Canada: This commonly prescribed cancer drug was supposed to help save his life, instead it killed him - 5FU

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This commonly prescribed cancer drug was supposed to help save his life, instead it killed him
Some provinces pre-screen patients at risk of toxic reactions, but experts say tests don't go far enough

CBC News - November 27, 2023

When Dr. Anil Kapoor was diagnosed with stage four colon cancer in January his prognosis was positive, and his family was hopeful treatment would buy him several more years.

But weeks later, the 58-year-old Burlington, Ont., resident was dead — killed not by the cancer, say doctors, but by the commonly prescribed cancer drug Fluorouracil (5-FU) that was supposed to help save his life.

"It was honestly a cruel rollercoaster of emotions," Anil's son, Akshay Kapoor, told Go Public. "I just feel like we were robbed of time together."

5-FU, used since the 1970s to treat many cancers including colorectal, stomach, breast and cervical cancer, can be toxic to certain patients.

Got a story you want investigated? Contact Rosa and the team at gopublic@cbc.ca
Some provinces now pre-screen for genetic variants — differences in people's DNA — that can lead to serious illness and even death.

But those tests may be giving some cancer patients and their families a false sense of security; failing to flag some of the people who could get sick or die from 5-FU, say experts.

Anil was pre-screened and got the all clear to receive the drug. Just a few days after his first and only dose, he went from being well enough to work to being bedridden.

Dr. Anil Kapoor died after taking one dose of fluorouracil, a commonly prescribed chemotherapy drug. Experts say his death could have been prevented.

"He started vomiting and feeling extremely nauseated. And then within 24 hours, he had inflammation in the mouth and throat. He could not eat or drink anything and he was also having profound diarrhea," brother Scott Kapoor told Go Public.

Three weeks later, on Feb. 28, Anil died. More testing later revealed he had a genetic variant that wasn't included in the pre-screening.

Anil's family says they were stunned to learn that current pre-screening guidelines are based on studies that largely leave out populations that aren't white, a known problem based on medical studies they found from North America and other parts of the world.

"We're shocked that this is allowed to happen in Canada," said Scott.

Patients dying from treatment, researcher says

Anil was a doctor — a urologist and head of transplants at St. Joseph's Healthcare, a hospital in Hamilton. His younger brothers are also doctors. Scott is an emergency room physician and the other surviving brother, Dr. Sunil Kapoor, is an anesthesiologist.

Even with all their medical knowledge, Scott says they'd never heard about the risks of 5-FU because cancer treatment is very specialized.

So, since Anil's death, his brothers have been scouring medical journals and speaking with researchers across Canada and around the world to find out why the medical system isn't doing more to inform and protect patients.

Of the provinces that pre-screen for potential toxic reactions, many check for what are considered the four most common genetic variants.

While many cancer drugs can be toxic, what sets 5-FU apart is that severe illness and death is largely preventable, according to Mayo Clinic researcher Steven Offer who has been studying the genetic factors that increase the risk of a toxic reaction to 5-FU for 14 years.

"One thing that strikes home is these patients are dying because of their treatment … and not necessarily dying because the cancer has progressed," Offer said from his office in Rochester, Minn.

Offer says ideally, medical systems should pre-screen for all of the at least 50 genetic variants that can lead to the deadly reaction.

It's called full genome sequencing. That's not happening in Canada, according to Go Public's research. Offer says that may be due to the added cost and infrastructure.

Go Public reached out to Health Canada to ask about pre-screening and what it's doing about the risks some patients face with 5-FU, but did not hear back in time for publication.

Studies favour white populations: expert

The problem, Offer says, is that the studies used to identify the four most common variants in pre-screening mostly involve patients who are white, leaving other populations more vulnerable.

Offer warns pre-screening for the four genetic variants could be leading to false negatives, like the one Anil got, for a large number of cancer patients.

The family had full genome sequencing done on Anil after his death and specialists confirmed he carried a genetic variant that likely caused a deadly reaction to 5-FU.

That variant isn't part of the pre-screening process and is considered rare based on current medical studies.

"When we start looking at individuals with ancestry outside of even northern and western Europe, we know less and less about which of the variants that they may carry will actually predispose them to an increased risk of toxicity to the drug," Offer said.

It's an issue flagged in an Ontario Health clinician guidance document published in April: "The lack of robust evidence around variants more prone in racial/ethnic groups has resulted in genetic tests that largely favour a Caucasian population."

Several liquid medication bottles sit on a stainless steel countertop. They are inside sealed clear plastic bags and have red plastic caps. Their labels say Fluorouracil.

Fluorouracil (5-FU) is a commonly prescribed chemotherapy drug that has proven beneficial to many patients, but for an unknown number of others it can lead to severe illness and, in some cases, death. (BC Cancer)

According to a 2020 Oncology journal article out of the U.S.: "for every 1,000 patients treated with either FU or capecitabine in the United States, 10 patients will die of treatment-related toxicity."

Capecitabine is the drug's pill form. Another study that looked at data collected from 14,000 patients throughout North America, Asia and Europe, found 2.3 per cent of patients with certain genetic variants died from 5-FU toxicity, compared to 0.1 per cent of patients without the variants.

Canada-specific numbers are less clear. Health Canada's adverse reactions website indicates more than 330 deaths involving patients with 5-FU among their prescriptions have been reported since 1975.

There have been 56 fatal adverse reactions reported from capecitabine, since 2011. It's unclear how many of those deaths were due specifically to 5-FU, a combination of medications or to the existence of genetic variants.

Pre-screening rules

Pre-screening rules differ from province to province.

Earlier this year, Ontario Health started routinely pre-screening. When asked why it doesn't pre-screen for more than four variants, it told Go Public "there is limited or no information available" on how other variants interact with 5-FU.

It says it will update its pre-screening recommendations when more research is done.

According to Statistics Canada census numbers released earlier this year, 26.5 per cent of the population is "visible minority" — about 9.6 million people.

It's unknown if the genetic variant involved in Anil's death is more common in people of South Asian ancestry. It's one of many unknowns in the research that leaves people of colour with questions about the risks they may face.

"I think the more important thing is that nobody's informing the patients," Scott told Go Public.

"So as you and I are sitting here right now, there are people sitting in the hospital being given this drug, who are not of northern and western European ethnicity, and they are completely vulnerable."

Quebec has been routinely pre-screening 5-FU patients for four genetic variants since 2019. New Brunswick and Nova Scotia have no current province-wide protocol for genetic pre-screening, it's left up to individual hospitals and oncologists to decide.

B.C. and Yukon pre-screen for six genetic variants after studying 5-FU's impact on Vancouver's diverse population.

"As we get more information, we should be prepared to expand our testing or make it most relevant to the populations that we're serving," said Dr. Bruce Carleton, who co-authored the study and is the Division Chair and clinical pharmacologist for the University of British Columbia's department of pediatrics.

He says the goal for B.C. is to make sure testing also recognizes populations that haven't been "well-served by this research," referring to B.C.'s large Chinese and South Asian populations.

Some jurisdictions tell Go Public they're following current medical guidelines, and there isn't enough information to suggest tests should be expanded. But they say they'll test for more variants as genetic research develops.

Antidote takes time to get in Canada

There is an antidote to toxic reactions called Uridine triacetate (brand name Vistogard) that can be brought into Canada from the U.S. manufacturer under Health Canada's Special Access Program, which takes time.

Anil's family says they were told about the antidote the day before he died — but it was too late.

SERB Pharmaceuticals tells Go Public it's considering making the antidote available here but hasn't applied for approval with Health Canada.

His family also wants better monitoring of cancer patients on 5-FU, so doses can be adjusted or 5-FU treatment stopped altogether if problems arise.

After his brother's death, Scott had full genome sequencing done and found out 5-FU was toxic to him, too. His brother Sunil, who also got sequencing done, does not have the same genetic variant. In their case, the cost of the sequencing was covered.

Anil's son, Akshay, says he also plans to get tested. "To find out that … it was preventable. That fills me with a lot of anger and sadness," he said.

The family says they contacted Go Public to warn cancer patients and their families about what could happen and to encourage the medical community to better disclose risks to certain populations.

"Just like my dad would want, just to save as many people as possible from this happening to them," said Akshay.

SOURCE:
https://www.cbc.ca/news/canada/toronto/ ... -1.7039145