First Chemo 'Antidote' Cuts Deaths From 5-FU Toxicity

Roxanne Nelson, BSN, RN

February 02, 2016

SAN FRANCISCO — The first and only antidote for a chemotherapy overdose appears to be a safe and effective life-saving emergency treatment.

The product, uridine triacetate (Vistogard, Wellstat Therapeutics Corporation), increased the chances of recovery from severe and rapid-onset toxicity related to a 5-fluorouracil (5-FU) infusion, or an overdose of 5-FU.

"Historically, for patients who have had an overexposure or who are susceptible to severe side effects of 5-FU, the mortality is over 95%," said lead researcher Wen Wee Ma, MD, from the GI cancers and drug development program at the Roswell Park Cancer Institute in Buffalo, New York. "For the patients in this trial, it was 4%, so it dramatically decreased the mortality."

"One-third recovered well enough to resume chemotherapy in 30 days," he told Medscape Medical News. "So this is a significant tool for oncologists in managing patients."

Dr Ma presented the study results during a poster session here at the Gastrointestinal Cancers Symposium 2016.

Both 5-FU and capecitabine (Xeloda, Genentech), an oral prodrug that is converted to 5-FU in the body, are widely used in the treatment of cancer. It is estimated that about 275,000 patients receive 5-FU alone or in a combination regimen. Of these patients, less than 10% will experience severe grade 3 to 5 toxicity.

This is a significant tool for oncologists in managing patients.

"In oncology, 5-FU and capecitabine are commonly used drugs, and it is expected that patients will have some side effects," said Dr Ma. "But some patients have unexpected side effects, such as cardiac events, severe GI events, or coma. We would normally give them supportive care."

"This drug came at the right time because there are more and more patients receiving 5-FU therapy," he added. "The percentage is small, but about 1300 patients pass away from the side effects, so this drug can save lives."

Newly Approved to Meet Extreme Need

Uridine triacetate was approved by the US Food and Drug Administration in December 2015 as an emergency treatment for adults and children who have received an unintended overdose of 5-FU or capecitabine.

5-FU is most commonly administered by infusion pump at or near what is considered to be the maximum tolerated dose. Expected adverse effects include myelosuppression, diarrhea, nausea, vomiting, and mucositis. An overdose is most often caused by a malfunction of the infusion pump or a miscalculation of the dose, Dr Ma explained.

Overexposure to 5-FU can lead to severe myelosuppression, gastrointestinal hemorrhage, septic shock, multiple organ failure, cardiac and neurologic complications, and death.

In addition, certain patients are more susceptible to severe toxicity, such as those who are deficient in dihydropyrimidine dehydrogenase (DPD), an enzyme that helps break down 5-FU and capecitabine. But regardless of DPD status, some patients will experience severe early-onset toxicity, even during the 5-FU infusion, such as encephalopathy or cardiotoxicity.

The drug is intended for use in patients who develop certain severe or life-threatening toxicities in the 96 hours after receiving these chemotherapies.

Uridine triacetate is not recommended for the nonemergency treatment of adverse reactions related to these agents, according to the prescribing information. The safety and efficacy of the drug initiated more than 96 hours after the end of 5-FU or capecitabine administration has not been established.

Dramatic Reduction in Death Rate

In their study, Dr Ma and his colleagues enrolled 135 patients who were at elevated risk for 5-FU toxicity — 111 because of overdose or accidental capecitabine ingestion and 24 because of DPD deficiency and/or rapid onset of severe toxicities. They were treated with uridine triacetate under emergency or expanded access protocols, and the drug was provided by the manufacturer.

The patients received uridine triacetate granules 10 g every 6 hours for 20 doses up to 96 hours after the termination of 5-FU therapy. Clinical end points included survival, time to resumption of chemotherapy, and safety.

Almost all of the patients treated with uridine triacetate were alive at 30 days or returned to chemotherapy within 30 days.

Of the 135 patients treated with uridine triacetate, 130 (96%) recovered fully in the 30 days after treatment. Recovery included a rapid reversal of cardiotoxicity (EKG abnormalities, chest pain) and neurotoxicity (altered mental status, ataxia).

Of the 111 5-FU overdoses, an infusion pump malfunction was responsible in 24 cases, a dose error in 49 cases, and accidental capecitabine ingestion in two adults and three 3 children. In 33 cases, the cause of the overdose was not known.

Of the five patients (3.7%) who died from 5-FU toxicity, two were treated after the 96-hour window of time.

In comparison, 38 of the 47 (81%) historic control subjects who experienced 5-FU overexposure died.

Of the 106 patients with a cancer diagnosis, 40 (37.7%) resumed chemotherapy within 30 days of the 5-FU overdose (median, 20.0 days), which is indicative of rapid recovery, the researchers report.

Adverse events attributable to uridine triacetate were mild and infrequent, and included diarrhea, nausea, and vomiting.

"Uridine triacetate should be administered to patients who experience an overdose of 5-fluorouracil or capecitabine, regardless of symptoms, or to patients who experience severe toxicity within 96 hours of the last 5-fluorouracil or capecitabine dose," said Smitha S. Krishnamurthi, MD, from the division of hematology and oncology at the University Hospitals Case Medical Center and Case Western Reserve University in Cleveland.

"Neurologic symptoms, such as a change in mental status or signs of cerebellar toxicity, are rare but of great concern, and should be treated with uridine triacetate. And any early cardiac toxicity would warrant treatment with uridine triacetate," Dr Krishnamurthi told Medscape Medical News.

The study was funded by Wellstat Therapeutics. Dr Ma and Dr Krishnamurthi have disclosed no relevant financial relationships. Several study coauthors report relationships with industry, including employment with Wellstat.

Gastrointestinal Cancers Symposium (GICS) 2016: Abstract 655. Presented January 23, 2016.


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