Screening for Dihydropyrimidine Dehydrogenase (DPD) Deficiency in Fluorouracil Patients: Why Not?
ISMP is aware of several reports of patients who suffered severe toxicities or even death from the fluoropyrimidine chemotherapy drugs, fluorouracil and capecitabine (XELODA), an oral prodrug that is metabolized to fluorouracil after ingestion. These patients had a genetic condition called dihydropyrimidine dehydrogenase (DPD) deficiency, a diagnosis that neither the patients nor their doctors were aware of until it was too late. The DPD enzyme is critical for the metabolism of fluoropyrimidine drugs. With deficient enzyme function, patients can experience severe toxicities with standard doses of fluoropyrimidine chemotherapy.1 While the incidence of DPD deficiency is relatively low, ranging from 1 to 7 percent of the population depending on ancestry,2 the consequences are potentially fatal.
A recently reported case involved a patient with breast cancer who was prescribed capecitabine. Within the first week of treatment, she began to develop mild drug-related symptoms including fatigue, weight loss, loss of appetite, and diarrhea. By the second week, her symptoms worsened, including mucositis, hand-foot syndrome (skin reaction caused by leakage of the chemotherapy through capillaries in the palms of the hands and soles of the feet), extreme weight loss, fatigue, diarrhea, and a cough. After completing her first 2 weeks of therapy, she had become so weak that she required hospitalization. After hospitalization, her symptoms continued to worsen, including hand and foot desquamation, severe mucositis, dry eyes requiring artificial tears, delirium, and prolonged leukopenia. Her mouth, lips, throat, and esophagus were covered with lesions and blood. Her hair was falling out. Eventually she became unresponsive. Only later was it found that she had a DPD deficiency, so her body was unable to clear the capecitabine. She died just one month after starting therapy.
ISMP was heartbroken to learn about this preventable death, as a DPD deficiency can be detected through genetic testing prior to starting fluoropyrimidine chemotherapy. Having this information beforehand allows providers to preemptively reduce the dose of the patient’s therapy and mitigate potential toxicities, or not give therapy at all if the patient is totally deficient, as no fluorouracil dose has been proven safe for patients with complete absence of DPD activity.
Screening for DPD Deficiency in Other Countries
Recently, the European Medicines Agency (EMA), the French regulatory agency (L’Agence nationale de sécurité du médicament et des produits de santé [ANSM]), and the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom, have all provided guidelines for preemptive DPD testing for patients scheduled for treatment with fluoropyrimidine chemotherapy.3 But in the US, the National Comprehensive Cancer Network (NCCN) has not recommended universal pretreatment DPD deficiency screening,4 and it is not currently the standard of care despite the known risks. Patient advocates have filed citizen petitions with the US Food and Drug Administration (FDA)5 requesting a Boxed Warning in product labeling to reflect the need for patient screening. FDA-approved labeling for fluorouracil and capecitabine discusses DPD deficiency and the risk to patients, noting that patients with partial DPD activity may have increased risk of severe, life-threatening, or fatal adverse reactions caused by fluorouracil. So far, nothing in US product labeling recommends (or requires) screening patients for DPD deficiency prior to initiating fluoropyrimidine chemotherapy.
Pros and Cons of Screening for DPD Deficiency
If the technology exists to detect the deficiency through genotyping, and the consequences of not doing so in advance of therapy with a fluoropyrimidine drug potentially may lead to patient harm and death, why wouldn’t providers preemptively screen patients? Several concerns have been raised regarding universal pretreatment screening.
Cost of screening. Insurance companies may not cover the cost of DPD genetic testing, citing the test to be investigational.6 However, analyses of cost effectiveness show that screening prior to therapy, combined with preemptive dose reductions, is a cost-effective option compared to no screening, given the severe toxicity-related hospitalization of patients who have a DPD deficiency and receive full-dose fluorouracil or capecitabine.7,8
Potential delay in care. Providers have expressed concern that preemptive screening for all patients scheduled to receive fluoropyrimidine chemotherapy may cause a delay in treatment.6 However, based on other discussions, it appears that the genetic testing can be completed in a reasonable amount of time. According to laboratory personnel who we spoke with, in-house testing results can be available in 2 to 3 days, and external laboratory testing results can be available in 3 to 10 days. In most (but not all) cases, waiting for the genetic testing results is reasonable as workup and decisions are being made regarding cancer treatment. Or, at least screening can take place concurrently with therapy initiation since coordinating the start of therapy may take a few days.
Potential lack of consensus on dosing. Some clinicians have also cited a lack of consensus on preemptive dose reductions for DPD deficiency to be a barrier to widespread testing. However, clear guidance is available from the Clinical Pharmacogenetics Implementation Consortium (CPIC), a leading authority on implementing pharmacogenetic testing for patient care.2,3 Their dosing recommendations address the varying degrees of DPD deficiency for safe and effective use of fluoropyrimidines in all patients.2
Potential decreased efficacy against cancer. Another concern raised is the uncertainty and potential negative impact on treatment efficacy if preemptive testing leads to a dose reduction. However, pharmacokinetic studies show that patients with DPD deficiency have significantly increased exposure to fluoropyrimidines.8 It has also been found that overall survival and progression-free survival of DPD-deficient patients who preemptively receives a dose reduction were not negatively impacted.9
NCCN does not support routine screening. The NCCN Clinical Practice Guidelines in Oncology for Colon Cancer acknowledge evidence from published studies that support the feasibility, cost effectiveness, and improved safety of pretreatment DPD deficiency screening.4,8,10 In the US, DPYD genotyping is the main test used to determine a DPD deficiency, which is defined as the presence of one or more variant DPYD alleles that are known to result in a DPD protein with partial or complete loss of function. However, the NCCN Colon Cancer Panel concludes that “because fluoropyrimidines are a pillar of therapy in [colorectal cancer] and it is not known with certainty that given DPYD variants are necessarily associated with this risk, universal pretreatment DPYD genotyping remains controversial and the NCCN Panel does not support it at this time.”4
Other. It should also be mentioned that uridine triacetate (VISTOGARD) has been used to treat patients with pyrimidine toxicity due to DPD deficiency, even when given past 96 hours as recommended in the product labeling.11 Such use, however, is not included in FDA-approved product labeling.
In reviewing the literature surrounding the hesitancy to adopt universal DPD deficiency screening prior to the use of fluoropyrimidines, 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 joins others who ask the question, “Why not?”
- Wigle TJ, Tsvetkova EV, Welch SA, Kim RB. DPYD and fluorouracil-based chemotherapy: mini review and case report. Pharmaceutics. 2019;11(5):199.
- Amstutz U, Henricks LM, Offer SM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. Clin Pharmacol Ther. 2018;103(2):210-6.
- Ciccolini J, Milano G, Guchelaar HJ. Detecting DPD deficiency: when perfect is the enemy of good. Cancer Chemother Pharmacol. 2021;87(5):717-9.
- Benson AB, Venook AP, Al-Hawary MM, et al. Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19(3):329-59.
- Surprenant KE (citizen’s petition). Regulations.gov. Posted November 18, 2020. Accessed June 10, 2021.
- Lau-Min KS, Varughese LA, Nelson MN, et al. Clinician perspectives on preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies. J Clin Oncol. 2021;39(3)(suppl):54.
- Brooks GA, Tapp S, Daly AT, Busam J, Tosteson ANA. Cost effectiveness of DPYD genotyping to screen for dihydropyrimidine dehydrogenase (DPD) deficiency prior to adjuvant chemotherapy for colon cancer. J Clin Oncol. 2021;39(3)(suppl):55.
- Deenen MJ, Meulendijks D, Cats A, et al. Upfront genotyping of DPYD*2A to individualize fluoropyrimidine therapy: a safety and cost analysis. J Clin Oncol. 2016;34(3):227-34.
- Henricks LM, van Merendonk LN, Meulendijks D, et al. Effectiveness and safety of reduced-dose fluoropyrimidine therapy in patients carrying the DPYD*2A variant: a matched pair analysis. Int J Cancer. 2019;144(9):2347-54.
- Henricks LM, Lunenburg CATC, de Man FM, et al. DPYD genotype-guided dose individualisation of fluoro-pyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol. 2018;19(11):1459-67.
- Ma WW, Saif MW, El‐Rayes BF, et al. Emergency use of uridine triacetate for the prevention and treatment of life‐threatening 5‐fluorouracil and capecitabine toxicity. Cancer. 2017;123(2):345–56.