In January 2021, 70-year-old Carol Rosen died in excruciating pain after three weeks of chemotherapy with incompatible drugs meant to treat metastatic breast cancer. Rosen suffered severe diarrhea, nausea, mouth sores, skin peeling, and organ failure, among other symptoms. These drugs, fluorouracil (5-FU) and capecitabine, can be deadly for patients who lack an enzyme that metabolizes the drugs, resulting in overdose levels in the body. The drugs can kill 1 in 1,000 patients and severely sicken or hospitalize 1 in 50. Testing for the deficiency can be done prior to treatment, but only 3% of U.S. oncologists routinely order these tests.
While British and European Union drug authorities have recommended testing for the deficiency since 2020, the National Comprehensive Cancer Network guidelines in the U.S. do not include routine testing. The FDA recently added warnings to the drug label about the lethal risks of 5-FU, but does not require testing before prescribing the chemotherapy. Advocates, including some medical professionals and health organizations, believe that this lack of mandatory testing is causing harm to patients and have been pushing for testing to become standard practice.
European hospitals have a practice of starting patients with a half- or quarter-dose of 5-FU if tests show poor metabolization, then increasing the dose if the patient responds well. However, many U.S. oncologists resist preemptive testing and believe in a “no pain, no gain” attitude towards chemotherapy toxicity. Daniel Hertz, an associate professor at the University of Michigan College of Pharmacy, has been advocating for warning labels on the drug urging prescribers to test for the deficiency. The FDA does not review most diagnostic tests and has not endorsed these tests, stating that it has never reviewed them.
Carol Rosen’s daughter, Lindsay Murray, has been advocating for mandatory testing after her mother’s death. Murray wrote to Dana-Farber Cancer Institute, where her mother was treated, urging routine testing and the hospital quickly adopted a testing system that detects risky genetic variants in more than 90% of prospective fluoropyrimidine patients. Different tests may be needed for different ancestries, as gene variants that slow metabolism of the drug differ among populations. Ontario, Canada, where Dr. Anil Kapoor was treated, recently began testing for four gene variants but Scott Kapoor, his brother, believes testing should be broader to encompass more diverse populations.
Dr. Alan Venook, a prominent oncologist, has led resistance to mandatory testing, citing murky answers from genetic tests that could lead to undertreatment. He believes that erring on the side of potential toxicity rather than undertreatment is necessary for curative therapy. However, cases of 5-FU toxicity resulting in death have sparked momentum towards mandatory testing. Lawsuits, settlements, and institutions implementing testing programs are slowly pushing providers towards mandatory testing. The future may see a shift towards routine testing for the deficiency in patients prescribed fluorouracil chemotherapy.
