Pre-treatment evaluation of 5-fluorouracil degradation rate: association of poor and ultra-rapid metabolism with severe toxicity in a colorectal cancer patients cohort

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.

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5-Fluorouracil degradation rate could predict toxicity in stages II–III colorectal cancer patients undergoing adjuvant FOLFOX

Anti-Cancer Drugs ◽

10.1097/cad.0000000000000453 ◽

2017 ◽

Vol 28 (3) ◽

pp. 322-326 ◽

Cited By ~ 8

Author(s):

Concetta E. Onesti ◽

Andrea Botticelli ◽

Marco La Torre ◽

Marina Borro ◽

Giovanna Gentile ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Degradation Rate ◽

Colorectal Cancer Patients

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Pre-treatment serum folate levels and toxicity in colorectal cancer patients treated with 5-fluorouracil and folinic acid.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.755 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 755-755 ◽

Cited By ~ 1

Author(s):

Michael Yan ◽

Mark David Vincent ◽

Cheryl Ho ◽

Eric Winquist ◽

Derek J. Jonker ◽

...

Keyword(s):

Colorectal Cancer ◽

Folinic Acid ◽

Cancer Patients ◽

Serum Folate ◽

Folate Level ◽

Serum Folate Level ◽

Pre Treatment ◽

Grade 3 ◽

Colorectal Cancer Patients ◽

Schedule Modification

755 Background: 5-fluorouracil (5-FU) chemotherapy is associated with severe and unpredictable toxicity in a significant proportion of patients.We hypothesized that susceptibility to 5-FU toxicity might be related to individual differences in components of reduced folate metabolism affecting intracellular 5,10-MTHF levels, detectable in blood prior to treatment. Methods: A prospective cohort of chemo-naive colorectal cancer patients planned to receive IV 5-FU and folinic acid for five consecutive days every four weeks were studied. Baseline clinical and laboratory data were collected prior to treatment. Biochemical data associated with folate metabolism was also collected and not revealed to treating physicians. The primary endpoint was occurrence of > grade 3 toxicity and/or toxicity mandating dose delay or reduction. Results: Of 78 eligible patients studied, 68% experienced > grade 3 toxicity, 69% had schedule modification, and 81% had either or both. Multivariable analyses identified only a higher pre-treatment serum folate level as an independent predictor of toxicity > grade 3 and/or mandating schedule modification (p = 0.016). An increasing toxicity trend was observed amongst folate-stratified patient cohorts, with an odds ratio of 2.87 (p = 0.09) comparing the highest and lowest quartiles. Concurrently, overall survival and relapse-free rates also increased with pretreatment folate levels in the adjuvant cohort with log rank values of 3.60 (p = 0.06) and 7.20 (p = 0.007) between the highest quartile and the lower quartiles, respectively. Conclusions: The incidence of severe toxicity with this schedule of 5-FU and folinic acid was high and positively correlated with the pretreatment serum folate level. Interestingly, a concurrent increase in overall and relapse free survival is observed with increasing serum folate levels. These results suggest that an optimal pretreatment folate level exists that balances chemotherapy treatment efficacy and toxicity.

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Predictive Role of the UGT1A1, UGT1A7, and UGT1A9 Genetic Variants and Their Haplotypes on the Outcome of Metastatic Colorectal Cancer Patients Treated With Fluorouracil, Leucovorin, and Irinotecan

Journal of Clinical Oncology ◽

10.1200/jco.2008.19.0314 ◽

2009 ◽

Vol 27 (15) ◽

pp. 2457-2465 ◽

Cited By ~ 158

Author(s):

Erika Cecchin ◽

Federico Innocenti ◽

Mario D'Andrea ◽

Giuseppe Corona ◽

Elena De Mattia ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Cancer Patients ◽

Objective Response ◽

Area Under The Curve ◽

Reference Sequence ◽

Hematologic Toxicity ◽

Pharmacokinetic Data ◽

Severe Toxicity ◽

Colorectal Cancer Patients

Purpose UGT1A1★28 is considered the main pharmacogenetic predictor of the toxicity outcome of irinotecan-treated patients. We evaluated the effect of other UGT1A variants and haplotypes involved in 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronidation on severe toxicity and efficacy of fluorouracil, leucovorin, and irinotecan (FOLFIRI). Patients and Methods In addition to UGT1A1★28, UGT1A1★60, UGT1A1★93, UGT1A7★3, and UGT1A9★22 were genotyped in 250 metastatic colorectal cancer patients, and associations with severe hematologic and nonhematologic toxicity, objective response, time to progression (TTP), and overall survival were evaluated. In a subset of 71 patients, pharmacokinetic data were also available. Results UGT1A7★3 was the only marker of severe hematologic toxicity after the first cycle (odds ratio [OR], 3.94; 95% CI, 1.05 to 14.82; P = .04) in a multivariate analysis. It was also associated with glucuronidation ratio (SN-38G area under the curve [AUC]/SN-38 AUC) and biliary index (irinotecan AUC) × (SN-38 AUC/SN-38G AUC). Haplotype I (all the reference sequence alleles but UGT1A9★22) was a predictor of severe hematologic toxicity during the entire course of therapy (OR, 0.39; 95% CI, 0.19 to 0.82; P = .01), together with sex (OR, 2.08; 95% CI, 1.01 to 4.28; P = .05). In addition to UGT1A1★28, haplotype II (all the variant alleles but UGT1A9★22) was associated with a response rate (OR, 8.61; 95% CI, 1.75 to 42.38; P = .01). UGT1A1★28 was the only marker associated with TTP. Conclusion We propose that UGT1A variants additional to UGT1A1★28 might improve the prediction of the outcome of colorectal cancer patients treated with FOLFIRI. A UGT1A haplotype-based approach might be an efficacious strategy to achieve treatment individualization of FOLFIRI.

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ABCC5 and ABCG1 polymorphisms predict irinotecan-induced severe toxicity in metastatic colorectal cancer patients

Pharmacogenetics and Genomics ◽

10.1097/fpc.0000000000000168 ◽

2015 ◽

Vol 25 (12) ◽

pp. 573-583 ◽

Cited By ~ 21

Author(s):

Sylvia Chen ◽

Lyne Villeneuve ◽

Derek Jonker ◽

Félix Couture ◽

Isabelle Laverdière ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Cancer Patients ◽

Severe Toxicity ◽

Colorectal Cancer Patients

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Drug–Drug Interactions and Pharmacogenomic Evaluation in Colorectal Cancer Patients: The New Drug-PIN® System Comprehensive Approach

Pharmaceuticals ◽

10.3390/ph14010067 ◽

2021 ◽

Vol 14 (1) ◽

pp. 67

Author(s):

Michela Roberto ◽

Alessandro Rossi ◽

Martina Panebianco ◽

Leda Marina Pomes ◽

Giulia Arrivi ◽

...

Keyword(s):

Colorectal Cancer ◽

Drug Interactions ◽

Cancer Patients ◽

Performance Status ◽

Severe Toxicity ◽

Chemotherapy Drugs ◽

Chi Squared ◽

Group 2 ◽

Concomitant Medications ◽

Colorectal Cancer Patients

Drug–drug interactions (DDIs) can affect both treatment efficacy and toxicity. We used Drug-PIN® (Personalized Interactions Network) software in colorectal cancer (CRC) patients to evaluate drug–drug–gene interactions (DDGIs), defined as the combination of DDIs and individual genetic polymorphisms. Inclusion criteria were: (i) stage II-IV CRC; (ii) ECOG PS (Performance status sec. Eastern coperative oncology group) ≤2; (iii) ≥5 concomitant drugs; and (iv) adequate renal, hepatic, and bone marrow function. The Drug-PIN® system analyzes interactions between active and/or pro-drug forms by integrating biochemical, demographic, and genomic data from 110 SNPs. We selected DDI, DrugPin1, and DrugPin2 scores, resulting from concomitant medication interactions, concomitant medications, and SNP profiles, and DrugPin1 added to chemotherapy drugs, respectively. Thirty-four patients, taking a median of seven concomitant medications, were included. The median DrugPin1 and DrugPin2 scores were 42.6 and 77.7, respectively. In 13 patients, the DrugPin2 score was two-fold higher than the DrugPin1 score, with 7 (54%) of these patients experiencing severe toxicity that required hospitalization. On chi-squared testing for any toxicity, a doubled DrugPin2 score (p = 0.001) was significantly related to G3–G4 toxicity. Drug-PIN® software may prevent severe adverse events, decrease hospitalizations, and improve survival in cancer patients.

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