scholarly journals Tegafur–uracil is a safe alternative for the treatment of colorectal cancer in patients with partial dihydropyrimidine dehydrogenase deficiency: a proof of principle

2012 ◽  
Vol 4 (4) ◽  
pp. 167-172 ◽  
Author(s):  
Daniel I.G. Cubero ◽  
Felipe Melo Cruz ◽  
Patrícia Santi ◽  
Ismael Dale C.G. Silva ◽  
Auro del Giglio
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Dehydrogenase Deficiency ◽  
Dihydropyrimidine Dehydrogenase ◽  
Gene Sequencing ◽  
Severe Toxicity ◽  
Safe Alternative ◽  
Grade 3 ◽  
Colorectal Cancer Patients ◽  
Proof Of Principle

Objective: The objective of this study was to evaluate the safety of using tegafur–uracil (UFT) in colorectal cancer patients with partial dihydropyrimidine dehydrogenase (DPD) deficiency. Patients and Methods: The study included five colorectal cancer patients who presented with acute toxicity (grades 3 and 4) after being given the first cycle of chemotherapy using 5-fluorouracil. The DPD deficiency was confirmed by gene sequencing. After a full recovery from all side effects, we changed the regimen to UFT (300 mg/m2/day) associated with leucovorin (90 mg/day) for 21 days, with an empirical dose reduction of at least 10% in the first cycle. Results: We prospectively analysed 22 UFT cycles in 5 patients. We did not observe any episodes of grade 3 or 4 toxicity. The predominant toxicities were of grades 1 and 2 (nausea, vomiting and diarrhoea). Conclusion: Here, we demonstrate a complete absence of severe toxicity in all patients and cycles analysed. We believe that UFT is a safe alternative for the treatment of patients with partial DPD deficiency.

scholarly journals Predictive Value of Clinical Toxicities to Chemotherapy with Fluoropyrimidines and Oxaliplatin in Colorectal Cancer by DPYD and GSTP1 Genes Polymorphisms

2020 ◽  
Author(s):  
Xunwei Deng ◽  
Jingyuan Hou ◽  
Qiaoting Deng ◽  
Zhixiong Zhong
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Direct Sequencing ◽  
Dihydropyrimidine Dehydrogenase ◽  
Severe Neutropenia ◽  
Severe Toxicity ◽  
Nucleotide Polymorphisms ◽  
Significant Difference ◽  
Grade 3 ◽  
Colorectal Cancer Patients

Abstract Background: Fluoropyrimidines and platinum are still widely used for colorectal cancer (CRC) management. Several studies have reported that mutations of dihydropyrimidine dehydrogenase (DPYD) and glutathione S-transferase pi-1 (GSTP1) polymorphisms are related to Chemotherapy-related adverse events. The present study was aimed to determine the role of DPYD and GSTP1 variants on patient chemotherapy toxicity risk among the Hakka population, minimize adverse events and in order to maximize therapy outcome for individualized treatment.Methods: Genotyping was examined in 104 patients diagnosed with CRC cases and receiving fluoropyrimidine and platinum drugs based chemotherapy regimen by direct sequencing of DPYD and GSTP1 polymorphisms. Three DPYD variants including *2A, *5A, *9A and GSTP1 c.313A>G were analyzed and clinical outcomes were assessed. Results: The data suggest that the incidence of DPYD*5A, DPYD*9A and GSTP1 c.313A>G variants were 37.5%, 24% and 31.7%, respectively. DPYD*2A variant was not found. A total of 38 patients (36.5%) suffered severe neutropenia and 23 patients (22.1%) suffered severe vomiting. DPYD*5A polymorphism was found significantly associated with grade 3/4 ulceration (p = 0.001). GSTP1 was determined to be an independent risk factor for severe neutropenia and ulceration (p = 0.010 and p = 0.034, respectively). Patients with GSTP1 c.313A>G wild type contributed to higher risk for grade severe toxicity compared with A/G + G/G genotype (p = 0.024). However, there was no significant difference between patients with DPYD*9A T/T and T/C + C/C genotype for chemotherapeutic toxicity.Conclusions: The results demonstrated that DPYD*5A and GSTP1 polymorphisms were useful predictors for severe events. Screening of single nucleotide polymorphisms of DPYD and GSTP1 in colorectal cancer patients prior to chemotherapy may help to realize personalized therapy.

scholarly journals Cost Implications of Reactive Versus Prospective Testing for Dihydropyrimidine Dehydrogenase Deficiency in Patients With Colorectal Cancer: A Single-Institution Experience

Dose-Response ◽  
2018 ◽  
Vol 16 (4) ◽  
pp. 155932581880304 ◽  
Author(s):  
Con Murphy ◽  
Stephen Byrne ◽  
Gul Ahmed ◽  
Andrew Kenny ◽  
James Gallagher ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dihydropyrimidine Dehydrogenase ◽  
Cost Savings ◽  
Cost Effective ◽  
Public Hospitals ◽  
Severe Toxicity ◽  
Care Payer ◽  
Input Variables ◽  
Grade 3 ◽  
The Cost

Background: Severe toxicity is experienced by a substantial minority of patients receiving fluoropyrimidine-based chemotherapy, with approximately 20% of these severe toxicities attributable to polymorphisms in the DPYD gene. The DPYD codes for the enzyme dihydropyrimidine dehydrogenase (DPD) important in the metabolism of fluoropyrimidine-based chemotherapy. We questioned whether prospective DPYD mutation analysis in all patients commencing such therapy would prove more cost-effective than reactive testing of patients experiencing severe toxicity. Methods: All patients experiencing severe toxicity from fluoropyrimidine-based chemotherapy for colorectal cancer in an Irish private hospital over a 3-year period were tested for 4 DPYD polymorphisms previously associated with toxicity. The costs associated with an index admission for toxicity in DPD-deficient patients were examined. A cost analysis was undertaken comparing the anticipated cost of implementing screening for DPYD mutations versus current usual care. One-way sensitivity analysis was conducted on known input variables. An alternative scenario analysis from the perspective of the Irish health-care payer (responsible for public hospitals) was also performed. Results: Of 134 patients commencing first-line fluoropyrimidine chemotherapy over 3 years, 30 (23%) patients developed grade 3/4 toxicity. Of these, 17% revealed heterozygote DPYD mutations. The cost of hospitalization for the DPYD-mutated patients was €232 061, while prospectively testing all 134 patients would have cost €23 718. Prospective testing would result in cost savings across all scenarios. Conclusions: The cost of hospital admission for severe chemotherapy-related toxicity is significantly higher than the cost of prospective DPYD testing of each patient commencing fluoropyrimidine chemotherapy.

scholarly journals Dihydropyrimidine Dehydrogenase Gene Variation and Its Association with 5-Fluorouracil Toxicity in Colorectal Patients

2018 ◽  
Vol 3 (3) ◽  
pp. 65-69
Author(s):  
Ebrahim Salehifar ◽  
Mohammad Javad Abd Haghighi ◽  
Reza Negarandeh ◽  
Ghasem Janbabai ◽  
Fatemeh Safgafi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Side Effects ◽  
Cancer Patients ◽  
Dihydropyrimidine Dehydrogenase ◽  
Venous Blood ◽  
Critical Role ◽  
Optimization Method ◽  
Gene Variation ◽  
North Of Iran ◽  
Colorectal Cancer Patients

Objective: Dihydropyrimidine dehydrogenase (DPD), an enzyme translated by DPD gene (DPYD), has a critical role in the metabolism of 5-fluorouracil (5FU). In this study we aimed to investigate the frequency of the IVS14+1 G>A, 2194G>A, 2846 A>T mutations in the DPYD gene in colorectal cancer patients in north of Iran and their association with side effects of 5FU.Methods: Venous blood samples of 89 colorectal cancer patients were drawn. After the DNA extraction from nuclear cells, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect the frequency of the IVS14+1 G>A and 2846 A>T mutations. Tetra-Primer ARMS PCR optimization method was used to detect the 2194 G>A mutation. Side effects were classified according to CTCAE (common terminology criteria for adverse events V. 4) and the association between different polymorphisms and side effects were evaluated.Results: Of 89 colorectal patients, the frequency of IVS14+1 G>A and 2846 A>T polymorphism was 4 (5.1%) and 1 (1.1%), respectively. The 2194 G>A polymorphism was not detected. All 4 patients were heterozygous for IVS14+1 G>A mutation, whereas the only patient with 2846 A>T polymorphism was homozygous. Some adverse effects of 5FU including diarrhea, vomiting, mucositis and stomatitis were more frequent in patients with IVS14+1 G>A polymorphism.Conclusion: The prevalence of IVS14+1 G>A mutation in our patients were relatively high and was associated with a higher occurrence of 5FU-associated toxicities.

The 2-13C-5-fluorouracil breath test (FUBT) as a novel, rapid method for assessment of dihydropyrimidine dehydrogenase (DPD) activity in cancer patients: Initial characterization and comparison to the 2-13C-uracil breath test (UraBT)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2551-2551
Author(s):  
J. Fourie ◽  
L. K. Mattison ◽  
T. E. Wood ◽  
J. A. Posey ◽  
A. Modak ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Single Dose ◽  
Oral Dose ◽  
Cancer Patients ◽  
Drug Administration ◽  
Breath Test ◽  
Dihydropyrimidine Dehydrogenase ◽  
Metabolite Formation ◽  
Colorectal Cancer Patients ◽  
Further Development

2551 Background: The UraBT is currently in development as a phenotypic test to screen for DPD deficiency. Following an oral dose of 2-13C-uracil, the UraBT shows a significant relationship between breath 13CO2 metabolite formation and plasma 2-13C-uracil and 2-13C-dihydrouracil pharmacokinetics. We herein describe a novel, potentially more clinically relevant test in which a small oral dose of 2-13C-5-fluorouracil (5-FU) is administered, followed by assessment of breath 13CO2 metabolite formation as previously described for the UraBT. We hypothesize that the FUBT can rapidly assess interindividual variability in 5-FU catabolism and predisposition to 5-FU toxicity. Methods: Over two sessions separated by a seven day washout, a single dose (6mg/kg, p.o.) of 2-13C-uracil or 2-13C-5-FU was administered to patients with stage III-IV colorectal cancer (n = 4). Subsequent to drug administration, in each session, 13CO2 catabolite formation was quantified in the breath over eight hours. In a separate investigation over two sessions separated by a seven day washout, a single dose (3mg/kg, p.o.) of 2-13C-uracil or 213C-5-FU was administered to colorectal cancer patients with previously documented severe (n=2) or moderate (n=2) 5-FU dose-related hematological/gastrointestinal toxicity. Following drug administration 13CO2 catabolite formation was quantified over eight hours. 13CO2 concentration was expressed as Delta Over Baseline (DOB) in all sessions. Results: Compared to the UraBT, the FUBT showed an increased Cmax (50.7 ± 6.6 DOB/mg vs. 36.8 ± 7.8 DOB/mg; mean ± SD) and decreased Tmax (25 ± 4 min vs. 45 ± 6 min) for 13CO2 formation (p<0.05). The FUBT was able to distinguish patients with previously reported severe and moderate 5- FU toxicity, with 13CO2 Cmax values of 35.5 ± 9.5 DOB/mg (mean ± SD) and 59.8 ± 7.3 DOB/mg, respectively. Importantly, FUBT Cmax values positively correlated with DPD activity (rs=1.00, p<0.01). Conclusions: These data lend support to further development of the FUBT as a rapid and informative test to assess DPD activity and to predict susceptibility to severe dose-related 5-FU toxicity. [CA116964] No significant financial relationships to disclose.

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