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In a featured article in our last newsletter (Screening for dihydropyrimidine dehydrogenase [DPD] deficiency in fluorouracil patients: Why not? July 15, 2021), we reviewed the literature surrounding the hesitancy to adopt universal dihydropyrimidine dehydrogenase (DPD) deficiency screening in patients prior to the use of fluoropyrimidines (fluorouracil and capecitabine). We mentioned that the National Comprehensive Cancer Network (NCCN) has not recommended universal pretreatment DPD deficiency screening, and that it is not currently the standard of care in the US. However, we concluded that the risk of patient harm and potential fatality seems clear when administering fluoropyrimidines to patients with a DPD deficiency, while the hurdles to implement widespread testing seem to be manageable. So, ISMP has joined others who have asked the question, “Why not test?”

In response to that article, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Panel for Colon/Rectal/Anal Cancers sent the following letter to ISMP:

The authors raise some important issues about screening for dihydropyrimidine dehydrogenase (DPD) deficiency; it is a complicated topic regarding a complex metabolic pathway. Our panel has discussed this issue extensively and we will continue to monitor any new developments in the literature.

There are a few comments we would like to make regarding DPD deficiency and pretreatment testing. The incidence of true total enzyme deficiency is probably less than 1% depending on the population while some level of deficient DPD activity occurs in about 5-10% of the population overall.¹ Deficient DPD activity is due to natural variations in the DPYD gene that make the patient less efficient in metabolizing the drug and its metabolites due to decreased activity of the patient’s particular enzymes in the pathway.

In promoting pretreatment testing for DPYD variants, the authors cite studies which looked at a few specific variants and did show the benefits of pretesting in terms of diminishing the incidence of very severe fluorouracil associated toxicities. However, these studies provide no survival data to inform whether reducing the dose of fluorouracil by 50% at the start of treatment impacts efficacy, which is especially important when fluorouracil or capecitabine are being used in the adjuvant setting for patients with potentially curable cancer. If we had more precise dosing recommendations based on specific variations and survival data—if in fact dosing would be totally dependent on that particular enzyme variant—it would be a reasonable test to run. In fairness, these are small select studies, but we still need to know if we diminish the chance of a cure.

As for capecitabine, which is an oral pro-drug, there are so many other variables regarding toxicities in individual patients, including age-related decreases in creatinine clearance, actual kidney disease and dysfunction, diet, and emerging data on the microbiome, that we would have no idea how to incorporate DPD findings into the dosing of that drug.

In summary, because of the integral role fluoropyrimidines play in the treatment of colon cancer, and the uncertainty regarding the impact of different DPYD variants on fluoropyrimidine metabolism and how dosing should be adjusted, the National Comprehensive Cancer Network (NCCN) panel does not support universal pretreatment DPYD genotyping at this time.

Al B. Benson III, MD, FACP, FASCO, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chair of the NCCN Guidelines Panel for Colon/Rectal/Anal Cancers

Alan Venook, MD, UCSF Helen Diller Family Comprehensive Cancer Center, Vice-Chair of the NCCN Guidelines Panel for Colon/Rectal/Anal Cancers

Reference

1. Pallet N, Hamdane S, Garinet S, et al. A comprehensive population-based study comparing the phenotype and genotype in a pretherapeutic screen of dihydropyrimidine dehydrogenase deficiency. Br J Cancer. 2020;123(5):811–8.