Enzymatic degradation of the fluoropyrimidines, 5-fluorouracil and capecitabine, is mediated by dihydropyrimidine dehydrogenase (DPD). Mutations in the DPYD gene that impair DPD activity can cause life-threatening toxicities from fluoropyrimidines. Uridine triacetate (UT) is a FDA-approved antidote for use in 5-fluorouracil or capecitabine overdose within 96 hours of last chemotherapy dose, but it is not readily accessible in Australia. UT treated patients have 96% 30-day survival after 5-fluorouracil overdose or serious toxicity compared with 16% in historical controls.
Our breast cancer patient presented on D11 cycle 1 capecitabine (dosed at 1g/m2 bd days 1-14), with grade 3 orogenital mucositis, diarrhoea and neutropenia, grade 2 thrombocytopenia and anaemia, and grade 1 palmar-plantar syndrome. Capecitabine was self-ceased on D9 due to significant toxicity. DPD deficiency was suspected (formal test result pending). UT was sourced after 48 hours from Wellstat therapeutics in the US, but required overnight email and phone calls to the US by 3 senior hospital staff and significant courier costs. UT was administered via nasogastric tube for 17 doses at 10g 6-hourly starting 129 hours from the last capecitabine dose. Worst toxicities during admission were grade 4 hypovolaemic shock, febrile neutropenia (requiring filgrastim), diarrhoea and mucositis, grade 3 hypoxia from pneumonia, left ventricular systolic dysfunction and palmar-plantar syndrome. On D20, neutrophils were 1.5 x10^9/L and filgrastim was stopped. At time of writing, 10 days after the completion of UT, all toxicities had resolved except residual grade 3 anaemia and thrombocytopenia and grade 1 palmar-plantar syndrome, and patient is discharged home. This case highlights the difficulty in timely access of this lifesaving medication for Australian patients. Following this case, the Peter MacCallum Cancer Centre, which is the sole Australian distributor for the methotrexate antidote, glucarpidase is in discussion with Wellstat therapeutics about being the main distributor of this antidote for Australia.