Benefit of uridine triacetate (Vistogard) in rescuing severe 5-fluorouracil toxicity in patients with dihydropyrimidine dehydrogenase (DPYD) deficiency.
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.


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.


CONCLUSIONS
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.
Division of Hematology/Oncology and Experimental Therapeutics, Tufts Medical Center, Tufts University School of Medicine, 800 Washington Street Box: 245, Boston, MA, 02111, USA. wsaif@tuftsmedicalcenter.org.
Muhammad Wasif
MW
Saif
Mayo Clinic, Rochester, MN, USA.
Robert B
RB
Diasio
D000085:Acetates / Q000627:therapeutic use*; D000368:Aged; D000931:Antidotes / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D054067:Dihydropyrimidine Dehydrogenase Deficiency / Q000150:complications*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D008297:Male; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D012720:Severity of Illness Index; D013997:Time Factors; D014529:Uridine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000085:Acetates; D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; C000609666:uridine triacetate; D005472:Fluorouracil; D014529:Uridine
5-Fluorouracil; DPYD gene; Fluoropyrimidines; PN401; Uridine