JoEllen Zembruski-Ruple, while in the care of New York City\u2019s renowned Memorial Sloan Kettering Cancer Center, swallowed the first three chemotherapy pills to treat her squamous cell carcinoma on Jan. 29, her family members said. They didn\u2019t realize the drug could kill her.<\/p>\n
Six days later, Zembruski-Ruple went to Sloan Kettering\u2019s urgent care department to treat sores in her mouth and swelling around her eyes. The hospital diagnosed oral yeast infection and sent her home, her sister and partner said. Two days later, they said, she returned in agony \u2014 with severe diarrhea and vomiting \u2014 and was admitted. \u201cEnzyme deficiency,\u201d Zembruski-Ruple texted a friend.<\/p>\n
The 65-year-old, a patient advocate who had worked for the National Multiple Sclerosis Society and other groups, would never go home.<\/p>\n
Covered in bruises and unable to swallow or talk, she eventually entered hospice care and died March 25<\/a> from the very drug that was supposed to extend her life, said her longtime partner, Richard Khavkine. Zembruski-Ruple was deficient in the enzyme that metabolizes capecitabine, the chemotherapy drug she took, said Khavkine and Susan Zembruski, one of her sisters. Zembruski-Ruple was among about 1,300 Americans each year who die<\/a> from the toxic effects of that pill<\/a> or its cousin, the IV drug fluorouracil known as 5-FU.<\/p>\n Doctors can test for the deficiency<\/a> \u2014 and then either switch drugs or lower the dosage<\/a> if patients have a genetic variant that carries risk. The FDA approved an antidote in 2015<\/a>, but it\u2019s expensive and must be administered within four days of the first chemotherapy treatment.<\/p>\n Newer cancer drugs sometimes include a companion diagnostic to determine whether a drug works with an individual patient\u2019s genetics. But 5-FU went on the market in 1962 and sells for about $17 a dose; producers of its generic aren\u2019t seeking approval for toxicity tests, which typically cost hundreds of dollars. Doctors have only gradually understood which gene variants are dangerous in which patients, and how to deal with them, said Alan Venook, a colorectal and liver cancer specialist at the University of California-San Francisco.<\/p>\n By the time Zembruski-Ruple\u2019s doctors told her she had the deficiency, she had been on the drug for eight days, said Khavkine, who watched over his partner with her sister throughout the seven-week ordeal.<\/p>\n Khavkine said he \u201cwould have asked for the test\u201d if he had known about it, but added \u201cnobody told us about the possibility of this deficiency.\u201d Zembruski-Ruple\u2019s sister also said she wasn\u2019t warned about the fatal risks of the chemo, or told about the test.<\/p>\n \u201cThey never said why they didn\u2019t test her,\u201d Zembruski said. \u201cIf the test existed, they should have said there is a test. If they said, \u2018Insurance won\u2019t cover it,\u2019 I would have said, \u2018Here\u2019s my credit card.\u2019 We should have known about it.\u201d<\/p>\n Guidance Moves at a Glacial Pace<\/strong><\/p>\n Despite growing awareness of the deficiency, and an advocacy group made up of grieving friends and relatives who push for routine testing<\/a> of all patients before they take the drug, the medical establishment has moved slowly.<\/p>\n A panel of the National Comprehensive Cancer Network, or NCCN \u2014 specialists from Sloan Kettering and other top research centers \u2014 until recently did not recommend testing, and the FDA does not require it.<\/p>\n In response to a query from KFF Health News about its policy, Sloan Kettering spokesperson Courtney Nowak said the hospital treats patients \u201cin accordance with NCCN guidelines.\u201d She said the hospital would not discuss a patient\u2019s care.<\/p>\n On Jan. 24, the FDA issued a warning<\/a> about the enzyme deficiency in which it urged health care providers to \u201cinform patients prior to treatment\u201d about the risks of taking 5-FU and capecitabine.<\/p>\n On March 31 \u2014 six days after Zembruski-Ruple\u2019s death \u2014 the network\u2019s expert panel for most gastrointestinal cancers took a first step toward recommending testing for the deficiency.<\/p>\n Worried that President Donald Trump\u2019s FDA might do nothing, Venook said, the panel \u2014 whose guidance shapes the practices of oncologists and health insurers \u2014 recommended that doctors consider testing before dosing patients with 5-FU or capecitabine.<\/p>\n However, its guidance stated that \u201cno specific test is recommended at this time,\u201d citing a lack of data to \u201cinform dose adjustments.\u201d<\/p>\n Sloan Kettering \u201cwill consider this guidance in developing personalized treatment plans for each patient,\u201d Nowak told KFF Health News.<\/p>\n The new NCCN guidance was \u201cnot the blanket recommendation we were working toward, but it is a major step toward our ultimate goal,\u201d said Kerin Milesky, a public health official in Brewster, Massachusetts, who\u2019s part of an advocacy group for testing. Her husband, Larry, died two years ago at age 73 after a single treatment of capecitabine.<\/p>\n European drug regulators<\/a> began urging oncologists to test patients for deficiency in May 2020. Patients with potentially risky genetics are started on a half-dose of the cancer drug. If they suffer no major toxicity, the dose is increased.<\/p>\n A Lifesaving Ultimatum?<\/strong><\/p>\n Emily Alimonti, a 42-year-old biotech salesperson in upstate New York, chose that path before starting capecitabine treatment in December. She said her doctors \u2014 including an oncologist at Sloan Kettering \u2014 told her they didn\u2019t do deficiency testing, but Alimonti insisted. \u201cNope,\u201d she said. \u201cI\u2019m not starting it until I get the test back.\u201d<\/p>\n The test showed that Alimonti had a copy of a risky gene variant, so doctors gave her a lower dose of the drug. Even that has been hard to tolerate; she\u2019s had to skip doses because of low white blood cell counts, Alimonti said. She still doesn\u2019t know whether her insurer will cover the test.<\/p>\n Around 300,000 people are treated with 5-FU or capecitabine in the United States each year, but its toxicity could well have prevented FDA approval were it up for approval today. Short of withdrawing a drug, however, U.S. regulators have little power to manage its use. And 5-FU and capecitabine are still powerful tools against many cancers.<\/p>\n At a January workshop that included FDA officials and cancer specialists, Venook, the NCCN panel\u2019s co-chair, asked whether it was reasonable to recommend that doctors obtain a genetic test \u201cwithout saying what to do with the result.\u201d<\/p>\n But Richard Pazdur, the FDA\u2019s top cancer expert, said it was time to end the debate and commence testing, even if the results could be ambiguous. \u201cIf you don\u2019t have the information, how do you have counseling?\u201d he asked.<\/p>\n Two months later, Venook\u2019s panel changed course. The price of tests has fallen below $300 and results can be returned as soon as three days, Venook said. Doubts about the FDA\u2019s ability to further confront the issue spurred the panel\u2019s change of heart, he said.<\/p>\n \u201cI don\u2019t know if FDA is going to exist tomorrow,\u201d Venook told KFF Health News. \u201cThey\u2019re taking a wrecking ball to common sense, and that\u2019s one of the reasons we felt we had to go forward.\u201d<\/p>\n On May 20, the FDA posted a Federal Register notice<\/a> seeking public input on the issue, a move that suggested it was considering further action.<\/p>\n Venook said he often tests his own patients, but the results can be fuzzy. If the test finds two copies of certain dangerous gene variants in a patient, he avoids using the drug. But such cases are rare \u2014 and Zembruski-Ruple was one of them, <\/strong>according to her sister and Khavkine.<\/p>\n Many more patients have a single copy of a suspect gene, an ambiguous result that requires clinical judgment to assess, Venook said.<\/p>\n A full-gene scan would provide more information but adds expense and time, and even then the answer may be murky, Venook said. He worries that starting patients on lower doses could mean fewer cures, especially for newly diagnosed colon cancer patients.<\/p>\n Power Should Rest With Patients<\/strong><\/p>\n Scott Kapoor, a Toronto-area emergency room physician whose brother Anil, a much-loved urologist and surgeon, died of 5-FU toxicity at age 58 in 2023, views Venook\u2019s arguments as medical paternalism. Patients should decide whether to test and what to do with the results, he said.<\/p>\n \u201cWhat\u2019s better \u2014 don\u2019t tell the patient about the test, don\u2019t test them, potentially kill them in 20 days?\u201d he said. \u201cOr tell them about the testing while warning that potentially the cancer will kill them in a year?\u201d<\/p>\n \u201cPeople say oncologists don\u2019t know what to do with the information,\u201d said Karen Merritt, whose mother died after an infusion of 5-FU in 2014. \u201cWell, I\u2019m not a doctor, but I can understand the Mayo Clinic report on it.\u201d<\/p>\n The Mayo Clinic recommends starting patients on half a dose if they have one suspect gene variant. And \u201cthe vast majority of patients will be able to start treatment without delays,\u201d Daniel Hertz, a clinical pharmacologist from the University of Michigan, said at the January meeting<\/a>.<\/p>\n Some hospitals began testing after patients died because of the deficiency, said Lindsay Murray, of Andover, Massachusetts, who has advocated for widespread testing since her mother was treated with capecitabine and died in 2021.<\/p>\n In some cases, Venook said, relatives of dead patients have sued hospitals, leading to settlements.<\/p>\n Kapoor said his brother \u2014 like many patients of non-European origin \u2014 had a gene variant that hasn\u2019t been widely studied and isn\u2019t included in most tests. But a full-gene scan would have detected it, Kapoor said, and such scans can also be done for a few hundred dollars.<\/p>\n The cancer network panel\u2019s changed language is disappointing, he said, though \u201cbetter than nothing.\u201d<\/p>\n In video tributes<\/a> to Zembruski-Ruple, her friends, colleagues, and clients remembered her as kind, helpful, and engaging. \u201cJoEllen was beautiful both inside and out,\u201d said Barbara McKeon, a former colleague at the MS Society. \u201cShe was funny, creative, had a great sense of style.\u201d<\/p>\n \u201cJoEllen had this balance of classy and playful misbehavior,\u201d psychotherapist Anastatia Fabris said. \u201cMy beautiful, vibrant, funny, and loving friend JoEllen.\u201d<\/p>\n\n KFF Health News<\/a> is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF\u2014an independent source of health policy research, polling, and journalism. 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