Fluoropyrimidine Tailored-dose Based on Uracil Concentration in Patients Treated for Digestive Carcinomas: Evaluation of Clinical Practice

Study Overview
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Brief Summary
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Digestive carcinomas chemotherapies regimen are mostly based on fluoropyrimidine drugs (5-Fluorouracil (5-FU) or capecitabine). 5-FU is mainly catabolised by dihydropyrimidine dehydrogenase (DPD) and partial or complete DPD deficiency can cause severe adverse reactions. Different strategies have been proposed to predict DPD deficiency; the two main approaches are phenotyping the enzyme activity (directly or indirectly), or genotyping the four main polymorphisms associated with 5-FU-toxicity. In February 2018, the French medicines agency (Agence nationale de sécurité du médicament et des produits de santé, ANSM) recommended DPD genotyping for all patients receiving fluoropyrimidine-based treatment to improve its safety as compared to the European Medicines Agency (EMA)13 and others pharmacogenetics working group. In December 2018, a new guideline from the French cancer institute (Institut National Du Cancer, INCa) and the French health authority (Haute Autorité de Santé, HAS) recommended the measurement of the uracil blood level before genotyping DPD and dose adaptation if this level is greater than 16 ng/mL. The aim herein is to assess how this recommendation has been implemented in clinical routine. 5-FU displays a dose-response relationship regarding both its efficacy and its toxicity, did tailored-dose impair the treatment efficacy as it decreased the risk of toxicity? To address that matter we conducted a retrospective study to evaluate how fluoropyrimidine dosage is adapted to uracil concentration with an emphasis on how patients outcome were affected. We compared time to failure and overall survival between patients with an uracil concentration < 16 ng/mL and > or = 16 ng/mL.

Official Title
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Fluoropyrimidine Tailored-dose Based on Uracil Concentration in Patients Treated for Digestive Carcinomas: Evaluation of Clinical Practice

Conditions
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Digestive Carcinoma

Intervention / Treatment
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* Drug: Fluoropyrimidine treatment (5-FU or capecitabine) and dosage
* Other: Uracil dosage
* Behavioral: Overall survival


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Digestive cancer An uracil dosage performed between February 2018 to January 2020 Received at least one cycle of fluoropyrimidine-based chemotherapy in one of the three oncology departments (Hopital Edouard Heriot [Lyon], Centre Hospitalier de Lyon Sud [Lyon], Hopital de la Croix Rousse [Lyon]). Exclusion Criteria: Age limit less than 18 years Not treated with fluoropyrimidine based chemotherapy Missing data for uracil concentration or chemotherapy dosage

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Uracil concentration <16 ng/mL<br>Patients were included in this arm if they have digestive cancer and an uracil dosage <16 ng/mL performed between February 2018 to January 2020, and if they received at least one cycle of fluoropyrimidine-based chemotherapy in one of the four oncology departments (Hopital Edouard Heriot [Lyon], Centre Hospitalier de Lyon Sud [Lyon], Hopital de la Croix Rousse [Lyon]. | Drug: Fluoropyrimidine treatment (5-FU or capecitabine) and dosage<br>* In each group with an uracil dosage; at cycle 1; capecitabine or continuous 5-FU dose percentage will be evaluate retrospectively in our database<br>Other: Uracil dosage<br>* For each patient, uracil concentration will be evaluate and patients will be compared based on 16 ng/mL as threshold.<br>Behavioral: Overall survival<br>* For each group of patient, on 16 ng/mL as threshold for uracil concentration, overall survival will be compared betwen the two groups of patients (Uracil <16 vs Uracil ≥16).<br>|
| Uracil concentration ≥16 ng/mL<br>Patients were included in this arm if they have digestive cancer and an uracil dosage <16 ng/mL performed between February 2018 to January 2020, and if they received at least one cycle of fluoropyrimidine-based chemotherapy in one of the four oncology departments (Hopital Edouard Heriot [Lyon], Centre Hospitalier de Lyon Sud [Lyon], Hopital de la Croix Rousse [Lyon]. | Drug: Fluoropyrimidine treatment (5-FU or capecitabine) and dosage<br>* In each group with an uracil dosage; at cycle 1; capecitabine or continuous 5-FU dose percentage will be evaluate retrospectively in our database<br>Other: Uracil dosage<br>* For each patient, uracil concentration will be evaluate and patients will be compared based on 16 ng/mL as threshold.<br>Behavioral: Overall survival<br>* For each group of patient, on 16 ng/mL as threshold for uracil concentration, overall survival will be compared betwen the two groups of patients (Uracil <16 vs Uracil ≥16).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival according to plasma uracil concentration |  | Last completion date March 30th 2021 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Uracil, DPYD, Toxicity, Clinical practice, Overall survival