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.

The US Food and Drug Administration (FDA) initial approved 5-Fluorouracil Injection on April 25, 1962. Manufactured and marketed as Adrucil® by Pharmacia (Now: Pfizer). Adrucil® (fluorouracil injection USP), a nucleoside metabolic inhibitor, is a colorless to faint yellow aqueous, sterile, nonpyrogenic injectable solution. Photo courtesy: National Museum of American History.

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. “Your body burns from the inside out,” said Rosen’s daughter, Lindsay Murray, of Andover, Massachusetts.

Rosen was one of more than 275,000 cancer patients in the United States who are infused each year with fluorouracil*, known as 5-FU, or, as in Rosen’s case, take a nearly identical drug in pill form called capecitabine (Xeloda®; Genentech/Roche)**. 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.[1]

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 who take them — hundreds each year — and severely sicken or hospitalize 1 in 50. Doctors can test for the deficiency and get results within a week — and then either switch drugs or lower the dosage if patients have a genetic variant that carries risk. [2][3]

Yet a recent survey found that only 3% of U.S. oncologists routinely order the tests before dosing patients with 5-FU or capecitabine. That’s because the most widely followed U.S. cancer treatment guidelines — issued by the National Comprehensive Cancer Network (NCCN) — don’t recommend preemptive testing. [4]

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The US Food and Drug Administration (FDA) added new warnings about the lethal risks of 5-FU to the drug’s label on March 21, 2024 following queries about its policy. However, it did not require doctors to administer the test before prescribing the chemotherapy. [5]

The agency, whose plan to expand its oversight of laboratory testing was the subject of a House hearing, also March 21, has said it could not endorse the 5-FU toxicity tests because it’s never reviewed them.[6][7]

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’s label urging prescribers to test for the deficiency.

“FDA has responsibility to assure that drugs are used safely and effectively,” he said. The failure to warn, he said, “is an abdication of their responsibility.”

The update is “a small step in the right direction, but not the sea change we need,” he said.

Europe Ahead on Safety
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.

In its latest guidelines 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.

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.

“I think it’s the intransigence of people sitting on these panels, the mindset of ‘We are oncologists, drugs are our tools, we don’t want to go looking for reasons not to use our tools,’” said Gabriel Brooks, an oncologist and researcher at the Dartmouth Cancer Center.

Oncologists are accustomed to chemotherapy’s toxicity and tend to have a “no pain, no gain” attitude, he said. 5-FU has been in use since the 1950s.

Yet “anybody who’s had a patient die like this will want to test everyone,” said Robert Diasio of the Mayo Clinic, who helped carry out major studies of the genetic deficiency in 1988.[8]

Oncologists often deploy genetic tests to match tumors in cancer patients with the expensive drugs used to shrink them. But the same can’t always be said for gene tests aimed at improving safety, said Mark Fleury, policy director at the American Cancer Society’s Cancer Action Network.

When a test can show whether a new drug is appropriate, “there are a lot more forces aligned to ensure that testing is done,” he said. “The same stakeholders and forces are not involved” with a generic like 5-FU, first approved in 1962, and costing roughly $17 for a month’s treatment. [9]

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 (Sanofi and Bristol-Myers Squibb), although it doesn’t prevent blood clots as it’s supposed to in a quarter of the 4 million Americans prescribed it each year. In 2021, the state of Hawaii won 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.

The fluoropyrimidine enzyme deficiency numbers are smaller — and people with the deficiency aren’t at severe risk 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. [10]

Her daughter was grief-stricken and furious after Rosen’s death. “I wanted to sue the hospital. I wanted to sue the oncologist,” Murray said. “But I realized that wasn’t what my mom would want.”

Instead, she wrote Dana-Farber’s 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.

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.

Different Tests May Be Needed for Different Ancestries
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.

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.

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.

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’s apparently associated with South Asian ancestry.

Scott Kapoor supports broader testing for the defect — only about half of Toronto’s inhabitants are of European descent — and argues that an antidote to fluoropyrimidine poisoning, 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.[11] ^^

Most importantly, he said, patients must be aware of the risk. “You tell them, ‘I 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, ‘I want to get that test and I’ll pay for it,’ or they’d just say, ‘Cut the dose in half.’”

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.

“If one patient is not cured, then you giveth and you taketh away,” he said. “Maybe you took it away by not giving adequate treatment.”

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. Photo courtesy: © 2020 Justin Murray/KFF/NBC News. Used with permission.

Instead of testing and potentially cutting a first dose of curative therapy, “I err on the latter, acknowledging they will get sick,” he said. About 25 years ago, one of his patients died of 5-FU toxicity and “I regret that dearly,” he said. “But unhelpful information may lead us in the wrong direction.”

In September, seven months after his brother’s 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.

“I was like … that’s exactly what happened to my brother.”

Murray senses momentum toward mandatory testing. In 2022, the Oregon Health & Science University paid $1 million to settle a suit after an overdose death.

“What’s going to break that barrier is the lawsuits, and the big institutions like Dana-Farber who are implementing programs and seeing them succeed,” she said. “I think providers are going to feel kind of bullied into a corner. They’re going to continue to hear from families and they are going to have to do something about it.”

This story is part of a partnership that includes NBC News and Kaiser Health News (KHN), a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism.

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Note: * In 1954, Abraham Cantarow (from 1945 until his retirement in 1966 professor and chairman of the biochemistry department at Thomas Jefferson University in Philadelphia) and Karl Ernst Paschkis (Professor and Head of the Endocrine and Cancer Unit at Thomas Jefferson University in Philadelphia) found rat liver tumors absorbed uracil (one of the four nucleobases in the nucleic acid RNA) more readily than did normal liver cells. [12] Charles Heidelberger, a professor of oncology at the University of Wisconsin (McArdle Laboratory), who had earlier found that fluorine in fluoroacetic acid (an organofluorine compound with formula CH2FCO2H) inhibited a vital enzyme, made a similar observation and reasoned that based on the exceptional toxicity of fluoroacetic acid through its metabolism to fluorocitric acid and his earlier findings substitution of a fluorine atom into the 5-position of uracil could prevent its metabolism thymidylic acid and, as a result interfere with DNA synthesis. After further research in which Heidelberger showed that 5-Fluorouracil inhibited the growth of transplanted tumors in rodents, he asked Robert Duschinsky and Robert Schnitzer at Hoffmann-La Roche (now Roche) to perfect the synthesize of 5-Fluorouracil, allowing more tests to establish the therapeutic effects of the novel compound.  These clinical studies, first conducted at the University of Wisconsin’s McArdle Laboratory by Anthony R. Curreri and Fred J. Ansfield, with Heidelberger’s help, confirmed that the investigational drug had clinical potential. In 1958, Anthony R. Curreri, Fred J. Ansfield, Forde A. McIver, Harry A. Waisman, and Charles Heidelberger reported the first clinical findings of 5-FU’s activity in cancer in humans. Based on the outcome of their work, Heidelberger and Duschinsky have been credited with the discovery that 5-Fluorouracil markedly inhibited tumors in mice. [13][14][15][16][17] 

5-Fluorouracil (5-FU), a generic anti-cancer drug sold under the brand name Adrucil® (among others), is a cytotoxic chemotherapy medication used to treat cancer. The drug, which derives its name from the fact that there is a fluorine atom on the 5th carbon of a uracil ring, was originally patented in 1956 (US2885396) (patent) and was approved in the United States in 1962 as the first drug for ‘the chemical treatment of cancer,’ and marketed by Hoffman-La Roche (now: Roche). Researchers found that 5-FU, a previously-discovered anti-tumor agent, blocked cell cycle replication by inhibiting thymine production in bacteria and phage, identifying a crucial target in preventing tumor growth. 5-FU is on the World Health Organization‘s (WHO) List of Essential Medicines. In 2021, it was the 281st most commonly prescribed medication in the United States, with more than 800,000 prescriptions. 5-FU, dosed via intravenous injection, is used for treatment of colorectal cancer, esophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer. Common side effects include inflammation of the mouth, loss of appetite, low blood cell counts, hair loss, and inflammation of the skin. Fluorouracil is in the antimetabolite and pyrimidine analog families of medications. It is believed to block the action of thymidylate synthase which stops the production of DNA. 5-FU is preferred by some patients because of its low incidence of alopecia, nausea, and vomiting, and it was a reasonable choice, especially for patients who had received multiple lines of therapy. However, today infusional (IV) 5-FU is rarely used because of the widespread availability of the oral agent, capecitabine (Xeloda®; Genentech/Roche) of which it is a direct precursor. 

** Capecitabine (n4-pentyloxycarbonyl-5′-deoxy-5-fluorocytidine; Xeloda®; Genentech/Roche),  is an oral fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) in tumor tissue, thereby mimicking the activity of Infusional (IV) 5-fluorouracil. Through a cascade of enzymes, including thymidine phosphorylase, capecitabine is converted to 5-fluorouracil. Capecitabine selectively targets malignant (cancer) tissue over healthy tissue because the former possesses higher thymidine phosphorylase activity. Capecitabine was first approved in the United States in 1998 and in Europe in 2001 as monotherapy for treating colorectal cancer. Since then, the drug has been approved for treating other forms of cancer such as gastric cancer and metastatic breast cancer. Capecitabine was approved to treat these cancers as monotherapy and in combination with other drugs. In March 2010, Capecitabine, in combination with Oxaliplatin (Eloxatin®; Sanofi), was approved in the European Union for the adjuvant treatment of patients suffering from early colon cancer. Capecitabine was developed at Roche’s research centre in Kamakura, Japan, and is still part of Roche’s current oncology portfolio.

*** Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency, a rare inherited disorder of pyrimidine metabolism may result in severe, life-threatening toxicity or fatal toxicity in patients diagnosed with various forms of cancer who are being treated with 5-Fluorouracil (5-FU) or its analogs.  This response is the result of a germline genetic variation in the DPYD gene. In short, this is a genetic predisposition with an established mechanistic basis that links genetic variation in the DPYD gene and results in an increase in systemic drug exposure, which leads to an increased risk of toxicity and treatment related adverse events. [3][4] Fluorouracil (5-Fluorouracil, 5-FU) and capecitabine are fluoropyrimidines that are metabolized and inactivated by DPD. Because reduced DPD activity is associated with the accumulation of active metabolites of these drugs, patients are at increased risk of early, severe, and life-threatening toxicities with standard doses. Therefore, fluorouracil and capecitabine are contraindicated in patients with complete or near-complete absence of DPD activity.

*^ The DPYD gene encodes the DPD enzyme. DPYD genotyping is now available to assess a patient’s enzymatic phenotype to guide fluorouracil and capecitabine dosing. [18][19][20]

^^ On December 11, 2015, the U.S. Food and Drug Administration (FDA) approved uridine triacetate (Vistogard®; Wellstat Therapeutics) for the emergency treatment of adult and pediatric patients following a fluorouracil or capecitabine overdose regardless of the presence of symptoms, and of those who exhibit early-onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system, and/or early onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration. Uridine triacetate

Highlights of prescribing information
Capecitabine (Xeloda®; Genentech/Roche) [Prescribing Information]
Oxaliplatin (Eloxatin®; Sanofi) [Prescribing Information]
Clopidogrel bisulfate (Plavix®; Sanofi and Bristol-Myers Squibb)[Prescribing Information]
5-Fluorouracil (5-FU) [Prescribing Information]
5-Fluorouracil (5-FU) (Adrucil®; Pharmacia (now Pfizer)[Prescribing Information]
Uridine triacetate (Vistogard®; Wellstat Therapeutics) [Prescribing Information]

Product Monograph and Patient Medication Information
Capecitabine (Xeloda®; Genentech/Roche) [Product Monograph]

Reference
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[16] Cohen SN. 50 years ago in cell biology: A virologist recalls his work on cell growth inhibition. January 29, 2008. The Scientist. [Online]
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[18] Wörmann B, Bokemeyer C, Burmeister T, Köhne CH, Schwab M, Arnold D, Blohmer JU, Borner M, Brucker S, Cascorbi I, Decker T, de Wit M, Dietz A, Einsele H, Eisterer W, Folprecht G, Hilbe W, Hoffmann J, Knauf W, Kunzmann V, Largiadèr CR, Lorenzen S, Lüftner D, Moehler M, Nöthen MM, Pox C, Reinacher-Schick A, Scharl A, Schlegelberger B, Seufferlein T, Sinn M, Stroth M, Tamm I, Trümper L, Wilhelm M, Wöll E, Hofheinz RD. Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper. Oncol Res Treat. 2020;43(11):628-636. doi: 10.1159/000510258. Epub 2020 Oct 23. PMID: 33099551.
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