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The Medical-financial Evaluation of Pre-therapeutic Screening by a Joint Phenotypic-pharmacogenetic Approach for Metabolic Fluoropyrimidine Enzyme Deficiency in Terms of Serious Toxicity Risk Prevention : a Multicentric Case Study

Phase 3
18 Years
Open (Enrolling)
Colorectal Cancer, Intravenous 5 Fluorouracile

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Trial Information

The Medical-financial Evaluation of Pre-therapeutic Screening by a Joint Phenotypic-pharmacogenetic Approach for Metabolic Fluoropyrimidine Enzyme Deficiency in Terms of Serious Toxicity Risk Prevention : a Multicentric Case Study

The fluoropyrimidines, of which 5-Fluorouracil is the most important, represent a family of
medication that is used in particular in cancerology. They are molecules widely used in
cancerology since they can be found in nearly 45% of chemotherapy protocols and in the
treatment of about 50% of cancers (colorectum, oesophagus, stomach, breast, upper digestive
and respiratory tracts). They are not only used in metastatic situations but also more and
more in adjuvant situations, in other words for patients treated for a localised tumour,
presenting a risk of relapse. A severe toxic risk cannot be tolerated in these conditions,
and the doctor should assure the maximum level of safety for his patients. These medicines
are the cause of 3% of grade IV toxicity from the first or second administration, and for
0.3% of deaths. To this one can add on a total of 20 to 25% grade III-IV toxic events.

Anticancer treatment is mostly administered by body size and in the best of cases after a
few basic biological examinations such as a haemogram and renal status, without taking into
consideration any individual particularities, whether genetic or epigenetic. Among potential
toxicity risk factors one can find individual metabolic differences linked to genetic
modifications of metabolism enzymes as well as differences in the chemical receptors and

For fluoropyrimidines, a polymorphism was found for the dihydropyrimidine dehydrogenase gene
(DPD), a major catabolism enzyme. A deficit of this enzyme is a major counter-indication for
the use of these medicines.

Early determination of DPD status would allow identification of patients at risk and would
thus help in subsequent dose adjustment or selection of other treatment modalities.

Inclusion Criteria:

- colorectal cancer, histologically confirmed, with all types included (including
adjuvant cases), requiring treatment with intravenous 5-fluorouracil.

- anterior chemotherapy authorised, with the exception of chemotherapy containing a
derivate of 5-Fluorouracil

- Age > or = 18 years

- WHO Performance status < or = 2

- Haematologic and hepatic parameters : neutrophils > or = 1000 /mm3, platelets > or =
100000/mm3, Total bilirubin < or = 2 x ULN, AST and ALT < or = 3 x ULN, APL < or = 5

- Complete initial assessment before first treatment administration for imaging and
pharmacogenetic, within 15 days for biology, and within 7 days for clinical

- Signed written informed consent

Exclusion Criteria:

- Prior chemotherapy with fluoropyrimidines

- Symptomatic or uncontrolled ventral nervous system metastases

- Psychiatric Disease disrupting the trial understanding and the enlightened and
voluntary consent character

- Patient who is pregnant or breast feeding

- Woman not consenting to use adequate contraceptive precautions during the study

- Patient who can not submit itself to the formal follow-up for psychological, social,
family or geographical reasons

- Significant serious pathology or any instable medical condition (cardiac pathology
uncontrolled, myocardial infarction within 6 months before enrollment, systemic
active uncontrolled infection)

- any investigational agent within 4 weeks before enrollment

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Outcome Measure:

Number and nature of grade IV toxicity.

Outcome Description:

The percentage of severe toxicity (grade IV) will be analyzed in each arm. We expect a reduction of the early, severe, grade IV acute side-effects from 3% to 0.6% in the detected group with adapted doses.

Outcome Time Frame:

Up to 4 weeks.

Safety Issue:


Principal Investigator

Olivier Capitain, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

ICO Paul Papin


France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Study ID:




Start Date:

June 2008

Completion Date:

December 2012

Related Keywords:

  • Colorectal Cancer
  • Intravenous 5 Fluorouracile
  • Colorectal Cancer
  • DihydroPyrimidine Dehydrogenase
  • Lethal toxicity
  • Fluoropyrimidine
  • Colorectal Neoplasms