Joellen Zembruski-Ruple swallowed the first three chemotherapy drugs to treat her squamous cell carcinoma on Jan. 29 while caring for New York City's famous Memorial Sloan Kettering Cancer Center, her family said. They didn't realize that the drug could kill her.
Six days later, Zembruski-Ruple went to Sloan Kettering's emergency department to treat pain in the mouth and stop the swelling around the eyes. The hospital diagnosed an oral yeast infection and sent her home, her sister and partner said. Two days later, they said she was admitted, returning to suffering from severe diarrhea and vomiting. “Enzyme deficiency,” Zembruski-Ruple texted a friend.
The 65-year-old, a patient advocate who worked for the National Multiple Sclerosis Association and other groups, never returned home.
Covered with bruises and unable to swallow or speak, she eventually joined Hospice Care and passed away on March 25th of the very drug that was supposed to extend her life, said her longtime partner Richard Havkin. Zembruski-ruple was deficient in the enzymes that metabolize the chemotherapy drug she took, Capecitabine, said one of her sisters, Khavkine and Susan Zembruski. Zembruski-Ruple is one of about 1,300 Americans each year and died from the toxic effects of the IV drug fluororacil, known as its pill or its cousin, 5-FU.
Doctors can test for shortages – and if the patient has a genetic variant with risk, they can switch drugs or reduce the dose. The FDA approved the antidote in 2015, but it is expensive and must be administered within four days of the initial chemotherapy treatment.
New cancer drugs may include companion diagnoses to determine whether the drug works with the genetics of an individual patient. However, the 5-Fu entered the market in 1962 and is available for sale for around $17. The generic producers have not sought approval for toxicity tests, which usually cost hundreds of dollars.
Alan Venuk, a colorectal and liver cancer expert at the University of California, San Francisco, only understands that doctors have a gradual understanding of which genetic variants deal with patients.
By the time Zembruski-Ruple doctors told her she had a shortage, she had been taking medication for eight days, said Khavkine, who had seen her sister and her partner throughout the seven-week ordeal.
Khavkine said if he had known about it he would have “sought a test” but added, “No one would have told us about the possibility of this shortage.” Zembruski-Ruple's sister also said she has not been warned about the fatal risk of chemotherapy or hasn't spoken about testing.
“They never said why they didn't test her,” Zembruski said. “If there was a test, they should have said there was a test. If they said, 'Insurance doesn't cover it,' I would have said, 'This is my credit card.' We should have known about it. ”
Guidance moves at the pace of a glacier
Despite growing awareness of the defect, advocacy groups consisting of grief friends and relatives who promote routine testing of all patients before all patients take the medication, healthcare organizations moved slowly.
The National Comprehensive Cancer Network, or NCCN (specialists at Sloan Kettering and other top research centers), panels did not recommend testing until recently, and the FDA did not require it.
In response to questions about KFF Health News' policy, Courtney Nowak, a spokesman for Sloan Kettering, said hospitals will treat patients “according to NCCN guidelines.” She said the hospital has not discussed patient care.
On January 24, the FDA issued a warning about enzyme deficiency, urging health care providers to “notify patients before treatment” of the risk of taking 5-FU and capecitabine.
March 31, 6 days after Zembruski-Ruple's death – A panel of experts in most gastrointestinal cancer networks has taken the first step to recommend testing for deficiency.
He is worried that President Donald Trump's FDA may do nothing, Venook said the panel in which guidance shapes practices for oncologists and health insurance companies recommended that doctors consider testing before administering patients with 5-FU or capecitabine.
However, the guidance states that “specific tests are not recommended at this time,” and there is a lack of data “informing dosage adjustments.”
Sloan Kettering “we will consider this guidance in developing individualized treatment plans for each patient,” Nowak told KFF Health News.
The new NCCN guidance said, “It's not a blanket recommendation we were working on, but it's a huge step towards our ultimate goal,” said Kellin Milekey, a public health official in Brewster, Massachusetts, who is part of the test advocacy group. Her husband, Larry, passed away two years ago at the age of 73 after one treatment with capecitabine.
European drug regulators began urging oncologists to test patients for shortages in May 2020. If there is no significant toxicity, the dose will increase.
The ultimate life-saving thing?
Emily Alimonty, a 42-year-old biotech sales representative from upstate New York, chose that path before starting capecitabine treatment in December. She said her doctors, including Sloan Kettering's oncologist, told her they hadn't had a deficiency test, but Alimonty insisted. “No,” she said. “I haven't started until I get my test back.”
The test showed that Alimonti had a copy of a dangerous genetic variant, so doctors administered her a lower medication. Even that was difficult to accept. Arimonty said she had to skip the dose due to her low white blood cell count. She doesn't know yet whether the insurance company will cover the tests.
Around 300,000 people are treated with 5-FU or capecitabine each year, and its toxicity may have prevented FDA approval for today's approval. However, other than withdrawing the drug, US regulators have little power to control its use. 5-Fu and capecitabine are also powerful tools against many cancers.
At a January workshop that included FDA officials, co-chairs of the NCCN panel and cancer expert Venook, asked whether it was reasonable to recommend doctors undergo genetic testing “without saying what they're going to do with the results.”
But Richard Puzzle, the FDA's top cancer expert, said it's time to finish the discussion and start testing, even if the results are vague. “If you don't have the information, how do you have counseling?” he asked.
Two months later, the Venook panel changed courses. The test price is below $300, and results could be returned in just three days, Venook said. He said doubts about the FDA's ability to further confront the issue have fueled a change in the panel's mind.
“I don't know if the FDA will exist tomorrow,” Venook told KFF Health News. “They're putting wrecking ball into common sense, and that's one of the reasons why we felt we had to move forward.”
On May 20, the FDA posted a federal registration notice seeking public information on the issue. This suggests that we are considering further action.
Venook said he often tests his patients, but the results can be ambiguous. If the test finds two copies of a patient's specific dangerous genetic variant, he avoids using the drug. However, such cases are rare. And according to her sister and Havkin, Zembruski-ruple was one of them.
Many patients have a single copy of a suspected gene. This is an ambiguous outcome that requires clinical judgment to be assessed, Venook said.
A full gene scan provides more information, but adds cost and time. Still, the answer may be vague, Venook said. He worries that starting patients with lower doses could mean less treatment, especially for newly diagnosed colon cancer patients.
Power should rest with the patient
Scott Kapoor, a doctor in the Toronto area emergency room, sees Venuk's argument as medical paternity, whose brother Anil, who died of 5-FU toxicity in 2023 at the age of 58, considers Venuk's argument. Patients will need to decide whether to test the results, he said.
“What's good – can you kill them in 20 days without telling the patient about the test, or not testing it?” he said. “Or tell them about the test, warning them that potentially cancer will kill them in a year?”
“People say oncologists don't know what to do with the information,” said Karen Merritt, whose mother passed away in 2014 after an infusion of 5-FU.
Mayo Clinic recommends starting patients at half the dose if there is one suspected gene variant. “The majority of patients will be able to start treatment without delay,” said Daniel Hertz, a clinical pharmacologist at the University of Michigan, at a meeting in January.
Lindsay Murray of Andover, Massachusetts, said that his mother was treated with capecitabine and has advocated widespread testing since his death in 2021, some hospitals have begun testing after a patient died due to a shortage.
In some cases, relatives of the deceased patient sued the hospital, leading to the village, Venck said.
Kapoor said that, like many patients of his siblings – non-European origin, there are genetic variants that have not been widely studied and are not included in most tests. But a full genetic scan would have detected it, Kapoor said, and such scans could also be done for hundreds of dollars.
The changed language of the Cancer Network Panel is unfortunate, he said, but “than nothing.”
In the video compliment to Zembruski-Ruple, her friends, colleagues and clients found her kind, kind and charming. “Lolen was beautiful both inside and outside,” said Barbara McKeon, a former colleague of the MS Association. “She was funny, creative and had a great sense of style.”
“Lolen had a balance of cheating that was elegant and playful,” said psychotherapist Anastachia Fabrice. “My beautiful, vibrant, interesting, loving friend Joren.”
