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Evaluation of the risk of toxicity of fluoropyrimidines

Pictogramme horloge Nicole COUPRIE Pictogramme horloge April 2018

ANSM (French National Agency for Medicines and Health Products Safety) recently published an information bulletin on the occurrence of serious undesirable effects related to dihydropyrimidine dehydrogenase (DPD) deficiency during treatment with fluoropyrimidines (5-fluorouracil and its oral prodrug, capecitabine).

Since 2015, the Eurofins Biomnis laboratory – in collaboration with the company ODPM – has offered an evaluation of this toxic risk, as part of its personalized medicine programme.

5-Fluorouracil (5-FU), an anti-cancer antimetabolite drug known since 1957, is a fluoropyrimidine (pyrimidine analogue) that is used in 60% of chemotherapies for solid tumours.

Fluoropyrimidines are widely used in cancers of the digestive tract (particularly metastatic colorectal cancer or in an adjuvant situation), ENT cancers and breast cancer. 5-FU is combined with folinic acid which increases its cytotoxic potency; it can be administered with or without a bolus prior to a continuous infusion lasting 46, 96 or 120 hours. 5-FU or capecitabine can be prescribed alone or in combination with other substances, depending on the respective treatment protocols. Accordingly colorectal cancers can be treated with 5-FU and irinotecan and/or oxaliplatin and/or targeted therapies (cetuximab, panitumumab); the FEC protocol (56FU/epirubicin/ cyclophosphamide) or capecitabine by itself may be used in the treatment of breast cancer; the treatment regimen of ENT cancers often includes cisplatin.

5-FU and capecitabine induce severe toxicities (grades 3-4) in 10-40% of patients according to the protocols, and lethal toxicities in 0.2-0.8% of patients. The bolus is usually the source of hematological toxicity, while prolonged infusions are responsible for digestive toxicity (diarrhea) or hand-foot syndrome.

The occurrence of such toxicity is related to a dihydropyrimidine dehydrogenase (DPD) deficiency. This enzyme involved in the metabolism of fluoropyrimidines ensures their elimination from the body by transforming 5-FU into relatively inactive dihydro-5-FU; in the physiological state, DPD transforms the natural pyrimidine bases uracil and thymine into their dihydrogenated derivatives dihydrouracil and dihydrothymine. There is a very large interindividual variability in the activity of DPD, partly due to genetic polymorphism. Complete DPD deficits are rare (0.1 to 0.5% of the general population); partial deficits are more frequent, reaching between 3 and 10% of subjects in the Caucasian population.

In the investigation of DPD deficiency, Eurofins Biomnis, following ODPM, has selected to combine two complementary approaches:

  • phenotypic (high sensitivity, lower specificity)
  • and genotypic (excellent specificity, lower sensitivity).

The phenotypic study is based on UPLC (ultra performance liquid chromatography) blood tests of uracil and dihydrouracil.

The genotypic profiling focuses on four variants of the DPD gene (DPYD): *2A (c.1905+1G>A, rs3918290), p.D949V (c.2846A>T, rs67376798), *13 (c.1679T>G, p.I560S, rs55886062) (found respectively in 0.9-1.5 %, 1.1-1.5 % and 0.1-0.2 % of Caucasians), and for c.delTCAT (rs72549309).

The results of these biological investigations (carried out before any chemotherapy or possibly at least one week after the last fluoropyrimidine-based treatment) are linked to certain characteristics of the patient, such as physiological (weight, size) and physiopathological parameters (tumour, type and grade of prior toxicity, chemotherapy protocol, any radiotherapy), to be analysed by the algorithm 5FUODPMTox TM, validated by the experience gained by the ICO (Institute of Cancer Research in Western France) in more than 20,000 patients. More than 90% of the partial deficit patients and 100% of the total deficits can thus be detected. Apart from the evaluation of the individual toxic risk, the SEu ODPM Tox calculator also performs an analysis, suggesting the most appropriate dose of fluoropyrimidine for the patient for the next chemotherapy treatment.

The risk screening strategy for fluopyrimidines makes it possible to both avoid the fluoropyrimidine-related toxicities, in particular severe ones and to optimize the therapeutic strategy in the context of a personalized medicine approach.

 


 Bibliography

 

  • Boisdron-Celle M, Gamelin E, Morel A. Suivi thérapeutique du 5-fluorouracile (5-FU) [Therapeutic monitoring of 5-fluorouracil (5-FU)]. EMC Biologie médicale 2017;12 (2):1-7 [Article 90-45-0075-A].
  • Loriot M.A, Ciccolini J, Thomas F, et al.  Dihydropyrimidine dehydrogenase (DPD) deficiency screening and securing of fluoropyrimidine-based chemotherapies: Update and recommendations of the French GPCO-Unicancer and RNPGx networks. Bull Cancer 2018, https://doi.org/10.1016/j.bulcan.2018.02.001

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