Clinical trial NCT04269369: Implementation of Pre-emptive Geno- and Phenotyping in 5-Fluorouracil- or Capecitabine-treated Patients
Official title: Implementation of Pre-emptive Geno- and Phenotyping in 5-Fluorouracil- or Capecitabine-treated Patients With the Aim of Reducing Toxicity
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Colon Cancer
Stomach Tumor
Anal Tumor
Pancreas Cancer
Esophageal Cancer
Lead sponsor: Jessa Hospital
Sponsor class: OTHER
First posted: 2020-02-13
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In a subgroup of patients, a parallel study model will be used. In the group of patients with genotype "wild type" and phenotype "intermediate metabolizer", a comparison will be made between group A with dosage according to French guidelines and group B with dosage according to literature. After obtaining written informed consent, patients will be randomized in a 1:1 ratio to one of the two study groups.
Primary purpose: TREATMENT

Brief summary: The aim of this study is to investigate if the systematic implementation of pre-emptive geno- and phenotyping, and therefore a dose reduction based on the French guidelines and the literature during the first month of treatment, reduces grade 3 or greater toxicity in patients treated with 5-FU (5-fluorouracil) or capecitabine.

Therefore, a monocentric, partial prospective and partial retrospective trail was designed.

Detailed description: 5-FU (5-fluorouracil) and its oral prodrug capecitabine are commonly used drugs in various chemotherapy regimens. According to the literature, approximately 30% of the patients experience at least a grade three toxicity during treatment, mainly characterized by diarrhea, mucositis, hematological toxicity or hand-foot syndrome. This toxicity can lead to discontinuation or interruption of the therapy, hospitalization and in 1% of the cases even to mortality. This leads to an increase in health care costs, mainly driven by the cost of hospitalization.

The metabolism of 5-FU and its prodrug is primarily determined by the dehydropyrimidine dehydrogenase (DPD) enzyme. The gene encoding for this enzyme, the DPYD, is known for his genetic polymorphism. Five percent of the population has a partial DPYD deficiency and 0.01 to 0.1 percent has a full DPYP deficiency. Partial deficiency leads to a reduced activity of DPD and therefore to a reduced degradation of 5-FU or capecitabine to its inactive metabolites. This leads to an increased toxicity. The four DPYD variants considered most clinically relevant are DPYD \* 2A, DPYD \* 13, c.1236G\> A and c.2846A\> T. Patients with polymorphisms DPYD \* 2A and DPYD \* 13 have no residual enzyme activity, while in patients with polymorphisms 1236G\> A and c.2846A\> T, there is still partial enzyme activity present. In addition to genotyping, partial DPYD deficiency can also be detected by phenotyping. In the case of reduced enzyme activity of DPYD, the degradation of uracil is disturbed, causing an increase in uracil and a decrease in UH2 in plasma. There is a strong correlation between the UH2 / U ratio in plasma and the halflife, clearance and plasma levels of 5-FU.

French guidelines, HAS (La Haute Autorité de santé), recommend to adjust the dose of these drugs at the start of treatment based on the results of both the genetic and phenotypic studies.

The aim of this study is to investigate if the systematic implementation of pre-emptive geno- and phenotyping, and therefore a dose reduction based on the French guidelines and the literature during the first month of treatment, reduces grade 3 or greater toxicity in patients treated with 5-FU or capecitabine.

Therefore, a monocentric, partial prospective and partial retrospective trail was designed.

Eligibility criteria: Inclusion Criteria:

* Patients aged 18 years or older
* WHO (world health organization) classification 0,1 or 2
* A suspected start with 5-FU or capecitabine in mono or combination therapy
* The knowledge of the result of the geno and phenotyping before the start of the treatment

Exclusion Criteria:

* Not meeting inclusion criteria
* Homozygote genotype or uracil 100 ng/ml or greater
* The lacking of the result of the geno and / or phenotyping before the start of treatment
* Patients who received 5-FU or capecitabine in the past

Primary outcomes:
measure: The frequency of severe ﬂuoropyrimidine-related toxicity
timeFrame: about 3 months
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Jessa Hospital
name: An Lambaerts
role: PRINCIPAL_INVESTIGATOR
References: