Federal Practitioner

Starting an exercise regimen with others can be a powerful fitness motivator, and new research spotlights the strategy’s particular importance for older adults.

In a randomized clinical trial published in JAMA Network Open, older adults who talked with peers about their exercise program were able to increase and sustain physical activity levels much better than those who focused on self-motivation and setting fitness goals.

Such self-focused — or “intrapersonal” — strategies tend to be more common in health and fitness than interactive, or “interpersonal,” ones, the study authors noted. Yet, research on their effectiveness is limited. Historically, intrapersonal strategies have been studied as part of a bundle of behavioral change strategies — a common limitation in research — making it difficult to discern their individual value.

“We’re not saying that intrapersonal strategies should not be used,” said study author Siobhan McMahon, PhD, associate professor and codirector of the Center on Aging Science and Care at the University of Minnesota, in Minneapolis, Minnesota, “but this study shows that interpersonal strategies are really important.”

Low physical activity among older adults is linked with “disability, difficulty managing chronic conditions, and increased falls and related injuries,” the authors wrote. Exercise can be the antidote, yet fewer than 16% of older adults meet the recommended guidelines (150 minutes of moderate aerobic activity and two muscle-strengthening sessions per week).

The study builds on previous research that suggests interpersonal strategies could help change that by encouraging more older adults to move.
 

Intrapersonal vs Interpersonal Behavior Change Strategies

More than 300 participants aged 70 years and older who did not meet physical activity guidelines were given a wearable fitness tracker and an exercise program and randomly split into four groups:

• One using intrapersonal behavior change strategies
• Another using interpersonal strategies
• A group combining both intrapersonal and interpersonal strategies
• A control group that received neither intervention

For 8 weeks, all participants exercised in meet-ups and discussed their progress in their groups. Afterward, they were left to their own devices and monitored for the remainder of the year.

“The intrapersonal strategies group involved personal reflection,” said Dr. McMahon. They set personal goals (increasing daily step count or exercise repetitions) and developed action plans for implementing physical activity into their daily routines.

“The interpersonal group involved more peer-to-peer conversation, collaborative learning, and sharing,” said Dr. McMahon. Participants talked among themselves about how they could sustain doing the prescribed exercises at home. “Through those conversations, they learned and experimented,” Dr. McMahon said. They problem-solved, determining what barriers might stop them from exercising and brainstorming ways around them.

The researchers evaluated the participants after 1 week, 6 months, and 12 months. The interpersonal group exhibited significant increases in physical activity — including light, moderate, and vigorous activity — for the entire year. They increased their average physical activity per day by 21-28 minutes and their daily step count by 776-1058.

The intrapersonal group, meanwhile, exhibited no significant changes in total physical activity. (The third experimental group, the intrapersonal plus interpersonal condition, had results similar to the interpersonal one.)

The results echoed the findings of a similar study Dr. McMahon conducted in 2017. “We followed people over a longer period of time in this [new] study,” she said, “12 months instead of 6 months. This is important in physical activity studies because a lot of evidence shows that after 6 months, people’s activity drops off.”
 

How Socializing Promotes Exercise Compliance

Research on the effectiveness of exercise in social groups dates back as far as the 19th century. It’s called the social facilitation theory: The idea that people will make an increased effort as a result of the real, imagined, or implied presence of others.

“Norman Triplett was a scientist who studied indoor cyclists, and he came up with the social facilitation theory in 1898,” said Robert Linkul, CSCS*D, who sits on the National Strength and Conditioning Association’s board of directors and specializes in exercise for older adults. “He noticed that during relays, the first cyclist would get slower as he fatigued, but as soon as his teammate came out, his last lap would be faster than his previous two laps. People try harder when there’s some other person present. They tend to feel pressure to perform because they don’t want to look bad.”

Dr. McMahon said the exact psychology of why socializing supports exercise isn’t clear yet but noted that talking to other people builds relationships and makes one feel connected to and involved with a community.

“I think connections between peers are really important,” said Dr. McMahon. “It goes beyond just being in the same room and doing the exercises together. It’s taking a little bit of time to talk about it. To acknowledge what they’re doing and their progress. To encourage each other and provide support.”

Some of the study participants even became friends and continued to meet on their own time over the course of the trial.

“They stayed in touch,” said Dr. McMahon. “One thing that people talked about after the study, even if they weren’t friends, was that the conversations within the meetings made them feel kind of a fellowship that helped them learn about themselves or people like them.”
 

Help Patients Find Their Own Fellowship of Active People

• Communicate the importance of exercise. During appointments, ask how the patient is doing with their exercise and listen for any obstacles to compliance, Dr. McMahon said.
• See if they have access to fitness classes. Many community-dwelling older adults do, Mr. Linkul said. If not, consider local or state agencies on aging — “in Minnesota, we have a program, Juniper,” Dr. McMahon said, that maintains a list of physical activity programs — or AARP’s free online group classes, or Silver Sneakers (free for those with eligible Medicare Advantage plans).
• Reach out to local qualified fitness professionals. Trainers with the Training the Older Adult certification (founded by Mr. Linkul) can be found here. Other qualified trainers can be found through the Functional Aging Institute, American Council on Exercise, and National Academy of Sports Medicine, Mr. Linkul said. “Many of these trainers will offer semiprivate sessions,” said Mr. Linkul, “which is usually four to eight people.” Groups of this size often facilitate better participation than larger classes. “You get more personalized attention from the instructor along with an environment that allows social engagement,” said Mr. Linkul. If you have exercise or rehab professionals in your network, you might consider reaching out to them. Some physical therapists lead activity groups, though reimbursement challenges mean they aren’t common, Dr. McMahon said.
• Prescribe short walks with a friend, family member, or neighbor. Have the person start with 30 minutes of walking or rucking (walking with a weighted backpack) most days, Mr. Linkul suggested, a recommendation that is echoed by the American College of Sports Medicine.
• Encourage patients to talk about their exercise. Even for those who prefer to exercise solo, “our studies suggest it might be helpful to have conversations with others about movement, and motivations for movement,” Dr. McMahon said. They can simply mention one idea, question, or observation related to physical activity during casual catchups or chats.
• Recommend resistance training. That goes for patients with preexisting health conditions too, Mr. Linkul said. Physicians “find out a patient has low bone mineral density, and they’ll often tell them not to pick up anything heavy because they’ll hurt themselves — and that’s the exact wrong answer,” Mr. Linkul said. A total of 32% of the participants in the JAMA Network study had cardiovascular disease, nearly 34% had osteoporosis, 70% had arthritis, and more than 20% were living with diabetes.
• Expect pushback. Encouraging older adults to exercise is hard because many are resistant to it, Mr. Linkul acknowledged. Do it anyway. Some will listen and that makes the effort worthwhile. “I try to provide as much information as I can about what happens to aging bodies if they don’t train,” said Mr. Linkul. “These people are more likely to fall, they’ll die earlier, and have a poorer quality of life. But when they start exercising, they feel better immediately.”

A version of this article appeared on Medscape.com.

Starting an exercise regimen with others can be a powerful fitness motivator, and new research spotlights the strategy’s particular importance for older adults.

In a randomized clinical trial published in JAMA Network Open, older adults who talked with peers about their exercise program were able to increase and sustain physical activity levels much better than those who focused on self-motivation and setting fitness goals.

Such self-focused — or “intrapersonal” — strategies tend to be more common in health and fitness than interactive, or “interpersonal,” ones, the study authors noted. Yet, research on their effectiveness is limited. Historically, intrapersonal strategies have been studied as part of a bundle of behavioral change strategies — a common limitation in research — making it difficult to discern their individual value.

“We’re not saying that intrapersonal strategies should not be used,” said study author Siobhan McMahon, PhD, associate professor and codirector of the Center on Aging Science and Care at the University of Minnesota, in Minneapolis, Minnesota, “but this study shows that interpersonal strategies are really important.”

Low physical activity among older adults is linked with “disability, difficulty managing chronic conditions, and increased falls and related injuries,” the authors wrote. Exercise can be the antidote, yet fewer than 16% of older adults meet the recommended guidelines (150 minutes of moderate aerobic activity and two muscle-strengthening sessions per week).

The study builds on previous research that suggests interpersonal strategies could help change that by encouraging more older adults to move.
 

Intrapersonal vs Interpersonal Behavior Change Strategies

More than 300 participants aged 70 years and older who did not meet physical activity guidelines were given a wearable fitness tracker and an exercise program and randomly split into four groups:

• One using intrapersonal behavior change strategies
• Another using interpersonal strategies
• A group combining both intrapersonal and interpersonal strategies
• A control group that received neither intervention

For 8 weeks, all participants exercised in meet-ups and discussed their progress in their groups. Afterward, they were left to their own devices and monitored for the remainder of the year.

“The intrapersonal strategies group involved personal reflection,” said Dr. McMahon. They set personal goals (increasing daily step count or exercise repetitions) and developed action plans for implementing physical activity into their daily routines.

“The interpersonal group involved more peer-to-peer conversation, collaborative learning, and sharing,” said Dr. McMahon. Participants talked among themselves about how they could sustain doing the prescribed exercises at home. “Through those conversations, they learned and experimented,” Dr. McMahon said. They problem-solved, determining what barriers might stop them from exercising and brainstorming ways around them.

The researchers evaluated the participants after 1 week, 6 months, and 12 months. The interpersonal group exhibited significant increases in physical activity — including light, moderate, and vigorous activity — for the entire year. They increased their average physical activity per day by 21-28 minutes and their daily step count by 776-1058.

The intrapersonal group, meanwhile, exhibited no significant changes in total physical activity. (The third experimental group, the intrapersonal plus interpersonal condition, had results similar to the interpersonal one.)

The results echoed the findings of a similar study Dr. McMahon conducted in 2017. “We followed people over a longer period of time in this [new] study,” she said, “12 months instead of 6 months. This is important in physical activity studies because a lot of evidence shows that after 6 months, people’s activity drops off.”
 

How Socializing Promotes Exercise Compliance

Research on the effectiveness of exercise in social groups dates back as far as the 19th century. It’s called the social facilitation theory: The idea that people will make an increased effort as a result of the real, imagined, or implied presence of others.

“Norman Triplett was a scientist who studied indoor cyclists, and he came up with the social facilitation theory in 1898,” said Robert Linkul, CSCS*D, who sits on the National Strength and Conditioning Association’s board of directors and specializes in exercise for older adults. “He noticed that during relays, the first cyclist would get slower as he fatigued, but as soon as his teammate came out, his last lap would be faster than his previous two laps. People try harder when there’s some other person present. They tend to feel pressure to perform because they don’t want to look bad.”

Dr. McMahon said the exact psychology of why socializing supports exercise isn’t clear yet but noted that talking to other people builds relationships and makes one feel connected to and involved with a community.

“I think connections between peers are really important,” said Dr. McMahon. “It goes beyond just being in the same room and doing the exercises together. It’s taking a little bit of time to talk about it. To acknowledge what they’re doing and their progress. To encourage each other and provide support.”

Some of the study participants even became friends and continued to meet on their own time over the course of the trial.

“They stayed in touch,” said Dr. McMahon. “One thing that people talked about after the study, even if they weren’t friends, was that the conversations within the meetings made them feel kind of a fellowship that helped them learn about themselves or people like them.”
 

Help Patients Find Their Own Fellowship of Active People

• Communicate the importance of exercise. During appointments, ask how the patient is doing with their exercise and listen for any obstacles to compliance, Dr. McMahon said.
• See if they have access to fitness classes. Many community-dwelling older adults do, Mr. Linkul said. If not, consider local or state agencies on aging — “in Minnesota, we have a program, Juniper,” Dr. McMahon said, that maintains a list of physical activity programs — or AARP’s free online group classes, or Silver Sneakers (free for those with eligible Medicare Advantage plans).
• Reach out to local qualified fitness professionals. Trainers with the Training the Older Adult certification (founded by Mr. Linkul) can be found here. Other qualified trainers can be found through the Functional Aging Institute, American Council on Exercise, and National Academy of Sports Medicine, Mr. Linkul said. “Many of these trainers will offer semiprivate sessions,” said Mr. Linkul, “which is usually four to eight people.” Groups of this size often facilitate better participation than larger classes. “You get more personalized attention from the instructor along with an environment that allows social engagement,” said Mr. Linkul. If you have exercise or rehab professionals in your network, you might consider reaching out to them. Some physical therapists lead activity groups, though reimbursement challenges mean they aren’t common, Dr. McMahon said.
• Prescribe short walks with a friend, family member, or neighbor. Have the person start with 30 minutes of walking or rucking (walking with a weighted backpack) most days, Mr. Linkul suggested, a recommendation that is echoed by the American College of Sports Medicine.
• Encourage patients to talk about their exercise. Even for those who prefer to exercise solo, “our studies suggest it might be helpful to have conversations with others about movement, and motivations for movement,” Dr. McMahon said. They can simply mention one idea, question, or observation related to physical activity during casual catchups or chats.
• Recommend resistance training. That goes for patients with preexisting health conditions too, Mr. Linkul said. Physicians “find out a patient has low bone mineral density, and they’ll often tell them not to pick up anything heavy because they’ll hurt themselves — and that’s the exact wrong answer,” Mr. Linkul said. A total of 32% of the participants in the JAMA Network study had cardiovascular disease, nearly 34% had osteoporosis, 70% had arthritis, and more than 20% were living with diabetes.
• Expect pushback. Encouraging older adults to exercise is hard because many are resistant to it, Mr. Linkul acknowledged. Do it anyway. Some will listen and that makes the effort worthwhile. “I try to provide as much information as I can about what happens to aging bodies if they don’t train,” said Mr. Linkul. “These people are more likely to fall, they’ll die earlier, and have a poorer quality of life. But when they start exercising, they feel better immediately.”

A version of this article appeared on Medscape.com.

Starting an exercise regimen with others can be a powerful fitness motivator, and new research spotlights the strategy’s particular importance for older adults.

In a randomized clinical trial published in JAMA Network Open, older adults who talked with peers about their exercise program were able to increase and sustain physical activity levels much better than those who focused on self-motivation and setting fitness goals.

Such self-focused — or “intrapersonal” — strategies tend to be more common in health and fitness than interactive, or “interpersonal,” ones, the study authors noted. Yet, research on their effectiveness is limited. Historically, intrapersonal strategies have been studied as part of a bundle of behavioral change strategies — a common limitation in research — making it difficult to discern their individual value.

“We’re not saying that intrapersonal strategies should not be used,” said study author Siobhan McMahon, PhD, associate professor and codirector of the Center on Aging Science and Care at the University of Minnesota, in Minneapolis, Minnesota, “but this study shows that interpersonal strategies are really important.”

Low physical activity among older adults is linked with “disability, difficulty managing chronic conditions, and increased falls and related injuries,” the authors wrote. Exercise can be the antidote, yet fewer than 16% of older adults meet the recommended guidelines (150 minutes of moderate aerobic activity and two muscle-strengthening sessions per week).

The study builds on previous research that suggests interpersonal strategies could help change that by encouraging more older adults to move.
 

Intrapersonal vs Interpersonal Behavior Change Strategies

More than 300 participants aged 70 years and older who did not meet physical activity guidelines were given a wearable fitness tracker and an exercise program and randomly split into four groups:

• One using intrapersonal behavior change strategies
• Another using interpersonal strategies
• A group combining both intrapersonal and interpersonal strategies
• A control group that received neither intervention

For 8 weeks, all participants exercised in meet-ups and discussed their progress in their groups. Afterward, they were left to their own devices and monitored for the remainder of the year.

“The intrapersonal strategies group involved personal reflection,” said Dr. McMahon. They set personal goals (increasing daily step count or exercise repetitions) and developed action plans for implementing physical activity into their daily routines.

“The interpersonal group involved more peer-to-peer conversation, collaborative learning, and sharing,” said Dr. McMahon. Participants talked among themselves about how they could sustain doing the prescribed exercises at home. “Through those conversations, they learned and experimented,” Dr. McMahon said. They problem-solved, determining what barriers might stop them from exercising and brainstorming ways around them.

The researchers evaluated the participants after 1 week, 6 months, and 12 months. The interpersonal group exhibited significant increases in physical activity — including light, moderate, and vigorous activity — for the entire year. They increased their average physical activity per day by 21-28 minutes and their daily step count by 776-1058.

The intrapersonal group, meanwhile, exhibited no significant changes in total physical activity. (The third experimental group, the intrapersonal plus interpersonal condition, had results similar to the interpersonal one.)

The results echoed the findings of a similar study Dr. McMahon conducted in 2017. “We followed people over a longer period of time in this [new] study,” she said, “12 months instead of 6 months. This is important in physical activity studies because a lot of evidence shows that after 6 months, people’s activity drops off.”
 

How Socializing Promotes Exercise Compliance

Research on the effectiveness of exercise in social groups dates back as far as the 19th century. It’s called the social facilitation theory: The idea that people will make an increased effort as a result of the real, imagined, or implied presence of others.

“Norman Triplett was a scientist who studied indoor cyclists, and he came up with the social facilitation theory in 1898,” said Robert Linkul, CSCS*D, who sits on the National Strength and Conditioning Association’s board of directors and specializes in exercise for older adults. “He noticed that during relays, the first cyclist would get slower as he fatigued, but as soon as his teammate came out, his last lap would be faster than his previous two laps. People try harder when there’s some other person present. They tend to feel pressure to perform because they don’t want to look bad.”

Dr. McMahon said the exact psychology of why socializing supports exercise isn’t clear yet but noted that talking to other people builds relationships and makes one feel connected to and involved with a community.

“I think connections between peers are really important,” said Dr. McMahon. “It goes beyond just being in the same room and doing the exercises together. It’s taking a little bit of time to talk about it. To acknowledge what they’re doing and their progress. To encourage each other and provide support.”

Some of the study participants even became friends and continued to meet on their own time over the course of the trial.

“They stayed in touch,” said Dr. McMahon. “One thing that people talked about after the study, even if they weren’t friends, was that the conversations within the meetings made them feel kind of a fellowship that helped them learn about themselves or people like them.”
 

Help Patients Find Their Own Fellowship of Active People

• Communicate the importance of exercise. During appointments, ask how the patient is doing with their exercise and listen for any obstacles to compliance, Dr. McMahon said.
• See if they have access to fitness classes. Many community-dwelling older adults do, Mr. Linkul said. If not, consider local or state agencies on aging — “in Minnesota, we have a program, Juniper,” Dr. McMahon said, that maintains a list of physical activity programs — or AARP’s free online group classes, or Silver Sneakers (free for those with eligible Medicare Advantage plans).
• Reach out to local qualified fitness professionals. Trainers with the Training the Older Adult certification (founded by Mr. Linkul) can be found here. Other qualified trainers can be found through the Functional Aging Institute, American Council on Exercise, and National Academy of Sports Medicine, Mr. Linkul said. “Many of these trainers will offer semiprivate sessions,” said Mr. Linkul, “which is usually four to eight people.” Groups of this size often facilitate better participation than larger classes. “You get more personalized attention from the instructor along with an environment that allows social engagement,” said Mr. Linkul. If you have exercise or rehab professionals in your network, you might consider reaching out to them. Some physical therapists lead activity groups, though reimbursement challenges mean they aren’t common, Dr. McMahon said.
• Prescribe short walks with a friend, family member, or neighbor. Have the person start with 30 minutes of walking or rucking (walking with a weighted backpack) most days, Mr. Linkul suggested, a recommendation that is echoed by the American College of Sports Medicine.
• Encourage patients to talk about their exercise. Even for those who prefer to exercise solo, “our studies suggest it might be helpful to have conversations with others about movement, and motivations for movement,” Dr. McMahon said. They can simply mention one idea, question, or observation related to physical activity during casual catchups or chats.
• Recommend resistance training. That goes for patients with preexisting health conditions too, Mr. Linkul said. Physicians “find out a patient has low bone mineral density, and they’ll often tell them not to pick up anything heavy because they’ll hurt themselves — and that’s the exact wrong answer,” Mr. Linkul said. A total of 32% of the participants in the JAMA Network study had cardiovascular disease, nearly 34% had osteoporosis, 70% had arthritis, and more than 20% were living with diabetes.
• Expect pushback. Encouraging older adults to exercise is hard because many are resistant to it, Mr. Linkul acknowledged. Do it anyway. Some will listen and that makes the effort worthwhile. “I try to provide as much information as I can about what happens to aging bodies if they don’t train,” said Mr. Linkul. “These people are more likely to fall, they’ll die earlier, and have a poorer quality of life. But when they start exercising, they feel better immediately.”

A version of this article appeared on Medscape.com.

As a cardiologist specializing in obesity medicine, I often encounter patients who would greatly benefit from the new generation of weight loss drugs that work as glucagon-like peptide 1 (GLP-1) agonists. In the recently published SELECT trial results, for example, semaglutide (marketed by Novo Nordisk as Wegovy for weight loss and Ozempic for type 2 diabetes) demonstrated a 20% risk reduction of heart attacks and strokes in overweight and obese individuals without diabetes and with cardiovascular disease, establishing it as a cardiovascular disease–modifying medication in people without type 2 diabetes.

Unfortunately, the high demand for these new weight loss medications has resulted in a frustrating, long-lasting shortage. The manufacturers of the two FDA-approved drugs, Novo Nordisk and Eli Lilly (tirzepatide, marketed as Zepbound for weight loss and Mounjaro for type 2 diabetes), are struggling to meet the overwhelming need.

To ensure continuation of patient care, federal law allows compounding pharmacies to make “essentially a copy” of the medications that are listed as “currently in shortage” on the US Food and Drug Administration (FDA) drug shortage list. Both semaglutide and tirzepatide are on that list. For Americans who suffer from obesity and other weight-related diseases, these drugs could be a lifeline.

Despite this, the medical community has broadly criticized the utilization of compounded GLP-1 agonists, even those obtained from reputable and legitimate compounding pharmacies.

Yes, high demand has led to the emergence of unregulated companies and scammers producing substandard or counterfeit versions of these medications.

The FDA has found fraudulent products (masquerading as the weight loss drugs) and has issued warning letters to stop the distribution of illegally marketed semaglutide. “These drugs may be counterfeit, which means they could contain the wrong ingredients, contain too little, too much or no active ingredient at all, or contain other harmful ingredients,” it cautions. Some products use a similar-sounding semaglutide sodium salt, which has uncertain safety and efficacy, and had generated warnings from the FDA and state boards of pharmacy.

Many of these products are marketed directly to consumers online through websites and social media, with little to no medical oversight. This practice is a significant concern, as it may affect patient safety, and should be discouraged.

However, according to a statement from the Alliance for Pharmacy Compounding (APC), legitimate compounding pharmacies aren’t the ones selling these dubious products on the black market, particularly online. This illegal practice has garnered media attention and is sometimes incorrectly associated with legitimate pharmacy compounding.

In contrast, legal and certified versions of GLP-1 agonist medications can be obtained from well-regulated and reputable compounding pharmacies. These pharmacies must adhere to all federal and state regulations and dispense medications only with a valid prescription from a licensed physician.

Meanwhile, the APC statement notes, Novo Nordisk and Eli Lilly have sued compounding companies in several states, questioning, among other things, the purity and potency of some compounded products.

There are different designations for compounding pharmacies: 503A and 503B. 503As are state-licensed pharmacies and physicians, and 503B pharmacies are federally regulated outsourcing facilities that are strictly regulated by the FDA. This regulation, established following a 2012 fungal meningitis outbreak linked to a compounding pharmacy, ensures higher-quality control and oversight, especially for medications intended for intravenous or epidural use. These standards exceed those required for subcutaneous injections like GLP-1 analogs.

In the face of this Wild West climate, where compounded drugs may vary in their source, formulation, potency, and purity, The Obesity Society, the Obesity Medical Association, and the Obesity Action Coalition published a joint statement that advised against the use of compounded GLP-1 agonists, citing safety concerns and lack of regulatory oversight.

This stance, while aimed at ensuring patient safety, inadvertently raises a critical issue.

By completely dismissing compounded medications, experts may unintentionally bolster the black market and overlook the needs of patients who could benefit from these medications, contrary to the intentions of the exemption provided in federal law for compounding during a drug shortage. In fact, the presence of unreliable suppliers highlights the need to direct the public toward trustworthy sources, rather than imposing a total ban on medically appropriate alternatives.

The joint statement calls compounded GLP-1 agonists “counterfeit.” This inaccurate overgeneralization probably stems from a misunderstanding of the compounding process and its regulations. Legitimate and regulated pharmacies compound base GLP-1 agonists, which are “essentially a copy” of FDA-approved medications, not counterfeits. Recognizing this is crucial for maintaining trust in both compounding pharmacies and regulatory bodies.

It is correct that “the only FDA-approved manufacturers of these medications are the companies that created the active pharmaceutical ingredients — Novo Nordisk and Eli Lilly,” but the joint statement fails to mention the exemptions provided by law that allow compounding copies of the branded medications if they are on the shortage list.

Compounding pharmacies must obtain active pharmaceutical ingredients (APIs) from FDA-registered facilities, which are required to adhere to Current Good Manufacturing Practices (cGMP). This ensures the APIs’ quality, potency, and purity, crucial for the safety and efficacy of compounded medications.

Compounded drugs are not FDA approved, but they aren’t inherently unsafe. Compounded medications include critical drugs such as resuscitation medications and antibiotics, and are often used in healthcare settings, especially when there’s a shortage. This raises the question of why compounded GLP-1 agonists would be treated any differently in such scenarios.

And in the case of alternative drugs for individuals with obesity who have a higher risk for cardiovascular disease, the brand-name FDA-approved alternative may be of more concern than the compounded GLP-1 agonist. The obesity societies advise: “If you cannot find or get access to a GLP-1-based treatment now, there are other treatments available,” echoing experts. While the statement doesn’t specify the names of the alternatives, experts have advised using alternatives such as Qsymia and Contrave, despite their potential cardiovascular concerns. This recommendation to the public may not represent a responsible risk-benefit analysis.

Courtesy Dr. Einav

Possible Solutions

When prescribing GLP-1 agonists for obesity treatment, doctors should consider all of the following steps to ensure patient safety and effective treatment:

Preference for FDA-approved brands: FDA-approved branded GLP-1 agonist medications should be the primary choice because of their established safety and efficacy.

Risk-benefit analysis for non–FDA-approved products: In cases where FDA-approved options are not available, doctors may consider prescribing a non–FDA-approved copy of the branded medication. Prior to this, conduct a thorough risk-benefit analysis with the patient, ensuring that they are fully informed about the potential risks and benefits of using a non–FDA-approved product.

Choosing semaglutide copies for specific cases: In patients with obesity and cardiovascular disease, the benefits of using a compounded copy of semaglutide, with its cardiovascular disease–modifying properties, may outweigh the risks compared with other FDA-approved antiobesity drugs that might pose cardiovascular risks or compared with no antiobesity treatment at all.

Informed consent and monitoring: When prescribing a non–FDA-approved version of a GLP-1 agonist, obtaining informed consent from the patient is advised. They should be made aware of the differences between the FDA-approved and nonapproved versions.

Choosing between 503A and 503B pharmacies: Prescriptions for non–FDA-approved GLP-1 agonists can be directed to either 503A or 503B compounding pharmacies. However, it’s advisable to check whether the product can be compounded by a 503B pharmacy, which is subject to an additional layer of FDA regulation, offering greater quality assurance.

Clear prescription specifications: Ensure that the prescription explicitly states that the compounded GLP-1 agonist should be the base compound without additives.

Requesting a Certificate of Analysis: To further ensure safety, request a Certificate of Analysis from the compounding pharmacy. This provides detailed quality and composition information about the product.

Ongoing monitoring: Continuously monitor the patient’s response to the medication and adjust the treatment plan as necessary, maintaining regular follow-ups.

By adhering to these guidelines, doctors can navigate the complexities of prescribing GLP-1 agonists in a way that prioritizes patient well-being, particularly in scenarios where conventional treatment options are limited.
 

Dr. Einav is a board-certified cardiologist and a Diplomate of the American Board of Obesity Medicine. He is a fellow of the American College of Cardiology and a member of the Obesity Medicine Association. He serves as the medical director of cardiometabolic health in Guthrie Lourdes in Binghamton, New York, and is the founder of myW8/Cardiometabolic Health located in Beverly Hills, California. This article solely reflects the personal views of Dr. Einav and should not be considered as representing the official stance of Guthrie Lourdes. Dr. Einav served as a promotional speaker for Novo Nordisk in 2022. As of now, he has not prescribed any compounded GLP-1 agonist medications in his medical practice.

A version of this article appeared on Medscape.com.

As a cardiologist specializing in obesity medicine, I often encounter patients who would greatly benefit from the new generation of weight loss drugs that work as glucagon-like peptide 1 (GLP-1) agonists. In the recently published SELECT trial results, for example, semaglutide (marketed by Novo Nordisk as Wegovy for weight loss and Ozempic for type 2 diabetes) demonstrated a 20% risk reduction of heart attacks and strokes in overweight and obese individuals without diabetes and with cardiovascular disease, establishing it as a cardiovascular disease–modifying medication in people without type 2 diabetes.

Unfortunately, the high demand for these new weight loss medications has resulted in a frustrating, long-lasting shortage. The manufacturers of the two FDA-approved drugs, Novo Nordisk and Eli Lilly (tirzepatide, marketed as Zepbound for weight loss and Mounjaro for type 2 diabetes), are struggling to meet the overwhelming need.

To ensure continuation of patient care, federal law allows compounding pharmacies to make “essentially a copy” of the medications that are listed as “currently in shortage” on the US Food and Drug Administration (FDA) drug shortage list. Both semaglutide and tirzepatide are on that list. For Americans who suffer from obesity and other weight-related diseases, these drugs could be a lifeline.

Despite this, the medical community has broadly criticized the utilization of compounded GLP-1 agonists, even those obtained from reputable and legitimate compounding pharmacies.

Yes, high demand has led to the emergence of unregulated companies and scammers producing substandard or counterfeit versions of these medications.

The FDA has found fraudulent products (masquerading as the weight loss drugs) and has issued warning letters to stop the distribution of illegally marketed semaglutide. “These drugs may be counterfeit, which means they could contain the wrong ingredients, contain too little, too much or no active ingredient at all, or contain other harmful ingredients,” it cautions. Some products use a similar-sounding semaglutide sodium salt, which has uncertain safety and efficacy, and had generated warnings from the FDA and state boards of pharmacy.

Many of these products are marketed directly to consumers online through websites and social media, with little to no medical oversight. This practice is a significant concern, as it may affect patient safety, and should be discouraged.

However, according to a statement from the Alliance for Pharmacy Compounding (APC), legitimate compounding pharmacies aren’t the ones selling these dubious products on the black market, particularly online. This illegal practice has garnered media attention and is sometimes incorrectly associated with legitimate pharmacy compounding.

In contrast, legal and certified versions of GLP-1 agonist medications can be obtained from well-regulated and reputable compounding pharmacies. These pharmacies must adhere to all federal and state regulations and dispense medications only with a valid prescription from a licensed physician.

Meanwhile, the APC statement notes, Novo Nordisk and Eli Lilly have sued compounding companies in several states, questioning, among other things, the purity and potency of some compounded products.

There are different designations for compounding pharmacies: 503A and 503B. 503As are state-licensed pharmacies and physicians, and 503B pharmacies are federally regulated outsourcing facilities that are strictly regulated by the FDA. This regulation, established following a 2012 fungal meningitis outbreak linked to a compounding pharmacy, ensures higher-quality control and oversight, especially for medications intended for intravenous or epidural use. These standards exceed those required for subcutaneous injections like GLP-1 analogs.

In the face of this Wild West climate, where compounded drugs may vary in their source, formulation, potency, and purity, The Obesity Society, the Obesity Medical Association, and the Obesity Action Coalition published a joint statement that advised against the use of compounded GLP-1 agonists, citing safety concerns and lack of regulatory oversight.

This stance, while aimed at ensuring patient safety, inadvertently raises a critical issue.

By completely dismissing compounded medications, experts may unintentionally bolster the black market and overlook the needs of patients who could benefit from these medications, contrary to the intentions of the exemption provided in federal law for compounding during a drug shortage. In fact, the presence of unreliable suppliers highlights the need to direct the public toward trustworthy sources, rather than imposing a total ban on medically appropriate alternatives.

The joint statement calls compounded GLP-1 agonists “counterfeit.” This inaccurate overgeneralization probably stems from a misunderstanding of the compounding process and its regulations. Legitimate and regulated pharmacies compound base GLP-1 agonists, which are “essentially a copy” of FDA-approved medications, not counterfeits. Recognizing this is crucial for maintaining trust in both compounding pharmacies and regulatory bodies.

It is correct that “the only FDA-approved manufacturers of these medications are the companies that created the active pharmaceutical ingredients — Novo Nordisk and Eli Lilly,” but the joint statement fails to mention the exemptions provided by law that allow compounding copies of the branded medications if they are on the shortage list.

Compounding pharmacies must obtain active pharmaceutical ingredients (APIs) from FDA-registered facilities, which are required to adhere to Current Good Manufacturing Practices (cGMP). This ensures the APIs’ quality, potency, and purity, crucial for the safety and efficacy of compounded medications.

Compounded drugs are not FDA approved, but they aren’t inherently unsafe. Compounded medications include critical drugs such as resuscitation medications and antibiotics, and are often used in healthcare settings, especially when there’s a shortage. This raises the question of why compounded GLP-1 agonists would be treated any differently in such scenarios.

And in the case of alternative drugs for individuals with obesity who have a higher risk for cardiovascular disease, the brand-name FDA-approved alternative may be of more concern than the compounded GLP-1 agonist. The obesity societies advise: “If you cannot find or get access to a GLP-1-based treatment now, there are other treatments available,” echoing experts. While the statement doesn’t specify the names of the alternatives, experts have advised using alternatives such as Qsymia and Contrave, despite their potential cardiovascular concerns. This recommendation to the public may not represent a responsible risk-benefit analysis.

Courtesy Dr. Einav

Possible Solutions

When prescribing GLP-1 agonists for obesity treatment, doctors should consider all of the following steps to ensure patient safety and effective treatment:

Preference for FDA-approved brands: FDA-approved branded GLP-1 agonist medications should be the primary choice because of their established safety and efficacy.

Risk-benefit analysis for non–FDA-approved products: In cases where FDA-approved options are not available, doctors may consider prescribing a non–FDA-approved copy of the branded medication. Prior to this, conduct a thorough risk-benefit analysis with the patient, ensuring that they are fully informed about the potential risks and benefits of using a non–FDA-approved product.

Choosing semaglutide copies for specific cases: In patients with obesity and cardiovascular disease, the benefits of using a compounded copy of semaglutide, with its cardiovascular disease–modifying properties, may outweigh the risks compared with other FDA-approved antiobesity drugs that might pose cardiovascular risks or compared with no antiobesity treatment at all.

Informed consent and monitoring: When prescribing a non–FDA-approved version of a GLP-1 agonist, obtaining informed consent from the patient is advised. They should be made aware of the differences between the FDA-approved and nonapproved versions.

Choosing between 503A and 503B pharmacies: Prescriptions for non–FDA-approved GLP-1 agonists can be directed to either 503A or 503B compounding pharmacies. However, it’s advisable to check whether the product can be compounded by a 503B pharmacy, which is subject to an additional layer of FDA regulation, offering greater quality assurance.

Clear prescription specifications: Ensure that the prescription explicitly states that the compounded GLP-1 agonist should be the base compound without additives.

Requesting a Certificate of Analysis: To further ensure safety, request a Certificate of Analysis from the compounding pharmacy. This provides detailed quality and composition information about the product.

Ongoing monitoring: Continuously monitor the patient’s response to the medication and adjust the treatment plan as necessary, maintaining regular follow-ups.

By adhering to these guidelines, doctors can navigate the complexities of prescribing GLP-1 agonists in a way that prioritizes patient well-being, particularly in scenarios where conventional treatment options are limited.
 

Dr. Einav is a board-certified cardiologist and a Diplomate of the American Board of Obesity Medicine. He is a fellow of the American College of Cardiology and a member of the Obesity Medicine Association. He serves as the medical director of cardiometabolic health in Guthrie Lourdes in Binghamton, New York, and is the founder of myW8/Cardiometabolic Health located in Beverly Hills, California. This article solely reflects the personal views of Dr. Einav and should not be considered as representing the official stance of Guthrie Lourdes. Dr. Einav served as a promotional speaker for Novo Nordisk in 2022. As of now, he has not prescribed any compounded GLP-1 agonist medications in his medical practice.

A version of this article appeared on Medscape.com.

As a cardiologist specializing in obesity medicine, I often encounter patients who would greatly benefit from the new generation of weight loss drugs that work as glucagon-like peptide 1 (GLP-1) agonists. In the recently published SELECT trial results, for example, semaglutide (marketed by Novo Nordisk as Wegovy for weight loss and Ozempic for type 2 diabetes) demonstrated a 20% risk reduction of heart attacks and strokes in overweight and obese individuals without diabetes and with cardiovascular disease, establishing it as a cardiovascular disease–modifying medication in people without type 2 diabetes.

Unfortunately, the high demand for these new weight loss medications has resulted in a frustrating, long-lasting shortage. The manufacturers of the two FDA-approved drugs, Novo Nordisk and Eli Lilly (tirzepatide, marketed as Zepbound for weight loss and Mounjaro for type 2 diabetes), are struggling to meet the overwhelming need.

To ensure continuation of patient care, federal law allows compounding pharmacies to make “essentially a copy” of the medications that are listed as “currently in shortage” on the US Food and Drug Administration (FDA) drug shortage list. Both semaglutide and tirzepatide are on that list. For Americans who suffer from obesity and other weight-related diseases, these drugs could be a lifeline.

Despite this, the medical community has broadly criticized the utilization of compounded GLP-1 agonists, even those obtained from reputable and legitimate compounding pharmacies.

Yes, high demand has led to the emergence of unregulated companies and scammers producing substandard or counterfeit versions of these medications.

The FDA has found fraudulent products (masquerading as the weight loss drugs) and has issued warning letters to stop the distribution of illegally marketed semaglutide. “These drugs may be counterfeit, which means they could contain the wrong ingredients, contain too little, too much or no active ingredient at all, or contain other harmful ingredients,” it cautions. Some products use a similar-sounding semaglutide sodium salt, which has uncertain safety and efficacy, and had generated warnings from the FDA and state boards of pharmacy.

Many of these products are marketed directly to consumers online through websites and social media, with little to no medical oversight. This practice is a significant concern, as it may affect patient safety, and should be discouraged.

However, according to a statement from the Alliance for Pharmacy Compounding (APC), legitimate compounding pharmacies aren’t the ones selling these dubious products on the black market, particularly online. This illegal practice has garnered media attention and is sometimes incorrectly associated with legitimate pharmacy compounding.

In contrast, legal and certified versions of GLP-1 agonist medications can be obtained from well-regulated and reputable compounding pharmacies. These pharmacies must adhere to all federal and state regulations and dispense medications only with a valid prescription from a licensed physician.

Meanwhile, the APC statement notes, Novo Nordisk and Eli Lilly have sued compounding companies in several states, questioning, among other things, the purity and potency of some compounded products.

There are different designations for compounding pharmacies: 503A and 503B. 503As are state-licensed pharmacies and physicians, and 503B pharmacies are federally regulated outsourcing facilities that are strictly regulated by the FDA. This regulation, established following a 2012 fungal meningitis outbreak linked to a compounding pharmacy, ensures higher-quality control and oversight, especially for medications intended for intravenous or epidural use. These standards exceed those required for subcutaneous injections like GLP-1 analogs.

In the face of this Wild West climate, where compounded drugs may vary in their source, formulation, potency, and purity, The Obesity Society, the Obesity Medical Association, and the Obesity Action Coalition published a joint statement that advised against the use of compounded GLP-1 agonists, citing safety concerns and lack of regulatory oversight.

This stance, while aimed at ensuring patient safety, inadvertently raises a critical issue.

By completely dismissing compounded medications, experts may unintentionally bolster the black market and overlook the needs of patients who could benefit from these medications, contrary to the intentions of the exemption provided in federal law for compounding during a drug shortage. In fact, the presence of unreliable suppliers highlights the need to direct the public toward trustworthy sources, rather than imposing a total ban on medically appropriate alternatives.

The joint statement calls compounded GLP-1 agonists “counterfeit.” This inaccurate overgeneralization probably stems from a misunderstanding of the compounding process and its regulations. Legitimate and regulated pharmacies compound base GLP-1 agonists, which are “essentially a copy” of FDA-approved medications, not counterfeits. Recognizing this is crucial for maintaining trust in both compounding pharmacies and regulatory bodies.

It is correct that “the only FDA-approved manufacturers of these medications are the companies that created the active pharmaceutical ingredients — Novo Nordisk and Eli Lilly,” but the joint statement fails to mention the exemptions provided by law that allow compounding copies of the branded medications if they are on the shortage list.

Compounding pharmacies must obtain active pharmaceutical ingredients (APIs) from FDA-registered facilities, which are required to adhere to Current Good Manufacturing Practices (cGMP). This ensures the APIs’ quality, potency, and purity, crucial for the safety and efficacy of compounded medications.

Compounded drugs are not FDA approved, but they aren’t inherently unsafe. Compounded medications include critical drugs such as resuscitation medications and antibiotics, and are often used in healthcare settings, especially when there’s a shortage. This raises the question of why compounded GLP-1 agonists would be treated any differently in such scenarios.

And in the case of alternative drugs for individuals with obesity who have a higher risk for cardiovascular disease, the brand-name FDA-approved alternative may be of more concern than the compounded GLP-1 agonist. The obesity societies advise: “If you cannot find or get access to a GLP-1-based treatment now, there are other treatments available,” echoing experts. While the statement doesn’t specify the names of the alternatives, experts have advised using alternatives such as Qsymia and Contrave, despite their potential cardiovascular concerns. This recommendation to the public may not represent a responsible risk-benefit analysis.

Courtesy Dr. Einav

Possible Solutions

When prescribing GLP-1 agonists for obesity treatment, doctors should consider all of the following steps to ensure patient safety and effective treatment:

Preference for FDA-approved brands: FDA-approved branded GLP-1 agonist medications should be the primary choice because of their established safety and efficacy.

Risk-benefit analysis for non–FDA-approved products: In cases where FDA-approved options are not available, doctors may consider prescribing a non–FDA-approved copy of the branded medication. Prior to this, conduct a thorough risk-benefit analysis with the patient, ensuring that they are fully informed about the potential risks and benefits of using a non–FDA-approved product.

Choosing semaglutide copies for specific cases: In patients with obesity and cardiovascular disease, the benefits of using a compounded copy of semaglutide, with its cardiovascular disease–modifying properties, may outweigh the risks compared with other FDA-approved antiobesity drugs that might pose cardiovascular risks or compared with no antiobesity treatment at all.

Informed consent and monitoring: When prescribing a non–FDA-approved version of a GLP-1 agonist, obtaining informed consent from the patient is advised. They should be made aware of the differences between the FDA-approved and nonapproved versions.

Choosing between 503A and 503B pharmacies: Prescriptions for non–FDA-approved GLP-1 agonists can be directed to either 503A or 503B compounding pharmacies. However, it’s advisable to check whether the product can be compounded by a 503B pharmacy, which is subject to an additional layer of FDA regulation, offering greater quality assurance.

Clear prescription specifications: Ensure that the prescription explicitly states that the compounded GLP-1 agonist should be the base compound without additives.

Requesting a Certificate of Analysis: To further ensure safety, request a Certificate of Analysis from the compounding pharmacy. This provides detailed quality and composition information about the product.

Ongoing monitoring: Continuously monitor the patient’s response to the medication and adjust the treatment plan as necessary, maintaining regular follow-ups.

By adhering to these guidelines, doctors can navigate the complexities of prescribing GLP-1 agonists in a way that prioritizes patient well-being, particularly in scenarios where conventional treatment options are limited.
 

Dr. Einav is a board-certified cardiologist and a Diplomate of the American Board of Obesity Medicine. He is a fellow of the American College of Cardiology and a member of the Obesity Medicine Association. He serves as the medical director of cardiometabolic health in Guthrie Lourdes in Binghamton, New York, and is the founder of myW8/Cardiometabolic Health located in Beverly Hills, California. This article solely reflects the personal views of Dr. Einav and should not be considered as representing the official stance of Guthrie Lourdes. Dr. Einav served as a promotional speaker for Novo Nordisk in 2022. As of now, he has not prescribed any compounded GLP-1 agonist medications in his medical practice.

A version of this article appeared on Medscape.com.

Two classes of chemicals present in common household products may impair the development of oligodendrocytes, the myelinating cells of the central nervous system (CNS), which are critical to brain development and function. However, the researchers as well as outside experts agree more research is needed before any firm conclusions can be drawn. 

Quaternary ammonium compounds, ubiquitous in disinfecting agents and personal care products, and organophosphate flame retardants, which are commonly found in household items such as furniture and electronics had “surprising effects specifically on the non-nerve cells in the brain,” said lead researcher Paul Tesar, PhD, professor and director of the Institute for Glial Sciences, Case Western Reserve University School of Medicine, Cleveland. 

“Other studies have shown that our exposures to the chemicals in disinfecting agents nearly doubled during the pandemic,” Dr. Tesar noted. The finding that quaternary ammonium chemicals in disinfecting agents are harmful to specific brain cells suggests “we need to think about our increased utilization and exposure,” he added.

The results were published online on March 25 in Nature Neuroscience. 
 

Motor Dysfunction

Exposure to various chemicals in the environment has been shown to impair brain development. However, most of this research has focused on neurons. Less is known about effects on oligodendrocytes, which form the electrical insulation around the axons of CNS cells. Oligodendrocyte development continues from before birth into adulthood, thus these cells may be particularly vulnerable to damage from toxic chemicals.

The researchers analyzed the effects of 1823 chemicals on mouse oligodendrocyte development in cell cultures. They identified 292 chemicals that cause oligodendrocytes to die and 47 that inhibit oligodendrocyte generation. These chemicals belonged to two different classes.

They found that quaternary compounds were potently and selectively cytotoxic to developing oligodendrocytes and that organophosphate flame retardants prematurely arrested oligodendrocyte maturation. These effects were confirmed in mice and cultured human oligodendrocytes.

In addition, an analysis of epidemiologic data from the National Health and Nutrition Examination Survey (2013-2018) showed that one flame retardant metabolite, bis(1,3-dichloro-2-propy) phosphate (BDCIPP), was present in nearly all urine samples of children aged 3-11 years who were examined (1753 out of 1763 children).

After adjustment for multiple confounding factors, results showed that compared with children with urinary BDCIPP concentration in the lowest quartile, those with concentrations in the highest quartile were twice as likely to require special education (adjusted odds ratio [aOR], 2.0; 95% CI, 1.0-3.8) and were six times as likely to have gross motor dysfunction (aOR, 6.0; 95% CI, 1.7-21.9).

Children with urinary BDCIPP concentration within the third quartile also had significantly increased odds of motor dysfunction (aOR, 4.2; 95% CI, 1.1-16.2). 

“These results suggest that the identified chemicals are potentially hazardous to human health. However, we want to be clear that more studies are needed to make definitive connections between chemical exposure and human disease,” said Dr. Tesar.

“Future studies will need to deepen our understanding of the duration and timing of exposure required to initiate or exacerbate disease. This information is needed before specific recommendations, such as behavioral interventions, can be made to reduce exposure. Some of these chemicals have useful roles in our homes, but we need to consider how they’re being used and what level of exposure might be considered safe,” Dr. Tesar said. 

In his view, the results “provide a starting point to understand what exposure levels to these chemicals might be putting ourselves or kids at risk for toxicity.”
 

Too Soon to Tell

Commenting for this news organization, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, who was not involved in the study, echoed the need for more research. 

“The biological mechanisms uncovered provide plausible pathways by which these chemicals could potentially impact human brain development related to oligodendrocytes and myelination. Oligodendrocytes play a critical role in plastic neurological processes throughout life, not just early neurodevelopment. So, disrupting their maturation and function theoretically could contribute to neurodevelopmental disorders as well as adult conditions like multiple sclerosis,” Dr. Lakhan said. 

“This study alone shouldn’t sound neurotoxicant alarms yet. We’ve seen many past chemical scares like saccharin and phthalates fizzle despite alarming lab results when real-world human brain impacts failed to materialize,” Dr. Lakhan cautioned. 

“Far more rigorous research directly linking household chemical exposures to cognitive deficits in people is still needed before drawing firm conclusions or prompting overreactions from the general public. Policymakers will eventually need to weigh potential risks vs benefits, but no definitive human health threat has currently been established,” Dr. Lakhan said. 

Sarah Evans, PhD, MPH, assistant professor in the Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai in New York, also emphasized the need for further study.

“Given that most of the experiments in this study were conducted in isolated cells and a mouse model, further research is needed to determine whether exposure to these chemicals at levels experienced by the general population during critical windows of development impairs myelination and leads to adverse health outcomes like learning and behavior problems in humans,” said Dr. Evans, who was involved in the study.

“The authors’ finding of an association between higher urinary levels of the organophosphate flame-retardant metabolite BDCIPP and gross motor problems or need for special education in children aged 3-11 years in the CDC National Health and Nutrition Examination Survey strengthens their laboratory findings and warrants further investigation,” Dr. Evans added. 

The research was supported by grants from the National Institutes of Health, National Multiple Sclerosis Society, Howard Hughes Medical Institute and New York Stem Cell Foundation, and philanthropic support by sTF5 Care and the Long, Walter, Peterson, Goodman, and Geller families. Dr. Tesar, Dr. Lakhan, and Dr. Evans report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

Two classes of chemicals present in common household products may impair the development of oligodendrocytes, the myelinating cells of the central nervous system (CNS), which are critical to brain development and function. However, the researchers as well as outside experts agree more research is needed before any firm conclusions can be drawn. 

Quaternary ammonium compounds, ubiquitous in disinfecting agents and personal care products, and organophosphate flame retardants, which are commonly found in household items such as furniture and electronics had “surprising effects specifically on the non-nerve cells in the brain,” said lead researcher Paul Tesar, PhD, professor and director of the Institute for Glial Sciences, Case Western Reserve University School of Medicine, Cleveland. 

“Other studies have shown that our exposures to the chemicals in disinfecting agents nearly doubled during the pandemic,” Dr. Tesar noted. The finding that quaternary ammonium chemicals in disinfecting agents are harmful to specific brain cells suggests “we need to think about our increased utilization and exposure,” he added.

The results were published online on March 25 in Nature Neuroscience. 
 

Motor Dysfunction

Exposure to various chemicals in the environment has been shown to impair brain development. However, most of this research has focused on neurons. Less is known about effects on oligodendrocytes, which form the electrical insulation around the axons of CNS cells. Oligodendrocyte development continues from before birth into adulthood, thus these cells may be particularly vulnerable to damage from toxic chemicals.

The researchers analyzed the effects of 1823 chemicals on mouse oligodendrocyte development in cell cultures. They identified 292 chemicals that cause oligodendrocytes to die and 47 that inhibit oligodendrocyte generation. These chemicals belonged to two different classes.

They found that quaternary compounds were potently and selectively cytotoxic to developing oligodendrocytes and that organophosphate flame retardants prematurely arrested oligodendrocyte maturation. These effects were confirmed in mice and cultured human oligodendrocytes.

In addition, an analysis of epidemiologic data from the National Health and Nutrition Examination Survey (2013-2018) showed that one flame retardant metabolite, bis(1,3-dichloro-2-propy) phosphate (BDCIPP), was present in nearly all urine samples of children aged 3-11 years who were examined (1753 out of 1763 children).

After adjustment for multiple confounding factors, results showed that compared with children with urinary BDCIPP concentration in the lowest quartile, those with concentrations in the highest quartile were twice as likely to require special education (adjusted odds ratio [aOR], 2.0; 95% CI, 1.0-3.8) and were six times as likely to have gross motor dysfunction (aOR, 6.0; 95% CI, 1.7-21.9).

Children with urinary BDCIPP concentration within the third quartile also had significantly increased odds of motor dysfunction (aOR, 4.2; 95% CI, 1.1-16.2). 

“These results suggest that the identified chemicals are potentially hazardous to human health. However, we want to be clear that more studies are needed to make definitive connections between chemical exposure and human disease,” said Dr. Tesar.

“Future studies will need to deepen our understanding of the duration and timing of exposure required to initiate or exacerbate disease. This information is needed before specific recommendations, such as behavioral interventions, can be made to reduce exposure. Some of these chemicals have useful roles in our homes, but we need to consider how they’re being used and what level of exposure might be considered safe,” Dr. Tesar said. 

In his view, the results “provide a starting point to understand what exposure levels to these chemicals might be putting ourselves or kids at risk for toxicity.”
 

Too Soon to Tell

Commenting for this news organization, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, who was not involved in the study, echoed the need for more research. 

“The biological mechanisms uncovered provide plausible pathways by which these chemicals could potentially impact human brain development related to oligodendrocytes and myelination. Oligodendrocytes play a critical role in plastic neurological processes throughout life, not just early neurodevelopment. So, disrupting their maturation and function theoretically could contribute to neurodevelopmental disorders as well as adult conditions like multiple sclerosis,” Dr. Lakhan said. 

“This study alone shouldn’t sound neurotoxicant alarms yet. We’ve seen many past chemical scares like saccharin and phthalates fizzle despite alarming lab results when real-world human brain impacts failed to materialize,” Dr. Lakhan cautioned. 

“Far more rigorous research directly linking household chemical exposures to cognitive deficits in people is still needed before drawing firm conclusions or prompting overreactions from the general public. Policymakers will eventually need to weigh potential risks vs benefits, but no definitive human health threat has currently been established,” Dr. Lakhan said. 

Sarah Evans, PhD, MPH, assistant professor in the Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai in New York, also emphasized the need for further study.

“Given that most of the experiments in this study were conducted in isolated cells and a mouse model, further research is needed to determine whether exposure to these chemicals at levels experienced by the general population during critical windows of development impairs myelination and leads to adverse health outcomes like learning and behavior problems in humans,” said Dr. Evans, who was involved in the study.

“The authors’ finding of an association between higher urinary levels of the organophosphate flame-retardant metabolite BDCIPP and gross motor problems or need for special education in children aged 3-11 years in the CDC National Health and Nutrition Examination Survey strengthens their laboratory findings and warrants further investigation,” Dr. Evans added. 

The research was supported by grants from the National Institutes of Health, National Multiple Sclerosis Society, Howard Hughes Medical Institute and New York Stem Cell Foundation, and philanthropic support by sTF5 Care and the Long, Walter, Peterson, Goodman, and Geller families. Dr. Tesar, Dr. Lakhan, and Dr. Evans report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

Two classes of chemicals present in common household products may impair the development of oligodendrocytes, the myelinating cells of the central nervous system (CNS), which are critical to brain development and function. However, the researchers as well as outside experts agree more research is needed before any firm conclusions can be drawn. 

Quaternary ammonium compounds, ubiquitous in disinfecting agents and personal care products, and organophosphate flame retardants, which are commonly found in household items such as furniture and electronics had “surprising effects specifically on the non-nerve cells in the brain,” said lead researcher Paul Tesar, PhD, professor and director of the Institute for Glial Sciences, Case Western Reserve University School of Medicine, Cleveland. 

“Other studies have shown that our exposures to the chemicals in disinfecting agents nearly doubled during the pandemic,” Dr. Tesar noted. The finding that quaternary ammonium chemicals in disinfecting agents are harmful to specific brain cells suggests “we need to think about our increased utilization and exposure,” he added.

The results were published online on March 25 in Nature Neuroscience. 
 

Motor Dysfunction

Exposure to various chemicals in the environment has been shown to impair brain development. However, most of this research has focused on neurons. Less is known about effects on oligodendrocytes, which form the electrical insulation around the axons of CNS cells. Oligodendrocyte development continues from before birth into adulthood, thus these cells may be particularly vulnerable to damage from toxic chemicals.

The researchers analyzed the effects of 1823 chemicals on mouse oligodendrocyte development in cell cultures. They identified 292 chemicals that cause oligodendrocytes to die and 47 that inhibit oligodendrocyte generation. These chemicals belonged to two different classes.

They found that quaternary compounds were potently and selectively cytotoxic to developing oligodendrocytes and that organophosphate flame retardants prematurely arrested oligodendrocyte maturation. These effects were confirmed in mice and cultured human oligodendrocytes.

In addition, an analysis of epidemiologic data from the National Health and Nutrition Examination Survey (2013-2018) showed that one flame retardant metabolite, bis(1,3-dichloro-2-propy) phosphate (BDCIPP), was present in nearly all urine samples of children aged 3-11 years who were examined (1753 out of 1763 children).

After adjustment for multiple confounding factors, results showed that compared with children with urinary BDCIPP concentration in the lowest quartile, those with concentrations in the highest quartile were twice as likely to require special education (adjusted odds ratio [aOR], 2.0; 95% CI, 1.0-3.8) and were six times as likely to have gross motor dysfunction (aOR, 6.0; 95% CI, 1.7-21.9).

Children with urinary BDCIPP concentration within the third quartile also had significantly increased odds of motor dysfunction (aOR, 4.2; 95% CI, 1.1-16.2). 

“These results suggest that the identified chemicals are potentially hazardous to human health. However, we want to be clear that more studies are needed to make definitive connections between chemical exposure and human disease,” said Dr. Tesar.

“Future studies will need to deepen our understanding of the duration and timing of exposure required to initiate or exacerbate disease. This information is needed before specific recommendations, such as behavioral interventions, can be made to reduce exposure. Some of these chemicals have useful roles in our homes, but we need to consider how they’re being used and what level of exposure might be considered safe,” Dr. Tesar said. 

In his view, the results “provide a starting point to understand what exposure levels to these chemicals might be putting ourselves or kids at risk for toxicity.”
 

Too Soon to Tell

Commenting for this news organization, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, who was not involved in the study, echoed the need for more research. 

“The biological mechanisms uncovered provide plausible pathways by which these chemicals could potentially impact human brain development related to oligodendrocytes and myelination. Oligodendrocytes play a critical role in plastic neurological processes throughout life, not just early neurodevelopment. So, disrupting their maturation and function theoretically could contribute to neurodevelopmental disorders as well as adult conditions like multiple sclerosis,” Dr. Lakhan said. 

“This study alone shouldn’t sound neurotoxicant alarms yet. We’ve seen many past chemical scares like saccharin and phthalates fizzle despite alarming lab results when real-world human brain impacts failed to materialize,” Dr. Lakhan cautioned. 

“Far more rigorous research directly linking household chemical exposures to cognitive deficits in people is still needed before drawing firm conclusions or prompting overreactions from the general public. Policymakers will eventually need to weigh potential risks vs benefits, but no definitive human health threat has currently been established,” Dr. Lakhan said. 

Sarah Evans, PhD, MPH, assistant professor in the Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai in New York, also emphasized the need for further study.

“Given that most of the experiments in this study were conducted in isolated cells and a mouse model, further research is needed to determine whether exposure to these chemicals at levels experienced by the general population during critical windows of development impairs myelination and leads to adverse health outcomes like learning and behavior problems in humans,” said Dr. Evans, who was involved in the study.

“The authors’ finding of an association between higher urinary levels of the organophosphate flame-retardant metabolite BDCIPP and gross motor problems or need for special education in children aged 3-11 years in the CDC National Health and Nutrition Examination Survey strengthens their laboratory findings and warrants further investigation,” Dr. Evans added. 

The research was supported by grants from the National Institutes of Health, National Multiple Sclerosis Society, Howard Hughes Medical Institute and New York Stem Cell Foundation, and philanthropic support by sTF5 Care and the Long, Walter, Peterson, Goodman, and Geller families. Dr. Tesar, Dr. Lakhan, and Dr. Evans report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

Regeneron Pharmaceuticals said in an interview that it may be the first company to have an accelerated approval application for its cancer drug rebuffed by the US Food and Drug Administration (FDA) due to concerns about the timing of completion of confirmatory research.

The company once had hoped to win this US clearance for odronextamab in relapsed/refractory (R/R) follicular lymphoma (FL) and in R/R diffuse large B-cell lymphoma (DLBCL) by March 31. Last year when Regeneron announced the FDA’s decision to grant priority review for odronextamab, the firm said that the end of this month was the US regulators’ target decision date.

But on March 25, Regeneron said the FDA issued two complete response letters (CRLs) in connection with odronextamab application. It will not approve the experimental medicine at this time.

In the release, Regeneron said the only approvability issue is related to the enrollment status of the confirmatory trials. The letters did not identify issues with the odronextamab clinical efficacy or safety, trial design, labeling, or manufacturing.

“While we acknowledge the general concerns that FDA has about sponsors failing to complete their postmarketing confirmatory trials, the relevant laws and regulatory guidances do not lay out rigid criteria for assessing whether the progress on a confirmatory trial is adequate to allow for an accelerated approval,” Tammy Allen, Regeneron’s director for product and pipeline communications, said in an email. “ And to our knowledge, this is the first time the FDA has issued a CRL for this reason.”

There has been rising concern in recent years about the gap between initial accelerated approvals for medicines and the completion of studies that show whether these promising therapies actually help patients live longer or better. Thus, a serious knowledge gap arises, often for many years, while patients and physicians use drugs with as yet unproven benefit. Recent studies highlighting this knowledge gap include work from Harvard’s Program on Regulation, Therapeutics, and Law (PORTAL) group and researchers at the University of Pennsylvania.

While Congress has long sought to speed approvals of new drugs, in 2022 lawmakers gave the FDA more clout for efforts to shorten the period of uncertainty between accelerated and traditional approval. Congress added a provision to a large spending package that said the federal government could require a study or studies to be underway prior to approval, or within a specified time period after the date of approval, of the applicable product.

“As this is new territory for us and for industry, we’re committed to working closely with them to address and plan on sharing updates on enrollment and regulatory timelines later this year,” Ms. Allen said.

The FDA generally does not comment on applications under review. In response to a question about Regeneron’s statements, an FDA spokeswoman pointed out by email that the 2022 law had made clear how the agency can decline approval if confirmatory clinical trials are not considered underway prior to approval.

Odronextamab is potentially part of a rapidly advancing field of lymphoma treatments, which include autologous chimeric antigen receptor (CAR T-cell) therapy in certain settings. There are severe constraints, though, on CAR-T therapy, including manufacturing delays and treatment-related toxicities. Odronextamab is part of what are called “off-the-shelf” drugs with the same aim as CAR-T. The bispecific antibodies (BsAb) are meant to teach the immune system to fight cancer.

Regeneron said it has been actively enrolling patients in multiple phase 3 trials for odronextamab as part of its OLYMPIA program. The company said this is intended to change the treatment paradigm of several B-cell non-Hodgkin lymphoma subtypes, including in earlier lines of therapy.

Enrollment in the dose-finding portion has begun, but the CRLs indicate that the confirmatory portions of these trials should be underway and that the timelines to completion should be agreed on prior to resubmission, Regeneron said. The company added that it is working closely with the FDA and investigators to bring odronextamab to patients with R/R FL and R/R DLBCL as quickly as possible. The company plans to share updates on enrollment and regulatory timelines later this year.

Regeneron Pharmaceuticals said in an interview that it may be the first company to have an accelerated approval application for its cancer drug rebuffed by the US Food and Drug Administration (FDA) due to concerns about the timing of completion of confirmatory research.

The company once had hoped to win this US clearance for odronextamab in relapsed/refractory (R/R) follicular lymphoma (FL) and in R/R diffuse large B-cell lymphoma (DLBCL) by March 31. Last year when Regeneron announced the FDA’s decision to grant priority review for odronextamab, the firm said that the end of this month was the US regulators’ target decision date.

But on March 25, Regeneron said the FDA issued two complete response letters (CRLs) in connection with odronextamab application. It will not approve the experimental medicine at this time.

In the release, Regeneron said the only approvability issue is related to the enrollment status of the confirmatory trials. The letters did not identify issues with the odronextamab clinical efficacy or safety, trial design, labeling, or manufacturing.

“While we acknowledge the general concerns that FDA has about sponsors failing to complete their postmarketing confirmatory trials, the relevant laws and regulatory guidances do not lay out rigid criteria for assessing whether the progress on a confirmatory trial is adequate to allow for an accelerated approval,” Tammy Allen, Regeneron’s director for product and pipeline communications, said in an email. “ And to our knowledge, this is the first time the FDA has issued a CRL for this reason.”

There has been rising concern in recent years about the gap between initial accelerated approvals for medicines and the completion of studies that show whether these promising therapies actually help patients live longer or better. Thus, a serious knowledge gap arises, often for many years, while patients and physicians use drugs with as yet unproven benefit. Recent studies highlighting this knowledge gap include work from Harvard’s Program on Regulation, Therapeutics, and Law (PORTAL) group and researchers at the University of Pennsylvania.

While Congress has long sought to speed approvals of new drugs, in 2022 lawmakers gave the FDA more clout for efforts to shorten the period of uncertainty between accelerated and traditional approval. Congress added a provision to a large spending package that said the federal government could require a study or studies to be underway prior to approval, or within a specified time period after the date of approval, of the applicable product.

“As this is new territory for us and for industry, we’re committed to working closely with them to address and plan on sharing updates on enrollment and regulatory timelines later this year,” Ms. Allen said.

The FDA generally does not comment on applications under review. In response to a question about Regeneron’s statements, an FDA spokeswoman pointed out by email that the 2022 law had made clear how the agency can decline approval if confirmatory clinical trials are not considered underway prior to approval.

Odronextamab is potentially part of a rapidly advancing field of lymphoma treatments, which include autologous chimeric antigen receptor (CAR T-cell) therapy in certain settings. There are severe constraints, though, on CAR-T therapy, including manufacturing delays and treatment-related toxicities. Odronextamab is part of what are called “off-the-shelf” drugs with the same aim as CAR-T. The bispecific antibodies (BsAb) are meant to teach the immune system to fight cancer.

Regeneron said it has been actively enrolling patients in multiple phase 3 trials for odronextamab as part of its OLYMPIA program. The company said this is intended to change the treatment paradigm of several B-cell non-Hodgkin lymphoma subtypes, including in earlier lines of therapy.

Enrollment in the dose-finding portion has begun, but the CRLs indicate that the confirmatory portions of these trials should be underway and that the timelines to completion should be agreed on prior to resubmission, Regeneron said. The company added that it is working closely with the FDA and investigators to bring odronextamab to patients with R/R FL and R/R DLBCL as quickly as possible. The company plans to share updates on enrollment and regulatory timelines later this year.

Regeneron Pharmaceuticals said in an interview that it may be the first company to have an accelerated approval application for its cancer drug rebuffed by the US Food and Drug Administration (FDA) due to concerns about the timing of completion of confirmatory research.

The company once had hoped to win this US clearance for odronextamab in relapsed/refractory (R/R) follicular lymphoma (FL) and in R/R diffuse large B-cell lymphoma (DLBCL) by March 31. Last year when Regeneron announced the FDA’s decision to grant priority review for odronextamab, the firm said that the end of this month was the US regulators’ target decision date.

But on March 25, Regeneron said the FDA issued two complete response letters (CRLs) in connection with odronextamab application. It will not approve the experimental medicine at this time.

In the release, Regeneron said the only approvability issue is related to the enrollment status of the confirmatory trials. The letters did not identify issues with the odronextamab clinical efficacy or safety, trial design, labeling, or manufacturing.

“While we acknowledge the general concerns that FDA has about sponsors failing to complete their postmarketing confirmatory trials, the relevant laws and regulatory guidances do not lay out rigid criteria for assessing whether the progress on a confirmatory trial is adequate to allow for an accelerated approval,” Tammy Allen, Regeneron’s director for product and pipeline communications, said in an email. “ And to our knowledge, this is the first time the FDA has issued a CRL for this reason.”

There has been rising concern in recent years about the gap between initial accelerated approvals for medicines and the completion of studies that show whether these promising therapies actually help patients live longer or better. Thus, a serious knowledge gap arises, often for many years, while patients and physicians use drugs with as yet unproven benefit. Recent studies highlighting this knowledge gap include work from Harvard’s Program on Regulation, Therapeutics, and Law (PORTAL) group and researchers at the University of Pennsylvania.

While Congress has long sought to speed approvals of new drugs, in 2022 lawmakers gave the FDA more clout for efforts to shorten the period of uncertainty between accelerated and traditional approval. Congress added a provision to a large spending package that said the federal government could require a study or studies to be underway prior to approval, or within a specified time period after the date of approval, of the applicable product.

“As this is new territory for us and for industry, we’re committed to working closely with them to address and plan on sharing updates on enrollment and regulatory timelines later this year,” Ms. Allen said.

The FDA generally does not comment on applications under review. In response to a question about Regeneron’s statements, an FDA spokeswoman pointed out by email that the 2022 law had made clear how the agency can decline approval if confirmatory clinical trials are not considered underway prior to approval.

Odronextamab is potentially part of a rapidly advancing field of lymphoma treatments, which include autologous chimeric antigen receptor (CAR T-cell) therapy in certain settings. There are severe constraints, though, on CAR-T therapy, including manufacturing delays and treatment-related toxicities. Odronextamab is part of what are called “off-the-shelf” drugs with the same aim as CAR-T. The bispecific antibodies (BsAb) are meant to teach the immune system to fight cancer.

Regeneron said it has been actively enrolling patients in multiple phase 3 trials for odronextamab as part of its OLYMPIA program. The company said this is intended to change the treatment paradigm of several B-cell non-Hodgkin lymphoma subtypes, including in earlier lines of therapy.

Enrollment in the dose-finding portion has begun, but the CRLs indicate that the confirmatory portions of these trials should be underway and that the timelines to completion should be agreed on prior to resubmission, Regeneron said. The company added that it is working closely with the FDA and investigators to bring odronextamab to patients with R/R FL and R/R DLBCL as quickly as possible. The company plans to share updates on enrollment and regulatory timelines later this year.

Blood-based screening for colorectal cancer (CRC), also known as a “liquid biopsy,” may be better than nothing among patients who skip established screening tests, but it can’t replace colonoscopy as the gold standard, according to two new modeling studies and an expert consensus commentary.

Although some patients find blood-based tests more convenient, the higher numbers of false positives and false negatives could lead to more CRC cases and deaths.

“Based on their current characteristics, blood tests should not be recommended to replace established colorectal cancer screening tests, since blood tests are neither as effective nor cost-effective and would worsen outcomes,” David Lieberman, MD, AGAF, chair of the American Gastroenterological Association’s CRC Workshop Panel, and lead author of the expert commentary, said in a statement.

AGA Institute

The blood tests detect circulating nucleotides, such as cell-free DNA or metabolic products associated with CRC and its precursors. Current tests are in development by Guardant Health and Freenome.

The two modeling studies, published in Gastroenterology on March 26, analyzed the effectiveness and cost-effectiveness of blood-based CRC screening that meets Centers for Medicare & Medicaid Services (CMS) coverage criteria, as well as the comparative effectiveness and cost-effectiveness of CRC screening with blood-based biomarkers versus fecal tests or colonoscopy.

Also published on March 26 in Clinical Gastroenterology and Hepatology, the expert commentary included key conclusions from the AGA CRC Workshop, which analyzed the two modeling studies.
 

Comparing CRC Screening Methods

In the first modeling study, an international team of researchers ran three microsimulation models for CRC to estimate the effectiveness and cost-effectiveness of triennial blood-based screening for ages 45-75, compared with no screening, annual fecal immunochemical testing (FIT), triennial stool DNA testing combined with a FIT assay, and colonoscopy screening every 10 years. The researchers used CMS coverage criteria for blood tests, with a sensitivity of at least 74% for detection of CRC and specificity of at least 90%.

Without screening, the models predicted between 77 and 88 CRC cases and between 32 and 36 deaths per 1,000 individuals, costing between $5.3 million to $5.8 million. Compared with no screening, blood-based screening was considered cost-effective, with an additional cost of $25,600 to $43,700 per quality-adjusted life-year gained (QALYG).

However, compared with the FIT, stool, and colonoscopy options, blood-based screening was not cost-effective, with both a decrease in QALYG and an increase in costs. FIT was more effective and less costly, with 5-24 QALYG and nearly $3.5 million cheaper than blood-based screening, even when blood-based uptake was 20 percentage points higher than FIT uptake.

In the second modeling study, US researchers compared triennial blood-based screening with established alternatives at the CMS thresholds of 74% sensitivity and 90% specificity.

Overall, a blood-based test at the CMS minimum reduced CRC incidence by 40% and CRC mortality by 52% versus no screening. However, a blood-based test was significantly less effective than triennial stool DNA testing, annual FIT, and colonoscopy every 10 years, which reduced CRC incidence by 68%-79% and CRC mortality by 73%-81%.

Assuming a blood-based test would cost the same as a multi-target stool test, the blood-based test would cost $28,500 per QALYG versus no screening. At the same time, FIT, colonoscopy, and stool DNA testing were less costly and more effective. In general, the blood-based test would match FIT’s clinical outcomes if it achieved 1.4- to 1.8-fold the participation rate for FIT.

Even still, the sensitivity for advanced precancerous lesion (APL) was a key determinant. A paradigm-changing blood-based test would need to have higher than 90% sensitivity for CRC and 80% for APL, 90% specificity, and cost less than $120 to $140, the study authors wrote.

“High APL sensitivity, which can result in CRC prevention, should be a top priority for screening test developers,” the authors wrote. “APL detection should not be penalized by a definition of test specificity that focuses on CRC only.”
 

Additional Considerations

The AGA CRC Workshop Panel met in September 2023 to review the two modeling studies and other data on blood-based tests for CRC. Overall, the group concluded that a triennial blood test that meets minimal CMS criteria would likely result in better outcomes than no screening and provide a simple process to encourage more people to participate in screening.

However, patients who may have declined colonoscopy should understand the need for a colonoscopy if blood-based tests show abnormal results, the commentary authors wrote.

In addition, because blood-based tests for CRC appear to be less effective and more costly than current screening options, they shouldn’t be recommended to replace established screening methods. Although these blood-based tests may improve screening rates and outcomes in unscreened people, substituting blood tests for other effective tests would increase costs and worsen patient outcomes.

Beyond that, they wrote, the industry should consider other potential benchmarks for an effective blood test, such as a sensitivity for stage I-III CRC of greater than 90% and sensitivity for advanced adenomas of 40%-50% or higher.

University of California San Diego

“Unless we have the expectation of high sensitivity and specificity, blood-based colorectal cancer tests could lead to false positive and false negative results, which are both bad for patient outcomes,” John M. Carethers, MD, AGAF, vice chancellor for health sciences at UC San Diego, AGA past president, and a member of the AGA CRC Workshop panel, said in a statement.

Several authors reported consultant roles and funding support from numerous companies, including Guardant Health and Freenome.

Blood-based screening for colorectal cancer (CRC), also known as a “liquid biopsy,” may be better than nothing among patients who skip established screening tests, but it can’t replace colonoscopy as the gold standard, according to two new modeling studies and an expert consensus commentary.

Although some patients find blood-based tests more convenient, the higher numbers of false positives and false negatives could lead to more CRC cases and deaths.

“Based on their current characteristics, blood tests should not be recommended to replace established colorectal cancer screening tests, since blood tests are neither as effective nor cost-effective and would worsen outcomes,” David Lieberman, MD, AGAF, chair of the American Gastroenterological Association’s CRC Workshop Panel, and lead author of the expert commentary, said in a statement.

AGA Institute

The blood tests detect circulating nucleotides, such as cell-free DNA or metabolic products associated with CRC and its precursors. Current tests are in development by Guardant Health and Freenome.

The two modeling studies, published in Gastroenterology on March 26, analyzed the effectiveness and cost-effectiveness of blood-based CRC screening that meets Centers for Medicare & Medicaid Services (CMS) coverage criteria, as well as the comparative effectiveness and cost-effectiveness of CRC screening with blood-based biomarkers versus fecal tests or colonoscopy.

Also published on March 26 in Clinical Gastroenterology and Hepatology, the expert commentary included key conclusions from the AGA CRC Workshop, which analyzed the two modeling studies.
 

Comparing CRC Screening Methods

In the first modeling study, an international team of researchers ran three microsimulation models for CRC to estimate the effectiveness and cost-effectiveness of triennial blood-based screening for ages 45-75, compared with no screening, annual fecal immunochemical testing (FIT), triennial stool DNA testing combined with a FIT assay, and colonoscopy screening every 10 years. The researchers used CMS coverage criteria for blood tests, with a sensitivity of at least 74% for detection of CRC and specificity of at least 90%.

Without screening, the models predicted between 77 and 88 CRC cases and between 32 and 36 deaths per 1,000 individuals, costing between $5.3 million to $5.8 million. Compared with no screening, blood-based screening was considered cost-effective, with an additional cost of $25,600 to $43,700 per quality-adjusted life-year gained (QALYG).

However, compared with the FIT, stool, and colonoscopy options, blood-based screening was not cost-effective, with both a decrease in QALYG and an increase in costs. FIT was more effective and less costly, with 5-24 QALYG and nearly $3.5 million cheaper than blood-based screening, even when blood-based uptake was 20 percentage points higher than FIT uptake.

In the second modeling study, US researchers compared triennial blood-based screening with established alternatives at the CMS thresholds of 74% sensitivity and 90% specificity.

Overall, a blood-based test at the CMS minimum reduced CRC incidence by 40% and CRC mortality by 52% versus no screening. However, a blood-based test was significantly less effective than triennial stool DNA testing, annual FIT, and colonoscopy every 10 years, which reduced CRC incidence by 68%-79% and CRC mortality by 73%-81%.

Assuming a blood-based test would cost the same as a multi-target stool test, the blood-based test would cost $28,500 per QALYG versus no screening. At the same time, FIT, colonoscopy, and stool DNA testing were less costly and more effective. In general, the blood-based test would match FIT’s clinical outcomes if it achieved 1.4- to 1.8-fold the participation rate for FIT.

Even still, the sensitivity for advanced precancerous lesion (APL) was a key determinant. A paradigm-changing blood-based test would need to have higher than 90% sensitivity for CRC and 80% for APL, 90% specificity, and cost less than $120 to $140, the study authors wrote.

“High APL sensitivity, which can result in CRC prevention, should be a top priority for screening test developers,” the authors wrote. “APL detection should not be penalized by a definition of test specificity that focuses on CRC only.”
 

Additional Considerations

The AGA CRC Workshop Panel met in September 2023 to review the two modeling studies and other data on blood-based tests for CRC. Overall, the group concluded that a triennial blood test that meets minimal CMS criteria would likely result in better outcomes than no screening and provide a simple process to encourage more people to participate in screening.

However, patients who may have declined colonoscopy should understand the need for a colonoscopy if blood-based tests show abnormal results, the commentary authors wrote.

In addition, because blood-based tests for CRC appear to be less effective and more costly than current screening options, they shouldn’t be recommended to replace established screening methods. Although these blood-based tests may improve screening rates and outcomes in unscreened people, substituting blood tests for other effective tests would increase costs and worsen patient outcomes.

Beyond that, they wrote, the industry should consider other potential benchmarks for an effective blood test, such as a sensitivity for stage I-III CRC of greater than 90% and sensitivity for advanced adenomas of 40%-50% or higher.

University of California San Diego

“Unless we have the expectation of high sensitivity and specificity, blood-based colorectal cancer tests could lead to false positive and false negative results, which are both bad for patient outcomes,” John M. Carethers, MD, AGAF, vice chancellor for health sciences at UC San Diego, AGA past president, and a member of the AGA CRC Workshop panel, said in a statement.

Several authors reported consultant roles and funding support from numerous companies, including Guardant Health and Freenome.

Blood-based screening for colorectal cancer (CRC), also known as a “liquid biopsy,” may be better than nothing among patients who skip established screening tests, but it can’t replace colonoscopy as the gold standard, according to two new modeling studies and an expert consensus commentary.

Although some patients find blood-based tests more convenient, the higher numbers of false positives and false negatives could lead to more CRC cases and deaths.

“Based on their current characteristics, blood tests should not be recommended to replace established colorectal cancer screening tests, since blood tests are neither as effective nor cost-effective and would worsen outcomes,” David Lieberman, MD, AGAF, chair of the American Gastroenterological Association’s CRC Workshop Panel, and lead author of the expert commentary, said in a statement.

AGA Institute

The blood tests detect circulating nucleotides, such as cell-free DNA or metabolic products associated with CRC and its precursors. Current tests are in development by Guardant Health and Freenome.

The two modeling studies, published in Gastroenterology on March 26, analyzed the effectiveness and cost-effectiveness of blood-based CRC screening that meets Centers for Medicare & Medicaid Services (CMS) coverage criteria, as well as the comparative effectiveness and cost-effectiveness of CRC screening with blood-based biomarkers versus fecal tests or colonoscopy.

Also published on March 26 in Clinical Gastroenterology and Hepatology, the expert commentary included key conclusions from the AGA CRC Workshop, which analyzed the two modeling studies.
 

Comparing CRC Screening Methods

In the first modeling study, an international team of researchers ran three microsimulation models for CRC to estimate the effectiveness and cost-effectiveness of triennial blood-based screening for ages 45-75, compared with no screening, annual fecal immunochemical testing (FIT), triennial stool DNA testing combined with a FIT assay, and colonoscopy screening every 10 years. The researchers used CMS coverage criteria for blood tests, with a sensitivity of at least 74% for detection of CRC and specificity of at least 90%.

Without screening, the models predicted between 77 and 88 CRC cases and between 32 and 36 deaths per 1,000 individuals, costing between $5.3 million to $5.8 million. Compared with no screening, blood-based screening was considered cost-effective, with an additional cost of $25,600 to $43,700 per quality-adjusted life-year gained (QALYG).

However, compared with the FIT, stool, and colonoscopy options, blood-based screening was not cost-effective, with both a decrease in QALYG and an increase in costs. FIT was more effective and less costly, with 5-24 QALYG and nearly $3.5 million cheaper than blood-based screening, even when blood-based uptake was 20 percentage points higher than FIT uptake.

In the second modeling study, US researchers compared triennial blood-based screening with established alternatives at the CMS thresholds of 74% sensitivity and 90% specificity.

Overall, a blood-based test at the CMS minimum reduced CRC incidence by 40% and CRC mortality by 52% versus no screening. However, a blood-based test was significantly less effective than triennial stool DNA testing, annual FIT, and colonoscopy every 10 years, which reduced CRC incidence by 68%-79% and CRC mortality by 73%-81%.

Assuming a blood-based test would cost the same as a multi-target stool test, the blood-based test would cost $28,500 per QALYG versus no screening. At the same time, FIT, colonoscopy, and stool DNA testing were less costly and more effective. In general, the blood-based test would match FIT’s clinical outcomes if it achieved 1.4- to 1.8-fold the participation rate for FIT.

Even still, the sensitivity for advanced precancerous lesion (APL) was a key determinant. A paradigm-changing blood-based test would need to have higher than 90% sensitivity for CRC and 80% for APL, 90% specificity, and cost less than $120 to $140, the study authors wrote.

“High APL sensitivity, which can result in CRC prevention, should be a top priority for screening test developers,” the authors wrote. “APL detection should not be penalized by a definition of test specificity that focuses on CRC only.”
 

Additional Considerations

The AGA CRC Workshop Panel met in September 2023 to review the two modeling studies and other data on blood-based tests for CRC. Overall, the group concluded that a triennial blood test that meets minimal CMS criteria would likely result in better outcomes than no screening and provide a simple process to encourage more people to participate in screening.

However, patients who may have declined colonoscopy should understand the need for a colonoscopy if blood-based tests show abnormal results, the commentary authors wrote.

In addition, because blood-based tests for CRC appear to be less effective and more costly than current screening options, they shouldn’t be recommended to replace established screening methods. Although these blood-based tests may improve screening rates and outcomes in unscreened people, substituting blood tests for other effective tests would increase costs and worsen patient outcomes.

Beyond that, they wrote, the industry should consider other potential benchmarks for an effective blood test, such as a sensitivity for stage I-III CRC of greater than 90% and sensitivity for advanced adenomas of 40%-50% or higher.

University of California San Diego

“Unless we have the expectation of high sensitivity and specificity, blood-based colorectal cancer tests could lead to false positive and false negative results, which are both bad for patient outcomes,” John M. Carethers, MD, AGAF, vice chancellor for health sciences at UC San Diego, AGA past president, and a member of the AGA CRC Workshop panel, said in a statement.

Several authors reported consultant roles and funding support from numerous companies, including Guardant Health and Freenome.

One in seven women will die within 2 months of being diagnosed with ovarian cancer, a new report from the United Kingdom states. But if diagnosed at the earliest stage, 9 in 10 women will survive. Two thirds of women are now diagnosed late, when the cancer is harder to treat.

Diagnosis is difficult for many reasons, among them that women sometimes think symptoms are a natural part of menopause and don’t acknowledge or report them. Clinicians may mistake abdominal symptoms for those of a bowel condition or bladder problem. Almost half of GPs (46%) in the UK mistakenly believe that ovarian cancer symptoms present in only the later stages of the disease.

Cervical Screening Does Not Detect Ovarian Cancer

Additionally, there are misconceptions regarding cervical cancer screening — one study found that “40% of women in the general public mistakenly believe that cervical screening detects ovarian cancer.” But there is no current screening program for ovarian cancer in the UK or United States.

During a pelvic exam, the physician feels the ovaries and uterus for size, shape, and consistency and that can be useful in finding some cancers early, but most early ovarian tumors are difficult or impossible to feel, the American Cancer Society notes.

Recognizing the Red Flags

Victoria Barber, MBBS, a general practitioner in Northamptonshire and a Primary Care Advisory Board member with the Target Ovarian Cancer program in the UK published a paper in the British Journal of Nursing (2024 Mar 7. doi: 10.12968/bjon.2024.33.5.S16) on the program’s efforts to urge clinicians to recognize ovarian cancer red flags and to “never diagnose new-onset irritable bowel syndrome or overactive bladder in women over 50 without ruling out ovarian cancer.”

She says nurses should be involved to help with earlier diagnosis of ovarian cancer as they are often involved in evaluating urine samples. Nurse practitioners, she notes, are typically included in consultations for abdominal symptoms and potential urinary tract infections.

“If the woman is recurrently presenting with urinary symptoms, sterile midstream urine samples should raise alarm,” she says. “The woman may have diabetes, an overactive bladder, or interstitial cystitis; however, urgency and frequency are some of the symptoms of ovarian cancer, and they need investigation.”

Persistent Systems Over Age 50

The paper lists ovarian cancer symptoms from the UK’s National Institute for Health and Care Excellence and notes that among red flags are having any of the following persistently/frequently (particularly more than 12 times per month and especially if the woman is 50 years or older):

• Early satiety and/or loss of appetite
• Abdominal bloating
• Pelvic or abdominal pain
• Urinary urgency/frequency

Other symptoms could include:

• Changes in bowel habits (e.g., diarrhea or constipation)
• Extreme fatigue
• Unexplained weight loss

Diagnosis Challenges Similar in US

Ernst Lengyel, MD, PhD, UChicago Medicine’s Chairman of the Department of Obstetrics and Gynecology in Chicago, Illinois, who was not involved with the paper, said the situation in the United States is similar to that described in the UK.

“The diagnosis is delayed because the symptoms are unspecific. The problem is that ovarian cancer is so rare, and primary care physicians or nurse practitioners have to consider over 100 differential diagnoses,” he says.

In the US, he says, it is likely easier to get in and see a physician because of the private insurance options and because there are more gynecologic oncologists in large urban areas. Getting imaging approved — such as ultrasound and computed tomography scans — is also easier in the US.

Still, “there is no effective way to diagnose ovarian cancer early,” he says. “No single test or combination of symptoms can be used as a screening test.”

The CA-125 blood test measures proteins that can be linked with ovarian cancer, but is not a screening test, he notes.

“Large UK and US studies have not been able to show a survival benefit with ultrasound, serial CA-125, or a combination thereof,” Dr. Lengyel said.

Weight Gain May Also be a Sign

A broad range of clinicians should be aware of the symptoms the author mentions, he says, especially primary care physicians, nurse practitioners, and obstetrician/gynecologists.

“Too often, symptoms that women report are ignored and treated as unspecific or psychosomatic,” Dr. Lengyel says. “It is easy to disregard recurrent complaints and move on instead of being vigilant and working them up. Ironically, women with ovarian cancer can initially gain weight, which is counterintuitive as most doctors believe that patients with cancer lose weight. However, if they develop abdominal fluid, a patient often gains weight.”

Dr. Barber and Dr. Lengyel report no relevant financial relationships.

One in seven women will die within 2 months of being diagnosed with ovarian cancer, a new report from the United Kingdom states. But if diagnosed at the earliest stage, 9 in 10 women will survive. Two thirds of women are now diagnosed late, when the cancer is harder to treat.

Diagnosis is difficult for many reasons, among them that women sometimes think symptoms are a natural part of menopause and don’t acknowledge or report them. Clinicians may mistake abdominal symptoms for those of a bowel condition or bladder problem. Almost half of GPs (46%) in the UK mistakenly believe that ovarian cancer symptoms present in only the later stages of the disease.

Cervical Screening Does Not Detect Ovarian Cancer

Additionally, there are misconceptions regarding cervical cancer screening — one study found that “40% of women in the general public mistakenly believe that cervical screening detects ovarian cancer.” But there is no current screening program for ovarian cancer in the UK or United States.

During a pelvic exam, the physician feels the ovaries and uterus for size, shape, and consistency and that can be useful in finding some cancers early, but most early ovarian tumors are difficult or impossible to feel, the American Cancer Society notes.

Recognizing the Red Flags

Victoria Barber, MBBS, a general practitioner in Northamptonshire and a Primary Care Advisory Board member with the Target Ovarian Cancer program in the UK published a paper in the British Journal of Nursing (2024 Mar 7. doi: 10.12968/bjon.2024.33.5.S16) on the program’s efforts to urge clinicians to recognize ovarian cancer red flags and to “never diagnose new-onset irritable bowel syndrome or overactive bladder in women over 50 without ruling out ovarian cancer.”

She says nurses should be involved to help with earlier diagnosis of ovarian cancer as they are often involved in evaluating urine samples. Nurse practitioners, she notes, are typically included in consultations for abdominal symptoms and potential urinary tract infections.

“If the woman is recurrently presenting with urinary symptoms, sterile midstream urine samples should raise alarm,” she says. “The woman may have diabetes, an overactive bladder, or interstitial cystitis; however, urgency and frequency are some of the symptoms of ovarian cancer, and they need investigation.”

Persistent Systems Over Age 50

The paper lists ovarian cancer symptoms from the UK’s National Institute for Health and Care Excellence and notes that among red flags are having any of the following persistently/frequently (particularly more than 12 times per month and especially if the woman is 50 years or older):

• Early satiety and/or loss of appetite
• Abdominal bloating
• Pelvic or abdominal pain
• Urinary urgency/frequency

Other symptoms could include:

• Changes in bowel habits (e.g., diarrhea or constipation)
• Extreme fatigue
• Unexplained weight loss

Diagnosis Challenges Similar in US

Ernst Lengyel, MD, PhD, UChicago Medicine’s Chairman of the Department of Obstetrics and Gynecology in Chicago, Illinois, who was not involved with the paper, said the situation in the United States is similar to that described in the UK.

“The diagnosis is delayed because the symptoms are unspecific. The problem is that ovarian cancer is so rare, and primary care physicians or nurse practitioners have to consider over 100 differential diagnoses,” he says.

In the US, he says, it is likely easier to get in and see a physician because of the private insurance options and because there are more gynecologic oncologists in large urban areas. Getting imaging approved — such as ultrasound and computed tomography scans — is also easier in the US.

Still, “there is no effective way to diagnose ovarian cancer early,” he says. “No single test or combination of symptoms can be used as a screening test.”

The CA-125 blood test measures proteins that can be linked with ovarian cancer, but is not a screening test, he notes.

“Large UK and US studies have not been able to show a survival benefit with ultrasound, serial CA-125, or a combination thereof,” Dr. Lengyel said.

Weight Gain May Also be a Sign

A broad range of clinicians should be aware of the symptoms the author mentions, he says, especially primary care physicians, nurse practitioners, and obstetrician/gynecologists.

“Too often, symptoms that women report are ignored and treated as unspecific or psychosomatic,” Dr. Lengyel says. “It is easy to disregard recurrent complaints and move on instead of being vigilant and working them up. Ironically, women with ovarian cancer can initially gain weight, which is counterintuitive as most doctors believe that patients with cancer lose weight. However, if they develop abdominal fluid, a patient often gains weight.”

Dr. Barber and Dr. Lengyel report no relevant financial relationships.

One in seven women will die within 2 months of being diagnosed with ovarian cancer, a new report from the United Kingdom states. But if diagnosed at the earliest stage, 9 in 10 women will survive. Two thirds of women are now diagnosed late, when the cancer is harder to treat.

Diagnosis is difficult for many reasons, among them that women sometimes think symptoms are a natural part of menopause and don’t acknowledge or report them. Clinicians may mistake abdominal symptoms for those of a bowel condition or bladder problem. Almost half of GPs (46%) in the UK mistakenly believe that ovarian cancer symptoms present in only the later stages of the disease.

Cervical Screening Does Not Detect Ovarian Cancer

Additionally, there are misconceptions regarding cervical cancer screening — one study found that “40% of women in the general public mistakenly believe that cervical screening detects ovarian cancer.” But there is no current screening program for ovarian cancer in the UK or United States.

During a pelvic exam, the physician feels the ovaries and uterus for size, shape, and consistency and that can be useful in finding some cancers early, but most early ovarian tumors are difficult or impossible to feel, the American Cancer Society notes.

Recognizing the Red Flags

Victoria Barber, MBBS, a general practitioner in Northamptonshire and a Primary Care Advisory Board member with the Target Ovarian Cancer program in the UK published a paper in the British Journal of Nursing (2024 Mar 7. doi: 10.12968/bjon.2024.33.5.S16) on the program’s efforts to urge clinicians to recognize ovarian cancer red flags and to “never diagnose new-onset irritable bowel syndrome or overactive bladder in women over 50 without ruling out ovarian cancer.”

She says nurses should be involved to help with earlier diagnosis of ovarian cancer as they are often involved in evaluating urine samples. Nurse practitioners, she notes, are typically included in consultations for abdominal symptoms and potential urinary tract infections.

“If the woman is recurrently presenting with urinary symptoms, sterile midstream urine samples should raise alarm,” she says. “The woman may have diabetes, an overactive bladder, or interstitial cystitis; however, urgency and frequency are some of the symptoms of ovarian cancer, and they need investigation.”

Persistent Systems Over Age 50

The paper lists ovarian cancer symptoms from the UK’s National Institute for Health and Care Excellence and notes that among red flags are having any of the following persistently/frequently (particularly more than 12 times per month and especially if the woman is 50 years or older):

• Early satiety and/or loss of appetite
• Abdominal bloating
• Pelvic or abdominal pain
• Urinary urgency/frequency

Other symptoms could include:

• Changes in bowel habits (e.g., diarrhea or constipation)
• Extreme fatigue
• Unexplained weight loss

Diagnosis Challenges Similar in US

Ernst Lengyel, MD, PhD, UChicago Medicine’s Chairman of the Department of Obstetrics and Gynecology in Chicago, Illinois, who was not involved with the paper, said the situation in the United States is similar to that described in the UK.

“The diagnosis is delayed because the symptoms are unspecific. The problem is that ovarian cancer is so rare, and primary care physicians or nurse practitioners have to consider over 100 differential diagnoses,” he says.

In the US, he says, it is likely easier to get in and see a physician because of the private insurance options and because there are more gynecologic oncologists in large urban areas. Getting imaging approved — such as ultrasound and computed tomography scans — is also easier in the US.

Still, “there is no effective way to diagnose ovarian cancer early,” he says. “No single test or combination of symptoms can be used as a screening test.”

The CA-125 blood test measures proteins that can be linked with ovarian cancer, but is not a screening test, he notes.

“Large UK and US studies have not been able to show a survival benefit with ultrasound, serial CA-125, or a combination thereof,” Dr. Lengyel said.

Weight Gain May Also be a Sign

A broad range of clinicians should be aware of the symptoms the author mentions, he says, especially primary care physicians, nurse practitioners, and obstetrician/gynecologists.

“Too often, symptoms that women report are ignored and treated as unspecific or psychosomatic,” Dr. Lengyel says. “It is easy to disregard recurrent complaints and move on instead of being vigilant and working them up. Ironically, women with ovarian cancer can initially gain weight, which is counterintuitive as most doctors believe that patients with cancer lose weight. However, if they develop abdominal fluid, a patient often gains weight.”

Dr. Barber and Dr. Lengyel report no relevant financial relationships.

Among diagnostic interventions recommended to manage the common CAR-T cell therapy–associated side effect of immune effector cell–associated neurotoxicity syndrome (ICANS), only electroencephalogram (EEG) shows significant therapeutic benefit — while magnetic resonance imaging (MRI) and lumbar puncture appear to have limited value, new research shows.

“Our results emphasize for the first time the role of EEG in the current guidelines [for ICANS] but question the need for systematic MRI and lumbar puncture,” reported the authors of the study, published in Blood Advances.

The study underscores that “EEG does more that depict insignificant anomalies and plays a key role in patient management in daily practice,” first author Mattéo Mauget, said in an interview. He is a resident in the intensive care unit at the University Hospital of Rennes in France.

ICANS is among the most common of acute neurotoxicities occurring after CAR T-cell therapy, and international guidelines recommend MRI, lumbar puncture, and EEG in the management of the toxicity, which is typically treated with anti-cytokine therapy and steroids.

However, the guidelines widely vary. All recommend the use of MRI for ICANS grade 3 or higher, but fewer recommend the approach for grade 2. Meanwhile, only some recommend the use of lumbar puncture, and even fewer guidelines recommend the use of EEG.

While these measures are expensive — and in the case of lumbar puncture, invasive and burdensome for patients — the recommendations on these measures “rely on empirical practices and are only based on expert opinions with low scientific evidence,” the authors wrote.

To evaluate the interventions in a cohort of real-life patients treated with CAR T-cell therapy, the authors identified 190 consecutive patients receiving the therapy at the University Hospital of Rennes, France, between August 2018 and January 2023.

Of the patients, 62% were male and their median age was 64. Overall, 91 (48%) developed ICANS.

The majority of patients (73%) received CAR-T cell therapy for a refractory/relapsed (R/R) DLBCL (73%), and most (60%) had received the CAR-T product axicabtagene-ciloleucel (axi-cel) after two or more prior therapies.

While MRI was performed in 78% of patients with ICANS, the measure was determined to have had a therapeutic impact in just 4% of patients, despite common observations of abnormal findings.

Lumbar puncture was meanwhile performed in 47% of patients, resulting in preemptive antimicrobial agents in 7% of patients, with no infection detected.

While systematic EEG was performed in 56% of patients, the intervention led to therapeutic modifications among 16% of those patients.

“Our findings highlight some divergences between guidelines and daily practice regarding diagnostic investigations,” the authors noted.

The study “shows that EEG is the diagnostic investigation with the greatest therapeutic impact, while MRI and lumbar puncture appear to have a limited therapeutic impact,” they concluded.
 

EEG Findings

Of note, only 18% of EEGs in the cohort were normal, ranging from 50% of those with ICANS grade 1 to 6% among those with ICANS grade 4.

Encephalopathy was the most common EEG finding, observed in 45% of patients, while 6 EEGs (12%) showed seizures or status epilepticus.

Two patients with ICANS grade 2 and 3 (6% of EEG) developed seizure or status epilepticus on their EEGs, despite the absence of clinical symptoms of epilepsy, while the rate was 4 (33%) among patients with ICANS grade 4.

Among the eight (16%) patients who received therapeutic modification as the result of the EEG, seven were in the severe and life-threatening ICANS (grade 3+) group (24%).

In addition, all EEGs detecting seizure or status epilepticus resulted in an increase in antiepileptic prophylaxis with levetiracetam or the introduction of a new antiepileptics, mainly phenytoin.

Surprisingly, there were no cases of diffuse edema in the entire cohort, even among those with grade 4 ICANS, which is one of the key concerns of treating physicians managing severe ICANS, the authors noted.

A notable caveat is that EEG can be a time- and physician-consuming examination not easily accessed on a 24/7 daily practice level.

With such challenges, “[we] advocate for a close partnership between hematologists and electrophysiologists to make EEG access as easy as possible for this kind of patient, as EEG is a key game changer in patient course,” Mr. Mauget said.

Commenting on the findings, Marcela V. Maus, MD, PhD, director of the Cellular Immunotherapy Program at the Massachusetts General Hospital Cancer Center in Boston, agreed that the study adds importantly to a topic in need of more data.

“This is a very interesting study that starts to provide data behind the consensus recommendations that were initially made based purely on expert opinion and collective practices,” she said in an interview.

“I think [the EEG findings] are interesting, because EEG is often the most non-specific of these tests, and I would not have predicted this result. I also think that monitoring of cerebral spinal fluid [through lumbar puncture] could have potentially higher impact if there was a way to routinely quantify and detect the CAR-T cells,” Dr. Maus said.

“Although admittedly I think this may be of greater benefit when patients present with neurologic findings outside the typical window of ICANS, such as what can occur with delayed neurologic toxicities such as Parkinsonism after BCMA-directed CAR T cells,” she added.

Senior author Guillaume Manson, MD, a hematologist also with the University Hospital of Rennes, underscored that the results shouldn’t be construed to suggest that MRI or LP should not be used in such cases, but may often not be necessary.

“Every patient’s case is different, and these findings certainly do not say that certain tests should or should not be performed,” he said in a press statement.

“We did this research to generate clinical evidence to inform guidelines that support physicians in making clinical decisions when treating patients with these complex, and sometimes severe conditions,” he added.

Dr. Manson reported relationships with BMS-Celgene, Gilead-Kite, and Takeda. Dr. Maus disclosed ties with Century Therapeutics, TCR2, Kite/Gilead, Novartis, and several other companies in the field of cellular therapies.

Among diagnostic interventions recommended to manage the common CAR-T cell therapy–associated side effect of immune effector cell–associated neurotoxicity syndrome (ICANS), only electroencephalogram (EEG) shows significant therapeutic benefit — while magnetic resonance imaging (MRI) and lumbar puncture appear to have limited value, new research shows.

“Our results emphasize for the first time the role of EEG in the current guidelines [for ICANS] but question the need for systematic MRI and lumbar puncture,” reported the authors of the study, published in Blood Advances.

The study underscores that “EEG does more that depict insignificant anomalies and plays a key role in patient management in daily practice,” first author Mattéo Mauget, said in an interview. He is a resident in the intensive care unit at the University Hospital of Rennes in France.

ICANS is among the most common of acute neurotoxicities occurring after CAR T-cell therapy, and international guidelines recommend MRI, lumbar puncture, and EEG in the management of the toxicity, which is typically treated with anti-cytokine therapy and steroids.

However, the guidelines widely vary. All recommend the use of MRI for ICANS grade 3 or higher, but fewer recommend the approach for grade 2. Meanwhile, only some recommend the use of lumbar puncture, and even fewer guidelines recommend the use of EEG.

While these measures are expensive — and in the case of lumbar puncture, invasive and burdensome for patients — the recommendations on these measures “rely on empirical practices and are only based on expert opinions with low scientific evidence,” the authors wrote.

To evaluate the interventions in a cohort of real-life patients treated with CAR T-cell therapy, the authors identified 190 consecutive patients receiving the therapy at the University Hospital of Rennes, France, between August 2018 and January 2023.

Of the patients, 62% were male and their median age was 64. Overall, 91 (48%) developed ICANS.

The majority of patients (73%) received CAR-T cell therapy for a refractory/relapsed (R/R) DLBCL (73%), and most (60%) had received the CAR-T product axicabtagene-ciloleucel (axi-cel) after two or more prior therapies.

While MRI was performed in 78% of patients with ICANS, the measure was determined to have had a therapeutic impact in just 4% of patients, despite common observations of abnormal findings.

Lumbar puncture was meanwhile performed in 47% of patients, resulting in preemptive antimicrobial agents in 7% of patients, with no infection detected.

While systematic EEG was performed in 56% of patients, the intervention led to therapeutic modifications among 16% of those patients.

“Our findings highlight some divergences between guidelines and daily practice regarding diagnostic investigations,” the authors noted.

The study “shows that EEG is the diagnostic investigation with the greatest therapeutic impact, while MRI and lumbar puncture appear to have a limited therapeutic impact,” they concluded.
 

EEG Findings

Of note, only 18% of EEGs in the cohort were normal, ranging from 50% of those with ICANS grade 1 to 6% among those with ICANS grade 4.

Encephalopathy was the most common EEG finding, observed in 45% of patients, while 6 EEGs (12%) showed seizures or status epilepticus.

Two patients with ICANS grade 2 and 3 (6% of EEG) developed seizure or status epilepticus on their EEGs, despite the absence of clinical symptoms of epilepsy, while the rate was 4 (33%) among patients with ICANS grade 4.

Among the eight (16%) patients who received therapeutic modification as the result of the EEG, seven were in the severe and life-threatening ICANS (grade 3+) group (24%).

In addition, all EEGs detecting seizure or status epilepticus resulted in an increase in antiepileptic prophylaxis with levetiracetam or the introduction of a new antiepileptics, mainly phenytoin.

Surprisingly, there were no cases of diffuse edema in the entire cohort, even among those with grade 4 ICANS, which is one of the key concerns of treating physicians managing severe ICANS, the authors noted.

A notable caveat is that EEG can be a time- and physician-consuming examination not easily accessed on a 24/7 daily practice level.

With such challenges, “[we] advocate for a close partnership between hematologists and electrophysiologists to make EEG access as easy as possible for this kind of patient, as EEG is a key game changer in patient course,” Mr. Mauget said.

Commenting on the findings, Marcela V. Maus, MD, PhD, director of the Cellular Immunotherapy Program at the Massachusetts General Hospital Cancer Center in Boston, agreed that the study adds importantly to a topic in need of more data.

“This is a very interesting study that starts to provide data behind the consensus recommendations that were initially made based purely on expert opinion and collective practices,” she said in an interview.

“I think [the EEG findings] are interesting, because EEG is often the most non-specific of these tests, and I would not have predicted this result. I also think that monitoring of cerebral spinal fluid [through lumbar puncture] could have potentially higher impact if there was a way to routinely quantify and detect the CAR-T cells,” Dr. Maus said.

“Although admittedly I think this may be of greater benefit when patients present with neurologic findings outside the typical window of ICANS, such as what can occur with delayed neurologic toxicities such as Parkinsonism after BCMA-directed CAR T cells,” she added.

Senior author Guillaume Manson, MD, a hematologist also with the University Hospital of Rennes, underscored that the results shouldn’t be construed to suggest that MRI or LP should not be used in such cases, but may often not be necessary.

“Every patient’s case is different, and these findings certainly do not say that certain tests should or should not be performed,” he said in a press statement.

“We did this research to generate clinical evidence to inform guidelines that support physicians in making clinical decisions when treating patients with these complex, and sometimes severe conditions,” he added.

Dr. Manson reported relationships with BMS-Celgene, Gilead-Kite, and Takeda. Dr. Maus disclosed ties with Century Therapeutics, TCR2, Kite/Gilead, Novartis, and several other companies in the field of cellular therapies.

Among diagnostic interventions recommended to manage the common CAR-T cell therapy–associated side effect of immune effector cell–associated neurotoxicity syndrome (ICANS), only electroencephalogram (EEG) shows significant therapeutic benefit — while magnetic resonance imaging (MRI) and lumbar puncture appear to have limited value, new research shows.

“Our results emphasize for the first time the role of EEG in the current guidelines [for ICANS] but question the need for systematic MRI and lumbar puncture,” reported the authors of the study, published in Blood Advances.

The study underscores that “EEG does more that depict insignificant anomalies and plays a key role in patient management in daily practice,” first author Mattéo Mauget, said in an interview. He is a resident in the intensive care unit at the University Hospital of Rennes in France.

ICANS is among the most common of acute neurotoxicities occurring after CAR T-cell therapy, and international guidelines recommend MRI, lumbar puncture, and EEG in the management of the toxicity, which is typically treated with anti-cytokine therapy and steroids.

However, the guidelines widely vary. All recommend the use of MRI for ICANS grade 3 or higher, but fewer recommend the approach for grade 2. Meanwhile, only some recommend the use of lumbar puncture, and even fewer guidelines recommend the use of EEG.

While these measures are expensive — and in the case of lumbar puncture, invasive and burdensome for patients — the recommendations on these measures “rely on empirical practices and are only based on expert opinions with low scientific evidence,” the authors wrote.

To evaluate the interventions in a cohort of real-life patients treated with CAR T-cell therapy, the authors identified 190 consecutive patients receiving the therapy at the University Hospital of Rennes, France, between August 2018 and January 2023.

Of the patients, 62% were male and their median age was 64. Overall, 91 (48%) developed ICANS.

The majority of patients (73%) received CAR-T cell therapy for a refractory/relapsed (R/R) DLBCL (73%), and most (60%) had received the CAR-T product axicabtagene-ciloleucel (axi-cel) after two or more prior therapies.

While MRI was performed in 78% of patients with ICANS, the measure was determined to have had a therapeutic impact in just 4% of patients, despite common observations of abnormal findings.

Lumbar puncture was meanwhile performed in 47% of patients, resulting in preemptive antimicrobial agents in 7% of patients, with no infection detected.

While systematic EEG was performed in 56% of patients, the intervention led to therapeutic modifications among 16% of those patients.

“Our findings highlight some divergences between guidelines and daily practice regarding diagnostic investigations,” the authors noted.

The study “shows that EEG is the diagnostic investigation with the greatest therapeutic impact, while MRI and lumbar puncture appear to have a limited therapeutic impact,” they concluded.
 

EEG Findings

Of note, only 18% of EEGs in the cohort were normal, ranging from 50% of those with ICANS grade 1 to 6% among those with ICANS grade 4.

Encephalopathy was the most common EEG finding, observed in 45% of patients, while 6 EEGs (12%) showed seizures or status epilepticus.

Two patients with ICANS grade 2 and 3 (6% of EEG) developed seizure or status epilepticus on their EEGs, despite the absence of clinical symptoms of epilepsy, while the rate was 4 (33%) among patients with ICANS grade 4.

Among the eight (16%) patients who received therapeutic modification as the result of the EEG, seven were in the severe and life-threatening ICANS (grade 3+) group (24%).

In addition, all EEGs detecting seizure or status epilepticus resulted in an increase in antiepileptic prophylaxis with levetiracetam or the introduction of a new antiepileptics, mainly phenytoin.

Surprisingly, there were no cases of diffuse edema in the entire cohort, even among those with grade 4 ICANS, which is one of the key concerns of treating physicians managing severe ICANS, the authors noted.

A notable caveat is that EEG can be a time- and physician-consuming examination not easily accessed on a 24/7 daily practice level.

With such challenges, “[we] advocate for a close partnership between hematologists and electrophysiologists to make EEG access as easy as possible for this kind of patient, as EEG is a key game changer in patient course,” Mr. Mauget said.

Commenting on the findings, Marcela V. Maus, MD, PhD, director of the Cellular Immunotherapy Program at the Massachusetts General Hospital Cancer Center in Boston, agreed that the study adds importantly to a topic in need of more data.

“This is a very interesting study that starts to provide data behind the consensus recommendations that were initially made based purely on expert opinion and collective practices,” she said in an interview.

“I think [the EEG findings] are interesting, because EEG is often the most non-specific of these tests, and I would not have predicted this result. I also think that monitoring of cerebral spinal fluid [through lumbar puncture] could have potentially higher impact if there was a way to routinely quantify and detect the CAR-T cells,” Dr. Maus said.

“Although admittedly I think this may be of greater benefit when patients present with neurologic findings outside the typical window of ICANS, such as what can occur with delayed neurologic toxicities such as Parkinsonism after BCMA-directed CAR T cells,” she added.

Senior author Guillaume Manson, MD, a hematologist also with the University Hospital of Rennes, underscored that the results shouldn’t be construed to suggest that MRI or LP should not be used in such cases, but may often not be necessary.

“Every patient’s case is different, and these findings certainly do not say that certain tests should or should not be performed,” he said in a press statement.

“We did this research to generate clinical evidence to inform guidelines that support physicians in making clinical decisions when treating patients with these complex, and sometimes severe conditions,” he added.

Dr. Manson reported relationships with BMS-Celgene, Gilead-Kite, and Takeda. Dr. Maus disclosed ties with Century Therapeutics, TCR2, Kite/Gilead, Novartis, and several other companies in the field of cellular therapies.

Use of statin drugs was associated with improved mortality in older nursing home residents, regardless of dementia status, a new study showed.

The study is among the first to explore whether statin use in older nursing home residents offers a mortality benefit, especially among individuals with dementia, a group largely excluded from earlier statin trials.

Investigators’ analysis of 4 years of data on nearly 300,000 nursing home residents revealed that statin use was associated with a 40% lower risk for all-cause mortality than statin nonuse in those without dementia and a 20% lower risk in those with dementia.

“These findings may provide evidence that supports the continued use of statins in older nursing home patients with multiple medical conditions,” wrote lead author Julie Lorraine O’Sullivan, PhD, of the Charité–Universitätsmedizin Berlin, Freie Universität Berlin, German Center for Mental Health, Berlin, and colleagues.

The study was published online on February 27 in Neurology.
 

Understudied Population

Statins are the first-line treatment for preventing atherosclerotic cardiovascular disease (ASCVD), but they are also known to carry risks to patients who are frail or care-dependent. Many prior clinical trials excluded older participants with multiple comorbidities, especially those with dementia. So, evidence regarding the drugs’ efficacy in this population was lacking.

Investigators retrospectively examined 5 years of claims data from a German health and long-term care insurance provider on 282,693 nursing home residents (mean age, 83 years) who had used statins consecutively for ≥ 6 months.

Researchers used propensity score matching in 96,162 individuals to adjust for potential imbalances in the distribution of covariates (eg, age, sex, atrial fibrillation, ASCVD, and other conditions, as well as medications) and to reduce bias. Cox regression models were similarly adjusted for these factors, as well as care level. Residents were followed for an average of 2 years.

There were 54,269 recorded deaths during the study period, with most patients requiring a high level of care and 65% with dementia.

Statin use was associated with lower all-cause mortality in residents with dementia (hazard ratio [HR], 0.80, P < .001) and those without dementia (HR, 0.73; P < .001) compared with nonusers. The benefits remained consistent even after excluding participants with a history of ASCVD and across subgroups stratified by age sex, care level, and dementia type.

Limitations included the potential for unknown confounders and a lack of information about previous statin use, smoking and sedentary behavior, and the cause of mortality.

“Although our findings suggest the benefits of statins ... it is vital to acknowledge the need for further research to understand the underlying mechanism and the need for replication of our results to understand the potential risks before making recommendations to clinicians and families regarding statin therapy,” investigators wrote.
 

‘First Step’

In an accompanying editorial, Ariela R. Orkaby, MD, MPH, assistant professor of medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, called the study a “first step” to a better understanding of statin use in an understudied population.

“These findings build on a limited body of observational evidence for statin use in high-risk older adults, which has generally demonstrated protective associations for statins and mortality, including those with dementia and frailty, although nursing home status has not been specifically explored,” Dr. Orkaby wrote.

Perhaps more important than gaining information about statins’ effect on mortality risk in older people with dementia may be a better understanding of how the drugs might improve quality of life by reducing the risk for stroke or other cardiovascular events.

“It may be time to reconsider the broad recommendations to avoid or deprescribe statins in nursing home residents and rather invest in high-quality evidence to guide the care of this vulnerable population. After all, a lack of evidence does not imply benefit or harm, rather a need for more data,” Dr. Orkaby added.

The research was funded by Stiftung Charité; Dr. O’Sullivan and coauthors reported no relevant financial relationships. Dr. Orkaby received funding from a VA CSR&D CDA-2 award.
 

A version of this article appeared on Medscape.com.

Use of statin drugs was associated with improved mortality in older nursing home residents, regardless of dementia status, a new study showed.

The study is among the first to explore whether statin use in older nursing home residents offers a mortality benefit, especially among individuals with dementia, a group largely excluded from earlier statin trials.

Investigators’ analysis of 4 years of data on nearly 300,000 nursing home residents revealed that statin use was associated with a 40% lower risk for all-cause mortality than statin nonuse in those without dementia and a 20% lower risk in those with dementia.

“These findings may provide evidence that supports the continued use of statins in older nursing home patients with multiple medical conditions,” wrote lead author Julie Lorraine O’Sullivan, PhD, of the Charité–Universitätsmedizin Berlin, Freie Universität Berlin, German Center for Mental Health, Berlin, and colleagues.

The study was published online on February 27 in Neurology.
 

Understudied Population

Statins are the first-line treatment for preventing atherosclerotic cardiovascular disease (ASCVD), but they are also known to carry risks to patients who are frail or care-dependent. Many prior clinical trials excluded older participants with multiple comorbidities, especially those with dementia. So, evidence regarding the drugs’ efficacy in this population was lacking.

Investigators retrospectively examined 5 years of claims data from a German health and long-term care insurance provider on 282,693 nursing home residents (mean age, 83 years) who had used statins consecutively for ≥ 6 months.

Researchers used propensity score matching in 96,162 individuals to adjust for potential imbalances in the distribution of covariates (eg, age, sex, atrial fibrillation, ASCVD, and other conditions, as well as medications) and to reduce bias. Cox regression models were similarly adjusted for these factors, as well as care level. Residents were followed for an average of 2 years.

There were 54,269 recorded deaths during the study period, with most patients requiring a high level of care and 65% with dementia.

Statin use was associated with lower all-cause mortality in residents with dementia (hazard ratio [HR], 0.80, P < .001) and those without dementia (HR, 0.73; P < .001) compared with nonusers. The benefits remained consistent even after excluding participants with a history of ASCVD and across subgroups stratified by age sex, care level, and dementia type.

Limitations included the potential for unknown confounders and a lack of information about previous statin use, smoking and sedentary behavior, and the cause of mortality.

“Although our findings suggest the benefits of statins ... it is vital to acknowledge the need for further research to understand the underlying mechanism and the need for replication of our results to understand the potential risks before making recommendations to clinicians and families regarding statin therapy,” investigators wrote.
 

‘First Step’

In an accompanying editorial, Ariela R. Orkaby, MD, MPH, assistant professor of medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, called the study a “first step” to a better understanding of statin use in an understudied population.

“These findings build on a limited body of observational evidence for statin use in high-risk older adults, which has generally demonstrated protective associations for statins and mortality, including those with dementia and frailty, although nursing home status has not been specifically explored,” Dr. Orkaby wrote.

Perhaps more important than gaining information about statins’ effect on mortality risk in older people with dementia may be a better understanding of how the drugs might improve quality of life by reducing the risk for stroke or other cardiovascular events.

“It may be time to reconsider the broad recommendations to avoid or deprescribe statins in nursing home residents and rather invest in high-quality evidence to guide the care of this vulnerable population. After all, a lack of evidence does not imply benefit or harm, rather a need for more data,” Dr. Orkaby added.

The research was funded by Stiftung Charité; Dr. O’Sullivan and coauthors reported no relevant financial relationships. Dr. Orkaby received funding from a VA CSR&D CDA-2 award.
 

A version of this article appeared on Medscape.com.

Use of statin drugs was associated with improved mortality in older nursing home residents, regardless of dementia status, a new study showed.

The study is among the first to explore whether statin use in older nursing home residents offers a mortality benefit, especially among individuals with dementia, a group largely excluded from earlier statin trials.

Investigators’ analysis of 4 years of data on nearly 300,000 nursing home residents revealed that statin use was associated with a 40% lower risk for all-cause mortality than statin nonuse in those without dementia and a 20% lower risk in those with dementia.

“These findings may provide evidence that supports the continued use of statins in older nursing home patients with multiple medical conditions,” wrote lead author Julie Lorraine O’Sullivan, PhD, of the Charité–Universitätsmedizin Berlin, Freie Universität Berlin, German Center for Mental Health, Berlin, and colleagues.

The study was published online on February 27 in Neurology.
 

Understudied Population

Statins are the first-line treatment for preventing atherosclerotic cardiovascular disease (ASCVD), but they are also known to carry risks to patients who are frail or care-dependent. Many prior clinical trials excluded older participants with multiple comorbidities, especially those with dementia. So, evidence regarding the drugs’ efficacy in this population was lacking.

Investigators retrospectively examined 5 years of claims data from a German health and long-term care insurance provider on 282,693 nursing home residents (mean age, 83 years) who had used statins consecutively for ≥ 6 months.

Researchers used propensity score matching in 96,162 individuals to adjust for potential imbalances in the distribution of covariates (eg, age, sex, atrial fibrillation, ASCVD, and other conditions, as well as medications) and to reduce bias. Cox regression models were similarly adjusted for these factors, as well as care level. Residents were followed for an average of 2 years.

There were 54,269 recorded deaths during the study period, with most patients requiring a high level of care and 65% with dementia.

Statin use was associated with lower all-cause mortality in residents with dementia (hazard ratio [HR], 0.80, P < .001) and those without dementia (HR, 0.73; P < .001) compared with nonusers. The benefits remained consistent even after excluding participants with a history of ASCVD and across subgroups stratified by age sex, care level, and dementia type.

Limitations included the potential for unknown confounders and a lack of information about previous statin use, smoking and sedentary behavior, and the cause of mortality.

“Although our findings suggest the benefits of statins ... it is vital to acknowledge the need for further research to understand the underlying mechanism and the need for replication of our results to understand the potential risks before making recommendations to clinicians and families regarding statin therapy,” investigators wrote.
 

‘First Step’

In an accompanying editorial, Ariela R. Orkaby, MD, MPH, assistant professor of medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, called the study a “first step” to a better understanding of statin use in an understudied population.

“These findings build on a limited body of observational evidence for statin use in high-risk older adults, which has generally demonstrated protective associations for statins and mortality, including those with dementia and frailty, although nursing home status has not been specifically explored,” Dr. Orkaby wrote.

Perhaps more important than gaining information about statins’ effect on mortality risk in older people with dementia may be a better understanding of how the drugs might improve quality of life by reducing the risk for stroke or other cardiovascular events.

“It may be time to reconsider the broad recommendations to avoid or deprescribe statins in nursing home residents and rather invest in high-quality evidence to guide the care of this vulnerable population. After all, a lack of evidence does not imply benefit or harm, rather a need for more data,” Dr. Orkaby added.

The research was funded by Stiftung Charité; Dr. O’Sullivan and coauthors reported no relevant financial relationships. Dr. Orkaby received funding from a VA CSR&D CDA-2 award.
 

A version of this article appeared on Medscape.com.

The Advanced Breast Cancer (ABC) 7th International Consensus Conference Guidelines for Advanced Breast Cancer will soon be released. This news organization discussed the new guidelines with Fatima Cardoso, MD, director of the Breast Unit at Champalimaud Clinical Center, Lisbon, Portugal. Dr. Cardoso is president of the ABC Global Alliance and chair of the guidelines committee. The interview has been edited for length and clarity.

Where do the ABC International Consensus Guidelines come from?

The 7th International Consensus Conference for Advanced Breast Cancer was held in November 2023. This is an international conference that takes place every 2 years. At the conference, we discuss new data that have come out in the past 2 years regarding advanced and metastatic breast cancer, and whether they should impact the guidelines or not. We look at whether there is any new treatment that is ready for clinical practice that wasn’t available 2 years ago. We look at whether there is anything else that has changed in the past 2 years.
 

How do the ABC International Consensus Guidelines differ from other guidelines, such as those from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), or the European Society for Medical Oncology (ESMO)?

These guidelines have some characteristics that are different from the NCCN guidelines. One of the major differences is that the ABC guidelines are developed together with patients and patient advocates. Patients and patient advocates are members of the consensus panel where we discuss important issues around this disease and how to manage it. We also do not discuss drugs exclusively because there are other needs for patients with advanced breast cancer, and we issue recommendations regarding the global care of these patients.
 

Can you tell me about the other issues discussed in the guidelines besides drugs?

For example, in the more general recommendations, we revisited the proper definition of endocrine resistance. A lot of clinical trials are based on selecting a population that is considered to be endocrine sensitive or endocrine resistant, but the definition is very heterogeneous. We have updated the definition because there have been quite a few advances in this particular subtype of cancer. This [new] definition of endocrine resistance and sensitivity will be used and implemented in the different clinical trials, allowing for a better interpretation of the results, with clear impact on clinical practice.
 

What subtype of metastatic breast cancer had the biggest advances in terms of drugs in the guidelines?

The subtype that had the biggest advances in the new guidelines is the hormonal-dependent breast cancer, the ER-positive, HER2-negative. For that particular subtype, we have new drugs either already approved or in the process of being evaluated. Some of them have been approved in the United States but not yet in Europe by the European Medicines Agency (EMA). We are starting to discuss whether these drugs should be approved, and if they are, how we should use them. It is relevant to know what the cost-effectiveness is of each new treatment, as well and the balance between efficacy and toxicity. Sometimes data are too preliminary and we need longer follow-up or more important endpoints, such as survival.

Elacestrant is one of the drugs that has been approved by the US Food and Drug Administration (FDA), and it is very controversial because the benefit it provides on progression-free survival is modest and we still lack data on survival. So, there was a discussion on whether to consider this drug as an option or wait until we have survival data. The majority on the panel thought we could consider elacestrant as a potential new option, when we do not have other endocrine options available.

We issued a recommendation on a drug that is not FDA approved because we think the FDA is going to approve it quite soon. The drug is capivasertib and it blocks the PIK3CA pathway. [Editor’s note: The drug has since been approved by the FDA.] We have a drug that targets this pathway, alpelisib, but it is quite toxic so it is not widely used. Capivasertib has a better toxicity profile so we believe it could be a good addition to our armamentarium for this particular subtype of breast cancer.

We have lots of new data about the antibody-drug conjugates, the ADCs. Initially, we had more data for HER2-positive and triple-negative disease, but now studies have been done to show the value of the ADCs also in the ER-positive, HER2-negative subtype, and so they are now options. In particular, we have trastuzumab deruxtecan for patients with HER2-low disease. Most of the HER2-low tumors are also hormone receptor–positive.
 

The ABC Guidelines discuss tough clinical situations. Can you explain?

The guidelines also discuss issues that in clinical practice are quite difficult because we don’t have strong data. There are certain tough clinical situations. One example is how to treat a woman who has metastatic disease and is pregnant. We discuss the possibilities of treatment in that situation and also what other support these patients need. We discussed that the only available therapy we can use is chemotherapy. We cannot use endocrine therapy, nor biological agents such as anti-HER2 agents and immunotherapy. So, this raises a lot of concerns for how to treat these women without hurting the fetus. But in these guidelines, we discuss other needs of these patients. It’s a hot topic in the US and we did issue a recommendation: that in some situations where the life of the mother may be at risk because we are not able to provide the most adequate treatment, then they should be free to choose to terminate the pregnancy.

It is important to realize that you can’t give most of the new treatments — and ones that have an impact on survival — to a woman when she is pregnant.
 

What other tough clinical situations do you discuss in the new guidelines?

We discuss someone who has metastatic disease and is HIV-positive. Can we use CDK4/6 inhibitors? Can we use immunotherapy? What are the recent data? We have very little data to show that we can possibly use immunotherapy, but we do not have any safety data regarding the CDK4/6 inhibitors.

It’s important to note that people who are HIV-positive tend to have a worse mortality rate from cancer and also suffer from more toxicity. Very often, there is a need to reduce the doses of the treatments we are going to give. The guidelines provide guidance on these issues so that in clinical practice, doctors can have some help managing these difficult situations.

Another example of a tough clinical situation is how to treat an elderly, frail patient who has metastatic disease. We discuss what geriatric evaluations you need to perform before deciding the treatment. We discuss the need very often to reduce the starting dose and then adapt according to what the patient can tolerate.

We have discussed quite a lot of topics that are really patient-oriented and clinically oriented. The aim is to help everyone in clinical practice to provide the best available care.
 

Do you want to expand a bit on the elderly, frail patient and what you have in the guidelines about that?

A very important message is that it doesn’t matter what age your ID card says; it’s the biological age that is important. There are some people who are in their 80s, but they are very fit and they have a very active, normal life. There are other people who are in their 50s and they struggle. It’s important to perform a geriatric evaluation to determine the probability of tolerating a cancer treatment, and we normally use a simple tool called G8. If this tool shows fragility, then it is crucial to have a full geriatric assessment and a full physical exam.

It’s also very important to look for drug-drug interactions in the elderly because these patients often take many different therapies for other diseases.

Another issue is chronic undertreatment in the elderly. If you look just at chronological age and you don’t provide the optimal treatment, there will be increased mortality.

We also recommend starting elderly patients on a lower dose. There are not strong data for that, but we think it is clinical common sense to start at a lower dose. Then, if there is good tolerance, you can move to the usual dose.

Often, the elderly are excluded from clinical trials. Some of the clinical trials for some of the newer agents have included elderly patients. For example, there were some elderly patients in the CDK4/6 inhibitor trials. We know that these patients can receive these treatments with a reduction in dose.

Very frail elderly patients are often excluded from clinical trials. If we continue to do that, we will never know how to treat them.
 

Is there anything you would like to add about the ABC Guidelines that we haven’t talked about?

In the general statement of the guidelines, we mention two things that I think are important for people to know. The first is that during the COVID-19 pandemic, a lot of cancer patients, particularly those with advanced disease, were not offered access to ventilators. Remember, we didn’t have enough ventilators for everyone, so there were exclusion criteria, and one of the exclusion criteria was having cancer. Cancer patients shouldn’t be excluded from having life-saving treatment based solely on the cancer diagnosis. There are many different cancers and many different stages of the disease.

Access to intensive care units is sometimes needed temporarily for a patient with advanced breast cancer. The new treatments, such as immunotherapies and ADCs, can have significant and life-threatening toxicities. You can die from some of these side effects. All over the world, this is a difficult situation because of the bias among many healthcare providers regarding access to intensive care units for cancer patients. It’s a bias we are fighting against.

The second thing we discuss in the beginning of the new guidelines is what is happening to cancer patients during periods of war or conflict. For example, in Ukraine, many of the patients were able to run away and go to another country, but all their health information was lost because the hospitals were destroyed. Patients arrive in a new country and they don’t have any information on the type of cancer they have nor the type of treatment they were undergoing. It was very difficult, for example, for the doctors in Poland to know how to continue to treat the Ukrainian patients. So, in the guidelines, we discuss how we can find a way to ensure that a patient has a copy of their important health data.

Dr. Cardoso, MD, has disclosed the following relevant financial relationships:Personal financial interest in form of consultancy role for: Amgen; Astellas/Medivation; AstraZeneca; Celgene; Daiichi-Sankyo; Eisai; GE Oncology; Genentech; Gilead; GlaxoSmithKline; Iqvia; Macrogenics; Medscape; Merck-Sharp; Merus BV; Mylan; Mundipharma; Novartis; Pfizer; Pierre-Fabre; prIME Oncology; Roche; Sanofi; Samsung Bioepis; Seagen; Teva; Touchime.

Institutional financial support for clinical trials from: Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol Myers Squibb; Bayer; Daiichi; Eisai; Fresenius GmbH; Genentech; GlaxoSmithKline; Ipsen; Incyte; Nektar Therapeutics; Nerviano; Novartis; Macrogenics; Medigene; MedImmune; Merck; Millennium; Pfizer; Pierre-Fabre; Roche; Sanofi-Aventis; Sonus; Tesaro; Tigris; Wilex; Wyeth.

A version of this article appeared on Medscape.com.