Patients with cancer who are to receive fluorouracil (multiple brands) given by injection or infusion should be tested for lack of an enzyme called dihydropyrimidine dehydrogenase (DPD) prior to the initiation of treatment, says the European Medicines Agency's (EMA) safety body, the Pharmacovigilance Risk Assessment Committee (PRAC).
The recommendation also applies to related drugs capecitabine (Xeloda, Genentech) and tegafur, which are converted to fluorouracil in the body.
These chemotherapeutic agents are very widely used in the treatment of a variety of cancer types, including colorectal, breast, and head and neck cancers.
There appears to be inconsistency among oncologists about the issue of DPD testing prior to using fluorouracil, as previously reported by Medscape Medical News.
New Recommendations for Testing
PRAC notes that the percentage of people with reduced or absent DPD is low in the white population: up to 8% have low-working levels of the enzyme and up to 0.5% completely lack it.
The committee recommends that testing prior to treatment can be done either by measuring uracil levels, which is broken down by DPD in the blood, or by assessing for the presence of specific mutations in the gene for DPD that have been associated with an elevated risk for severe side effects.
Fluorouracil injection or infusion, capecitabine, or tegafur should not be administered to patients with a known complete DPD deficiency, as a complete lack of this enzyme will put them at a high risk of severe and life-threatening side effects, the committee warns.
If a partial DPD deficiency is observed, then a lower starting dose should be considered.
However, PRAC points out that the effectiveness of a reduced dose has not been established, and therefore subsequent doses may be increased in the absence of serious side effects.
In addition, regular monitoring of fluorouracil blood levels is needed for patients receiving the agent by continuous infusion.
PRAC also noted that for flucytosine (Ancobon, Valeant Pharmaceuticals), which is used for severe fungal infections and is also converted to fluorouracil after administration, pretreatment testing is not required so as not to delay the initiation of treatment.
It adds that, although pretreatment testing for DPD deficiency is not required for flucytosine, its use should be avoided in patients with a known DPD deficiency because of the risk of life-threatening side effects. Those with a partial DPD deficiency also face an increased risk of severe side effects, and if an adverse event occurs, stopping treatment should be considered.
Pretreatment testing is also not needed for patients who are treated with topical fluorouracil, which is used for a variety of cutaneous conditions.
Differing Views About Testing
As previously reported by Medscape Medical News, the EMA in 2019 began a review into the screening of patients before they begin treatment with these antineoplastic agents. The EMA review came in the wake of several high-profile cases of treatment-related fatal reactions.
In France, following the death of four patients linked to these chemotherapies, families filed a lawsuit demanding to know why testing wasn't done prior to beginning treatment. Their argument was that testing may have prevented these deaths. Additionally, there was also a fatal reaction in a patient treated in the United Kingdom.
These patient deaths led some European experts to openly question whether DPD testing should be incorporated into routine oncology practice as a safety measure, and potentially prevent lethal reactions to fluoropyrimidine treatment.
David Kerr, MD, professor of cancer medicine at the Oxford Cancer and Haematology Centre in Oxford, England, argued in a Medscape commentary in favor of germline testing for DPD deficiency, and suggested "that in those who we find have significant defects in DPD in germline genetic testing, we should make a 50% dose reduction in fluoropyrimidine and follow those patients carefully."
However, others disagreed.
Another UK expert, Karol Sikora, PhD, MB BChir, professor of cancer medicine at the University of Buckingham, argued against routine testing at this time. In his video commentary, he noted that there are many other factors involved, and DPD polymorphisms are not the only cause of an increased sensitivity to these agents. Even with the genomics, "not all patients with an abnormal polymorphism will actually develop increased toxicity."
In his experience, less than 10% of patients experience significant problems and only about 1% require treatment. Sometimes dose reduction is needed, or other changes need to be made, but "we don't really have to stop that often," he said, also pointing out that a little used antidote — a drug called uridine triacetate (Vistogard, Wellstat Therapeutics) — is available.
Experts in the United States also appear not to be convinced about routine testing, at least the few who were approached by Medscape Medical News for an article in March 2019. Several Medscape readers, however, commented that they do carry out regular testing.
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Cite this: Europe Recommends DPD Testing BeforeIV Fluorouracil - Medscape - Mar 16, 2020.
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