The Value of Dihydrouracil/Uracil Plasma Ratios in Predicting 5-Fluorouracil-Related Toxicity in Colorectal Cancer Patients

Kristensen, MH; Pedersen, Palle; Mejer, Johannes

doi:10.1177/147323001003800413

Cited by 44 publications

(45 citation statements)

References 41 publications

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“…Several studies have investigated the correlation between the ratio of UH2/Ura and DPD activity levels or 5-FU treatment toxicity and have reported that the systemic measurement of DPD activity levels using the UH2/Ura ratio in plasma could optimize 5-FU-based chemotherapy and minimize life-threatening toxicity. 15,[37][38][39][40] Given the relationship between the systemic plasma levels of 5-FU and treatment efficacy and toxicity, these observations suggest that pretherapeutic assessment of the UH2/Ura ratio in plasma would be useful for predicting 5-FU PK, thereby enabling the adjustment of an individual's 5-FU dose and improving the clinical efficacy of 5-FU treatment while preventing toxicity. However, at least two limitations of this study were identified.…”

Section: Discussionmentioning

confidence: 99%

Pre-therapeutic Assessment of Plasma Dihydrouracil/Uracil Ratio for Predicting the Pharmacokinetic Parameters of 5-Fluorouracil and Tumor Growth in a Rat Model of Colorectal Cancer

Kobuchi

Ito

Okada

et al. 2013

Biological & Pharmaceutical Bulletin

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We investigated the correlation between plasma ratio of dihydrouracil/uracil (UH2/Ura), a possible surrogate biomarker of hepatic dihydropyrimidine dehydrogenase (DPD) activity, and 5-fluorouracil (5-FU) treatment efficacy in rats with colorectal cancer (CRC). 5-FU pharmacokinetic and pharmacodynamic studies were performed using DPD circadian variation in rats with 1,2-dimethylhydrazine-induced CRC. By plotting tumor volume after 5-FU treatment against pre-therapeutic plasma UH2/Ura, we inferred a linear relationship (r 2 =0.988). 5-FU concentration fluctuations induced by DPD activity variation affected tumor volume. In CRC patients receiving proper dosing regimens, plasma UH2/Ura could be an indirect biomarker for predicting 5-FU treatment efficacy, tumor growth, and 5-FU doses.Key words pharmacokinetics; biomarker; dihydropyrimidine dehydrogenase; anti-cancer agent Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality in Western and welldeveloped countries.1) Several environmental factors, including lifestyle, food, and body mass, play important roles in the induction and progression of CRC.2) Generally, surgery is the first-line treatment for patients with early-stage CRC (stage I or II), and it has been reported to afford a positive prognosis.3,4) However, surgery is less effective in patients with more advanced CRC (stage III); furthermore, patients with involvement of the lymph nodes are at a 50% risk of relapse following resection.3,4) Therefore, adjuvant chemotherapy is often prescribed for patients with lymph node involvement in order to reduce the risk of recurrence.5-Fluorouracil (5-FU), an analogue of the natural pyrimidine uracil (Ura), is an anti-cancer agent that is widely used in the management of patients with cancers of the gastrointestinal tract, breast, head, and neck.5-7) At present, 5-FU remains the single, most effective chemotherapeutic agent for the treatment of CRC. 8) Some studies have shown a relationship between systemic plasma levels of 5-FU and treatment efficacy. 9,10) Increased objective responses have been demonstrated when higher 5-FU area under the curve (AUC) values are maintained.9,10) However, the optimal method of using 5-FU remains debatable. Gamelin et al. conducted a randomized, phase III multicentre clinical trial involving 208 patients with metastatic CRC and reported wide pharmacokinetic (PK) variability and a large distribution of the optimal dose of 5-FU to achieve target 5-FU plasma levels.11) To achieve the prescribed target concentration levels, dose increase was required in 68% of the patients. The study investigators concluded that individual 5-FU dose adjustment on the basis of PK monitoring, not body surface area, is needed for an improved objective response rate, a higher survival rate, and fewer grade III/IV toxicities. In the field of oncology, researchers are focusing on the identification of predictive markers to improve the efficacy of 5-FU and decrease the likelihood of severe toxicity, which remain a challeng...

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Section: Discussionmentioning

confidence: 99%

Pre-therapeutic Assessment of Plasma Dihydrouracil/Uracil Ratio for Predicting the Pharmacokinetic Parameters of 5-Fluorouracil and Tumor Growth in a Rat Model of Colorectal Cancer

Kobuchi

Ito

Okada

et al. 2013

Biological & Pharmaceutical Bulletin

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“…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]. Sistonen et al found a statistically significant decrease in DHU/U ratio compared with wild-type patients (p = 0.044).…”

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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“…Several studies have shown that the DHU/U ratio correlates with clearance of 5-FU and with patients’ risk of toxicity (Gamelin et al , 1999; Ciccolini et al , 2004; Jiang et al , 2004; Boisdron-Celle et al , 2007; Zhou et al , 2007; Kristensen et al , 2010; Wettergren et al , 2012; Mueller et al , 2013; Galarza et al , 2016). However, the clinical applicability of the DHU/U ratio has thus far been limited, mainly due to lack of robust evidence on clinical validity.…”

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confidence: 99%

Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity

et al. 2017

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Background:We investigated the predictive value of dihydropyrimidine dehydrogenase (DPD) phenotype, measured as pretreatment serum uracil and dihydrouracil concentrations, for severe as well as fatal fluoropyrimidine-associated toxicity in 550 patients treated previously with fluoropyrimidines during a prospective multicenter study.Methods:Pretreatment serum concentrations of uracil and dihydrouracil were measured using a validated LC-MS/MS method. The primary endpoint of this analysis was global (any) severe fluoropyrimidine-associated toxicity, that is, grade ⩾3 toxicity according to the NCI CTC-AE v3.0, occurring during the first cycle of treatment. The predictive value of uracil and the uracil/dihydrouracil ratio for early severe fluoropyrimidine-associated toxicity were compared. Pharmacogenetic variants in DPYD (c.2846A>T, c.1679T>G, c.1129-5923C>G, and c.1601G>A) and TYMS (TYMS 5′-UTR VNTR and TYMS 3′-UTR 6-bp ins/del) were measured and tested for associations with severe fluoropyrimidine-associated toxicity to compare predictive value with DPD phenotype. The Benjamini-Hochberg false discovery rate method was used to control for type I errors at level q<0.050 (corresponding to P<0.010).Results:Uracil was superior to the dihydrouracil/uracil ratio as a predictor of severe toxicity. High pretreatment uracil concentrations (>16 ng ml−1) were strongly associated with global severe toxicity (OR 5.3, P=0.009), severe gastrointestinal toxicity (OR 33.7, P<0.0001), toxicity-related hospitalisation (OR 16.9, P<0.0001), as well as fatal treatment-related toxicity (OR 44.8, P=0.001). None of the DPYD variants alone, or TYMS variants alone, were associated with severe toxicity.Conclusions:High pretreatment uracil concentration was strongly predictive of severe, including fatal, fluoropyrimidine-associated toxicity, and is a highly promising phenotypic marker to identify patients at risk of severe fluoropyrimidine-associated toxicity.

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The Value of Dihydrouracil/Uracil Plasma Ratios in Predicting 5-Fluorouracil-Related Toxicity in Colorectal Cancer Patients

Cited by 44 publications

References 41 publications

Pre-therapeutic Assessment of Plasma Dihydrouracil/Uracil Ratio for Predicting the Pharmacokinetic Parameters of 5-Fluorouracil and Tumor Growth in a Rat Model of Colorectal Cancer

Pre-therapeutic Assessment of Plasma Dihydrouracil/Uracil Ratio for Predicting the Pharmacokinetic Parameters of 5-Fluorouracil and Tumor Growth in a Rat Model of Colorectal Cancer

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

Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity

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