Original Title: Avis: traitements à base de fluoropyrimidines : meilleures stratégies pour réduire le risque de toxicités sévères causées par une déficience en dihydropyrimidine déshydrogénase

Authors' objectives: To improve the quality of fluoropyrimidine-based therapies, the Direction générale de cancérologie of the MSSS asked INESSS to 1) identify the other DPYD variants that have been associated with an increased risk of severe fluoropyrimidine-induced toxicities, 2) determine the most appropriate therapeutic strategy in cases of a positive genotyping result for a DPYD allele, and 3) determine the time at which DPYD genotyping test should be proposed.

Authors' results and conclusions: RESULTS: Dose adjustments based on the prediction of residual DPD activity in carriers of a DPYD variant have been proposed by the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC). The clinical utility of these adjustments has been demonstrated in carriers of the variant c.1905+1G>A: a 50 % reduction in the standard initial fluoropyrimidine dose resulted in a rate of severe adverse effects similar to that observed in noncarriers of this variant who received a standard dose. In patients who were carriers of a c.2846A>T or c.1129-5923C>G variant, a 25 % reduction in the initial standard fluoropyrimidine dose was insufficient to reduce the risk of severe toxicity to a level comparable to that observed in noncarriers of a consensus DPYD variant. Besides, the CPIC recommends reducing the initial dose by 25 to 50 % when these alleles are detected. Lastly, a single study has evaluated the impact of a therapeutic adjustment in carriers of a c.1679T>G allele. In that study, a 50 % dose reduction proved safe for the only patient who carried this allele. Given that the impact of the c.1679T>G allele on DPD enzyme activity is comparable to that observed in carriers of the c.1905+1G>A allele, the experts consulted consider that the effect observed after a 50 % dose reduction is clinically significant. Limited data are available for determining whether fluoropyrimidine dose reductions are effective in treating the disease. The few studies considered in this evaluation suggest that therapeutic adjustments made on the basis of the DPD phenotype or the DPYD genotype make it possible to maintain severe toxicity at a frequency comparable to (or less than) that observed in patients with no deficiency (or carriers of the reference genotype) treated with a standard dose, without compromising therapeutic efficacy. However, these studies had significant limitations in terms of 1) the approach used to screen for deficiency (DPD phenotype vs. DPYD genotype), 2) the method used to define status (in the absence of clinical validity) and 3) the number of patients evaluated for the purpose of demonstrating a significant difference in efficacy between the therapeutic adjustments and a standard fluoropyrimidine dose. Nonetheless, the experts consulted consider that the uncertainty associated with the efficacy of DPD status-based dose adjustments is similar to that observed for adjustments made regularly on the basis of other patient characteristics (age, sex, performance status, renal or hepatic failure, and tolerance). In addition, they said that they were reassured by the fact that the initial dose reduction will be further titrated based on each patient's tolerance in order to maximize therapeutic effectiveness. Several issues limit the implementation of prospective DPD deficiency screening in everyday practice. Unlike DPD phenotyping, genotyping is an accessible, reliable, rapid and inexpensive approach. However, the correlation between the DPYD genotype and the DPD phenotype is imperfect. Certain carriers of a DPYD variant are normal metabolizers and do not show any signs of severe toxicity after the administration of a standard fluoropyrimidine dose. In contrast, a negative genotyping result for specific DPYD alleles (even combined) is not a guarantee of no DPD activity impairment or no severe fluoropyrimidine-induced toxicities. At the organizational level, a large increase in the number DPYD genotyping requests is anticipated in the event of prospective genotyping implementation, given the widespread use of fluoropyrimidine-based therapies. The resulting costs and the pre-treatment test result turnaround time were concerns on the part of the experts consulted. Lastly, several of the patients interrogated preferred that the test be proposed to those for whom fluoropyrimidine-based therapy is being considered.

Authors' recommendations: Having examined this matter, INESSS makes the following recommendations:  The clinician should inform the patient of the risks associated with DPD deficiency, the currently available screening methods for this deficiency, and the consequences of a positive or negative genotyping result for DPYD alleles.  Prospective genotyping for selected DPYD alleles should be included in the planning of fluoropyrimidine-based therapies.  Screening for the DPYD variants c.1679T>G, c.2846A>T and c.1129-5923C>G should be added to the current genotyping test (c.1905+1G>A; DPYD*2A).  Initial fluoropyrimidine dose adjustements are proposed according to the DPYD genotype identified. Details concerning these recommendations:  A maximum test result turnaround time of 10 business days should be respected as the ministerial target for all Québec facilities that order this test, so as not to delay the start of treatment.  During subsequent cycles, the recommended initial dose should be readjusted according to each patient's tolerance to ensure that the treatment is not administered at a nonoptimal dose.  A negative genotyping result for specific DPYD alleles (even combined) is not a guarantee of no DPD activity impairment or no severe toxicities following fluoropyrimidine-based therapy. Vigilance should be maintained during the initial exposure to fluoropyrimidines. Since the genetic variations targeted by this test are germ-line variants, there is no need to order a repeat test for a given patient when the result is unambiguous.

Authors' methods: An exhaustive review of the scientific literature led to the identification of other DPYD variants that can explain severe fluoropyrimidine-induced toxicity. A significant association has been demonstrated between the variants c.1679T>G and c.2846A>T and the development of severe adverse effects after the administration of a standard fluoropyrimidine dose. The significance of the association between the variant c.1129-5923C>G and severe toxicity is less well demonstrated. However, because of its higher frequency and of recent data supporting a fluoropyrimidine dose reduction in carriers of this allele, the experts consulted were in favour of screening for it. They also mentioned that the information provided by genotyping for the four consensus alleles is clinically significant and should lead to changes in clinical practice.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/traitements-a-base-de-fluoropyrimidines-meilleures-strategies-pour-reduire-le-risque-de-toxicites-severes-causees-par-une-deficience-en-dihydropyrimidine-deshydrogenase.html

Year Published: 2019

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/traitements-a-base-de-fluoropyrimidines-meilleures-strategies-pour-reduire-le-risque-de-toxicites-severes-causees-par-une-deficience-en-dihydropyrimidine-deshydrogenase.html

Requestor: Minister of Health

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: Gouvernement du Québec