The goal of this clinical trial is to establish guidelines for fluoropyrimidine dose reduction according to uracilemia in patients with DPD deficiency in the treatment of digestive cancers. The main question it aims to answer is:

- Which reduction dose of fluoropyrimidine is needed for patient with DPD deficiency?

Participants will:

• Take the treatment with the reduction of dose stated by the protocol
• Visit the clinic once every 2-3 weeks for checkups and tests for collection of adverse events

Multicenter phase II trial evaluating different strategies of pre-specified fluoropyrimidine-dose adjustment according to [U] in DPD-deficient patients with gastrointestinal cancer.

Inclusion Criteria:

1. Patients with pre-treatment screening based on [U] value according to INCa/HAS recommendations.

2. Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2

3. Fluoropyrimidine-naïve patients with gastrointestinal cancer starting chemotherapy combining fluoropyrimidine (5-FU or capecitabine) and oxaliplatin whatever the context (adjuvant, neoadjuvant, palliative) including the following regimens (the most frequently prescribed in gastrointestinal cancers):

   • biweekly 5-FU and oxaliplatin (FOLFOX) +/- targeted therapy (TT)
   • three-weekly capecitabine and oxaliplatin (CAPOX) +/- TT

4. Age ≥ 18 years

5. Patients eligible for full standard fluoropyrimidine and oxaliplatin doses regardless of DPD deficiency

6. Adequate bone marrow function (cell blood count (CBC)), estimated glomerular filtration rate (DFG) ≥ 50 ml/min, alkaline phosphatase (ALP) / aspartate aminotransferase (ASAT) / alanine aminotransferase (ALAT) ≤ 5 upper limit of normal (ULN), and bilirubin ≤ 50 micromol/L

7. Patient must have signed and dated a written informed consent form prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient's consent.

8. Women of childbearing potential must have a negative serum or urine pregnancy test.

9. Patients must agree to remain abstinent or use contraceptive methods with a failure rate of < 1% per year for the duration of study treatment and within 6 months after completing treatment.

10. Patients must be affiliated to a Social Security System (or equivalent).

11. Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up.

Exclusion Criteria:

1. Patients with complete DPD deficiency based on [U] ≥150 ng/mL
2. Any prior treatment including a fluoropyrimidine
3. Patients with any contraindication to treatment with fluoropyrimidine or oxaliplatin regardless of DPD deficiency
4. Patients not eligible for full standard dose fluoropyrimidine and oxaliplatin for clinical reasons including older age and/or comorbidity regardless of a DPD deficiency
5. Patients unwilling or unable to comply with trial obligations for geographic, social, or physical reasons, or who are unable to understand the purpose and procedures of the trial
6. Recent or concomitant treatment with brivudine
7. Pregnant or breastfeeding woman.
8. Participation in another therapeutic trial within 30 days prior to inclusion.
9. Persons deprived of their liberty or under protective custody or guardianship.

Individual Participant Data will not be shared at an individual level. Those data will be part of the study database including all enrolled patients.