Emergency use of uridine triacetate for the prevention and treatment of life-threatening 5-fluorouracil and capecitabine toxicity

Abstract

Background: Increased susceptibility to 5-fluorouracil (5-FU)/capecitabine can lead to rapidly occurring toxicity caused by impaired clearance, dihydropyrimidine dehydrogenase deficiency, and other genetic variations in the enzymes that metabolize 5-FU. Life-threatening 5-FU overdoses occur because of infusion pump errors, dosage miscalculations, and accidental or suicidal ingestion of capecitabine. Uridine triacetate (Vistogard) was approved in 2015 for adult and pediatric patients who exhibit early-onset severe or life-threatening 5-FU/capecitabine toxicities or present with an overdose. Uridine triacetate delivers high concentrations of uridine, which competes with toxic 5-FU metabolites.

Methods: In 2 open-label clinical studies, patients who presented with a 5-FU/capecitabine overdose or an early onset of severe toxicities were treated. Patients received uridine triacetate as soon as possible (most within the first 96 hours after 5-FU/capecitabine). Outcomes included survival, resumption of chemotherapy, and safety. Their survival was compared with the survival of a historical cohort of overdose patients who received only supportive care.

Results: A total of 137 of 142 overdose patients (96%) treated with uridine triacetate survived and had a rapid reversal of severe acute cardiotoxicity and neurotoxicity; in addition, mucositis and leukopenia were prevented, or the patients recovered from them. In the historical cohort, 21 of 25 patients (84%) died. Among the 141 uridine triacetate-treated overdose patients with a diagnosis of cancer (the noncancer patients included 6 intentional or accidental pediatric overdoses), 53 resumed chemotherapy in < 30 days (median time after 5-FU, 19.6 days), and this indicated a rapid recovery from toxicity. Adverse reactions in patients receiving uridine triacetate included vomiting (8.1%), nausea (4.6%), and diarrhea (3.5%).

Conclusions: In these studies, uridine triacetate was a safe and effective lifesaving antidote for capecitabine and 5-FU overexposure, and it facilitated the rapid resumption of chemotherapy. Cancer 2017;123:345-356. © 2016 American Cancer Society.

Keywords: 5-fluorouracil; capecitabine; fluoropyrimidines; overdose; toxicity; uracil.

Figure 1

5‐FU (see structure) is converted into 3 main active metabolites: FdUMP, FdUTP, and FUTP. The main mechanism of 5‐FU activation is conversion to FUMP; this occurs either directly by OPRT with PRPP as the cofactor or indirectly via FUR through the sequential action of UP and UK. FUMP is then phosphorylated to FUDP, which can be either further phosphorylated to the active metabolite FUTP or converted to FdUDP by RR. In turn, FdUDP can be either phosphorylated or dephosphorylated to generate the active metabolites FdUTP and FdUMP, respectively. An alternative activation pathway involves the TP‐catalyzed conversion of 5‐FU to FUDR, which is then phosphorylated by TK to FdUMP. The DPD‐mediated conversion of 5‐FU to DHFU is the rate‐limiting step of 5‐FU catabolism in normal and tumor cells. Up to 80% of administered 5‐FU is broken down by DPD in the liver.56 Abbreviations: DHFU, dihydrofluorouracil; DPD, dihydropyrimidine dehydrogenase; FdUDP, fluorodeoxyuridine diphosphate; FdUMP, fluorodeoxyuridine monophosphate; FdUTP, fluorodeoxyuridine triphosphate; 5‐FU, 5‐fluorouracil; FUDP, fluorouridine diphosphate; FUDR, fluorodeoxyuridine; FUMP, fluorouridine monophosphate; FUR, fluorouridine; FUTP, fluorouridine triphosphate; OPRT, orotate phosphoribosyltransferase; PRPP, phosphoribosyl pyrophosphate; RR, ribonucleotide reductase; TK, thymidine kinase; TP, thymidine phosphorylase; TS, thymidylate synthase; UK, uridine kinase; UP, uridine phosphorylase. Longley et al.33 Used with permission.

Figure 2

Disposition of the patients. ^aThree of the 5 deaths in this group were attributed to progression of the underlying cancer; 1 death was attributed to septic shock associated with acute ischemic enteritis and ileus, gram‐negative bacteremia, and respiratory failure; and 1 death was due to apparent tumor lysis syndrome. ^bIn all these patients, uridine triacetate was started more than 96 hours after 5‐fluorouracil or capecitabine was stopped. These deaths were attributed to sequelae of 5‐fluorouracil toxicities: acute respiratory distress syndrome (n = 1), multisystem organ failure secondary to sepsis (n = 1), and septic shock (n = 3).

Figure 3

Historical case outcomes as a function of the 5‐fluorouracil infusion rate and dose. The expected tolerated zone is defined by the maximum tolerated doses of a variety of 5‐fluorouracil regimens. Patients in the expected lethal zone would be expected to die on the basis of the infusion rate and dose; patients in the expected tolerated zone as well as those in the expected serious toxicity zone would be expected to survive. Patients 19 to 25 in Table 2 were supposed to have received a 5‐day continuous infusion of 1000 mg/m²/d but instead were given 5 daily bolus doses of 1000 mg/kg/d. These patients are not included in the nomogram in this figure because the nomogram is based on a single infusion or bolus/infusion in order to compare the relative severity of the most common overdose situations.

Figure 4

5‐Fluorouracil overdose case outcomes as a function of the 5‐fluorouracil infusion rate and dose. The expected tolerated zone is defined by the maximum tolerated doses of a variety of 5‐fluorouracil regimens. Patients in the expected lethal zone would be expected to die on the basis of the infusion rate and dose; patients in the expected tolerated zone as well as those in the expected serious toxicity zone would be expected to survive.