Chemotherapy treatment can be deadly for enzyme-deficient patients and yet, hardly any oncologists call for simple pre-emptive testing that could save thousands of lives annually.
Every year, more than 275 000 cancer patients in the US are infused with common chemotherapy treatments, but for those who are deficient in an enzyme that metabolises these drugs, the treatment can be torturous – or deadly.
Patients essentially overdose because the drugs stay in the body for hours rather than being quickly metabolised and excreted.
The drugs kill about one in 1 000 patients who take them, and severely sicken or hospitalise one 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, but a recent survey found that only 3% of US oncologists routinely order the tests before dosing patients with 5-FU or capecitabine.
That’s because the most widely followed US cancer treatment guidelines – issued by the National Comprehensive Cancer Network (NCCN) – don’t recommend pre-emptive testing, reports KFF Health News.
On 21 March this year, after queries about this policy from KFF Health News, the FDA added new warnings about the lethal risks of 5-FU to the drug’s label.
However, it did not require doctors to administer the test before prescribing the chemotherapy.
The agency has said it could not endorse the 5-FU toxicity tests because it has never reviewed them.
But the FDA at present does not review most diagnostic tests, said Daniel Hertz, PharmD, PhD, of 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.
“The FDA has a responsibility to assure that drugs are used safely and effectively,” he said. Failure to warn was “an abdication of their responsibility”.
Europe ahead on safety
British and EU drug authorities have recommended the testing since 2020, but only a small number of American hospital systems, professional groups, and health advocates, including the American Cancer Society (ACS), also endorse routine testing.
In its latest guidelines on colon cancer, the NCCN 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 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 metaboliser, they then raise the dose if the patient responds well.
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 oncologist and researcher Gabriel Brooks, MD, MPH, of the Dartmouth Cancer Centre in New Hampshire.
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 had had a patient die like this will want to test everyone, said Robert Diasio, MD, of the Mayo Clinic in Rochester, Minnesota, who helped carry out major studies of the genetic deficiency in 1988.
Gene tests
Oncologists often deploy genetic tests to match tumours 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, PhD, policy director at the ACS Cancer Action Network in Washington.
“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.
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’t prevent blood clots as it’s supposed to in a quarter of the 4m Americans prescribed it each year.
In 2021, Hawaii won an $834m judgment from drugmakers it accused of falsely advertising the treatment 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 in Boston, where Carol Rosen was among more than 1 000 patients treated with fluoropyrimidine in 2021, and who died a terrible death.
The 70-year-old passed her final days in anguish, enduring severe diarrhoea 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 her daughter, Lindsay Murray, who was grief-stricken and furious after her mother’s death.
“I wanted to sue the hospital. I wanted to sue the oncologist,” she said, “but I realised that wasn’t what my mom would want.”
Instead, she wrote to Dana-Farber's chief quality officer, Joe Jacobson, MD, 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 an 11-variant test, while most others check for only four variants.
Different tests 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.
Alan Venook, MD, of the University of California San Francisco, who co-chairs the NCCN, has led resistance to mandatory testing because the answers provided by the test, in his view, are often murky and could lead to under-treatment.
“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.”
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 he regrets that dearly.
“But unhelpful information may lead us in the wrong direction.”
Murray senses momentum toward mandatory testing. In 2022, Oregon Health & Science University in Portland paid $1m 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 programmes 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.”
Study details
Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis
Bhavina Sharma, Karan Rai, Gabriel Brooks et al.
Published in PubMed on 26 December 2021
Abstract
Background
Pathogenic variants of the DPYD gene are strongly associated with grade ≥3 toxicity during fluoropyrimidine chemotherapy. We conducted a systematic review and meta-analysis to estimate the risk of treatment-related death associated with DPYD gene variants.
Materials and methods
We searched for reports published prior to September 17, 2020, that described patients receiving standard-dose fluoropyrimidine chemotherapy (5-fluorouracil or capecitabine) who had baseline testing for at least one of four pathogenic DPYD variants (c.1129-5923C>G [HapB3], c.1679T>G [*13], c.1905+1G>A [*2A], and c.2846A>T) and were assessed for toxicity. Two reviewers assessed studies for inclusion and extracted study-level data. The primary outcome was the relative risk of treatment-related mortality for DPYD variant carriers versus no-ncarriers; we performed data synthesis using a Mantel-Haenszel fixed effects model.
Results
Of the 2,923 references screened, 35 studies involving 13,929 patients were included. DPYD variants (heterozygous or homozygous) were identified in 566 patients (4.1%). There were 14 treatment-related deaths in 13,363 patients without identified DPYD variants (treatment-related mortality, 0.1%; 95% confidence interval [CI], 0.1-0.2) and 13 treatment-related deaths in 566 patients with any of the four DPYD variants (treatment-related mortality, 2.3%; 95% CI, 1.3%-3.9%). Carriers of pathogenic DPYD gene variants had a 25.6 times increased risk of treatment-related death (95% CI, 12.1-53.9; p < .001). After excluding carriers of the more common but less deleterious c.1129-5923C>G variant, carriers of c.1679T>G, c.1905+1G>A, and/or c.2846A>T had treatment-related mortality of 3.7%.
Conclusion
Patients with pathogenic DPYD gene variants who receive standard-dose fluoropyrimidine chemotherapy have greatly increased risk for treatment-related death.
Implications for practice
The syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency is an uncommon but well-described cause of severe toxicity related to fluoropyrimidine chemotherapy agents (5-fluorouracil and capecitabine). Patients with latent DPD deficiency can be identified pre-emptively with genotyping of the DPYD gene, or with measurement of the plasma uracil concentration. In this systematic review and meta-analysis, the authors study the rare outcome of treatment-related death after fluoropyrimidine chemotherapy.
DPYD gene variants associated with DPD deficiency were linked to a 25.6 times increased risk of fluoropyrimidine-related mortality. These findings support the clinical utility of DPYD genotyping as a screening test for DPD deficiency.
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