One January morning in 2021, Carol Rosen took a standard treatment for metastatic breast cancer. Three gruesome weeks later, she died in excruciating pain from the very drug meant to prolong her life.<\/p>\n

Rosen, a 70-year-old retired schoolteacher, passed her final days in anguish, enduring severe diarrhea and nausea and terrible sores in her mouth that kept her from eating, drinking, and, eventually, speaking. Skin peeled off her body. Her kidneys and liver failed. \u201cYour body burns from the inside out,\u201d said Rosen\u2019s daughter, Lindsay Murray, of Andover, Massachusetts.<\/p>\n

Rosen was one of more than 275,000 cancer patients<\/u> <\/a>in the United States who are infused each year with fluorouracil, known as 5-FU, or, as in Rosen\u2019s case, take a nearly identical drug in pill form called capecitabine. These common types of chemotherapy are no picnic for anyone, but for patients who are deficient in an enzyme that metabolizes the drugs, they can be torturous or deadly.<\/p>\n

Those patients essentially overdose because the drugs stay in the body for hours rather than being quickly metabolized and excreted. The drugs kill an estimated 1 in 1,000 patients<\/a> who take them \u2014 hundreds each year<\/a> \u2014 and severely sicken or hospitalize 1 in 50. Doctors can test for the deficiency and get results within a week \u2014 and then either switch drugs or lower the dosage if patients have a genetic variant that carries risk.<\/p>\n

Yet a recent survey found that only 3% of U.S. oncologists<\/a> routinely order the tests before dosing patients with 5-FU or capecitabine. That\u2019s because the most widely followed U.S. cancer treatment guidelines \u2014 issued by the National Comprehensive Cancer Network \u2014 don\u2019t recommend preemptive testing.<\/p>\n

The FDA added new warnings<\/a> about the lethal risks of 5-FU to the drug\u2019s label on March 21 following queries from KFF Health News about its policy. However, it did not require doctors to administer the test before prescribing the chemotherapy.<\/p>\n

The agency, whose plan to expand<\/a> its oversight of laboratory testing was the subject of a House hearing<\/a>, also March 21, has said it could not endorse the 5-FU toxicity tests because it\u2019s never reviewed them.<\/p>\n

But the FDA at present does not review most diagnostic tests, said Daniel Hertz, an associate professor at the University of Michigan College of Pharmacy. For years, with other doctors and pharmacists, he has petitioned the FDA to put a black box warning on the drug\u2019s label urging prescribers to test for the deficiency.<\/p>\n

\u201cFDA has responsibility to assure that drugs are used safely and effectively,\u201d he said. The failure to warn, he said, \u201cis an abdication of their responsibility.\u201d<\/p>\n

The update is \u201ca small step in the right direction, but not the sea change we need,\u201d he said.<\/p>\n

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Europe Ahead on Safety<\/strong><\/p>\n
British and European Union drug authorities have recommended the testing since 2020. A small but growing number of U.S. hospital systems, professional groups, and health advocates, including the American Cancer Society, also endorse routine testing. Most U.S. insurers, private and public, will cover the tests, which Medicare reimburses for $175, although tests may cost more depending on how many variants they screen for.<\/p>\n
In its latest guidelines<\/a> on colon cancer, the Cancer Network panel noted that not everyone with a risky gene variant gets sick from the drug, and that lower dosing for patients carrying such a variant could rob them of a cure or remission. Many doctors on the panel, including the University of Colorado oncologist Wells Messersmith, have said they have never witnessed a 5-FU death.<\/p>\n
In European hospitals, the practice is to start patients with a half- or quarter-dose of 5-FU if tests show a patient is a poor metabolizer, then raise the dose if the patient responds well to the drug. Advocates for the approach say American oncology leaders are dragging their feet unnecessarily, and harming people in the process.<\/p>\n
\u201cI think it\u2019s the intransigence of people sitting on these panels, the mindset of \u2018We are oncologists, drugs are our tools, we don\u2019t want to go looking for reasons not to use our tools,\u2019\u201d said Gabriel Brooks, an oncologist and researcher at the Dartmouth Cancer Center.<\/p>\n
Oncologists are accustomed to chemotherapy\u2019s toxicity and tend to have a \u201cno pain, no gain\u201d attitude, he said. 5-FU has been in use since the 1950s.<\/p>\n
Carol Rosen (left) and her daughter, Lindsay Murray, celebrate Thanksgiving in 2020. Rosen, a 70-year-old retired schoolteacher, passed her final days in anguish, after three weeks of chemotherapy with incompatible drugs.(Justin Murray)<\/span><\/figcaption><\/figure>\n
Yet \u201canybody who\u2019s had a patient die like this will want to test everyone,\u201d said Robert Diasio of the Mayo Clinic, who helped carry out major studies<\/a> of the genetic deficiency in 1988.<\/p>\n
Oncologists often deploy genetic tests to match tumors in cancer patients with the expensive drugs used to shrink them. But the same can\u2019t always be said for gene tests aimed at improving safety, said Mark Fleury, policy director at the American Cancer Society\u2019s Cancer Action Network.<\/p>\n
When a test can show whether a new drug is appropriate, \u201cthere are a lot more forces aligned to ensure that testing is done,\u201d he said. \u201cThe same stakeholders and forces are not involved\u201d with a generic like 5-FU, first approved in 1962<\/a>, and costing roughly $17 for a month\u2019s treatment<\/a>.<\/p>\n
Oncology is not the only area in medicine in which scientific advances, many of them taxpayer-funded, lag in implementation. For instance, few cardiologists test patients before they go on Plavix, a brand name for the anti-blood-clotting agent clopidogrel, although it doesn\u2019t prevent blood clots as it\u2019s supposed to in a quarter of the 4 million Americans prescribed it each year. In 2021, the state of Hawaii won<\/a> an $834 million judgment from drugmakers it accused of falsely advertising the drug as safe and effective for Native Hawaiians, more than half of whom lack the main enzyme to process clopidogrel.<\/p>\n
The fluoropyrimidine enzyme deficiency numbers are smaller \u2014 and people with the deficiency aren\u2019t at severe risk<\/a> if they use topical cream forms of the drug for skin cancers. Yet even a single miserable, medically caused death was meaningful to the Dana-Farber Cancer Institute, where Carol Rosen was among more than 1,000 patients treated with fluoropyrimidine in 2021.<\/p>\n
Her daughter was grief-stricken and furious after Rosen\u2019s death. \u201cI wanted to sue the hospital. I wanted to sue the oncologist,\u201d Murray said. \u201cBut I realized that wasn\u2019t what my mom would want.\u201d<\/p>\n
Instead, she wrote Dana-Farber\u2019s chief quality officer, Joe Jacobson, urging routine testing. He responded the same day, and the hospital quickly adopted a testing system that now covers more than 90% of prospective fluoropyrimidine patients. About 50 patients with risky variants were detected in the first 10 months, Jacobson said.<\/p>\n
Dana-Farber uses a Mayo Clinic test that searches for eight potentially dangerous variants of the relevant gene. Veterans Affairs hospitals use a 11-variant test, while most others check for only four variants.<\/p>\n
Different Tests May Be Needed for Different Ancestries<\/strong><\/p>\n
The more variants a test screens for, the better the chance of finding rarer gene forms in ethnically diverse populations. For example, different variants are responsible for the worst deficiencies in people of African and European ancestry, respectively. There are tests that scan for hundreds of variants that might slow metabolism of the drug, but they take longer and cost more.<\/p>\n
These are bitter facts for Scott Kapoor, a Toronto-area emergency room physician whose brother, Anil Kapoor, died in February 2023 of 5-FU poisoning.<\/p>\n
Anil Kapoor was a well-known urologist and surgeon, an outgoing speaker, researcher, clinician, and irreverent friend whose funeral drew hundreds. His death at age 58, only weeks after he was diagnosed with stage 4 colon cancer, stunned and infuriated his family.<\/p>\n
In Ontario, where Kapoor was treated, the health system had just begun testing for four gene variants discovered in studies of mostly European populations. Anil Kapoor and his siblings, the Canadian-born children of Indian immigrants, carry a gene form that\u2019s apparently associated with South Asian ancestry.<\/p>\n
Scott Kapoor supports broader testing for the defect \u2014 only about half of Toronto\u2019s inhabitants are of European descent \u2014 and argues that an antidote to fluoropyrimidine poisoning<\/a>, approved by the FDA in 2015, should be on hand. However, it works only for a few days after ingestion of the drug and definitive symptoms often take longer to emerge.<\/p>\n
Most importantly, he said, patients must be aware of the risk. \u201cYou tell them, \u2018I am going to give you a drug with a 1 in 1,000 chance of killing you. You can take this test. Most patients would be, \u2018I want to get that test and I\u2019ll pay for it,\u2019 or they\u2019d just say, \u2018Cut the dose in half.\u2019\u201d<\/p>\n
Alan Venook, the University of California-San Francisco oncologist who co-chairs the National Comprehensive Cancer Network, has led resistance to mandatory testing because the answers provided by the test, in his view, are often murky and could lead to undertreatment.<\/p>\n
\u201cIf one patient is not cured, then you giveth and you taketh away,\u201d he said. \u201cMaybe you took it away by not giving adequate treatment.\u201d<\/p>\n
Instead of testing and potentially cutting a first dose of curative therapy, \u201cI err on the latter, acknowledging they will get sick,\u201d he said. About 25 years ago, one of his patients died of 5-FU toxicity and \u201cI regret that dearly,\u201d he said. \u201cBut unhelpful information may lead us in the wrong direction.\u201d<\/p>\n
In September, seven months after his brother\u2019s death, Kapoor was boarding a cruise ship on the Tyrrhenian Sea near Rome when he happened to meet a woman whose husband, Atlanta municipal judge Gary Markwell, had died the year before after taking a single 5-FU dose at age 77.<\/p>\n
\u201cI was like \u2026 that\u2019s exactly what happened to my brother.\u201d<\/p>\n
Murray senses momentum toward mandatory testing. In 2022, the Oregon Health & Science University paid $1 million<\/a> to settle a suit after an overdose death.<\/p>\n
\u201cWhat\u2019s going to break that barrier is the lawsuits, and the big institutions like Dana-Farber who are implementing programs and seeing them succeed,\u201d she said. \u201cI think providers are going to feel kind of bullied into a corner. They\u2019re going to continue to hear from families and they are going to have to do something about it.\u201d<\/p>\n
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