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
transporters.

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.