Tolerance-based capecitabine dose escalation after DPYD genotype-guided dosing in heterozygote DPYD variant carriers

Kleinjan, Jan P.; Brinkman, Ithamar; Bakema, Robbert; Zanden, Jelmer J. van; Rooijen, Johan M. van

doi:10.1097/cad.0000000000000748

Cited by 8 publications

(6 citation statements)

References 19 publications

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“…Of the potential 112 articles assessed for eligibility, after considering the inclusion and exclusion criteria, 22 studies were included in the analysis [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Table 3 shows such studies subdivided with respect to the analysed DPYD polymorphisms ( DPYD -PGx), the used phenotyping methods and the presence of clinical monitoring.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, as shown in Table 3, three studies have performed a combined DPYD-PGx/phenotyping [27,37,41] approach, and eleven carried out the DPYD-PGx together with clinical monitoring. However, among these, only 2/11 genotyped all the four DPYD SNPs recommended in the CPIC and DPWG guidelines [29,39]; the other studies performed at least one of such SNPs, together with other DPYD genetic variants [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40].…”

Section: Discussionmentioning

confidence: 99%

“…Among the studies with a DPYD-PGx/clinical monitoring combination, five out of eleven studies confirmed the importance of DPYD variants in predicting FP-related toxicity, although a too-short clinical monitoring was performed (only two treatment cycles) [21,23,29,31,39]. Two studies [24,34] analysed only DPYD*2A of the DPYD SNPs currently recommended.…”

Section: Systematic Reviewmentioning

confidence: 97%

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A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

Conti

Bellis

Manzo

et al. 2020

JPM

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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 mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Systematic Reviewmentioning

confidence: 97%

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A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

Conti

Bellis

Manzo

et al. 2020

JPM

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“…Since the publication of the study, the CPIC has updated its guidelines on their website to recommend a 50% dose reduction of heterozygous carriers of c.1129‐5923C>G and c.2846A>T 10 . A study conducted by Kleinjan and colleagues in 2019 supports the practice of DPYD genotype‐guided dosing, as initial dose reductions of capecitabine in heterozygous DPYD variant carriers followed by tolerance‐based dose escalation did not lead to higher toxicity when compared with wild‐type patients (37.9% vs 27.3%, p = 0.54) 12 . Of the 11 variant carriers, only 6 (54.5%) tolerated dose escalations, achieving a median increase of 8.5% (4–31%).…”

Section: Dpyd and Fluoropyrimidinesmentioning

confidence: 99%

“…The relationship between these variants and fluoropyrimidine-induced severe toxicity has been widely explored and confirmed in the literature (Table 2). 8,[12][13][14][15][16][17][18] In 2013, Terrazzino and colleagues confirmed the clinical validity of variant DPYD*2A and c.2846A>T alleles as risk factors for severe toxicities after fluoropyrimidine use. 15 Pooled data showed that individuals with DPYD*2A polymorphisms were likely to experience grade ≥ 3 hematologic toxicity, mucositis, and diarrhea.…”

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confidence: 99%

DPYD and UGT1A1 Pharmacogenetic Testing in Patients with Gastrointestinal Malignancies: An Overview of the Evidence and Considerations for Clinical Implementation

et al. 2020

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Gastrointestinal (GI) malignancies are among the most commonly diagnosed cancers worldwide. Despite the introduction of targeted and immunotherapy agents in the treatment landscape, cytotoxic agents, such as fluoropyrimidines and irinotecan, remain as the cornerstone of chemotherapy for many of these tumors. Pharmacogenetics (PGx) is a rapidly evolving field that accounts for interpatient variability in drug metabolism to predict therapeutic response and toxicity. Given the significant incidence of severe treatment-related adverse events associated with cytotoxic agents, utilizing PGx can allow clinicians to better anticipate drug tolerability while minimizing treatment interruptions or delays. In this review, the PGx profiles of drug-gene pairs with potential impact in GI malignancy therapy-DPYD-5-fluorouracil/capecitabine and UGT1A1-irinotecanand the available clinical evidence of their roles in reducing severe adverse events are discussed. Considerations for clinical implementation, such as optimal laboratory workflows, electronic health record integration, and stakeholder engagement, as well as provider education, are addressed. Last, exploratory PGx markers in GI malignancy treatment are described. As the PGx knowledge base rapidly evolves, pharmacists will be vital in leveraging their pharmacology knowledge and clinical skills to implement PGx testing in the clinic.

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Capecitabine

2019

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Tolerance-based capecitabine dose escalation after DPYD genotype-guided dosing in heterozygote DPYD variant carriers

Cited by 8 publications

References 19 publications

A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

DPYD and UGT1A1 Pharmacogenetic Testing in Patients with Gastrointestinal Malignancies: An Overview of the Evidence and Considerations for Clinical Implementation

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