Predicting 5-Fluorouracil Toxicity: DPD Genotype and 5,6-Dihydrouracil: Uracil Ratio

Sistonen, Johanna; Büchel, Barbara; Froehlich, Tanja K.; Kummer, Dominic; Fontana, Stefano; Joerger, Markus; Kuilenburg, André B. P.; Largiadèr, Carlo R.

doi:10.2217/pgs.14.126

Cited by 56 publications

(78 citation statements)

References 51 publications

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“…In contrast to this study is recent work conducted by investigators from Switzerland who found that the baseline UH 2 /U plasma ratio was a relatively poor predictor of reduced DPD activity and associated 5-FU toxicity [81]. This group determined that the UH 2 /U ratio was a reflection of first-order DPD kinetics where the enzyme was not saturated, which then explains their finding of overlap between ratios of carriers of DPD risk variants and non-carriers.…”

Section: Dihydrouracil/uracil Ratio and Uracil Breath Testmentioning

confidence: 65%

Therapeutic drug monitoring of 5-fluorouracil

Lee

Beumer

Chu

2016

Cancer Chemother Pharmacol

178

150

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Purpose For over 50 years, 5-FU has played a critical role in the systemic chemotherapy of cancer patients. 5-FU serves as the main backbone of combination chemotherapy for patients with colorectal cancer (CRC) in both the adjuvant and metastatic disease settings. Herein, we review the current status of 5-FU therapeutic drug monitoring (TDM) and discuss its potential role in the clinical practice setting. Method PubMed and abstracts from the American Society of Clinical Oncology (ASCO) were searched up through September 2015 for clinical data relating to 5-FU TDM. Results 5-FU dosing has been typically determined by using body surface area (BSA). However, it is now well-established that BSA-based 5-FU dosing is correlated with a wide variation of 5-FU systemic exposure. Pharmacokinetic (PK) studies of 5-FU systemic exposure have shown a wide range of interpatient variation of 5-FU plasma drug levels. Over the past 30 years, increasing efforts have been placed on optimizing 5-FU dosing with the main goals of increasing antitumor efficacy while reducing drug-associated toxicity. There is growing evidence to show that 5-FU dosing based on plasma 5-FU drug level is feasible and that 5-FU TDM can improve clinical outcomes by improving efficacy of 5-FU-based combination regimens and reducing toxicities. Conclusion Dose adjustment of 5-FU is feasible and PK-based dosing can significantly improve clinical outcomes by reducing toxicities and improving efficacy.

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Section: Dihydrouracil/uracil Ratio and Uracil Breath Testmentioning

confidence: 65%

Therapeutic drug monitoring of 5-fluorouracil

Lee

Beumer

Chu

2016

Cancer Chemother Pharmacol

178

150

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“…The c.1129-5923C>G intronic polymorphism (rs75017182) results in aberrant splicing and is likely to be the responsible variant for the effect on DPD enzyme activity [3,14]. The frequency of heterozygous patients in Caucasian populations was reported to vary between 2.6 and 6.3% [14,15,42,49,50]. DPD enzyme activity for c.1236G>A carriers was measured in PBMCs in two studies [14,46].…”

Section: Previous Guidelines and Recommendationsmentioning

confidence: 99%

“…Furthermore we observed two homozygous patients with this variant in our own institute with a relevant DPD enzyme activity left of around 50%, showing that this variant does not result in a completely nonfunctional enzyme (Author's Unpublished Data). In the study of Sistonen et al the ratio between endogenous dihydrouracil (DHU) and uracil (U) was measured in patients carrying the c.1129-5923C>G variant [50]. This ratio can be used as a phenotyping marker for DPD enzyme activity, as described in several studies [51][52][53][54][55].…”

Section: Previous Guidelines and Recommendationsmentioning

confidence: 99%

Translating DPYD Genotype into DPD Phenotype: Using the DPYD Gene Activity Score

et al. 2015

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The dihydropyrimidine dehydrogenase enzyme (DPD, encoded by the gene DPYD) plays a key role in the metabolism of fluoropyrimidines. DPD deficiency occurs in 4-5% of the population and is associated with severe fluoropyrimidine-related toxicity. Several SNPs in DPYD have been described that lead to absent or reduced enzyme activity, including DPYD*2A, DPYD*13, c.2846A>T and c.1236G>A/haplotype B3. Since these SNPs differ in their effect on DPD enzyme activity, a differentiated dose adaption is recommended. We propose the gene activity score for translating DPYD genotype into phenotype, accounting for differences in functionality of SNPs. This method can be used to standardize individualized fluoropyrimidine dose adjustments, resulting in optimal safety and effectiveness.

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“…As a result, we could not confirm that the pharmacokinetics of S-1 differed between the high- and low-dose groups, and it might have been affected not only by the initial dose but by other factors, such as catabolic enzyme and renal function. Dihydropyrimidine dehydrogenase and thymidylate synthase are the rate-limiting enzymes that catabolize 5-fluorouracil, and these enzymes were reported to correlate with the effect of S-1 [22,23,24]; however, these enzyme levels were not examined in the current study. Renal function may also affect the deviation of the plasma concentration of S-1.…”

Section: Discussionmentioning

confidence: 93%

Unexpected Side Effects of a High S-1 Dose: Subanalysis of a Phase III Trial Comparing Gemcitabine, S-1 and Combinatorial Treatments for Advanced Pancreatic Cancer

Kobayashi

Ueno²,

Irie³

et al. 2016

Oncology

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Objective: In this subanalysis of a phase III trial using three categorized doses of S-1, the influence of the actual doses on safety and efficacy was evaluated. Methods: We compared the efficacy and safety of the S-1 or gemcitabine plus S-1 combination (GS) arm between the top 10% group and the bottom 10% group according to the initial doses of S-1: ≥77.6 versus ≤65.9 mg/m²/day (n = 28 vs. 28) in the S-1 arm, and ≥65.1 versus ≤53.8 mg/m²/day (n = 27 vs. 28) in the GS arm. Results: Overall and progression-free survival were not significantly different between these two groups: hazard ratios of 0.818 and 0.761 with p values of 0.498 and 0.330 in the S-1 arm, and hazard ratios of 0.836 and 0.759 with p values of 0.557 and 0.323 in the GS arm, respectively. Incidences of grade 3-4 hematological toxicities were significantly higher in the top 10% group than in the bottom 10% group: 42.9 versus 14.3 and 85.2 versus 57.1%, with p values of 0.037 and 0.037 in the S-1 and the GS combination arm, respectively. Conclusions: Higher actual doses of S-1 were associated with a higher incidence of hematological toxicity even in the same dose setting.

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Predicting 5-Fluorouracil Toxicity: DPD Genotype and 5,6-Dihydrouracil: Uracil Ratio

Abstract: These results suggest that the baseline UH2:U plasma ratio in most individuals reflects the nonsaturated state of DPD and is not predictive of decreased DPD activity. It may, however, be highly predictive at increased substrate concentrations, as observed during 5-FU administration.

Cited by 56 publications

References 51 publications

Therapeutic drug monitoring of 5-fluorouracil

Therapeutic drug monitoring of 5-fluorouracil

Translating DPYD Genotype into DPD Phenotype: Using the DPYD Gene Activity Score

Unexpected Side Effects of a High S-1 Dose: Subanalysis of a Phase III Trial Comparing Gemcitabine, S-1 and Combinatorial Treatments for Advanced Pancreatic Cancer

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