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Benefit of uridine triacetate (Vistogard) in rescuing severe 5-fluorouracil toxicity in patients with dihydropyrimidine dehydrogenase (DPYD) deficiency
Ist Teil von
Cancer chemotherapy and pharmacology, 2016-07, Vol.78 (1), p.151-156
Ort / Verlag
Berlin/Heidelberg: Springer Berlin Heidelberg
Erscheinungsjahr
2016
Quelle
MEDLINE
Beschreibungen/Notizen
Background
5-Fluorouracil (5-FU), an analog of uracil, is one of the most commonly used chemotherapeutic agents and like other agents has a narrow therapeutic index limited by toxicity. Compared to previous attempts, uridine triacetate (Vistogard) has shown to increase the potential efficacy of 5-FU by allowing administering a higher dose and decreasing the toxicity. Recently, Vistogard received orphan drug designation from the FDA as an antidote in the treatment of 5-FU poisoning and from the European Medicines Agency as a treatment for 5-FU overdose. However, no data have been published to date in humans who were rescued by this agent following severe toxicity associated with 5-FU due to dihydropyrimidine dehydrogenase (
DPYD
) deficiency, the enzyme which is responsible for the elimination of approximately 80 % of the administered dose of 5-FU.
Patients and methods
We identified two patients with advanced pancreatic cancer who were referred to us for testing of
DPYD
status following severe toxicity associated with 5-FU administered at a dose of 1400 mg/m
2
weekly bolus high-dose 5-FU followed by oral uridine triacetate as a part of a clinical trail. One patient developed grade 3 thrombocytopenia and grade 3 skin rash that resolved with discontinuation of 5-FU and supportive care, while second patient developed grade 4 thrombocytopenia, grade 3 coagulopathy and grade 3 neurological toxicity with a fatal outcome.
DPYD
status was evaluated as we have previously published.
Results
The first patient was found to have an abnormally low
DPYD
activity of 0.087-nmol/min/mg protein by radioisotopic assay (reference normal range 0.182–0.688 nmol/min/mg protein). Because of pancytopenia,
DPYD
enzyme activity could not be assessed in patient 2; genotypic analysis of
DPYD
during autopsy revealed the presence of the heterozygous mutation, IVS14+1 G>A,
DPYD
*2A, now recognized as the most common cause of
DPYD
deficiency.
Conclusion
These two patients present the first two cases of
DPYD
deficiency that had either delay in severe toxicity or recovered from severe toxicity as they received oral Vistogard as a part of the conical trial. Toxicity was delayed in both patients by a mean of 3.5 weeks (range 3–4 weeks), indicating that Vistogard might be able to delay 5-FU toxicity despite higher doses than standard bolus dose of 5-FU used in gastrointestinal malignancies and the appearance of a potentially less toxic adverse effect of 5-FU at an unusual site (cutaneous) in one patient. The role of uridine triacetate with 5-FU in
DPYD
-deficient patients needs further investigation.