastatic
Frontiers in Pharmacology
Introduction: The fluoropyrimidines (FP) (5-Fluorouracil, capecitabine, and tegafur) are commonly used anti-cancer drugs, but lead to moderate to severe toxicity in about 10-40% of patients. DPD testing [either the enzyme activity of dihydropyrimidine dehydrogenase (DPD) or the DPYD genotype] identifies patients at higher risk for toxicity who may be treated more safely with a lower drug dose. The Netherland's National guideline for colon carcinoma was updated in 2017 to recommend DPYD genotyping before treatment with FP. Pretreatment DPYD genotyping identifies approximately 50% of the patients that will develop severe FP toxicity. The aim of the study was to assess the uptake of DPD testing in the Amsterdam University Medical Centers over time and to evaluate stakeholder experiences to indicate barriers and facilitators of implementation in routine clinical care.
Clinical Colorectal Cancer, 2010
Although now 50-years-old, 5-fluorouracil (5-FU) unquestionably remains a reference drug for the treatment of colorectal cancer and other malignancies. However, its use is followed by a high percentage (10%-20%) of severe drug-related adverse events that usually lead to postponement or interruption of the chemotherapy and subsequent decrease in cure rate. The most common side effects related to 5-FU are hematologic toxicities, mucositis, diarrhea, and neurotoxicity. Pharmacogenetic studies have mainly focused on the human dihydropyrimidine dehydrogenase (DPYD) gene encoding dihydropyrimidine dehydrogenase (DPD), which is the key enzyme of 5-FU catabolism. Today, numerous clinical reports show that genetic variants of DPYD resulting in partially or totally abolished capacity for patients to detoxify 5-FU, have a dramatic effect on drug disposition. It is now fully acknowledged that DPD deficiency is responsible for most potentially lethal toxicities in patients to whom the drug has been administered at standard dos-ages. Today, the issue of detecting DPYD genetic polymorphism affecting 5-FU pharmacokinetics for anticipating its toxicity is paradigmatic of what pharmacogenetics could bring to personalized medicine in oncology.
Cancer Chemotherapy and Pharmacology, 2021
We report the case of a 44-year-old patient who experienced severe toxicity while being treated with capecitabine at standard dose for metastatic breast cancer. As the patient had already received 5-FU within the FEC protocol (5-FU 500 mg/m 2 , epirubicin 100 mg/m 2 , and cyclophosphamide 500 mg/m 2) 10 years ago without experiencing any severe adverse event, no DPD deficiency testing was performed before capecitabine treatment. Nevertheless, she experienced severe diarrhea and grade 2 hand-foot syndrome from the first cycle, forcing her to stop the treatment. Phenotypic and genotypic investigation of DPD activity revealed that the patient had a partial deficiency and had therefore been exposed to a higher risk of developing severe toxicities on fluoropyrimidines. This case proves that tolerance to low-dose fluoropyrimidines does not preclude DPD deficiency and the occurrence of severe toxicities if higher doses of fluoropyrimidines are used as a second-line treatment. It emphasizes the role of DPD phenotyping testing based on uracilemia in patients scheduled for fluoropyrimidine drugs, even if previous courses with low-dose 5-FU were safely administered.
Journal of Personalized Medicine
Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem...