Overdosing on Chemo: A Common Gene Test Could Save Hundreds of Lives Each Year
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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.
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. 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.
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.
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 — don’t recommend preemptive testing.
The FDA added new warnings about the lethal risks of 5-FU to the drug’s 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.
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.
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.
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.
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 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.
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.
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 panel that sets guidelines for colorectal cancers at 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.”
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.”
KFF Health News is 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. Learn more about KFF.
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The Many Health Benefits Of Garlic
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The Many Health Benefits of Garlic
We’re quite confident you already know what garlic is, so we’re going to leap straight in there with some science today:
First, let’s talk about allicin
Allicin is a compound in garlic that gives most of its health benefits. A downside of allicin is that it’s not very stable, so what this means is:
- Garlic is best fresh—allicin breaks down soon after garlic is cut/crushed
- So while doing the paperwork isn’t fun, buying it as bulbs is better than buying it as granules or similar
- Allicin also breaks down somewhat in cooking, so raw garlic is best
- Our philosophy is: still use it in cooking as well; just use more!
- Supplements (capsule form etc) use typically use extracts and potency varies (from not great to actually very good)
Read more about that:
- Short-term heating reduces the anti-inflammatory effects of fresh raw garlic extracts
- Allicin Bioavailability and Bioequivalence from Garlic Supplements and Garlic Foods
Now, let’s talk benefits…
Benefits to heart health
Garlic has been found to be as effective as the drug Atenolol at reducing blood pressure:
It also lowers LDL (bad cholesterol):
Benefits to the gut
We weren’t even looking for this, but as it turns out, as an add-on to the heart benefits…
Benefits to the immune system
Whether against the common cold or bringing out the heavy guns, garlic is a booster:
- Preventing the common cold with a garlic supplement: a double-blind, placebo-controlled survey
- Supplementation with aged garlic extract improves both NK and γδ-T cell function and reduces the severity of cold and flu symptoms: a randomized, double-blind, placebo-controlled nutrition intervention
Benefits to the youthfulness of body and brain
Garlic is high in antioxidants that, by virtue of reducing oxidative stress, help slow aging. This effect, combined with the cholesterol and blood pressure benefits, means it may also reduce the risk of Alzheimer’s and other forms of dementia:
- Antioxidant health effects of aged garlic extract
- Effects of garlic consumption on plasma and erythrocyte antioxidant parameters in elderly subjects
- Garlic reduces heart disease and dementia risk
There are more benefits too…
That’s all we have time to dive into study-wise today, but for the visually-inclined, here are yet more benefits to garlic (at a rate of 3–4 cloves per day):
An incredible awesome recipe using lots of garlic:
- Take small potatoes (still in their skins), cut in half
- Add enough peeled cloves of garlic so that you have perhaps a 1:10 ratio of garlic to potato by mass
- Boil (pressure-cooking is ideal) until soft, and drain
- Keeping them in the pan, add a lashing of olive oil, and any additional seasonings per your preference (consider black pepper, rosemary, thyme, parsley)
- Put a lid on the pan, and holding it closed, shake the pan vigorously
- Note: if you didn’t leave the skins on, or you chopped much larger potatoes smaller instead of cutting in half, the potatoes will break up into a rough mash now. This is actually also fine and still tastes (and honestly, looks) great, but it is different, so just be aware, so that you get the outcome you want.
- The garlic, which—unlike the potatoes—didn’t have a skin to hold it together, will now have melted over the potatoes like butter
You can serve like this (it’s delicious already) or finish up in the oven or air-fryer or under the grill, if you prefer a roasted style dish (an amazing option too).
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- Garlic is best fresh—allicin breaks down soon after garlic is cut/crushed
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Honeydew vs Cantaloupe – Which is Healthier?
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Our Verdict
When comparing honeydew to cantaloupe, we picked the cantaloupe.
Why?
In terms of macros, there’s not a lot between them—they’re both mostly water. Nominally, honeydew has more carbs while cantaloupe has more fiber and protein, but the differences are very small. So, a very slight win for cantaloupe.
Looking at vitamins: honeydew has slightly more of vitamins B5 and B6 (so, the vitamins that are in pretty much everything), while cantaloupe has a more of vitamins A, B1, B2, B3, C, and E (especially notably 67x more vitamin A, whence its color). A more convincing win for cantaloupe.
The minerals category is even more polarized: honeydew has more selenium (and for what it’s worth, more sodium too, though that’s not usually a plus for most of us in the industrialized world), while cantaloupe has more calcium, copper, iron, magnesium, manganese, phosphorus, potassium, and zinc. An overwhelming win for cantaloupe.
No surprises: adding up the slight win for cantaloupe, the convincing win for cantaloupe, and the overwhelming win for cantaloupe, makes cantaloupe the overall best pick here.
Enjoy!
Want to learn more?
You might like to read:
From Apples to Bees, and High-Fructose Cs: Which Sugars Are Healthier, And Which Are Just The Same?
Take care!
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The DASH Diet Mediterranean Solution – by Dr. Marla Heller
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Sometimes, an author releases a series of books that could have just been one book, with various padding and rehashes. In some cases, naming no names
Dr. Mark Hyman, it means we have to carefully pick out the honestly very good and highly recommendable ones from the “you just republished for the extra income, didn’t you?” ones.In this case, today’s book is part of a series of books with very similar titles, and this one seems the most useful as a standalone book
The Mediterranean Diet is still the scientific world’s current “gold standard” in terms of most evidence-based diet for general health, and as we’ve written about, it can be tweaked to focus on being best for [your particular concern here]. In this case, it’s the DASH variant of the Mediterranean Diet, considered best for heart health specifically.
The style is repetitive, and possibly indicative of the author getting into a habit of having to pad books. Nevertheless, saying things too often is better than forgetting to say them, so hey. On which note, it is more of an educational book than a cookbook—it does have recipes, but not many.
Bottom line: if you’d like an introduction to the DASH variant of the Mediterranean Diet, this book will get you well-acquainted.
Click here to check out The DASH Diet Mediterranean Solution, and learn all about it!
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Age Later – by Dr. Nir Barzilai
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Dr. Barzilai discusses why we age, why supercentenarians age more slowly, and even, why it is so often the case that supercentenarians outside of Blue Zones have poor lifestyles (their longevity is because of protective genes that mitigate the harmful effects of those poor lifestyles—the ultimate in “survivorship bias”).
He also talks not just genetics, but also epigenetics, and thus gene expression. Bearing in mind, there’s a scale of modifiability there: with current tech, we can’t easily change a bad gene… But we often can just switch it off (or at least downregulate its expression). This is where studies in supercentenarians are helpful even for those who don’t have such fortunate genes—the supercentenarian studies show us which genes we want on or off, what gene expressions to aim for, etc. Further clinical studies can then show us what lifestyle interventions (exercise, diet, nutraceuticals, etc) can do that for us.
With regard to those lifestyle interventions, he does cover many, and that’s where a lot of the practical value of the book comes from. But it’s not just “do this, do that”; understanding the reasons behind why things work the way they do is important, so as to be more likely to do it right, and also to enjoy greater adherence (we tend to do things we understand more readily than things we have just been told to do).
There are areas definitely within the author’s blind spots—for example, when talking about menopausal HRT, he discusses at great length the results of the discredited WHI study, and considers it the only study of relevance. So, this is a reminder to not believe everything said by someone who sounds confident (Dr. Barzilai’s professional background is mostly in treating diabetes).
In terms of style, it is very much narrative; somewhat pop-science, but more “this doctor wants to tell stories”. So many stories. Now, the stories all have informational value, so this isn’t padding, but it is the style, so we mention it as such. As for citations, there aren’t any, so if you want to look up the science he mentions, you’re going to need a bit of digital sleuthery to find the papers from the clues in the stories.
Bottom line: if you’re interested in the science of aging and how that has been progressing for the past decades and where we’re at, this book will give you so many jumping-off points, and is an engaging read.
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How To Escape From A Despairing Mood
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When we are in a despairing mood, that’s when it can feel hardest to actually implement anything we know about getting out of one. That’s why sometimes, the simplest solutions are the best:
Imagination Is Key
Despairing moods occur when it’s hard to envision a better life. Imagination is the power to envision alternatives, such as new jobs, relationships, or lifestyle, but sadness can cloud our ability to imagine solutions like changing careers, moving house, or starting fresh. With enough imagination, most problems can be worked around—and new opportunities can always be found.
Importantly: we are not bound by our past or present circumstances; we have the freedom and flexibility to choose new paths. That doesn’t mean it’ll always be a walk in the park, but “this too shall pass”.
You may be thinking: “sometimes the hardship does pass, but can last many years”, and that is true. All the more reason to check if there’s a freer lane you can slip into to speed ahead. Even if there isn’t, the mere act of imagining such lanes is already respite from the hardships—and having envisioned such will make it much easier for you to recognise when opportunities for change do come along.
To foster imagination, we are advised to expose ourselves to different narratives, preparing ourselves for alternative ways of living. Thus, we can reframe life’s challenges as intellectual puzzles, urging us to rebuild creatively and find new solutions!
For more on all this, enjoy:
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Want to learn more?
You might also like to read:
Behavioral Activation Against Depression & Anxiety
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Feminist narratives are being hijacked to market medical tests not backed by evidence
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Corporations have used feminist language to promote their products for decades. In the 1980s, companies co-opted messaging about female autonomy to encourage women’s consumption of unhealthy commodities, such as tobacco and alcohol.
Today, feminist narratives around empowerment and women’s rights are being co-opted to market interventions that are not backed by evidence across many areas of women’s health. This includes by commercial companies, industry, mass media and well-intentioned advocacy groups.
Some of these health technologies, tests and treatments are useful in certain situations and can be very beneficial to some women.
However, promoting them to a large group of asymptomatic healthy women that are unlikely to benefit, or without being transparent about the limitations, runs the risk of causing more harm than good. This includes inappropriate medicalisation, overdiagnosis and overtreatment.
In our analysis published today in the BMJ, we examine this phenomenon in two current examples: the anti-mullerian hormone (AMH) test and breast density notification.
The AMH test
The AMH test is a blood test associated with the number of eggs in a woman’s ovaries and is sometimes referred to as the “egg timer” test.
Although often used in fertility treatment, the AMH test cannot reliably predict the likelihood of pregnancy, timing to pregnancy or specific age of menopause. The American College of Obstetricians and Gynaecologists therefore strongly discourages testing for women not seeking fertility treatment.
The AMH test can’t predict your chance of getting pregnant.
Anastasia Vityukova/UnsplashDespite this, several fertility clinics and online companies market the AMH test to women not even trying to get pregnant. Some use feminist rhetoric promising empowerment, selling the test as a way to gain personalised insights into your fertility. For example, “you deserve to know your reproductive potential”, “be proactive about your fertility” and “knowing your numbers will empower you to make the best decisions when family planning”.
The use of feminist marketing makes these companies appear socially progressive and champions of female health. But they are selling a test that has no proven benefit outside of IVF and cannot inform women about their current or future fertility.
Our recent study found around 30% of women having an AMH test in Australia may be having it for these reasons.
Misleading women to believe that the test can reliably predict fertility can create a false sense of security about delaying pregnancy. It can also create unnecessary anxiety, pressure to freeze eggs, conceive earlier than desired, or start fertility treatment when it may not be needed.
While some companies mention the test’s limitations if you read on, they are glossed over and contradicted by the calls to be proactive and messages of empowerment.
Breast density notification
Breast density is one of several independent risk factors for breast cancer. It’s also harder to see cancer on a mammogram image of breasts with high amounts of dense tissue than breasts with a greater proportion of fatty tissue.
While estimates vary, approximately 25–50% of women in the breast screening population have dense breasts.
Dense breasts can make it harder to detect cancer.
Tyler Olsen/ShutterstockStemming from valid concerns about the increased risk of cancer, advocacy efforts have used feminist language around women’s right to know such as “women need to know the truth” and “women can handle the truth” to argue for widespread breast density notification.
However, this simplistic messaging overlooks that this is a complex issue and that more data is still needed on whether the benefits of notifying and providing additional screening or tests to women with dense breasts outweigh the harms.
Additional tests (ultrasound or MRI) are now being recommended for women with dense breasts as they have the ability to detect more cancer. Yet, there is no or little mention of the lack of robust evidence showing that it prevents breast cancer deaths. These extra tests also have out-of-pocket costs and high rates of false-positive results.
Large international advocacy groups are also sponsored by companies that will financially benefit from women being notified.
While stronger patient autonomy is vital, campaigning for breast density notification without stating the limitations or unclear evidence of benefit may go against the empowerment being sought.
Ensuring feminism isn’t hijacked
Increased awareness and advocacy in women’s health are key to overcoming sex inequalities in health care.
But we need to ensure the goals of feminist health advocacy aren’t undermined through commercially driven use of feminist language pushing care that isn’t based on evidence. This includes more transparency about the risks and uncertainties of health technologies, tests and treatments and greater scrutiny of conflicts of interests.
Health professionals and governments must also ensure that easily understood, balanced information based on high quality scientific evidence is available. This will enable women to make more informed decisions about their health.
Brooke Nickel, NHMRC Emerging Leader Research Fellow, University of Sydney and Tessa Copp, NHMRC Emerging Leader Research Fellow, University of Sydney
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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